ACP medicine, 3rd Edition

Infectious Disease


Christopher J. Hoffmann MD, MPH1

Joel E. Gallant MD, MPH2

1Fellow, Department of Medicine, Johns Hopkins University School of Medicine

2Professor of Medicine and Epidemiology, Johns Hopkins University School of Medicine

Christopher J. Hoffmann, M.D., M.P.H., has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

Joel E. Gallant, M.D., M.P.H., has received grant or research support from, been a consultant for, or been a member of the speakers' bureau of Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Panacos, Pfizer, Roche Pharmaceuticals, Tibotec, and Monogram Biosciences.

March 2007

In June 1981, five cases of Pneumocystis jiroveci (formerly, P. carinii) pneumonia were reported in previously healthy young men in Los Angeles—the first published report of what was later termed the acquired immunodeficiency syndrome.1 Although these initial case reports involved men who had sex with men, AIDS was soon also identified in hemophiliacs, blood transfusion recipients, and injection drug users. Shortly thereafter, heterosexual transmission was recognized. Early on, before the cause of AIDS was identified, a case definition was created for AIDS surveillance, consisting of symptoms and a list of conditions—principally opportunistic infections and malignancies—associated with the decline in immune function. This case definition was successively revised, most recently in 1993, with the addition of CD4+ T cell count categories,2 and it remains a useful epidemiologic tool [see Table 1].

Table 1 Centers for Disease Control and Prevention Classification System for HIV Infection2

CD4+ T Cell Categories

Clinical Categories

(asymptomatic, first-degree HIV or progressive generalized lymphadenopathy)

(symptomatic, but does not satisfy conditions in categories A or C)

(AIDS-indicator conditions)

Category 1: ≥ 500 cells/mm3




Category 2: 200–499 cells/mm3




Category 3: < 200 cells/mm3




*B conditions include bacterial endocarditis, meningitis, or sepsis; candidiasis (oral); candidiasis (persistent vulvovaginal); cervical dysplasia (or carcinoma in situ); constitutional illness (persistent unexplained fever, diarrhea or weight loss, or disabling weakness); herpes zoster (multidermatomal); listeriosis; myelopathy; nocardiosis; oral hairy leukoplakia; pelvic inflammatory disease; peripheral neuropathy; and thrombocytopenic purpura (idiopathic).
C conditions are listed in Table 4.

Three years after AIDS was first reported, the causative agent, human immunodeficiency virus, was discovered. In the quarter century since the first report of AIDS, HIV has spread throughout the United States, disproportionately affecting black women, Hispanic women, and men who have sex with men. Without the current drug regimens that effectively suppress HIV replication, nearly everyone infected with HIV would be expected to die of HIV-related complications.

Medical progress in in the management of HIV infection has been extraordinary. The discovery of HIV led to the development of a serologic test for HIV infection, a variety of tests to measure the viral burden, and improved treatment and prophylaxis for opportunistic infections. The first HIV treatment breakthrough came in 1987, with the early termination of a clinical trial of zidovudine because of significantly decreased mortality in patients receiving the drug, as compared with patients receiving placebo.4 Unfortunately, in longer-term follow-up, therapeutic benefit diminished as a result of rapid development of HIV escape mutants that conferred resistance to zidovudine. Approximately 10 years later, in 1996, the introduction of multidrug combination therapy allowed for sustained virologic suppression and immune restoration. This approach was soon dubbed highly active antiretroviral therapy (HAART). The underlying principle of HAART is that a combination of potent antiretrovirals, each of which requiring different mutations in the HIV genome for resistance to develop, can suppress replication sufficiently to prevent mutation and the emergence of resistance. Although currently available antiretrovirals offer many advantages over the combinations used in 1996, the same principle continues to underpin antiretroviral therapy. The prospect that current HAART regimens may suppress HIV replication indefinitely offers the hope that patients started on them will have life expectancies similar to those of age-matched uninfected individuals. For these patients, HIV care has shifted from an emphasis on the treatment and prevention of the complications of HIV disease itself to a focus on suppression of HIV replication and the management of short- and long-term complications of HIV, HAART toxicities, and aging.

This evolution of therapy has also brought about a change in management, which in many cases is now shared by HIV experts and primary care providers. This chapter highlights important aspects of HIV care for physicians who are not HIV experts.


In 2005, it was estimated that 38 million people were living with HIV worldwide, that 4.1 million were newly infected, and that 2.8 million had died of AIDS.5 It is estimated that in sub-Saharan Africa alone, 24 million people are infected with HIV, with a prevalence of over 30% in some countries. In these regions, AIDS has been socially and economically devastating, reducing the trained workforce, orphaning children, and eliminating the most productive members of society.

Heterosexual sex accounts for the majority of infections in Africa. Men who have sex with men continue to account for the majority of infections in the United States, Mexico, Australia, and parts of Europe. Injection drug use has been driving epidemics in former republics of the Soviet Union, Southeast Asia, and much of South America. The regional variations in mode of transmission and availability of medical resources have led to a divergence of the global HIV pandemic into separate epidemics, each with distinct epidemiology, appropriate prevention strategies, and treatment needs. It remains unclear why the prevalence is so high in some regions, particularly southern Africa. Current research suggests that the southern African AIDS epidemic owes its explosive growth to a combination of social, health-related, and economic forces, including higher rates of untreated genital ulcer disease, lack of empowerment of women, multiple concurrent sexual partners, lack of male circumcision, extensive migrant labor, and lack of access to or acceptance of condoms. Despite up to 20 years of prevention efforts, few countries with high rates of HIV infection have succeeded in stabilizing the prevalence of the disease; the only exceptions are Thailand, Uganda, and Zimbabwe.6 Two countries with low prevalence, Senegal and Brazil, have succeeded in further reducing HIV prevalence.

In the United States in 2005, 1.2 million persons were living with HIV (0.6% of the adult population), and there were approximately 16,000 AIDS-related deaths. Between 2001 and 2004, 68% of all patients newly diagnosed with either HIV or AIDS were black or Hispanic, compared with 52% of those newly diagnosed with AIDS between 1981 and 1995. Men who have sex with men constitute the largest transmission category, at 43%, but heterosexual transmission has risen in importance, accounting for 34% of infections from 2001 to 2004, compared with 10% from 1981 to 1995. Consistent with shifts in the proportion of transmission is an increasing fraction of new cases occurring in women: 29% from 2001 to 2004, versus 15% from 1981 to 1995.7,8

An important group of HIV-infected persons are those who are unaware of their infection. An estimated 252,000 to 312,000 individuals in the United States fall into this group.9 This has important implications for delivery of optimal preventive health care services, diagnosis and management of acute illness, and effective prevention services. Prevention is significantly improved when individuals are aware of being infected with HIV; the annual risk of transmitting HIV is approximately 6.9% to 10.8% for those unaware of being infected, compared with 1.7% to 2% per year for those aware of their infection status.10,11 The differential in transmission between those who are and those who are not aware adds support for the 2006 guidelines from the Centers for Disease Control and Prevention (CDC), which recommends routine HIV testing of all persons between 13 and 64 years of age, unless they specifically “opt out.”12

It is estimated that HAART has effectively extended three million years of life in the United States.13 This has led to an increase in HIV prevalence; in 2005, new HIV infections occurred at a rate of 40,000 per year while mortality declined to 16,000 deaths [see Figure 1].


Figure 1. Annual AIDS cases, deaths, and prevalence in the United States from 1985 to 2004.215

Pathophysiology and Pathogenesis

HIV is a member of the lentivirus family of retroviruses. Its hallmark is the induction of profound immunodeficiency through the progressive depletion of CD4+ T helper cell populations.

HIV Structure and Life Cycle

HIV is a spherical particle approximately 110 nm in diameter, with knoblike projections from the lipid surface and a cone-shaped viral core [see Figure 2].14 The lipid envelope is very sensitive to environmental degradation when outside of the host and is rapidly inactivated. HIV particles contain two copies of an RNA genome, each of which is approximately 10,000 base pairs in length and encodes nine genes. The genome is organized into three major regions (gag, pol, and env) that are flanked by the HIV-1 promoter or long terminal repeat, similar to all other retroviruses [see Figure 3]. The gag region contains the structural genes for HIV (i.e., matrix, capsid, nucleocapsid, and two small peptides), the pol region contains the genes for the viral enzymes needed to carry out the life cycle (i.e., reverse transcriptase, integrase, and protease), and the env region encodes the genes for the viral envelope proteins (i.e., gp160, which is cleaved by host proteases to gp120 and gp41). The gp120 glycoprotein contributes to immune evasion through the exposed and highly variable V3 domain.


Figure 2. The structure of HIV.14


Figure 3. The genomic organization of HIV-1 and HIV-2. The structural genes gag, poland env give rise to several proteins: matrix (MA), capsid (CA), nucleic-acid binding (NB), nucleocapsid core proteins (NC), protease (PR), reverse transcriptase (RT), surface subunit glycoprotein (SU), and a smaller transmembrane protein (TM). In addition, HIV pol encodes an integrase (IN). There are additional regulatory gene products translated. HIV-1 and HIV-2 have six accessory gene products: tat, rev, vif, nef, vpr, and either vpu (in HIV-1) or vpx (in HIV-2). (LTR—long terminal repeat)

HIV-1 has six regulatory genes that are vital for its life cycle and pathogenicity: tat (the transactivating gene) upregulates transcription of the genome; rev coordinates the expression of the regulatory and nonregulatory genes by orchestrating the transport of spliced and unspliced RNA transcripts out of the nucleus; nef helps the virus evade the host immune response by downregulating expression of CD4 and major histocompatibility complex (MHC) class I molecules on the cell surface and also contributes to viral virulence; vpu reduces host cell CD4 expression and is involved in cellular release of virions; vpr is important for infection of nondividing cells by facilitating nuclear localization of the viral preintegration complex and regulating cell cycle arrest; and vif is important for virion assembly, infectivity, inactivation of the host cell antiviral factor APOBEC3G, and gp120 membrane insertion.15,16

The first step in the life cycle is the attachment of the virus to the host target cell, which involves the binding of the HIV envelope surface protein (gp120) with the CD4 receptor on the host cell [see Figure 4]. For infection to proceed, cellular coreceptors must also bind gp120, causing conformational change and the exposure of the other HIV envelope protein, gp41. The gp41 protein mediates fusion of the virus and cell membranes by inserting itself into the cell membrane and undergoing a conformational change that draws the cell and viral membranes together, facilitating fusion and viral entry. Although investigators have discovered numerous coreceptors that can potentially bind HIV, the coreceptors CCR5 and CXCR4 appear to play the most important role.17 CD4+ T cells express either CCR5 or CXCR4 receptor, whereas monocytes predominantly express only CCR5. Sexually transmitted HIV typically involves strains that preferentially bind to CCR 5 (i.e., R5-tropic strains) initially, until mutations in gp120 allow binding to CXCR4 (X4-tropic strains). The shift to the X4-tropic phenotype is associated with more advanced AIDS and more rapid progression of disease, although the causal relationship has not been determined.


Figure 4. The binding of HIV-1 with a CD4+ T cell. In unbound virions, gp41 exists in a stable, nonfusogenic conformation in which the fusion peptides are buried within the envelope trimer complex (a). When gp120 binds to the CD4 receptor, a conformational change exposes the chemokine receptor attachment site on gp120 (either CXC chemokine receptor-4 [CXCR4] or CC chemokine receptor-5 [CCR5]) (b). This in turn triggers a transition of gp41 to the prehairpin intermediate(c), with exposure of the fusion peptide attached to the trimeric coiled-coil N-peptide region. The fusin peptide inserts into the target membrane (c). In this form, the C-peptide has not associated with the N-peptide because of continued association with gp120; at this stage, the intermediate gp41 polypeptide is vulnerable to C-peptide inhibition (e.g., T-20). When the C-peptide region binds to the N-peptide region coiled-coil, the complex adopts a helical conformation of the fusion-active hairpin, which brings the two membranes into apposition (d). The precise mechanism of membrane fusion is not clear, but after fusion is complete, the fusion peptide and transmembrane segment of gp41 lie in the same membrane(e). A similar mechanism presumably applies to the fusion of a cell infected with HIV-1 that expresses viral envelope on the plasma membrane surface with an uninfected CD4+ T cell, which leads to syncytium formation among infected and uninfected cells in vitro.215,216

There is significant genetic variation in CCR5 coreceptor expression, and some individuals who are homozygous for a CCR5 deletion mutation (a 32-base-pair deletion) can be repeatedly exposed to HIV without becoming infected.18 Individuals who are heterozygous for this ?32 mutation are not protected against HIV infection but may initially manifest a slower rate of disease progression.

After the fusion of the viral and cellular membranes, the viral capsid enters the cell [see Figure 5] and the HIV reverse transcriptase enzyme converts the single-stranded HIV RNA into a double-stranded DNA called proviral DNA. The HIV reverse transcriptase is very error-prone and introduces mutations at a rate of approximately 1 in 104, or about one mutation in every virion produced. In addition, during normal replication, the reverse transcriptase enzyme jumps from one strand of nucleic acid to another to complete the synthesis of daughter strands. This strand-jumping enables recombination between different viral strains infecting the same cell. Mutation and recombination generates a large pool of genetically related but distinct HIV strains called quasispecies, each of which has the potential to develop into the dominant strain. Most of these quasispecies have either deleterious mutations or mutations that make their growth rate slower than that of other quasispecies. However, even a small proportion of functional mutations will generate a significant population of modified genomes because of the high overall replication rate: approximately 109 to 1010 virions are produced daily, with a serum half-life of approximately 30 minutes.19 Strains with a mutation that provides a growth advantage in a particular environment (e.g., in the presence of specific antiretroviral drugs) will outcompete the other quasispecies and become the dominant viral strain in the population. Even strains with mutations that cause impaired replication (compared with a nonmutant strain) can still accumulate additional mutations during replication, some of which can overcome the strain's replicative defect.


Figure 5. The replication cycle of HIV-1. The virus must first attach to the CD4 receptor and chemokine coreceptor on the cell surface [see Figure 2]. After fusion of the viral envelope with the plasma membrane of the target cell, the nucleocapsid undergoes uncoating, which is facilitated by the presence of cyclophilin A. The viral RNA genome is reverse-transcribed to double-stranded viral DNA (vDNA), which enters the nucleus as a preintegration complex that contains vpr protein and integrase. Only linear vDNA is capable of integrating randomly into the host chromosome; other forms of partially transcribed linear vDNA fragments and 1-long-terminal repeat (LTR) and 2-LTR circularized, episomal vDNA are not capable of integration. The integrated linear vDNA (now termed the provirus) serves as the template for viral transcription. Transcription of the proviral DNA template yields genomic viral RNA, and alternative messenger RNA (mRNA) splicing creates spliced viral mRNA species that encode the viral accessory proteins and the unspliced viral mRNA species that encode the viral structural polyproteins. All of the transcripts are exported to the cytoplasm, where translation processing and assembly begins to occur in the endoplasmic reticulum and Golgi complex. The viral polypeptides, protease, viral RNA, and other constituents of the viral core condense at areas of the plasma membrane that have already accumulated viral envelope proteins (gp120/gp41). Budding of the virion ensues, and the immature virion nucleocapsid core undergoes further proteolytic maturation in the extracellular milieu.217

The proviral DNA forms a preintegration complex with HIV integrase, HIV reverse transcriptase, and other host and HIV proteins. This complex localizes to the nucleus and catalyzes the integration of the HIV provirus into active genes of the host cell chromosome. Subsequently, cellular enzymes transcribe the provirus into spliced and nonspliced messenger RNA that encode the regulatory genes (tatand rev) and the structural genes and that serve as full-length genomic transcripts. This process proceeds in an organized fashion with the regulatory genes tat and rev (on spliced transcripts) expressed first, followed by the transport of full-length transcripts into the cytoplasm, which are then translated into the structural proteins or which serve as genomic RNA for progeny virions. The late stages of viral replication involve both the assembly of the viral particles, with each viral core incorporating two copies of the viral RNA genome, and the budding and release of the virus from the cell surface. The HIV protease enzyme plays an important role in this late process by cleaving the gagpolyprotein into smaller functional components, which allows for the formation of mature, infectious virions.

Early Events and Disease Progression

Most HIV infections occur by sexual transmission across mucosal surfaces. The R5-tropic viruses are preferentially transferred across epithelial cell membranes,20 where they may encounter dendritic cells, CD4+ T cells, or macrophages.21 HIV may productively infect any of these cell types, but more commonly, HIV becomes tethered to dendritic cells by means of DC-SIGN (dendritic cell-specific intercellular adhesion molecule [ICAM]-grabbing nonintegrin) or other C-type lectin receptors.22,23 HIV infection of CD4+ T cells is enhanced when the virus is presented to the CD4+ T cells attached to either of these receptors.24,25,26 Locally infected T cells or dendritic cells coated with HIV then traffic to regional lymph nodes, where the virus propagates rapidly in the abundant CD4+ T cell pool before disseminating.27

Early explosive expansion in HIV occurs in mucosal lymphoid tissue, which also houses the majority of CD4+ T cells in the body. Up to 60% of memory CD4+ T cells in gut-associated lymphoid tissue (GALT) are infected and killed within the first weeks of HIV infection.28 How this phase of CD4+ T cell destruction is terminated is unclear, but it may be a result of the depletion of target cells or the development of host immunity. At this point, patients may experience symptoms of an acute retroviral syndrome before mounting the cytotoxic T lymphocyte (CTL) response that partially controls viral replication.29 Regardless of how robust this CTL response is, it never eradicates the infection.30

The second phase of CD4+ T cell depletion is marked initially by a steady state of both rapid T cell proliferation and rapid destruction, with the CD4+ T cell count maintained at relatively normal levels; this phase was formerly known as latent infection. Infected activated CD4+ T cells are quickly destroyed, having a half-life of 1 to 2 days. The paradox of this phase is that the total number of T cells infected with HIV is only a very small fraction of the total population experiencing rapid turnover.31 Depletion of uninfected CD4+ T cells appears to be driven by immune activation, possibly through interaction with the HIV gp120, leading to programmed cell death.32 The selective depletion of HIV-directed CD4+ T cells cripples the effectiveness of HIV-directed CD8+ T cells, which rely on CD4+ T cell help for proper functioning. Furthermore, the high mutation rate of the virus allows it to escape the control of immune responses. Eventually, CD4+ T cell destruction occurs faster than proliferation, and the CD4+ T cell count declines.

During all periods of HIV replication, a small subset of CD4+ T cells that are infected by HIV escape rapid cell death and return to a quiescent state. These cells remain latently infected and persist, with a half-life of up to 44 months,33 forming a latent reservoir of HIV that can reactivate even after years of suppressive antiviral therapy. Because this process occurs whenever active HIV propagation is occurring, HIV DNA integrated into latent CD4+ T cells forms a genetic archive of all previous circulating HIV quasispecies, including those with drug resistance mutations.34,35 The persistence of this reservoir is the major obstacle to the goal of eradicating HIV from the body. Current estimates suggest that it would take more than 60 years to deplete all the latently infected quiescent memory T cells.36 Trials of agents, such as valproic acid, to activate latently infected T cells and hasten their death are at early stages and, thus far, of limited promise.37

Within 6 months of primary HIV infection, the plasma level of HIV becomes fairly stable. This level, which is referred to as the set point, is determined by a number of host and viral factors and varies from person to person, with the HIV-directed CTL response appearing to be among the most important factors. Indeed, the development of the HIV CTL response coincides with the initial decline in HIV RNA levels.38Patients who mount a weak CTL response typically have a high set point and rapid progression of HIV disease; in contrast, patients with a strong CTL response have a low set point and slower disease progression.38 The strength and effectiveness of the T cell response are influenced by the human leukocyte antigen (HLA) genotype of the individual, with certain genotypes reportedly associated with different rates of disease progression; HLA-B27 and HLA-B57, in particular, have been strongly associated with long-term nonprogression.39,40Several reports have also described a small number of persons with delayed disease progression who are infected with HIV strains containing particular sequence variations or deletions, such as an absence of the regulatory gene nef. These genetic variations appear to render the virus less pathogenic.41,42

The Origins of HIV

Two different species of HIV have been identified: HIV-1 and HIV-2. Isolates of HIV-1 are further classified into the three major phylogenetic groups: M (main), N (neither M nor O), and O (outlier).43,44 These three groups of HIV-1 share approximately 55% to 70% homology. Of these, the M group has global distribution and is the cause of the global HIV pandemic. The M group has been further subdivided into 10 distinct subtypes, or clades, termed A through J. Patients can be infected with more than one clade, and recombination of viruses from different clades occur. In some regions, recombinants have become the predominant circulating strains. The M subtypes A through J and recombinant subtypes are geographically distributed and appear to have variation in disease progression. Although subtle differences likely exist in treatment response between subgroups of HIV-1 group M, the same treatment approach is currently applied to all subgroups.

HIV-1 probably jumped species from Pan troglodytes troglodytes chimpanzees to bush-meat hunters in central Africa through several independent events early in the 20th century.45 The global pandemic group, group M, likely originated with a species transfer from chimpanzees to humans in southeastern Cameroon.45 From there, the spread of the virus followed trade routes, eventually reaching regional African cities. The oldest known human serum sample containing HIV-1 RNA was obtained in 1959 in Kinshasa.46 The oldest United States serum sample containing HIV-1 is from 1967.47

HIV-2 infection is essentially limited to people living in or emigrating from West Africa. HIV-2 was transferred to humans through several independent events of species jump from the sooty mangabey.48 HIV-2 has enough genetic difference from HIV-1 to make the nonnucleotide reverse transcriptase inhibitor class ineffective.

Transmission of HIV

HIV is transmitted via multiple routes, including sexual contact, sharing of injection needles, mother-to-child transmission, blood transfusion, and occupational exposures. The risk of transmission varies with the nature of the exposure; the characteristics of the host infection, including viral load and disease stage; the characteristics of the exposed individual; and viral factors. The estimated risk of infection per exposure ranges from over 60% for transfusion with infected blood to 0.04% for receptive oral sex [see Table 2]. Direct blood-to-blood contact—such as occurs with blood transfusion, venous puncture with a hollow-bore needle containing infected blood, or significant mucosal disruption during sexual activities—results in the highest risk for transmission. The following do not pose a risk for HIV transmission: holding hands, hugging, social kissing, sharing drinking glasses, coughing, sneezing, eating together or sharing utensils, bathing together, and sharing toilets.

Table 2 Risk of HIV Transmission by Route of Exposure218,219,220,221

Exposure Route

Cases per 10,000 Exposures

Blood transfusion




Needle sharing with I.V. drug use


Needlestick injury


Anal intercourse


Vaginal intercourse


Receptive oral sex


Sexual Contact

Globally, sexual contact is the major mode of HIV transmission. The risk of infection varies between individuals, even with the same sexual activity. High HIV RNA levels (because serum levels correlate with vaginal and seminal levels) and recent infection (possibly because of very high HIV RNA levels during acute infection), cervical ectopia, genital ulcer disease, and genital herpes simplex virus (HSV) infection all increase the risk of infection.49,50 Risk of transmission is believed to be higher with anal sex than with vaginal sex because the anal mucosa is thinner, more friable, and rich in dendritic cells. Receptive oral sex poses lower risk than either anal or vaginal sex but is not completely without risk, because the tonsils and adenoids are rich in dendritic cells. The presence of other sexually transmitted infections is associated with increased risk of HIV infection because of increased inflammation, which leads to increases in dendritic cells. Reducing dendritic cell number, as occurs with male circumcision, reduces infection risk.

Injection Drug Use

Injection drug use is most likely to result in transmission when shared needles are used for intravenous injection, especially when the injection technique involves diluting the prepared drug with blood.

Mother-to-Child Transmission

In low-income countries, mother-to-child transmission of HIV accounts for a substantial proportion of HIV cases. Such transmission mostly occurs at the time of delivery but can also occur during gestation and post partum via breast-feeding.51,52 In the absence of antiretroviral therapy, mother-to-child transmission rates range from 20% to 30%,53 with higher rates occurring in low-income countries, from women who breast-feed, and from women with high HIV RNA levels.54,55

Occupational Transmission

Occupational transmission of HIV is rare. As of December 2002, the CDC had reported 57 cases of occupational HIV transmission and an additional 139 cases of possible occupational HIV transmission; no new documented cases had occurred since December 2001.56 Of the 57 cases, 48 involved a percutaneous exposure, five involved a mucocutaneous exposure, two involved both percutaneous and mucocutaneous exposures, and two occurred by an unknown route of exposure. On the basis of available 8data, the average risk of HIV transmission to a health care worker who experiences a percutaneous exposure to HIV-infected blood but who does not receive postexposure prophylaxis is approximately 0.3%; the risk associated with a mucous membrane exposure to HIV-infected blood is approximately 0.09%.57 There are no documented cases of HIV transmission to health care workers from exposure to intact skin.

Risk factors associated with increased risk of transmission include deep needle-stick injuries, use of hollow-bore needles, use of a device visibly contaminated with blood, exposure events involving the transference of a large volume of blood, a needle-stick injury in which the needle had been placed directly in an artery or vein of an HIV-infected patient, and the source patient having advanced AIDS.57 Prompt use of postexposure prophylaxis is believed to significantly reduce the risk of transmission [see Treatment, below].

Blood Products

Contaminated blood products pose the greatest risk for HIV infection. Perhaps the most dramatic example occurred in the 1980s, in persons with hemophilia A who received clotting factor concentrates derived from pooled blood that was donated before the screening of blood became routine; in that population, the prevalence of HIV infection reached approximately 70%.58 Screening of blood for HIV, which was instituted in 1985, has virtually eliminated the risk of HIV transmission from blood products in the United States. Many developing countries lack resources for blood screening, however, and transmission via transfusion remains a risk in those parts of the world.


Several approaches have proved effective in reducing HIV transmission in certain situations. Some approaches are in current use; others are under study [see Table 3].

Table 3 Approaches to HIV Prevention

Exposure Route



Blood products

Screening of blood and donors

Screening has reduced risk of receiving HIV-contaminated blood to 1 in a million in the United States222

Mother-to-child transmission

Antiretroviral agents during pregnancy and labor
Use of cesarean section
Formula-feeding (no breast-feeding)

Injection drug use

Needle exchange and safe injection site programs
Methadone and buprenorphine programs

Use of clean needles and safe injection sites can reduce transmission by as much as 37% without increasing intravenous drug use223

Occupational exposure

Postexposure prophylaxis started within hours of exposure

Sexual assault

Postexposure prophylaxis

Sexual transmission

Education and peer counseling
The ABC approach (“Abstinence, Be faithful, or use a Condom”)
HIV testing and counseling to reduce high-risk behavior in HIV-infected persons


Treatment of symptomatic STIs

Treatment of symptomatic STIs decreases mucosal inflammation and may decrease HIV transmission

Long-term suppression of HSV

Long-term suppression of HSV is undergoing international trials

Male circumcision

Male circumcision is highly effective at reducing HIV transmission224

Use of vaginal and rectal microbicides

Vaginal and rectal microbicides are undergoing early clinical trials

HIV vaccination

HIV vaccination remains a focus of research, although an effective vaccine remains elusive

HSV—herpes simplex virus STIs—sexually transmitted infections


HIV infection is defined by the presence of HIV-specific antibodies, HIV antigens, or HIV RNA in serum. AIDS is defined by the presence of AIDS indicator conditions [see Table 4] or a CD4+ T cell count of less than 200/mm3. In addition, the CDC has developed a staging system for further stratification of patients by CD4+ T cell count, symptoms, and AIDS-defining conditions [see Table 1].

Table 4 Indicator Conditions for AIDS*

Candidiasis of esophagus, bronchi, trachea, or lungs
Cervical cancer, invasive
Coccidioidomycosis, extrapulmonary
Cryptococcus, extrapulmonary
Cryptosporidosis, chronic intestinal (> 1 mo duration)
Cytomegalovirus disease of any organ other than the liver, spleen, or nodes
Encephalopathy, HIV-related
Herpes simplex infection with mucocutaneous ulcer > 1 mo duration, or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, extrapulmonary
Isosporiasis, chronic intestinal (> 1 mo duration)
Kaposi sarcoma
Lymphoma; Burkitt, immunoblastic, or primary CNS
Mycobacterium avium complex or M. kansasii extrapulmonary infection
Mycobacterium tuberculosis infection, any site
Pneumocystis jiroveci (formerly P. carinii)
Pneumonia, recurrent bacterial (two or more episodes in 12 mo)
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis, CNS
Wasting syndrome from HIV

*According to the Centers for Disease control and Prevention 1993 AIDS surveillance case definition2 
CNS—central nervous system

Laboratory Testing

HIV Serologic Tests

The HIV testing algorithm recommended by the United States Public Health Service and followed by clinical laboratories in the United States consists of initial screening with an enzyme immunoassay (EIA) followed by confirmatory testing of reactive (positive) specimens. The confirmatory test is either a Western blot assay or an immunofluorescence assay. The combination of two types of assay provides high sensitivity with very high specificity. The specificity of current EIAs is over 99.5%. When the EIA and Western blot are reactive, the positive predictive value is greater than 99.99%.59 False positive results on EIAs usually occur in patients who have immunologic disease, are pregnant, or have received multiple transfusions.60 When the tested serum has antibodies to some, but not a sufficient number, of the HIV proteins assessed by Western blot, the results are classified as indeterminant. This can occur early during seroconversion or because of cross-reactivity between HIV and non-HIV antibodies. Repeat serologic testing at 3 and 6 months can help distinguish the two conditions. Alternatively, a test for HIV RNA can be used; when negative, such a test provides adequate evidence that HIV infection is not present.

Rapid serologic tests have been introduced for use in obstetrics and acute care settings and are widely used in low-income countries. These tests include both fingerstick and saliva tests. All are variations of EIA tests, with HIV antigens mounted on a solid phase; results appear on a colorimetric readout. Positive results must be confirmed with a Western blot assay or indirect immunofluorescence assay.

Both standard and rapid serologic testing methods suffer from low sensitivity during acute HIV infection. During the first 2 to 6 weeks after infection, these tests may be negative because antibodies have not been produced in sufficient quantity. This period before seroconversion is known as the window period. When acute HIV infection is suspected, another test may be added to the EIA, such as quantitative testing for HIV RNA (see below).

Tests of HIV RNA (Viral Load)

Three major methods are commercially available for measuring HIV RNA levels in plasma: reverse transcriptase-polymerase chain reaction (RT-PCR; Amplicor HIV Monitor 1.5, Roche Diagnostics), nucleic acid sequence-based amplification (NASBA; NucliSens HIV QT assay, bioMerieux Inc.), and branched-chain DNA (bDNA; in the United States, Versant HIV RNA 3.0 HIV assay; in Europe, Quantiplex HIV RNA 3.0 assay Bayer Corporation).61,62 Each of these tests has variability within the same test of log10 0.15 to 0.33 copies/ml; greater variability exists between tests. Because of variation between tests, the same test should be used consistently for monitoring a patient. All tests have been evaluated for all subtypes of genotype M and perform reasonably well, although there is less experience with the NASBA technique with multiple clades.61,63,64

Resistance Testing

Substitutions in specific nucleic acid base pairs can lead to changes in the amino acid sequence of HIV proteins targeted by antiretroviral agents. Some of these changes may have minimal effect on antiretroviral activity; others confer high-level resistance. Knowledge of resistance profiles is essential in determining the optimal HAART regimen for a patient. Two techniques are used to identify resistance to specific agents: genotyping and phenotyping. With genotyping, regions of the HIV genome are sequenced and the sequences are evaluated to identify site mutations known to confer resistance. Genotype reports include the site of a mutation (e.g., K103N is a lysine-to-asparagine substitution at amino acid position 103 of the reverse transcriptase enzyme) and the predicted resistance interpretation using computer-based algorithms. For phenotype testing, HIV pol gene from the patient is spliced into a laboratory virus, which is then grown in the presence of varying concentrations of antiretroviral agents, and replication is compared with the replication of a wild type laboratory virus in the absence of drugs. Phenotypes are generally reported as the concentration of agent required to suppress 50% (IC50) or 90% (IC90) of viral replication, the fold resistance in IC50 susceptibility when compared with wild type, and a cut-off for activity.

Genotyping is less expensive and is usually the preferred initial choice. Phenotyping may have advantages over genotyping in highly treatment-experienced patients with many resistance mutations; in these patients, interpretation of a genotype may be complex and may not reflect interactions among mutations. In these situations, quantitative information about partial or relative susceptibility may be helpful. A limitation of both genotype and phenotype assays is that only the dominant currently circulating quasispecies are assayed. The assays generally do not detect resistant quasispecies that make up less than 20% of the total population, nor do they detect those species that are archived in latent memory CD4+ T cells. Thus, viruses resistant to current HAART agents or agents that were very recently used can be expected to be identified, but earlier mutations no longer being selected for or maintained may be missed. Resistance testing to evaluate treatment failure is optimally performed while the patient is still on treatment. Generally, the HIV RNA level must be above 1,000 copies/ml for amplification by either genotype or phenotype assays. Interpretation of geneotypic and phenotypic resistance testing can be complicated and nuanced. Improved viro logic outcomes can be achieved with expert guidance in applying resistance data and treatment history to select a new regimen.65

CD4+ T Cell Count

The CD4+ T cell count is the best currently available means of assessing immune function and is valuable both for deciding when to initiate HAART and for building differential diagnoses during the management of acute or chronic illnesses. The CD4+ T cell count is measured by flow cytometry. Results are usually expressed as both the absolute value and the CD4+ T cell percentage; the former is more widely used in treatment guidelines. In general, an absolute CD4+ T cell count of 200/mm3 corresponds to a CD4+ T cell percentage of 14, and an absolute CD4+ T cell count of 500/mm3 corresponds to 28%. Some studies have suggested that a discordantly low CD4+ T cell percentage carries a higher risk of AIDS-defining condition or death, whereas others have found no added predictive value of the CD4+ T cell percentage.66,67Because the CD4+ T cell percentage is directly measured, it is less variable than the absolute CD4+ T cell count, which is often calculated on the basis of the total white blood cell count, the lymphocyte percentage, and the CD4+ T cell percentage. As a result, the CD4+ T cell percentage can be useful for interpreting fluctuations in the absolute count, which may occur with acute illnesses or treatment of hepatitis C.

Acute HIV Infection

Acute retroviral syndrome is an illness with protean and nonspecific manifestations; it may be confused with infectious mononucleosis or influenza [see Table 5]. Even experienced clinicians often overlook this diagnosis.68 Symptoms occur in 50% to 90% of persons, typically from 4 to 28 days after infection, corresponding to the peak in HIV viremia.69 The most common presenting symptoms are low-grade fever, malaise, and headache [see Table 6]. Symptoms usually last 1 to 4 weeks (median, 2 weeks) and may evolve to include lymphadenopathy, anorexia, and weight loss.70 A similar acute illness develops in approximately 5% of patients after the discontinuance of suppressive HAART, as HIV RNA levels increase exponentially.71,72

Table 5 Differential Diagnosis of Acute Retroviral Illness

Infectious mononucleosis (Epstein-Barr virus or cytomegalovirus)
Secondary syphilis
Acute early hepatitis B or A
Acute toxoplasmosis
Acute herpes simplex virus infection
Still disease

Table 6 Common Clinical Manifestations in Symptomatic Acute Retroviral Syndrome*225

Sign or Symptom

Frequency (%)





Myalgia or arthralgia


Rash (usually maculopapular)


Night sweats




*Less common manifestations are pharyngitis, lymphadenopathy, oral ulcers, mild transaminitis, aseptic meningitis, thrombocytopenia, neutropenia, and weight loss (average, 10 lb).


Physical Examination

A maculopapular rash that may extend to the palms and soles develops in 23% to 67% of patients with acute retroviral syndrome.73 Other common findings are pharyngeal erythema, oral ulcerations, and oropharyngeal candidiasis. Lymphadenopathy and splenomegaly usually occur later in the course of the acute retroviral syndrome. Cervical, 2axillary, and inguinal lymphadenopathies are common. Patients with specific neurologic manifestations such as meningoencephalitis, neuropathy, radiculopathy, and Guillain-Barré syndrome may have corresponding physical findings.

Laboratory Testing

HIV tests are required to make the diagnosis of acute retroviral syndrome. Two methods of diagnosis are used, depending on the clinical setting [see Table 7].

Table 7 Diagnostic Criteria for Acute Retroviral Syndrome

Diagnostic Method 1

Diagnostic Method 2

Symptoms consistent with acute retroviral syndrome

Symptoms consistent with acute retroviral syndrome

Negative HIV ELISA within past 6 mo

Negative HIV ELISA at current testing

Positive HIV ELISA at current testing

High HIV RNA titer at current testing (usually > 100,000 copies/ml)

ELISA—enzyme-linked immunosorbent assay

Once acute HIV infection has been diagnosed, the patient should be screened for other sexually transmitted infections, including syphilis, gonorrhea, Chlamydia infection, and human papillomavirus (HPV) infection. In addition, in over 8% of cases of HIV infection in the United States and Europe, resistance mutations are present. Baseline genotype testing is now recommended, regardless of whether immediate antiretroviral therapy is to be instituted.74,75


Treatment of acute retroviral syndrome includes symptomatic relief, education and counseling, and consideration of antiretroviral therapy. There are numerous hypothetical reasons for treating acute retroviral syndrome with HAART, including the potential for better preservation of immune function, preservation of lymphoid CD4+ T cells, prevention of complications of progressive HIV, and prevention of further transmission.71 At one time it was also hoped that early treatment would eradicate the virus and lead to cure of HIV infection.76 It is now recognized that eradication and cure do not occur, nor has clear long-term virologic, clinical, or immunologic benefit been demonstrated. Because of the lack of supporting data, together with the known long-term side effects of HAART, there is currently no recommendation for routine use of early treatment.77,78 Even patients with a significant decline in CD4+ T cell counts during acute infection are likely to experience a rebound in the CD4+ T cell count after resolution of the acute retroviral syndrome without treatment. The current recommendations from the Department of Health and Human Services (DHHS) are that HAART is optional in the setting of acute HIV infection.74 Randomized clinical trials of early treatment are ongoing and will provide further data on the risks and benefits of starting HAART during acute or early infection.


Complications rarely occur during the acute retroviral syndrome. In some patients, however, the initial immunologic insult may so significantly diminish CD4+ T cell counts that the patient is vulnerable to opportunistic infections, including Candida esophagitis and P. jiroveci pneumonia. In other patients, neurologic complications or opportunistic infections may develop. Meningoencephalitis is the most common neurologic complication in patients with acute retroviral illness. Retro-orbital pain is a common symptom; cerebrospinal fluid typically demonstrates a lymphocytic pleocytosis. Even in patients without symptoms, CSF findings may be mildly abnormal. Aseptic meningoencephalitis is usually a self-limiting condition that resolves without residual complications. More serious neurologic conditions may occur, including Guillain-Barré syndrome, psychosis, and neuropathies. HAART may have a role in managing some of these complications.


Persons with acute HIV infection universally progress to chronic infection. Time from infection to clinical progression is highly variable, but the average time from infection to clinically defined AIDS in an untreated patient is within 10 years. Antiretroviral therapy started at the appropriate CD4+ T cell count can prevent the progression to AIDS and enable a patient to maintain a robust immune system and live a normal life. In the absence of HAART, death is almost inevitable. The natural history of HIV infection is discussed elsewhere [see Prognosis,below].

Chronic HIV Infection


Chronic HIV infection is diagnosed either as a result of routine HIV testing or during evaluation of illness. With the increasing emphasis on routine HIV screening for all persons 13 to 64 years of age in the United States,12 ideally, more HIV-infected persons will be identified before their disease progresses to AIDS. In undiagnosed patients, presentation with an AIDS-defining condition or unexplained lymphadenopathy, anemia, leukopenia/lymphopenia, or elevations in the total protein level should raise the suspicion of HIV and lead to HIV testing.

In addition to HIV status, the clinician should assess transmission risk, past medical history, and family history and should conduct laboratory screening for sexually transmitted infections and HIV-related indices. This information will be important for long-term management.

Initial History

The initial history should include the date of the first positive HIV test, as well as information that might help to estimate when infection occurred. Patients should be asked about HIV-related symptoms and opportunistic infections, and conditions that may affect the choice of antiretroviral agents, including hyperlipidemia, diabetes mellitus, renal disease, chronic viral hepatitis, gastrointestinal disease (including frequent diarrhea), gastroduodenal ulcers, gastroesophageal reflux disease, and psychiatric illnesses. It is important to ask about tuberculosis exposure and results of tuberculin skin tests and about exposure to endemic fungal diseases (e.g., coccidioidomycosis or histoplasmosis) that may reactivate with waning immunity. For patients who have been treated with HAART, a detailed treatment history, including the regimens used, adherence, virologic and immunologic response, results of past resistance tests, and adverse events, is essential.

Review of Systems

A useful review of systems for HIV-infected patients includes questions about fever, night sweats, weight loss, headaches, visual changes, thrush, oral ulcerations, dysphagia or odynophagia, dyspnea, diarrhea, rashes or skin lesions, neurologic symptoms (e.g., weakness, neuropathy, and incontinence), urogenital problems, sexual dysfunction, changes in mentation, and depression. This list is effective for screening for many of the more common conditions affecting HIV-infected patients and is useful both for the initial encounter and each subsequent visit.

Physical Examination

A complete physical examination is necessary to detect evidence of opportunistic conditions in patients with significant immune deficiency and to detect evidence of drug toxicity in patients receiving HAART. In patients on HAART, the clinician should look for changes in fat distribution, including lipoatrophy in the face, extremities, and buttocks, as well as enlargement of the dorsocervical fat pad (so-called buffalo hump), fat accumulation in the neck, gynecomastia, and the accumulation of abdominal visceral fat. On oropharyngeal examination, white patches that scrape off to reveal an erythematous base suggest oral candidiasis (thrush), white plaques along the lateral border of the tongue that cannot be scraped off suggest oral hairy leukoplakia, and purplish macules on the mucosa, especially on the hard palate, suggest Kaposi sarcoma. Genital and anal examinations should be performed to look for evidence of sexually transmitted diseases; women should have a cervical Papanicolaou smear, and anal Pap smears should be considered for both men and women. A neurologic examination should be performed to evaluate for peripheral neuropathy and early dementia. A psychiatric screening should evaluate for depression and anxiety disorders.

Laboratory Studies

The baseline laboratory evaluation includes an HIV test to confirm infection, if no laboratory records are available. The CD4+ T cell count and HIV RNA level should also be determined and, ideally, confirmed with repeat testing. The 2006 DHHS guidelines recommend resistance testing with an HIV genotype assay before starting therapy in patients with chronic HIV infection.76 The detection of drug resistance mutations is helpful in selecting the initial regimen, but the absence of mutations does not guarantee the absence of subspecies of resistant virus in circulation or in the reservoir of latent T cells, especially if the test is performed years after infection. The recommended testing for initial and follow-up evaluation of an HIV-infected patient are listed [see Table 8].

Table 8 Initial and Followup Evaluations in HIV-infected Patients


Initial Visit

Follow-up Visits

Not on HAART


HIV antibody

If not documented



Complete physical examination




Pap smear*


Twice in first yr, then annually if normal

Twice in first yr, then annually if normal

Anal Pap smear (men and women)226


Consider annually

Consider annually

Complete blood count


Every 3–6 mo

Every 3–6 mo

Chemistry panel


Every 3–6 mo

Every 3–6 mo

Liver enzymes


Every 3–6 mo

Increased frequency initially in patients taking higher-risk drugs, including NVP and TPV

Renal function



Every 3–6 mo, especially in patients taking tenofovir or indinavir

Urine protein



Every 3–6 mo with TDF

Lipid panel


Follow standard guidelines

8 wk after starting HAART and annually

Fasting glucose





If symptomatic

If symptomatic

If symptomatic



Every 3–6 mo; use regular HIV RNA assay, detection threshold 400 copies/ml

2–8 wk after starting or changing therapy, monthly until HIV RNA < 50, and then every 3–4 mo; use ultrasensitive HIV RNA assay, detection threshold 50 copies/ml

CD4+ T cell count (2)


Every 3–6 mo

Monthly until HIV RNA < 50 then every 3–4 mo

HIV genotype



For evaluation of treatment failure


If clinically indicated

If clinically indicated

If clinically indicated

Bone density

Age > 65 yr or standard risks for osteopenia

Age > 65 yr or standard risks for osteopenia

Age > 65 yr or standard risks for osteopenia

Syphilis screen (RPR)









As per standard guidelines

As per standard guidelines

As per standard guidelines

G6PD deficiency testing§

Consider for patients at risk

Baseline only

Baseline only

Anti-Toxoplasma IgG


If previously negative, when CD4 falls to < 100 cells/mm3

If previously negative, when CD4 falls to < 100 cells/mm3

Anti-CMV IgG




Pregnancy test

As indicated

As indicated

As indicated||


If patient > 40 yr

When clinically indicated

When clinically indicated

Tuberculin skin test


Consider annually if at high risk (e.g., incarceration, homeless)

Consider annually if at high risk

Hepatitis C antibody


Perform HCV RNA if Ab-positive (or if Ab-negative in patients at high risk) with unexplained transaminase elevations

Hepatitis B surface antibody (anti-HBs)




Hepatitis B surface antigen (HBsAg)

Yes; if results positive, test for HBV DNA

As indicated for evaluation of acute hepatitis

As indicated for evaluation of acute hepatitis

Hepatitis A (IgG+IgM)


As indicated for evaluation of acute hepatitis

As indicated for evaluation of acute hepatitis

*HIV increases risk of squamous intraepithelial lesions (SIL) and progression of cervical dysplasia. Abnormal Pap results, including SIL and atypical squamous cells of undetermined significance, should be evaluated further with colposcopy and directed biopsy.227
Defer until 2–3 wk after acute illness or vaccination.
 Steroid therapy, early menopause, hypogonadism, hyperthyroidism.
§To assess risk of hemolytic anemia before using medications leading to oxidative stress (e.g., dapsone, primaquine).
||Patients with AIDS-related amenorrhea may resume normal menstrual cycles after HAART initiation and are at high risk for pregnancy.
Perform HBV DNA, HBeAg assays if the patient is Ag-positive; consider measuring HBV DNA in antigen-negative patients at high risk who have unexplained transaminase elevations.
CMV—cytomegalovirus G6PD—glucose-6-phosphate dehydrogenase HAART—highly active antiretroviral therapy HCV—hepatitis C virus NVP—nevirapin Pap—Papanicolaou RPR—rapid plasma reagin TDF—tenofovir TPV—tiptanavir TSH—thyroid-stimulating hormone

Differential Diagnosis

Patients who are suspected of having HIV infection may sometimes test negative by HIV serology and HIV RNA, in which case other causes of low CD4+ T cell counts or impaired cell-mediated immunity need to be considered. Rarely, patients with advanced HIV disease may have a negative serology because of HIV-related humoral immunodeficiency with loss of antibody response. However, in such cases, the HIV RNA level is very high. The most common alternative cause of immunodeficiency is use of immunosuppressive medications, a diagnosis that should be readily apparent. The differential diagnosis may also include some of the following: idiopathic CD4+ lymphocytopenia (diagnostic criteria are CD4+ T cell counts below 300/mm3 on at least two measurements and no evidence of HIV); Sjögren syndrome; sarcoidosis; lymphoma; and congenital immunodeficiency syndromes affecting T cells, including severe combined immunodeficiency, interleukin-2 (IL-2) deficiency, purine nucleoside phosphorylase deficiency, defective major histocompatibility complex (MHC) molecules, adenosine deaminase deficiency, ataxia-telangiectasia, and Wiskott-Aldrich syndrome. Consultation with an immunologist is valuable when considering these syndromes.


Education and Counseling

Patient education and support are critical aspects of managing HIV infection. Support from family and friends is essential and can improve the quality of life and enhance medication adherence.79 The clinician and the patient should discuss disclosure of HIV status, support structures, and—for patients who have not yet disclosed their HIV status—ways to facilitate disclosure. Counseling and follow-up are important because many patients experience depression and suicidal ideation after learning that they are HIV positive.80 Patients with HIV should be counseled regarding the availability of effective therapy and the need for behavior modification to reduce the chance of superinfection, infection with sexually transmitted pathogens, and transmitting HIV to others. It is important to also review the behaviors that pose no risk of HIV transmission [see HIV Transmission, above], so that patients do not needlessly isolate themselves from family and friends.


HIV-infected patients should follow an immunization schedule [see Table 9]. Two important considerations apply in the immunization of these patients: (1) live vaccines should generally be avoided, especially in patients with significant immunodeficiency, and (2) significant immunodeficiency reduces the likelihood of the patient establishing immunity in response to vaccination. Immunizations can be deferred until after the patient has responded immunologically and virologically to HAART, or immunizations can be repeated after the restoration of immunity in patients starting HAART (i.e., when the CD4+ T cell count exceeds 200/mm3).

Table 9 Immunizations for HIV-infected Adults




Every 5 yr; consider deferring until CD4+ cell count > 200 cells/ml

Influenza (inactivated)


Hepatitis B

Three-injection series, if not immune

Hepatitis A

Two-injection series for patients with underlying liver disease and no immunity; three injections when using combined HAV-HBV vaccine


Every 10 yr


Not recommended if CD4 < 200, otherwise per routine


Not recommended for HIV-infected patients

Prophylaxis against Opportunistic Infections

Patients with with significant immunodeficiency (CD4+ T cell count < 200/mm3) are at high risk for opportunistic infections and require prophylaxis. Recommendations for prophylaxis are listed [see Table 10].

Table 10 Prophylaxis of Opportunistic Infection in HIV-infected Patients228


Criteria for Starting Prophylaxis*

Criteria for Discontinuing Prophylaxis*

Recommended Agents

Alternative Agents

Pneumocystis jiroveci

CD4+ T cell count < 200

CD4+ count > 200 for ≥ 3 mo

TMP-SMX: single strength, one tablet q.d.; double strength, one tablet q.d. or 3x/wk

Dapsone, 100 mg q.d.; aerosolized pentamidine, 300 mg/mo; atovaquone, 1,500 mg q.d.

Mycobacterium avium complex

CD4+ count < 50

CD4+ count > 100 for ≥ 3 mo

Azithromycin, 1,200 mg/wk or clarithromycin, 500 mg b.i.d.

Rifabutin, 300 mg q.d.


CD4+ count < 100 and positive anti-Toxoplasma IgG assay

CD4+ count > 200 for ≥ 3 mo

TMP-SMX double strength, one tablet daily

Dapsone, 50 mg q.d. + pyrimethamine, 50 mg/wk + leucovorin, 25 mg/wk


Induration > 5 mm on TST

Complete 9 mo of therapy

INH 300mg q.d. + pyridoxine 100 mg 2x/wk for 9 mo


*CD4+ counts in cells/mm3
INH—isoniazid TMP-SMX—trimethoprim-sultamethoxazole   TST—tuberculin skin test

Principles of Antiretroviral Therapy

The goal of HAART is to inhibit infection of uninfected CD4+ T cells. This goal is achieved when the level of plasma viremia drops below the level of detection by ultrasensitive assays for HIV RNA (i.e., to 50 copies/ml or less). This can be accomplished if the clinician prescribes a combination of potent agents with varying pathways to resistance and the patient adheres scrupulously to the regimen.


Adherence is the single most important factor in achieving and maintaining virologic suppression with a potent HAART regimen. Early studies using regimens that included only a single protease inhibitor suggested that achieving the maximum likelihood of virologic suppression required adherence of approximately 95% to 100%.81,82 However, this high a degree of adherence may not be necessary with regimens that include nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors pharmacologically boosted with low-dose ritonavir.83,84

Multiple factors affect adherence, including regimen simplicity, side effects, social support, substance abuse, psychiatric illness, and other individual barriers [see Table 11]. Side effects are the most common cause of lack of adherence.85 Two other major barriers are mental illness, including depression; and substance abuse, including abuse of alcohol and illicit drugs. These conditions should not exclude HAART use but should be addressed as part of comprehensive HIV care.

Table 11 Barriers to Adherence to Antiretroviral Therapy

Lack of education about or understanding of HIV disease
Denial or anxiety
Depression or other mental illness
Substance abuse
Medication side effects
Complicated dosing regimens
Poor social situation
Lack of a family or community support structure
Inadequate health insurance
Poor clinician-patient relationship

Specific interventions for supporting adherence include the use of pill boxes, pharmacy support programs, cell phone reminder alarms, treatment of side effects or switching therapy to minimize side effects, improving convenience, improving patient self-efficacy, enlisting family and community supporters, treatment of substance abuse, and management of depression. Patient adherence can be improved when the health care team works together to impress upon the patient the importance of adherence and to identify patient-specific ways to improve adherence.

Antiretroviral Resistance

Resistance usually arises after a period of incompletely suppressed viremia as a result of inadequate adherence. The distribution of the risk of resistance follows a right-skewed bell curve, with the risk peaking when adherence is between 75% and 90%.83,86 This distribution results from an absence of the development of resistance with high adherence, when viral replication is completely suppressed, and at low levels of adherence, where there is insufficient selective pressure to drive the emergence of resistance. The risk at the peak of the bell curve varies between agents, with the lowest risk of developing resistance occurring with the use of ritonavir-boosted protease inhibitors. Resistance to NNRTIs, on the other hand, may develop after even a single dose.87 Once present, resistance mutations compromise the regimen being used, limit alternative options, and become banked as part of the permanent repertoire stored in the reservoir of quiescent memory CD4+ T cells, even when they are not detected with resistance testing.

Timing of HAART Initiation

The current paradigm for starting HAART is based on the trade-off between drug toxicity and the chance of resistance on the one hand and long-term consequences of high viremia and immune decline on the other. Current guidelines recommend starting HAART in any patient with symptomatic HIV infection or an AIDS-related condition, regardless of the CD4+ T cell count, or when the CD4+ T cell count falls below 200/mm3 [see Table 12]. Therapy should be considered for asymptomatic patients with CD4+ T cells counts between 200 and 350/mm3 and for those with HIV RNA above 100,000 copies/ml, regardless of CD4+ T cell count. Currently, experts favor starting HAART when the CD4+ T cell count approaches 350/mm3. Clearly, any decision to start HAART must also involve the patient's readiness for starting therapy.

Table 12 Recommendations for Initiation of HAART in Treatment-naïve, Nonpregnant Adults75

Patient Status*


Symptomatic HIV disease

HAART recommended

CD4+ T cell count ≤ 200

HAART recommended

CD4+ T cell count < 350 but > 200

Consider HAART, individualize to patient

CD4+ T cell count ≥ 350 but ≤ 500

HAART generally not recommended (see text)

CD4+ T cell count > 500

HAART generally not recommended

*CD4+ T cell counts in cells/mm3.
The closer the CD4+ T cell count is to 200, the stronger the recommendation, particularly if the plasma HIV RNA level is high (> 100,000/ml) or the CD4+ T cell count is declining rapidly (> 100 cells/mm3/yr).
HAART—highly active antiretroviral therapy

Recommendations for optimal timing of the initiation of HAART are likely to evolve. Future guidelines may recommend starting HAART at higher CD4+ T cell counts, because safer agents have become available and evidence of improved outcomes with HAART initiation at CD4+ T cell counts above 350/mm3 continues to accumulate.88

Selection of HAART Regimens

Considerations in choosing an initial HAART regimen include potency, barrier to resistance, simplicity of dosing, tolerability, long-term toxicity, convenience, and drug interactions. Several combinations have become popular as initial regimens because they perform well on all these criteria and have proven track records. Current guidelines for initial therapy from the International AIDS Society-United States of America (IAS-USA) recommend the use of one of three dual nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) combinations—tenofovir/emtricitabine (Truvada), abacavir/lamivudine (Epzicom, Kivexa), or zidovudine/lamivudine (Combivir)—plus either the NNRTI efavirenz or one of four ritonavir-boosted protease inhibitors: lopinavir, atazanavir, fosamprenavir, or saquinavir. Of these agents, only zidovudine/lamivudine and saquinavir/ritonavir require twice-daily dosing; the others can be given in single daily doses in treatment-naive patients. The DHHS guidelines recommend tenofovir/emtricitabine or zidovudine/lamivudine plus efavirenz or ritonavir-boosted atazanavir, fosamprenavir, or lopinavir as preferred combinations. The DHHS and the IAS-USA routinely update guidelines for selecting HAART regimens.74,75 Additional considerations for regimen selection are listed [see Table 13].

Table 13 Factors to Consider When Selecting a HAART Regimen



Comorbid tuberculosis, chronic liver disease, mental illness, cardiovascular disease, chemical dependency, pregnancy, gastritis or gastroesophageal reflux disease, lipid disorders, or renal disease

Medications for treatment of comorbid illness (e.g., antituberculosis drugs, antiviral drugs for hepatitis C, proton pump inhibitors); HAART may worsen conditions such as lipid abnormalities, renal disease, atherosclerotic disease, or mental illness; HAART agents may be active against the comorbid condition (e.g., hepatitis B)

Adherence potential

HAART regimens with higher genetic barriers to resistance (boosted-PI based rather than NNRTI based) may be superior in patients at risk for treatment interruption

Dosing convenience

Once-a-day dosing may improve adherence in some patients

Potential side effects

Patient preference and comorbidities should be considered

Pregnancy potential

Efavirenz is class D for use during pregnancy because of association with neural tube defects (risk greatest during first trimester)

Pretreatment CD4+ T cell count

Nevirapine is contraindicated for women with CD4+ T cell > 250 or men with CD4+ T cell > 400 at the start of treatment because of greater risk of hypersensitivity, including fulminant hepatic necrosis

Genotype test results

Avoid agents to which the virus is resistant

HAART—highly active antiretroviral therapy   NNRTI—nonnucleoside reverse transcriptase inhibitor   PI—protease inhibitor

Classes of Antiretroviral Agents

Each class of antiretroviral drug targets a different step in the HIV lifecycle [see Figure 6]. Currently, three classes of medications form the backbone of HIV treatment: NRTIs, NNRTIs, and protease inhibitors; additional classes of antiretroviral drugs inhibit entry, integration into host DNA, and viral maturation [see Table 14].


Figure 6. Sites of action of the major classes of antiretroviral medications.

Table 14 Antiretroviral Medications


Trade Name


Nucleoside RTIs



  Abacavir (ABC)


600 mg q.d.

  Didanosine (ddI)

Videx, Videx EC

< 60 kg, 250 mg q.d.; ≥ 60 kg, 400 mg q.d.

  Emtricitabine (FTC)


200 mg p.o., q.d.

  Lamivudine (3TC)


300 mg q.d.

  Stavudine (d4T)


< 60 kg, 30 mg q.d.; ≥ 60 kg, 40 mg q.d.

  Zalcitabine (ddC)


0.75 mg t.i.d.

  Zidovudine (AZT)


300 mg b.i.d.

Nucleotide RTI



  Tenofovir (TDF)


300 mg q.d.

Nonnucleoside RTIs



  Delavirdine (DLV)


400 mg t.i.d.

  Efavirenz (EFV)


600 mg h.s.

  Nevirapine (NVP)


200 mg q.d. × 14 days, then 200 mg b.i.d.

Protease inhibitors



  Atazanavir (ATV)


400 mg q.d.

  Darunavir (DRV) + ritonavir


600/100 mg b.i.d.

  Fosamprenavir (FPV)


1,400 mg q.d. or 700 mg b.i.d.

  Fosamprenavir (FPV) + ritonavir


700/100 b.i.d. or 1400/200 q.d. (treatment-naïve patients only)

  Indinavir (IDV)


800 mg q. 8 hr

  Indinavir (IDV) + ritonavir


800/100 mg b.i.d. (preferred)

  Lopinavir + ritonavir


Two 200/50 mg tablets b.i.d. or four tablets q.d. (treatment-naïve only); take with food



1,250 mg b.i.d. with food

  Ritonavir (RTV)


Used only for boosting levels of other PIs, at doses of 100–400 mg/day

  Saquinavir (SQV) + ritonavir


1,000/100 mg b.i.d. (or 2,000/100 mg q.d., investigational)

  Tipranavir (TPV) + ritonavir


500/200 b.i.d. with food

  Fusion inhibitor Efuvirtide (ENF, T-20)


90 mg S.Q. b.i.d.

  Fixed-dose combinations



  Abacavir + lamivudine

Epzicom, Kivexa

One tablet daily

  Efavirenz + emtricitabine + tenofovir


One tablet daily

  Emtricitabine + tenofovir


One tablet daily

  Zidovudine + lamivudine


One tablet b.i.d.

  Zidovudine + lamivudine + abacavir


One tablet b.i.d.

*All agents given orally unless otherwise indicated
Generic formulation also available
PI—protease inhibitor RTI—reverse transcriptase inhibitor

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

NRTIs are nucleoside or nucleotide analogues. After phosphorylation by host enzymes, NRTIs are incorporated into the growing nucleic acid chain, where they then prevent chain elongation because they lack a 3′ hydroxyl group. NRTI affinity for HIV reverse transcriptase is far higher than for human polymerases; nevertheless, inhibition of DNA synthesis by mitochondrial polymerase-γ is believed to contribute to adverse effects of some of the NRTIs, especially didanosine, stavudine, and zidovudine [see Table 15]. Most NRTIs are eliminated through the renal route; the exception is abacavir, which undergoes hepatic metabolism.

Table 15 Side Effects, Contraindications, and Interactions of Nucleoside and Nucleotide Reverse Transcriptase Inhibitors


Common Side Effects

Serious Side Effects




Abacavir (ABC)

Hypersensitivity (5–8%) with morbilliform rash; GI complaints; fever, dyspnea, cough, malaise, usually in first 6 weeks, may be confused with influenza or other intercurrent illnesses; nausea, vomiting; headache

Life-threatening systemic hypersensitivity reaction if rechallenged after developing hypersensitivity (usually within hours of dose after restarting)

History of ABC hypersensitivity; avoid with end-stage liver disease

Overlapping resistance with ddI, insufficient data for recommendation

Hepatic metabolism

Didanosine (ddI)


Pancreatitis, lactic acidosis, peripheral neuropathy

Use with ribavirin contraindicated because of increased toxicity

TDF increases ddI concentration, is antagonistic, and inhibits T cell recovery; avoid combination or dose reduce ddI; d4T increases risk of pancreatitis and lactic acidosis, avoid co-administration

Renal elimination, do not take with food

Emtricitabine (FTC)

Minimal; occasional hyperpigmentation of palms and soles, especially in dark-skinned persons



3TC has similar action and resistance profile, avoid co-administration

Renal elimination

Lamivudine (3TC)




FTC has similar action and resistance profile; avoid co-administration

Renal elimination

Stavudine (d4T)

Headache, nausea (uncommon)

Lactic acidosis and hepatic steatosis, pancreatitis, lipodystrophy, peripheral neuropathy

Avoid in patient with neuropathy, lipoatrophy, previous NRTI-associated lactic acidosis

Antagonism with AZT, increased pancreatitis and lactic acidosis with ddI, avoid co-administration

Renal elimination

Tenofovir (TDF)


Nephrotoxicity, especially in patients with pre-existing renal disease


ddI: avoid co-administration or use reduced dose of ddI; ATV must be boosted with ritonavir (300/100 q.d.); caution when used in patients with underlying renal disease

Renal elimination

Zidovudine (AZT, ZDV)

Headache, nausea, malaise, macrocytosis; within 4 wk after start of therapy, nearly all patients have MCV>100 µm3

Bone marrow suppression with anemia or neutropenia, lactic acidosis and hepatic steatosis, lipoatrophy, myopathy (leg pain, increased CPK)

Avoid in patients with anemia

d4T: antagonism avoid co-administration, Ribavirin: increased risk for anemia
Methadone: increases AZT levels

Dose adjustment needed with renal impairment

CPK—creatine phosphokinase MCV—mean corpuscular volume NRTI—nucleoside reverse transcriptase inhibitors

Nonnucleoside Reverse Transcriptase Inhibitors

NNRTIs act by directly binding HIV reverse transcriptase, causing a conformation change that inhibits its enzymatic activity. All current NNRTIs are metabolized via hepatic cytochromes P-450 3A4 and 2B6; they have half-lives of 25 to 30 hours and serum levels that remain detectable for weeks.89 High-level resistance to first-generation NNRTIs develops rapidly because it requires only a single point mutation. Etravirine and other second-generation NNRTIs currently in development are active against viral strains that are resistant to currently available NNRTIs, and the development of resistance to these drugs requires more than one mutation. Side effects and interactions are listed [see Table 16].

Table 16 Side Effects, Contraindications, and Interactions of Nonnucleoside Reverse Transcriptase Inhibitors


Serious Side Effects



Delavirdine (DLV)

Hepatotoxicity, Stevens-Johnson syndrome

Not recommended for use in pregnancy

Cytochrome P450 metabolites

Efavirenz (EFV)


Not recommended for use in pregnancy; can cause neural tube defects

Cytochrome P450 metabolites

Nevirapine (NVP)

Severe hepatotoxicity and/or rash, including Stevens-Johnson syndrome

Do not start in women with CD4 > 250 or men with CD4 > 400 because of risk of fulminant hepatic necrosis

Cytochrome P450 metabolites

*NNRTIs decrease PI concentrations; PI dose adjustment needed with many PIs (FPV, ATV, LPV); discontinuance of NNRTI-based regimens may lead to NNRTI resistance because of long half-life; consider step-wise discontinuance or substitution of PI
e.g., rifamicins, terfenadine, midazolam, voriconazole, methadone (reduces levels 50%), simvastatin, lovastatin, clarithromycin
NNRTI—Nonnucleoside reverse transcriptase inhibitor PI—protease inhibitor

Protease Inhibitors

Protease inhibitors act by directly binding the active site of the protease enzyme, inhibiting the cleavage of viral peptides into structural proteins. Viral particles may still be released from the host CD4+ T cell, but they lack essential structural proteins and are unable to infect other cells. All protease inhibitors except nelfinavir are principally metabolized by cytochrome P-450 3A4 (Cyp3A4). Nelfinavir is metabolized by both cytochromes 3A4 and 2C19. Inhibition of Cyp3A4 has emerged as an important adjunct for maintaining higher trough concentrations of protease inhibitors. Ritonavir, originally developed as a protease inhibitor, is the most potent pharmacologic inhibitor of Cyp3A4. Because of its toxicity and poor tolerability, ritonavir is no longer used at full antiviral doses; however, low doses of ritonavir are now given along with most other protease inhibitors. This ritonavir boosting results in increased trough concentrations and longer half-lives [see Figure 7]. Patients who experience failure of therapy with ritonavir-boosted protease inhibitors tend not to have protease inhibitor resistance at the time of failure. All protease inhibitors can be boosted by ritonavir, with the exception of nelfinavir. The use of lopinavir, saquinavir, tipranavir, and darunavir requires ritonavir boosting. Side effects and interactions of protease inhibitors are listed [see Table 17].


Figure 7. Boosting with low doses of ritonavir increases the trough concentration and extends the half-life of other protease inhibitors. (IC90—concentration of drug required to inhibit 90% of viral replication)

Table 17 Side Effects, Contraindications, and Interactions of Protease Inhibitors


Common Side Effects

Serious Side Effects




Atazanavir (ATV)

GI intolerance, indirect hyperbilirubinemia ± jaundice/scleral icterus

Prolonged QTc; less metabolic toxicity (hyperlipidemia, insulin resistance) than with other PIs

Contraindicated with PPIs; dosing separation required with H2-inhibitor or antacids

Cytochrome P450 metabolites,*antacids, PPIs; RTV boosting required when combined with TDF, EFV, and probably NVP; avoid use with IDV because of increased risk for hyperbilirubinemia


Darunavir (DRV)

GI intolerance

Hepatotoxicity hyperlipidemia, insulin resistance +/- diabetes, fat accumulation


Cytochrome P450 metabolites*

Indicated for PI-experienced patients; RTV boosting required

Fosamprenavir (FPV)

Rash; GI intolerance

Hepatotoxicity, hyperlipidemia, insulin resistance +/- diabetes, fat accumulation

Use with caution in patients with sulfonamide allergy

Cytochrome P450 metabolites*


Indinavir (IDV)

Asymptomatic indirect hyperbilirubinemia, nephrolithiasis, hyperlipidemia, insulin resistance, xerosis, alopecia, paronychia

Nephrolithiasis, indinavir nephropathy with azotemia, diabetes, hyperlipidemia, fat accumulation


Cytochrome P450 metabolites,*avoid use with ATV because of increased risk for hyperbilirubinemia


Lopinavir/ritonavir (LPV/RTV)

GI intolerance

Hepatotoxicity, hyperlipidemia, insulin resistance ± diabetes, fat accumulation


Cytochrome P450 metabolites*


Nelfinavir (NFV)

Diarrhea, altered taste

Hyperlipidemia, insulin resistance ± diabetes, fat accumulation, hepatotoxicity


Cytochrome P450 metabolites*

The only PI that cannot be boosted; less effective than boosted PIs or EFV; administer with food to increase drug levels; fiber supplements decrease diarrhea

Ritonavir (RTV)

GI intolerance and diarrhea, improved when taken with food; perioral paresthesias

Hyperlipdemia, insulin resistance ± diabetes, hepatotoxicity, fat accumulation


Cytothrome P450 metabolites*

Better tolerated and less toxic at boosting doses (100–400 mg/day)

Saquinavir (SQV)

GI intolerance, headache

Hyperlipidemia (possibly less than with other PIs except ATV), fat accumulation, insulin resistance ± diabetes


Cytochrome P450 metabolites*

RTV boosting required

Tipranavir (TPV)

GI intolerance

Hepatotoxicity, hyperlipidemia, intracerebral hemorrhage

Not for HAART-naïve; bleeding diathesis or recent neurosurgery

Cytochrome P450 metabolites,*vardenafil

Greater risk of hepatotoxicity and hyperlipidemia than other PIs; only for PI-experienced patients; RTV boosting required

*Cytochrome P450 metabolites: rifamicins, terfenadine, midazolam, voriconazole, methadone (reduces levels 50%), simvastatin, lovastatin, clarithromycin
GI—gastrointestinal   HAART—highly active antiretroviral therapy   PI—protease inhibitor   PPI—proton pump inhibitor

Entry Inhibitors

HIV entry inhibitors include three types of agents: CCR5 receptor antagonists, CD4 receptor antagonists, and fusion inhibitors. CCR5 receptor antagonists block gp120 from binding to the CCR5 receptor after undergoing conformational change mediated by gp120-CD4 interaction. Two CCR5 inhibitors, maraviroc and vicriviroc, are the most promising agents in this category and are currently in phase III trials. A CD4 receptor antagonist under development, TNX-355, is a monoclonal antibody that partially binds CD4 and thereby inhibits viral coreceptor binding and entry into the cell. Although TNX-355 binds to CD4, it does not interfere with normal immunologic function. Phase II studies with highly treatment-experienced patients are ongoing.

Fusion Inhibitors

Fusion inhibitors target a step after the binding of gp120 to CCR5, preventing the conformational change in gp41 that leads to insertion into the cell membrane and fusion of the virus with the cell. Enfuvirtide is the only fusion inhibitor currently approved by the Food and Drug Administration [see Table 14]. Unlike other antiretroviral agents, enfuvirtide is injected subcutaneously, rather than taken orally; injection site reactions are a common side effect. Enfuvirtide may increase the risk of bacterial pneumonia. Resistance to enfuvirtide develops rapidly when this agent is used as monotherapy, and a special resistance assay must be requested for resistance testing. Enfuvirtide increases tipranavir levels, possibly increasing hepatotoxicity risk.

Integrase Inhibitors

Integrase inhibitors prevent integration of the proviral DNA into the host chromosome by the integrase enzyme. Two promising integrase inhibitors, MK-0518 and GS-9137, are in phase III trials.

Maturation Inhibitors

Maturation inhibitors disrupt effective budding of infection-competent virions. One maturation inhibitor with favorable results from a phase IIa trial is bevirimat (PA-457), which functions by inhibiting multimerization of gag to form the nuclear capsid.

Common Drug-Drug Interactions

HIV management is complicated by multiple drug-drug interactions. All medications should be reviewed before being started.90 Several common interactions are discussed here.

Oral Contraceptives

Concentrations of ethinyl estradiol, norethindrone, and norgestimate are reduced by most protease inhibitors and NNRTIs and by some NRTIs; this interaction may result in a failure to prevent pregnancy. Effective alternative forms of contraception are depo-medroxyprogesterone acetate (Depo-Provera) and barrier methods.

Erectile Dysfunction Agents

Protease inhibitors can increase the concentration of sildenafil, tadalafil, and vardenafil by twofold to 10-fold. Patients should use these erectile dysfunction agents at the lowest doses and avoid use on consecutive days.


Rifampin causes reduced concentrations of protease inhibitors and nevirapine and thus should be avoided, when possible, in patients taking those antiretrovirals. Rifampin can be safely combined with efavirenz, though efavirenz levels are decreased; the clinician should consider increasing the efavirenz dose to 800 mg daily. Rifabutin has less impact than rifampin, but it also reduces protease inhibitor and NNRTI levels, requiring dose modifications when these agents are combined.

Gastric Acid-Reducing Agents

Several protease inhibitors require low gastric pH for optimal absorption. Atazanavir has the strongest dependence on gastric acidity and should not be used with proton pump inhibitors. Atazanavir can be used with H2 receptor blockers, although it should be given 2 hours before or 10 hours after the H2 receptor blocker. Tipranavir levels may also be reduced with proton pump inhibitors and H2 receptor blockers. Clinicians should consider alternative protease inhibitors in patients who require control of gastric acidity.


Ritonavir-containing HAART increases levels of some steroids. This interaction is most problematic with the inhaled steroid fluticasone. Cushing syndrome and adrenal suppression have been reported with concomitant use of fluticasone and ritonavir-containing HAART.91,92


Levels of simvastatin and lovastatin are significantly increased when these agents are administered with protease inhibitors. Patients who require statin therapy should instead receive pravastatin or low-dose atorvastatin (i.e., 10 to 40 mg/day).

St. John's Wort

St. John's wort may significantly decrease levels of protease inhibitors and NNRTIs. Patients taking those antiretrovirals should be cautioned to avoid St. John's wort.

Evaluating Treatment Response

Successful HAART results in a decline in HIV RNA levels and an increase in the CD4+ T cell count (i.e., a virologic and an immunologic response). HIV RNA levels should be tested 2 to 4 weeks after initiating or changing HAART, every month until the HIV RNA count is below 50 copies/ml, and every 3 to 4 months in patients on a stable regimen with suppressed HIV RNA levels. The HIV RNA level declines within days of starting HAART; within 2 weeks, a 2 log10 decline is expected.93 The second phase of HIV RNA decline is slower, but HIV RNA should be undetectable by 24 weeks. After suppression has been achieved, the goal of HAART is to maintain the HIV RNA level below the level of detection with ultrasensitive tests (i.e., < 50 copies/ml).

As HIV RNA levels decline, the CD4+ T cell count rises. This rise occurs in two phases. The first represents a redistribution of memory CD4+T cells from lymphoid tissue during the initial 3 months of suppressive HAART.94 Although highly variable, the extent of the increase is typically 50 to 120/mm3.95 The second phase is slower and occurs through the expansion of naive CD4+ T cells. During this phase, the average increase in the CD4+ T cell count is 2 to 7/mm3 per month. This second phase continues for at least 4 to 6 years during suppressive HAART.88,95

Regardless of the duration of suppression, the temptation to reduce the number of agents in the regimen should be avoided. The strategy of induction with multiple agents and maintenance with one or two potent agents has not proved successful. On the other hand, there is also no evidence that patients with drug-susceptible virus require more than three agents, regardless of baseline viral load or CD4+ T cell count, provided they are started on a potent regimen.96


Many patients on effective HAART show transient increases, or blips, on routine HIV RNA testing. A blip is defined as an increase to an HIV RNA level of 50 to 400 copies/ml on a single assay in a patient whose previous and subsequent assays show undetectable levels. Blips may occur as a result of random laboratory variation around a mean HIV RNA level below the limit of detection with ultrasenstive HIV RNA assays.88,97 Indeed, simultaneous blips are rarely seen in both assays when a single sample is divided and sent to two laboratories for simultaneous HIV RNA assays. In some cases, blips may result from nonadherence, but there is no evidence of increased risk of virologic failure or development of resistance mutations during these episodes.

Until repeat testing is performed, it is impossible to determine whether a single detectable HIV RNA level represents a blip or early virologic failure. Repeat testing should be undertaken 1 to 2 weeks after a low-level elevation to differentiate between a blip and virologic failure.

Laboratory Error

False positive HIV RNA tests may occur as a result of improper laboratory technique. The most common cause is improper specimen handling with use of spun and frozen plasma preparation tubes (PPT), which can lead to cell lysis.98 Ethylenediaminetetraacetic acid (EDTA) tubes should be used for sample collection if possible, or PPT should be spun and the plasma separated before freezing or transporting.

Treatment Failure

Treatment failure may be virologic, immunologic, or a combination of the two. Virologic failure is defined as failure to achieve an HIV RNA level below 400 copies/ml by 24 weeks or below 50 copies/ml by 48 weeks, or two sequential elevations above 400 copies/ml after suppression has been achieved.74 Declines or inappropriately small increases in the CD4+ T cell count indicate immunologic failure.

Virologic failure in the setting of an appropriate rise in the CD4+ T cell count occurs in 5% to 10% of patients starting HAART. Virologic suppression but immunologic failure occurs in 10% to 20% of patients started on HAART. The reasons for these discordant responses are unclear, but they are associated with older age, a lower nadir CD4+ T cell count, and a lower baseline HIV RNA level.95,99 There is some evidence that regimens containing lopinavir/ritonavir, and perhaps boosted protease inhibitor therapy in general, are associated with a better CD4+ T cell response than efavirenz-based regimens, despite lower virologic efficacy.100

The optimal approach to patients with a discordant CD4+ T cell response has not been determined, though such patients tend to do well, and continued therapy leads to an increase in the CD4+ T cell count in half of the patients who initially have a discordant response.99 Another option is to switch to a ritonavir-boosted protease inhibitor if the patient is on an NNRTI regimen, although this approach has not been well studied. Treatment with IL-2 increases the CD4+ T cell count, but no clear clinical benefit has been demonstrated, and 2this agent has significant side effects.

Management of Treatment Failure

Treatment failure should prompt a rapid assessment of the cause of failure and appropriate intervention, because continuation of a failing regimen may lead to accumulation of drug resistance mutations. The first step in the evaluation of failure should be to repeat viral load testing; a genotype test is sometimes ordered, as well. Nonadherence is often the initial cause of treatment failure and must be addressed to ensure future treatment success. Continued incomplete suppression of HIV replication inevitably results in the development of drug resistance. If resistance testing does not show 2evidence of resistance to drugs in the current regimen, improving adherence may be all that is required. In many cases, resistance will have developed and the HAART regimen will have to be modified to reflect the resistance test results.

Patients with early treatment failure may have viral loads too low to allow for resistance testing. So-called intensification of therapy with the addition of a single drug, often an additional NRTI, is sometimes practiced in this setting despite the relative lack of supporting data, because of the concern that by the time the viral load is high enough to make resistance testing possible, more mutations will have emerged. This concern applies especially with NNRTI-based regimens, because NNRTI resistance can emerge rapidly with early failure. When the viral load is above 500 to 1,000 copies/ml, modification of the regimen on the basis of resistance testing results is always preferred over so-called blind intensification or empirical treatment modification.

When the use of lamivudine or emtricitabine has resulted in the selection of the M184V mutation in the infecting HIV strain, continuation of these agents is often recommended when designing n2ew regimens after failure of an initial regimen. This approach is justified by the drugs' low toxicity profiles together with a number of demonstrated benefits associated with this mutation. The M184V mutation can increase susceptibility to tenofovir and thymidine analogues (i.e., zidovudine and stavudine), partially restore thymidine analogue potency in the setting of thymidine-associated mutations, and partially restore potency of tenofovir in the setting of the K65R mutation, a mutation that otherwise leads to clinically significant tenofovir resistance.101,102,103 Maintaining M184V in a nonsuppressive HAART regimen may also be beneficial because of the lower replication fitness of virions containing that mutation,104,105 partial virologic suppression exerted by lamivudine or emtricitabine despite resistance,105 and a delay in the emergence of thymidine-associated mutations.

In some highly treatment-experienced patients with extensive multiclass resistance, two active agents may not be available, and it may not be possible to fully suppress HIV RNA levels. Such patients usually derive some benefit from continuing a nonsuppressive regimen, especially one that contains lamivudine, other NRTIs, and possibly protease inhibitors.105,106,107 The drawback to continued therapy is the development of additional mutations that may render ineffective the use of different agents in the future. The management of treatment-experienced patients with drug resistance is complex and should always involve expert consultation.

Structured Treatment Interruptions

Structured treatment interruptions have been evaluated in the setting of both virologic failure and treatment success. Treatment interruptions for either scenario have failed to be beneficial and have increased the risk of adverse outcome and other complications.108Interrupting HAART after the development of resistance leads to a rapid rise in HIV RNA dominated by the drug-susceptible, wild-type HIV, but this is associated with a more rapid decline in CD4+ T cell counts. Reintroduction of HAART results in a rapid reemergence of the archived resistant quasispecies.

Special Situations

Occupational Exposure

Exposures considered to pose a risk of HIV transmission are percutaneous injury and contact of mucous membrane or nonintact skin with blood, tissue, semen, vaginal secretions, CSF, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, or amniotic fluid. The risk of transmission is approximately 0.3% for percutaneous exposure and 0.09% for mucous membrane exposure, but the risk varies, depending on the volume of infectious fluid and the HIV RNA level of the source patient. The following are not considered infectious: feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus.

Rapid implementation of postexposure prophylaxis (PEP) reduces the risk of transmission. Optimally, PEP should be initiated within 2 hours of exposure and continued for 4 weeks. The initial evaluation includes a detailed description of the exposure and exposure source, an HIV antibody test, and tests for hepatitis B and C. Obtaining this information should not delay initiation of PEP. United States Public Health Service guidelines for PEP are available online (

For lower-risk exposures, two-drug PEP is recommended. Either zidovudine/lamivudine or tenofovir/emtricitabine is a reasonable choice. Abacavir is not recommended in this setting because of the risk of hypersensitivity. Three-drug therapy, recommended for high-risk exposures, combines either of the above two NRTI regimens with a protease inhibitor such as ritonavir-boosted lopinavir or atazanavir. The NNRTI efavirenz may also be used if pregnancy is unlikely, although the early neuropsychiatric side effects can be problematic. Nevirapine should be avoided because of the risk of hepatic necrosis in patients with normal immune function. Frequent follow-up with laboratory testing and monitoring of side effects is recommended, with HIV antibody testing repeated 6 months after exposure.


An HIV-infected woman who is pregnant or wishes to become pregnant ideally should be referred to an obstetrician who specializes in HIV care, because of drug interactions and pregnancy-specific dosing considerations. The management of pregnant women has two goals: treating the mother and preventing transmission to the infant. Treatment of the mother should be based on adult treatment guidelines, generally with the inclusion of zidovudine, if appropriate, and avoidance of efavirenz, which has known teratogenicity. Without HAART or specific measures to prevent mother-to-child transmission, such transmission occurs in approximately 24% of cases, principally during labor and delivery or via breast milk. The risk of mother-to-child transmission is greatly reduced through the use of zidovudine monotherapy; by administering zidovudine or nevirapine during labor; or with delivery via cesarean section; however, these methods are less desirable than standard HAART in women receiving prenatal care. Women not on HAART at the time of conception should begin HAART during the second trimester. Those who become pregnant while on HAART should generally continue therapy. Another agent should be substituted for women on efavirenz. Untreated women presenting in labor can be treated with a single 200 mg dose of nevirapine, followed by 2 mg/kg orally to the infant 48 to 72 hours after delivery, although this may increase the risk of NNRTI resistance in the mother and in infants who become infected despite therapy.110

Elective cesarean section can reduce the risk of perinatal transmission in women whose viral loads are detectable during the third trimester. There is no evidence that cesarean section is necessary in women whose viral loads are fully suppressed. With prevention of mother-to-child transmission during pregnancy and avoidance of breast-feeding, the risk of infection of the child can be reduced to less than 1%.

Common Coinfections

Hepatitis C

Hepatitis C virus (HCV) is primarily transmitted by percutaneous exposure to blood, either via unscreened blood products or injection drug use; 85% to 90% of injection drug users are infected. In the United States, approximately 30% of HIV-infected persons are coinfected with HCV. HIV-infected individuals are less likely to clear HCV, and they have higher HCV RNA levels and more rapid progression of HCV-related liver disease. They have a sixfold higher risk of end-stage liver disease than persons with HCV monoinfection. In settings where HIV-HCV coinfection is common, liver-related complications have become a leading cause of hospitalization of HIV-infected patients and the second leading cause of death.111,112,113

Treatment of HCV infection can be effective at reducing the risk of complications. Pretherapy evaluation should include measurement of HCV RNA level, HCV genotyping, and a liver biopsy; liver biopsy is the best indicator of the need for therapy. Elevations in the levels of transaminase are not predictive of disease progression or the need for therapy. The current regimen of pegylated interferon and ribavirin is poorly tolerated by many patients and achieves sustained virologic response in only 17% to 73%, depending on HCV genotype.114,115,116,117Improved therapy with new agents, including HCV protease inhibitors, is on the horizon, offering the possibility of improved virologic response when used in conjunction with pegylated interferon.

During treatment of HCV, use of didanosine or zidovudine is not recommended, the former because of increased risk of pancreatitis and lactic acidosis and the latter because of profound anemia. Even if zidovudine is not used, bone marrow suppression is likely; such suppression can lead to anemia, leukopenia, and a decline in the absolute CD4+ T cell count. In a patient with stable HIV infection, the CD4+T cell percentage should remain constant during anti-HCV therapy.

Hepatitis B

In the United States and Europe, hepatitis B virus (HBV), like HIV, is primarily transmitted sexually or through injection drug use.118 One quarter of those persons with chronic HBV infection who are not infected with HIV are expected to develop cirrhosis or hepatocellular carcinoma.119 Anti-HBV therapy reduces the risk of progressive liver disease.120 Because few patients mount an effective immune response—as manifested by seroconversion from HBV surface antigen (HBsAg) to surface antibody (HBVsAb)—and most anti-HBV therapy suppresses rather than cures the infection, treatment is usually prolonged; indeed, to maintain HBV suppression, anti-HBV therapy may need to be continued indefinitely.121,122

The presence of HBsAg, persistently elevated liver enzyme levels, and high levels of HBV DNA suggest active disease with necroinflammatory activity and the need for anti-HBV therapy. Seven agents are currently used for treating chronic HBV infection in the United States: pegylated interferon, adefovir dipivoxil, entecavir, tenofovir, lamivudine, and emtricitabine. HBV-specific agents, such as adefovir dipivoxil and interferon alfa, can be used for HBV suppression in patients in whom there is no intention to simultaneously treat HIV infection. Patients who require treatment of both infections should be treated with a HAART regimen that includes tenofovir plus either lamivudine or emtricitabine.123 Unless surface antigen seroconversion occurs, anti-HBV agents should be continued indefinitely to maintain HBV suppression.

Premature discontinuance of HBV-suppressive nucleoside analogue therapy can result in acute hepatitis.127 Acute hepatitis can also occur despite continuation of nucleoside therapy if resistance develops. During lamivudine therapy, HBV resistance occurs at a rate of 25% per year, with nearly 100% resistance by 4 years of therapy in persons coinfected with HIV.128,129,130 Coinfected patients should be screened for hepatocellular carcinoma with liver ultrasound and serum ?-fetoprotein measurements. Early detection of hepatocellular carcinoma can allow effective surgical management.


When a patient on HAART is hospitalized, the HAART regimen should be continued unless it is clear that the regimen itself is causing the condition leading to hospitalization (e.g., pancreatitis, lactic acidosis, or hypersensitivity reaction). Whenever possible, the clinician should replace the offending agent with another agent rather than discontinue the entire regimen. Unfortunately, HAART is often incorrectly prescribed in the inpatient setting. Good coordination between the outpatient provider, the inpatient team, and the patient may help to ensure uninterrupted continuation of the correct regimen.131


Experience from early in the HIV epidemic suggested that patients with uncontrolled HIV viral replication and low CD4+ T cell counts had higher rates of surgical complications. At that time, the balance between the need for surgical intervention and the potential complications of surgery sometimes favored nonsurgical management. Since the introduction of HAART, however, this balance has shifted; patients with controlled HIV infection have surgical outcomes similar to noninfected patients.132 Thus, HIV infection itself should not be considered a contraindication to surgery.

Preoperative screening in HIV-infected patients should follow accepted age-specific guidelines. Care should be taken to minimize interruption of HAART in the perioperative period. HAART agents that are taken in the morning can be taken before surgical procedures and continued afterward, because HAART agents do not interact with general anesthetic agents or most other standard operating room medications.133However, midazolam should not be used in patients who are taking protease inhibitors or NNRTIs, because the midazolam level can be substantially elevated in such patients. Lorazepam is an acceptable alternative.90

If oral intake is likely to be contraindicated for a prolonged period, HAART may have to be stopped. Patients on NNRTIs may be at high risk for developing resistance if their entire regimen is stopped simultaneously, because of the much longer half-life of NNRTIs compared with other agents. The risk of NNRTI resistance may be reduced if the NNRTI is stopped 1 to 4 weeks before the rest of the regimen. However, the timing of NNRTI discontinuance has not been well defined. Some experts substitute a protease inhibitor for the NNRTI for several weeks before discontinuing therapy to allow the NNRTI to “wash out.”

International Travel

Immunocompromised individuals are at higher risk for some travel-related illnesses and should not receive certain live virus vaccinations. Recommendations for HIV-infected patients vary depending on their CD4+ T cell count. Patients with CD4+ T cell counts above 200/mm3have travel-related risks similar to those of other travelers. Patients with CD4+ T cell counts below 200/mm3 are considered are at higher risk for some travel-related infections, as well as opportunistic infections. Generally, such patients are best advised to postpone travel to developing countries until effective HAART leads to immune restoration.

Vaccination is an important method of reducing the risk of acquiring infections while traveling. Hepatitis A, hepatitis B, inactivated influenza, Japanese encephalitis, meningococcal, pneumococcal, rabies, tetanus-diphtheria, and inactivated typhoid vaccines are recommended for use as for a healthy person. Live vaccines are generally contraindicated for patients with severe immunodeficiency. Bacillus Calmette-Guérin, live attenuated influenza, oral typhoid (Ty21a), oral polio, and varicella vaccines should be avoided in all HIV-infected patients. The risks of the live yellow fever vaccine must be balanced against the risk of disease.34 Prophylactic medications for malaria should be taken as for any traveler, on the basis of the region and resistance patterns of local malaria. HIV-infected travelers should consider bringing a fluoroquinolone to treat travelers' diarrhea.135

Country-specific recommendations and additional information on travel and HIV are available in the CDC's Health Information for International Travelers (“Yellow Book”) (


Before the development of HAART, opportunistic infections and other AIDS-defining conditions [see Table 1] were the major causes of morbidity in HIV-infected persons. Many of these conditions occur only when CD4+ T cell counts have fallen to low levels [see Table 18]. Currently, metabolic complications of HIV or HAART are becoming more common. In addition, many HIV-infected patients have laboratory abnormalities that are not associated with symptoms and are clinically insignificant [see Table 19].

Table 18 CD4+ Count and Opportunistic Conditions in HIV Infection229

CD4+ (Count Cells/mm3)

Infectious Complications

Noninfectious Complications

> 500

Acute retroviral syndrome
Candidal vaginitis

Persistent generalized lymphadenopathy
Guillain-Barré syndrome
Aseptic meningitis


Pneumococcal and other bacterial pneumonias
Pulmonary tuberculosis
Herpes zoster
Oropharyngeal candidiasis
Kaposi sarcoma
Oral hairy leukoplakia

Cervical neoplasia and cancer
B-cell lymphoma
Mononeuropathy multiplex
Idiopathic thrombocytopenic purpura
Hodgkin lymphoma
Lymphocytic interstitial pneumonia

< 200

Pneumocystis pneumonia
Disseminated histoplasmosis and coccidioidomycosis
Miliary and extrapulmonary tuberculosis
Progressive multifocal leukoencephalopathy

Peripheral neuropathy
HIV-associated dementia
Vacuolar myelopathy
Progressive polyradiculopathy
Non-Hodgkin lymphoma

< 100

Disseminated herpes simplex
Cryptosporidiosis, chronic
Candidal esophagitis


< 50

Disseminated cytomegalovirus
Disseminated Mycobacterium aviumcomplex


Table 19 Common Laboratory Abnormalities in HIV-infected Patients




Elevated TSH with normal free T4and free T3; or low free T4 with other normal labs

May be related to HAART

No intervention if asymptomatic

Elevated indirect bilirubin

Occurs with indinavir and atazanavir

Consider change of therapy for visible jaundice or scleral icterus (ATV only)


AZT leads to enlarged RBCs with average MCV from 100–110 fl; lower degrees of macrocytosis can be seen with other antiretroviral agents

Inconsequential if no anemia, but consider other causes (vitamin B12 or folate deficiency, hypothyroidism, alcoholism), especially with MCVs above 110 fl


Of the antiretroviral agents, only AZT causes anemia (usually macrocytic); consider other causes, including non-HIV-related conditions, as well as HIV infection or complication of HIV causing bone marrow suppression

Rule out standard causes; for suspected AZT-related anemia, change to different NRTI if possible; consider erythropoietin if correctable causes not identified


Generally caused by HIV infection, not anti-retroviral therapy

Typically responds to HAART


May be caused by AZT, other drugs, opportunistic infections, and advanced HIV infection

Stop offending agents if possible; consider nondrug causes; consider using G-CSF, especially if absolute neutrophil count < 500

AZT—zidovudine   G-CSF—granulocyte colony-stimulating factor   HAART—highly active antiretroviral therapy   MCV—mean corpuscular volume   NRTI—nucleoside/nucleotide reverse transcriptase inhibitor   RBC—blood cell   T3—triiodothyronine  T4—thyroxine TSH—thyroid-stimulating hormone


The approach to the HIV-infected patient with fever is determined by the level of immunodeficiency, as measured by the CD4+ T cell count, and whether HAART is currently being taken.

CD+ T Cell Counts below 200/mm3

With CD4+ T cell counts below 200/mm3, the differential diagnosis is long and includes typical infections seen at all ranges of immunity, as well as opportunistic infections. The list of potential opportunistic infections and conditions becomes longer as the CD4+ T cell count declines further, to below 100/mm3, and longer still when the count drops below 50/mm3 [see Table 18]. The most common causes of prolonged fever (longer than 7 days) in patients with CD4+ T cell counts below 200/mm3 are disseminated Mycobacterium avium complex (MAC) infection, P. jiroveci pneumonia, disseminated tuberculosis, non-Hodgkin lymphoma, disseminated cytomegalovirus (CMV) infection,Salmonella and pneumococcal bacteremia, histoplasmosis, and drug fever.136,137,138

Tuberculosis in persons with advanced HIV disease is more likely to be extrapulmonary or disseminated than in individuals with more intact immune systems. Manifestations may consist only of fever, lymphadenopathy, or nonspecific laboratory findings (e.g., anemia and an increased serum alkaline phosphatase concentration).137,138,139,140 Biopsy may be required for diagnosis.

Disseminated MAC infection usually develops in patients who have CD4+ T cell counts below 50/mm3. These patients present with fever and other nonspecific symptoms and signs, such as weight loss, anemia, neutropenia, and an elevated alkaline phosphatase level. MAC can also cause diarrhea, colitis, and malabsorption.141 The diagnosis is usually made by mycobacterial blood culture (BACTEC), which turns positive on average in 2 weeks.142

  1. jiroveciusually causes pneumonia, although fever, night sweats, and fatigue can predominate over pulmonary symptoms. The CD4+T cell count is typically below 200/mm3. Giemsa or Gomori methamine silver stains of induced sputum or bronchoalveolar lavage are appropriate diagnostic procedures, even in patients with minimal pulmonary symptoms.

CMV disease is essentially limited to patients with CD4+ T cell counts below 50/mm3. It typically presents as retinitis or, less commonly, as colitis or neurologic disease; it may also present as isolated fever. A dilated funduscopic examination may confirm the presence of CMV retinitis, whereas endoscopic esophageal, gastric, or intestinal biopsy is needed to diagnose gastrointestinal CMV disease. Serum CMV polymerase chain reaction (PCR) and antigen tests can aid in diagnosis.

Further evaluation of fever can include serologic testing for cryptococcal antigen, urine Histoplasma antigen testing, and lysis centrifugation fungal isolator cultures. Bone marrow biopsy generally has low yield but may be useful in patients with fever accompanied by neutropenia or anemia.143,144

CD4+ T Cell Counts above 200/mm3

When the CD4+ T cell count is above 200/mm3, standard diagnostic approaches employed for the general population can be followed, with the proviso that tuberculosis, pneumococcal bacteremia, and sinusitis occur at increased rates in HIV-infected persons.137,145,146 In addition, influenza and other pulmonary infections that are common causes of fever in the general population may present as fever and nonspecific symptoms without respiratory localization and last longer in HIV-infected persons.147 Blood cultures for bacteria, a tuberculin skin test, nasopharyngeal aspirate for influenza during influenza season, and a chest radiograph are appropriate initial diagnostic evaluations.

Drug Fever

Drug fever may occur as either a drug hypersensitivity reaction or as a result of immune reconstitution; it may result from HAART agents and other medications commonly used in the management of HIV disease. Multiple agents, including antibiotics such as trimethoprim-sulfamethoxazole (TMP-SMX), are associated with drug fevers. Medication-related fevers usually develop within the first months of starting the medication. Abacavir can cause drug fever as part of the abacavir hypersensitivity syndrome. This syndrome usually develops within 6 weeks of initiating therapy. It can occur at any CD4+ T cell count and is characterized by fever and systemic, often flulike symptoms, with rash evident in 70% of cases.148 If the source of fever is unclear, a careful review of all medications can be fruitful.

Immune Reconstitution

Fever is a common presenting sign of immune reconstitution inflammatory syndrome (IRIS). IRIS occurs as immune surveillance of previous and current infections improves during CD4+ T cell recovery, usually in patients who have a substantial rise in CD4+ T cell count from a low nadir.149 The syndrome is characterized by an acute deterioration in clinical condition after initiating HAART, usually within 8 weeks of initiation, generally with fever, lymphadenopathy, and localized inflammation—often hepatic, with accompanying elevated transaminase levels. The organisms most commonly associated with IRIS are mycobacteria, HBV, HCV, Cryptococcus, and CMV.

Diagnosis of IRIS involves exclusion of other common causes of fever and usually a tissue biopsy, depending on the site of infection. Treatment involves continuation of HAART, antimicrobial therapy directed against the causative pathogen, and symptomatic therapy with nonsteroidal anti-inflammatory drugs or corticosteroids.150

Respiratory Symptoms

Respiratory symptoms, including chronic and progressive or acute cough or dyspnea, are common in HIV-infected patients, and the risks of several infectious and noninfectious conditions are increased. In patients who present with fever and cough or dyspnea, the chest x-ray results can help in determining the differential diagnosis [see Figure 8]. Acute respiratory symptoms can be caused by acute bronchitis, asthma, sinusitis, pneumococcal pneumonia, tuberculosis, influenza (during the winter), and Staphylococcus aureus pneumonia or endocarditis. Community-acquired pneumonia (e.g., from Streptococcus pneumoniae, Haemophilus influenzae, S. aureus, or Pseudomonas aeruginosa) occurs at a rate 25-fold higher than in the general population and is far more commonly accompanied by bacteremia.151,152Patients with a CD4+ T cell count below 200/mm3 are at increased risk for Pneumocystis pneumonia (PCP), cryptococcal pneumonia, M. kansasii infection, and pulmonary Kaposi sarcoma. A rare cause of acute dyspnea is NRTI-associated lactic acidosis [see Gastrointestinal Symptoms, below].


Figure 8. Diagnostic algorithm for HIV-positive patients who present with fever and cough or dyspnea. (ABGs—arterial blood gases; AFB—acid-fast bacteria; CHF—congestive heart failure; CXR—chest x-ray; LDH—lactate dehydrogenase; KS—Kaposi sarcoma; MAC—Mycobateria avium complex; MRSA—methicillin-resistant Staphylococcus aureus; PCP—Pneumocystispneumonia; TB—tuberculosis; URI—upper respiratory infection)

  1. jiroveciis the most common cause of pneumonia in HIV-infected patients whose CD4+T cell counts are under 200/mm3. PCP presents either acutely or subacutely as fever, night sweats, fatigue, and dyspnea on exertion. Nonproductive cough and interstitial infiltrates on chest radiography are typical; 10% to 20% of patients have a normal chest radiograph, but high-resolution chest CT nearly always shows abnormalities, most commonly ground-glass opacities.153,154 Oxygen desaturation may occur during ambulation, and the alveolar-arterial difference in oxygen (A-aDO2) is often elevated. If PCP is suspected clinically, Giemsa or Gomori methamine silver stains of induced sputum or bronchoalveolar lavage samples are required to make the diagnosis. Induced sputum staining has a sensitivity of 56%,155 whereas bronchoalveolar lavage has a 95% sensitivity. PCP is treated with TMP-SMX for 21 days at a dosage of 15 mg/kg/day (calculated on the basis of the trimethoprim component) orally or intravenously every 8 hours. In addition, patients with hypoxia (i.e., PO2 below 70 mm Hg or A-aDO2 greater than 35 mm Hg) should receive prednisone at a dosage of 40 mg twice daily for 5 days, then 40 mg once daily for 5 days, then 20 mg daily for 11 days. Patients who cannot take sulfonamides can be treated with dapsone plus pyrimethamine, clindamycin plus primaquine, atovaquone, or, in severe cases, I.V. pentamidine.

Chronic dyspnea or cough in HIV-infected persons may be caused by pulmonary disease or cardiac disease. Infectious causes include tuberculosis, PCP, and a host of less common pathogens. The diagnosis and treatment of tuberculosis in HIV-infected patients are discussed in detail elsewhere [see 7:II Tuberculosis]. Alternative diagnoses should be considered for patients with cavitary lung lesions and low CD4+T cell counts (< 200/mm3), including M. kansasii, S. aureus, Pseudomonas, Rhodococcus, or Nocardia infections.153

The noninfectious pulmonary processes of chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, lymphoid interstitial pneumonitis (LIP), and pulmonary Kaposi sarcoma are also more common in HIV-infected persons than in the general population. These conditions may present as progressive dyspnea. Patients with LIP, which is an uncommon condition in adults, often also have a dry cough, fevers, and night sweats. Pulmonary function testing and chest CT are valuable initial studies. Echocardiography is useful for estimating pulmonary arterial pressures in the evaluation of suspected pulmonary hypertension. Biopsy is required to diagnose LIP. Pulmonary Kaposi sarcoma can produce bilateral infiltrates and can be confused on chest radiography with PCP.

Heart Failure

Heart failure is more common in HIV-infected persons than in the general population. Patients with advanced HIV infection are at increased risk for HIV-related dilated cardiomyopathy, which can lead to congestive heart failure. HAART and standard management of heart failure are indicated for this condition. Patients with long-term HIV infection, including those whose infection is well-controlled, are at increased risk for atherosclerotic coronary disease, angina, and myocardial infarction, which can lead to ischemic cardiomyopathy. Zidovudine can also cause cardiomyopathy, although this occurred more commonly with the higher doses used in the past.

Gastrointestinal Symptoms

Oral Lesions

Oral lesions associated with HIV infection are a significant cause of discomfort. Oropharyngeal candidiasis (thrush) is common in patients with CD4+ T cell counts below 300/mm3. Patients with thrush may complain of oral discomfort, pharyngeal dysphagia or odynophagia, or fissured lips. Physical examination generally reveals white curdlike plaques, which can be easily scraped off, on the buccal mucosa, palate, tongue, or posterior pharynx. Treatment with clotrimazole troches (five lozenges a day for 7 to 14 days) is usually effective. Oral hairy leukoplakia (OHL) is found on the lateral margins of the tongue and appears as vertically oriented, white, linear plaques that cannot be scraped off with a tongue blade. OHL responds to effective HAART and immune restoration.

Common etiologies of ulcerative oral lesions include aphthous stomatitis and HSV, adenovirus, and CMV infection. Oral lesions from syphilis, lymphoma, and medications are less common.

Dysphagia and Odynophagia

Dysphagia and odynophagia are common symptoms in patients with advanced HIV disease. Candida esophagitis is the most common cause; therefore, most patients with esophageal symptoms are treated empirically for candidiasis—typically with fluconazole, 100 to 200 mg orally or intravenously for 14 to 21 days. The likelihood of Candida esophagitis is increased when oral thrush is also present, although thrush may be absent, especially in patients taking topical antifungals that suppress thrush. The diagnosis of Candida esophagitis is typically established by a response to fluconazole within days of starting treatment. In patients who do not respond to empirical therapy, alternative etiologies (e.g., aphthous esophagitis, CMV or HSV infection, or azole-resistant candidiasis) should be considered and further evaluated with upper endoscopy. Esophageal symptoms in patients with CD4+ T cell counts above 200/mm3 are more likely to be the result of reflux disease, esophageal stricture or spasm, pill esophagitis, or other non-HIV-related conditions.

Nausea, Vomiting, and Anorexia

Nausea, vomiting, and anorexia can be side effects of medication (including antiretrovirals and antimicrobials) or may result from lactic acidosis, acute gastroenteritis, hypogonadism, pregnancy, depression (in the case of isolated anorexia), substance abuse, and gastrointestinal disease caused by opportunistic infections or other conditions. Evaluation should include a detailed medication history and timing of onset of symptoms with respect to medication initiation. A gastrointestinal evaluation, usually with upper endoscopy, lactate level, or, more rarely, a neurologic evaluation for central nervous system lesions, may be appropriate. If the patient is taking an NRTI, lactic acidosis should be considered and a serum lactic acid level should be obtained promptly. Additional signs and symptoms of lactic acidosis may include constitutional symptoms, nausea, dyspnea, weight loss, myalgias, and hepatitis. The mortality associated with severe lactic acidosis (levels above 10 mM) approaches 50%, so prompt withdrawal of combination antiretroviral therapy and institution of supportive care are critical. After recovery from lactic acidosis, patients should be treated with regimens that do not include stavudine, zidovudine, or didanosine.


Diarrhea may be the most frequently reported HIV-related symptom, especially in patients with advanced disease.156 Its etiology is often multifactorial, and the differential diagnosis includes opportunistic diseases, medications, and non-HIV-related conditions. Diarrhea is a common side effect of protease inhibitors, including ritonavir-boosted regimens. Regular use of fiber supplements, such as psyllium, may control this symptom. The diarrheal syndromes of greatest concern are those caused by opportunistic infections, which usually occur with CD4+ T cell counts below 100/mm3. The most common causes are Cryptosporidium species and microsporidia, Clostridium difficile, CMV, disseminated MAC, and Kaposi sarcoma.157 In addition, anal HSV lesions may result in fecal incontinence. For patients with higher CD4+ T cell counts, more common conditions are viral gastroenteritis, bacterial colitis, lactose intolerance, and inflammatory bowel disease. Stool culture, stains for Cryptosporidium, and C. difficile toxin assays are appropriate initial evaluation. If diarrhea persists and the diagnosis remains elusive, colonoscopy should be pursued. Assessment and management of diarrhea are discussed in detail elsewhere [see 4:III Diarrheal Diseases].

Abdominal Pain

Abdominal pain may be caused by pancreatitis, lactic acidosis, AIDS cholangiopathy, non-Hodgkin lymphoma, abdominal tuberculosis, and IRIS. Acute pancreatitis is usually associated with nausea and vomiting; it may be seen at any CD4+ T cell count and is associated with didanosine, especially when that agent is taken with stavudine, ribavirin, or hydroxyurea.158 Alcohol, obstructive gallstones, and hypertriglyceridemia, which can be caused or exacerbated by some protease inhibitors, should also be considered as possible causes of pancreatitis.

AIDS cholangiopathy is associated with low CD4+ T cell counts; patients present with abdominal pain and elevated alkaline phosphatase and direct bilirubin levels. Imaging studies and endoscopic retrograde cholangiopancreatography help to confirm the diagnosis.

A rare cause of abdominal pain in patients with CD4+ T cell counts less than 100/mm3 is lymphoma, most commonly non-Hodgkin lymphoma, which often is accompanied by weight loss and other constitutional symptoms. CT scan and biopsy, if feasible, are necessary to make the diagnosis. Other common causes of abdominal pain in persons with advanced immunodeficiency include CMV colitis, disseminated MAC with mesenteric lymphadenopathy, and abdominal tuberculosis disease.159

Acute Hepatitis

Acute hepatitis, both drug-induced and viral, is an important problem for HIV-infected patients.160,161 Antiretroviral agents cause liver injury through direct toxicity; through inhibition of mitochondrial DNA polymerase gamma, leading to hepatic steatosis and lactic acidosis; and through idiosyncratic reactions, such as occur with nevirapine and abacavir.162 Drug-induced hepatitis has been most strongly associated with nevirapine, especially when started in patients with higher CD4+ T cell counts (above 250/mm3 for women and above 400/mm3 for men).163,164 Nevirapine-related hepatoxicity is often associated with a rash and occurs a median of 30 days after starting nevirapine.165 Most protease inhibitors can cause hepatitis, especially in patients with chronic viral hepatitis. Both atazanavir and indinavir can cause an asymptomatic and benign indirect hyperbilirubinemia without elevation in transaminase levels. With the use of atazanavir, jaundice, scleral icterus, or both can occur; therapy is sometimes discontinued for cosmetic reasons.

Acute hepatitis from hepatitis A virus (HAV), HBV, or HCV occurs frequently in HIV-infected patients. When a patient's transaminase level is found to be newly elevated over the baseline level, the clinician should obtain levels of anti-HAV IgM, HBsAg, anti-HBc IgM, and anti-HCV antibodies. If the patient tests negative for these antibodies but acute HBV or HCV infection is still suspected, quantitative PCR studies for HBV and HCV should be conducted. Other conditions that can lead to transaminase elevations are leptospirosis, tuberculosis, Wilson disease, lymphoma, autoimmune hepatitis, and toxins (including alcohol and naturopathic medications). In asymptomatic patients, mild elevations in transaminase levels are often caused by drug toxicity, alcohol use, or chronic HBV or HCV infection; in these settings, the bilirubin level is normal. A patient presenting with a febrile illness, moderately to severely increased transaminase levels, and an increased bilirubin level will most likely have acute HAV or HBV infection, although other etiologies, including acute drug reaction and obstructive cholelithiasis, are also possible. A cholestatic profile on serum chemistry raises the possibility of obstruction from stones or malignancy, lactic acidosis with hepatic steatosis, cholangiopathy, or medication-induced cholestasis (e.g., from TMP-SMX, amitriptyline, ampicillin, naproxen, or phenytoin). Abdominal ultrasonography or CT or MRI scanning may be useful in these settings. If no diagnosis is made and hepatitis persists, a liver biopsy may be diagnostic.

Metabolic and Endocrine Complications

The metabolic syndrome has increasingly been recognized as a major cause of morbidity and mortality in patients with well-controlled HIV infection. Lipodystrophy was the first well-described part of the syndrome, becoming a recognized complication of antiretroviral therapy soon after the introduction of HAART.166 This condition is characterized by abnormal fat accumulation—specifically, visceral obesity, dorsocervical fat pad enlargement, gynecomastia, and multiple cutaneous lipomas—and by loss of subcutaneous fat (lipoatrophy) in the face, extremities, and buttocks. However, it was later recognized that fat accumulation and lipoatrophy can occur separately and have different mechanisms of action. Lipoatrophy appears to be caused by mitochondrial toxicity from NRTIs, especially stavudine, zidovudine, and possibly didanosine. Fat accumulation has been most strongly related to protease inhibitor therapy, though it is unclear whether there is a direct causal connection; fat accumulation can occur secondary to protease inhibitor-induced hypertriglyceridemia, insulin resistance, or improved health, sometimes in the setting of decreased subcutaneous fat stores resulting from NRTI-induced lipoatrophy.167

Hyperlipidemia and insulin resistance are the other components of the metabolic syndrome that occurs in patients receiving HAART.168,169Hyperlipidemia and insulin resistance are more common in patients who also have 2body shape change, especially those receiving protease inhibitors. Of patients with lipoatrophy or visceral fat accumulation and buffalo hump, 35% have insulin resistance and 7% have diabetes. Of patients taking protease inhibitor-based HAART, 27% have hypercholesterolemia (total cholesterol above 240 mg/dl) and 40% have hypertriglyceridemia (triglyceride levels above 200 mg/dl). Hyperlipidemia can be managed with dietary modification, aerobic exercise, statins, fibrates, and the use of HAART regimens that have less effect on lipids and glucose metabolism. Of the protease inhibitors, atazanavir and possibly saquinavir are less associated with lipid elevations and are good choices for patients with hyperlipidemia when the use of these agents is appropriate from a resistance standpoint. Atazanavir also appears to have a better insulin resistance profile than many of the other protease inhibitors.170

Optimal management of insulin resistance is still to be determined but may involve the use of insulin-sensitizing agents (i.e., metformin or thiazolidinediones); if diabetes develops, management should follow guidelines for the general population.

Early cardiovascular disease is increased by hyperlipidemia, insulin resistance, and HIV-induced endothelial dysfunction.171 Myocardial infarction occurs at earlier age. Unfortunately, HIV-infected patients appear to have higher restenosis rates after percutaneous coronary interventions.172 Reducing atherosclerotic disease requires aggressive risk factor modification, including smoking cessation, dietary change, and increased exercise. Discontinuance of HAART is not an effective way to reduce metabolic complications; indeed, structured treatment interruption trials have suggested that interruption may lead to greater metabolic and cardiovascular complications.108

Adrenal or gonadal insufficiency occurs frequently in advanced AIDS. Hypotension, a low serum sodium level, and an elevated serum potassium level point to the possibility of either adrenal insufficiency or isolated mineralocorticoid deficiency. All three disorders may be associated with weight loss [see Table 20]. Patients with hypogonadism may also complain of general malaise, fatigue, sexual dysfunction or loss of libido, or depressed mood. Appropriate serum hormone testing can be used to identify these disorders. Management with hormone replacement is appropriate for patients with low testosterone levels or for symptomatic patients with testosterone levels in the low end of the normal range. In addition, hypogonadal patients are at increased risk for osteopenia and osteoporosis and should be considered for bone density testing.

Table 20 Causes of Weight Loss in HIV-infected Patients

HIV wasting


Lactic acidosis

Chronic diarrhea

Adrenal insufficiency





Substance abuse

HIV-infected persons commonly have abnormal results on thyroid testing, although the rates of overt hypothyrodism and hyperthryroidism are similar to those seen in the general population. Subclinical hypothyroidism (elevated levels of thyroid-stimulating hormone but normal levels of free thyroxine and free tri-iodothyronine) appears to be more common in HIV-infected patients on HAART and may result from a pathophysiologic mechanism different from that in the general population. Unless symptoms are present, thyroid replacement therapy is unnecessary. Hyperthyroidism caused by Graves disease may occur more frequently during immune restoration 1 to 3 years after HAART initiation.

Bone disease, including osteonecrosis, osteopenia, and osteoporosis, is common in HIV-infected persons. Osteonecrosis, also known as avascular necrosis, occurs in 0.08% to 1.3% of HIV patients, usually involving the femoral head and presenting as hip pain exacerbated with internal rotation. The most common reported risk factors are dyslipidemia, alcohol abuse, and corticosteroid use.173 Diagnosis usually requires MRI of the affected joint.

On bone density testing, up to a quarter of HIV-infected patients on HAART have osteopenia or osteoporosis.174,175 Loss of bone density may be related to specific HAART agents, HIV-related inflammatory states, or other unidentified factors, as well as traditional risk factors, including early menopause, hypogonadism, hyperthyroidism, and vitamin D deficiency. Vitamin D and calcium, along with bisphosphonates, are safe for use in HIV-infected patients.

Renal Disease

Renal disease is common in patients with high HIV RNA and low CD4+ T cell counts who are not receiving HAART; 2% to 10% of such patients are affected.176 The renal disease that occurs most often in this setting is HIV-associated nephropathy (HIVAN). HIVAN occurs predominantly in blacks and is characterized by proteinuria, often in the nephrotic range (i.e., greater than 3 g/dl), polyuria, minimal edema, and echogenic kidneys. HIVAN is rare in patients with suppressed HIV RNA levels.177 The diagnosis is generally suspected in a patient with proteinuria in the nephrotic range who is found to have large echogenic kidneys on ultrasound; the diagnosis is confirmed by biopsy results indicating collapsing focal and segmental glomerulosclerosis.178 Complete suppression of HIV replication with HAART can reverse pathogenic changes and lead to recovery of renal function. Use of steroids is controversial in this setting. In patients on HAART in whom HIV replication is suppressed, hypertensive nephropathy is the leading cause of kidney disease.177

Medication-associated renal disease is uncommon with antiretroviral therapy but can occur with indinavir and tenofovir. Indinavir, especially when boosted with ritonavir, can cause nephrolithiasis, as well as a chronic tubolointerstitial nephritis characterized by pyuria and crytstalluria that can progress to renal insufficiency.179 Tenofovir has been associated with cases of Fanconi syndrome and other causes of kidney impairment, though the incidence is low; the syndrome tends to occur in patients with preexisting renal impairment.180 If tenofovir must be continued in patients with impaired renal function, the d2osing interval should be adjusted in patients with calculated creatinine clearances below 50 ml/min. On a population level, tenofovir appears to lead to a slight decrease in creatinine clearance that stabilizes with continued treatment.181

Neurologic Symptoms


In HIV-infected persons, as in those without HIV infection, headache usually results from conditions such as muscle tension or migraine; in patients with a CD4+ T cell count above 200/mm3, sinusitis is also common.182 In patients with lower CD4+ T cell counts, opportunistic conditions must also be considered in the differential diagnosis, and the diagnosis should be aggressively pursued, because a missed diagnosis may have unfortunate consequences [see Figure 9]. The three most common opportunistic conditions that can cause headache are cryptococcal meningitis, Toxoplasma encephalitis, and primary CNS lymphoma; less frequent infections include bacterial meningitis, viral encephalitis, coccidioidomycosis, histoplasmosis, tuberculosis, nocardiosis, and pyogenic brain abscess. In patients with a CD4+ T cell count below 200/mm3, a serum cryptococcal antigen assay should be obtained to screen for cryptococcal disease. A negative result essentially excludes cryptococcal meningitis. A positive result must be followed up with a lumbar puncture and assay for cryptococcal antigen in the CSF. Successful management of cryptococcal meningitis hinges on controlling intracranial pressure (ICP) with serial lumbar punctures or, in severe cases, placement of an intraventricular drain (elevated ICP is not a contraindication for lumbar puncture in this setting). Patients should be treated with a combination of amphotericin B (0.7 mg/kg/day I.V.) and flucytosine (100 mg p.o.) for 14 days, followed by fluconazole (400 mg p.o., q.d.) for 8 weeks, and finally fluconazole prophylaxis (200 mg p.o., q.d.) indefinitely or until substantial immune recovery has occurred. Other useful CSF tests are cell count, chemistries, Venereal Disease Research Laboratory (VDRL) testing, cytology, stains and cultures for specific suspected pathogens, and PCR testing for CMV, HSV, JC virus (for progressive multifocal leukoencephalopathy [PML]), and Epstein-Barr virus (EBV; for primary CNS lymphoma). Neuroimaging with a CT scan or MRI should be performed before lumbar puncture to rule out a mass lesion, particularly in a patient with focal neurologic signs.183,184


Figure 9. Algorithm for evaluation and management of headache in HIV-infected patients. (AFB—acid-fast bacteria; CMV—cytomegalovirus; CrAg—cryptococcal antigen; CSF—cerebrospinal fluid; EBV—Epstein-Barr virus; LP—lumbar puncture; PCR—polymerase chain reaction; RPR—rapid plasma reagin; SPECT—single-photon emission CT; VDRL—Venereal Disease Research Laboratory)

When enhancing mass lesions are present on CT or MRI scan, the most likely diagnoses are either toxoplasmosis or primary CNS lymphoma.184,185 Toxoplasmosis 2lesions generally appear as multiple ring-enhancing lesions within the gray matter, whereas lesions caused by lymphoma are more likely to be solitary, periventricular, and have substantial surrounding edema and mass effect. In patients who are seropositive for Toxoplasma antibodies or in seronegative patients with characteristic CNS lesions, empirical anti-Toxoplasmatherapy is usually warranted (i.e., pyrimethamine, leukovorin, and sulfadiazine). If a clinical and radiologic response is not seen within 10 to 14 days, thallium single-photon emission CT (SPECT) scan and CSF EBV PCR (which has a sensitivity of 50% to 80% and a specificity of greater than 94%) can be considered for the diagnosis of CNS lymphoma.187,188 Other less common causes of CNS mass lesions that need to be considered include PML, tuberculoma, cryptococcoma, Nocardia abscess, pyogenic brain abscess, and tumor metastases from non-CNS primary sites.

Altered Mental Status

Altered mental status is common in HIV infection. The evaluation should follow the approach to this condition that is used for the general population, with recognition of an increased risk of infectious and neoplastic causes. All of the CNS processes discussed previously can present as a change in mental status, and several other diagnoses should be considered in the patient with advanced HIV disease. The most common cause is HIV-associated dementia (HAD), which occurs in patients with more advanced immunodeficiency. The annual incidence of HAD has declined from nearly 10% in 1989 to 1% in 2000 because of effective antiretroviral therapy.189 HAD usually develops over months (rarely faster, although it may go unnoticed) and is characterized by cognitive, behavioral, and motor dysfunction. In early stages, patients often present with fluctuating memory and concentration loss, slowing of motor skills, and ataxia. As HAD progresses over weeks to months, global dementia and paraplegia can develop. Some patients present with intermittent lower extremity weakness or ataxia. MRI often shows diffuse atrophy. HAART can lead to improvement or reversal of HAD.

Extremity Pain or Weakness

Peripheral neuropathy in HIV-infected patients may present as a distal sensory polyneuropathy, with symmetrical numbness, tingling, burning, or pain in the feet or hands without motor weakness. The two most common causes are toxic neuropathy from medications (usually stavudine, didanosine, or both) or HIV itself. Other causes or contributing factors include alcoholism, thyroid disease, vitamin B12deficiency, syphilis, or diabetes mellitus, including diabetes caused by protease inhibitors. In drug-induced neuropathy, early interruption of the offending agent gradually leads to complete resolution of symptoms.

CMV myelitis and polyradiculitis present as rapidly progressive weakness and numbness in the upper and lower extremities. These syndromes generally occur only in patients with a CD4+ T cell count below 50/mm3, many of whom already have been diagnosed with CMV infection at other sites. PML characteristically causes unilateral focal weakness (see above). Diffuse nonenhancing white-matter abnormalities on MRI are characteristic of PML and should prompt CSF testing for JC virus. However, a negative PCR assay for JC virus does not rule out the diagnosis of PML because of the low sensitivity (~ 80%) of this test.189 No effective specific treatment is available for PML, but HAART may lead to some improvement.

Myopathy related to HIV or to medications (e.g., zidovudine or statins) also presents as pain in the muscles, usually in the thighs and shoulders, as well as proximal weakness. It is usually associated with an increased serum creatine phosphokinase level.

Gynecologic Symptoms

Gynecologic complaints may be the initial manifestation of HIV infection in women.190 Many common conditions, including vulvovaginal candidiasis, cervical abnormalities and cancer, and pelvic inflammatory disease (PID), are more frequent, severe, or refractory to therapy in HIV-infected women. Recurrent vaginal candidiasis is characterized by pruritus and a thick white discharge. Bacterial vaginosis has been found to be more prevalent and more persistent in HIV-infected women, as compared with noninfected women, especially in women with CD4+ T cell counts below 200/mm3.191 Trichomoniasis is seen at the same rates in HIV-infected women and seronegative women.192 Genital HSV infection, which is more common and more severe in HIV-infected patients, usually manifests as localized discomfort and ulceration; it is less commonly associated with discharge.

Vaginal discharge and pelvic pain are common complaints in HIV-infected women.193 These symptoms can be caused by vaginitis, PID, ectopic pregnancy, HSV infection, and cervical cancer. Management of these conditions is similar to that in patients who are not infected with HIV, although suppressive therapy for HSV and candidiasis is more frequently required.

Dermatologic Symptoms

Dermatologic complaints affected over 90% of HIV-infected patients before the introduction of HAART; they are less common in patients with higher CD4+ T cell counts. A common condition at lower CD4+ T cell counts is prurigo nodularis, characterized by highly pruritic, hyperpigmented, and often excoriated papular lesions involving the extremities and torso. Over time, prurigo nodularis may result in the development of lichen simplex chronicum. Emollients and high-potency topical corticosteroids can break the cycle of pruritus and excoriation, but symptom control is often difficult. HAART and immune restoration may also lead to resolution of symptoms.

Eczematous conditions including seborrheic dermatitis, atopic dermatitis, and xerotic eczema are also more common in HIV-infected patients.194,195 For example, in longitudinal studies from the pre-HAART era, seborrheic dermatitis occurred in 3% of the general population but nearly 50% of HIV-infected individuals with low CD4+ T cell counts.196 Seborrheic dermatitis is characterized by erythematous, often pruritic plaques with greasy scales and indistinct margins on the scalp, face, and postauricular area. Steroids of medium potency may be used for control of a flare; ketoconazole cream/shampoo or selenium shampoo may be effective for long-term management. Scabies should also be considered in the differential diagnosis of a pruritic skin rash, and patients with more advanced immunosuppression are at risk for more severe, crusted (so-called Norwegian) scabies.

Eosinophilic folliculitis presents as small, often pruritic, perifollicular papular and pustular lesions, usually on the upper body and proximal upper extremities; it may be associated with immune reconstitution.197 Treatment with corticosteroids of medium potency may control symptoms. Larger, diffusely distributed papules and pustules may be caused by S. aureus, Pseudomonas aeruginosa, and dermatophytes.

As immune function declines to CD4+ T cell counts below 500/mm3, reactivation herpes zoster (shingles) may occur. Zoster presents as a painful vesicular rash in a dermatomal distribution; more rarely, it may involve multiple dermatomes or become disseminated. There is also a brief period of increased risk for zoster as immune function improves after initiation of antiretroviral therapy. Patients with advanced immunodeficiency may also present with extensive herpes simplex ulcerations appearing as painful, beefy red perineal and perianal ulcerations. Acyclovir or famciclovir are treatments of choice for both zoster and herpes simplex reactivation.

Psoriasis may develop as immunity wanes; it is more refractory to treatment than in persons without HIV infection.198 The pox virus, molluscum contagiosum, forms small papules with central umbilication, usually on the face and neck; involvement is often more extensive, with larger and harder-to-treat lesions occurring as immunodeficiency advances. Conditions that may be confused with molluscum contagiosum are disseminated cryptococcosis and blastomycosis. An uncommon red or purple nodular or pedunculated lesion may be bacillary angiomatosis caused by Bartonella species and associated with disseminated infection [see 7:11 Infections Caused by Brucella, Francisella, Yersinia Pestis, and Bartonella].199 Kaposi sarcoma is another uncommon disease in high-income countries. It is characterized by nonpruritic, painless, firm, indurated, violaceous papules, nodules, or plaques that appear on the face, body, or extremities.

Drug reactions are a common cause of rashes.194,200 The most well-known reactions are to sulfonamides, notably TMP-SMX and sulfadiazine. Other agents that commonly cause rash include abacavir (in the setting of a systemic hypersensitivity reaction), efavirenz, nevirapine, and fosamprenavir. Drug reactions typically present as pruritic maculopapular, morbilliform, or urticarial eruptions, but they may also appear as erythema multiforme, erythema nodosum, or exfoliative dermatitis (toxic epidermal necrolysis and Stevens-Johnson syndrome) [see 6:XIV Drug Allergies]. Manifestations of systemic involvement may include fever, elevated transaminase levels, and interstitial nephritis. Management consists of symptomatic treatment, drug discontinuance, and careful observation.


The incidence of AIDS-defining malignancies has declined since the development of HAART. This decline has been most notable for primary CNS lymphoma. The incidence of other lymphomas, including Burkitt lymphoma, has also declined, but to a lesser degree. Kaposi sarcoma, a malignancy that can affect the skin, mucosal surfaces, lungs, gastrointestinal tract, and internal organs, remains the most common AIDS-defining malignancy, although most patients who develop Kaposi sarcoma have not yet started HAART.201 The incidence of cervical and anal squamous cell carcinoma is increased in HIV-infected persons. For this reason, screening for cervical dysplasia with a Papanicolaou smear is essential. Some experts also advocate anal Pap smears to screen for anal dysplasia and squamous cell carcinoma.202

Many malignancies not associated with HIV, including lung cancer and liver cancer, also occur at higher rates in HIV-infected persons than in the general population. The increased frequency of risk factors such as smoking and chronic viral hepatitis infection in HIV-infected persons may explain these higher rates.203 No specific screening is recommended for these malignancies.


All patients infected with HIV can expect to progress to chronic infection, and nearly all untreated patients can expect to develop AIDS-defining conditions. The natural history of untreated chronic infection involves an asymptomatic period that averages 10 years and is followed by immunologic decline, opportunistic infections, and death 1 to 2 years after the first AIDS-defining illness.204,205 The time course, however, varies considerably between individual patients. Some patients remain asymptomatic, with near-normal CD4+ T cell counts, for over 20 years, whereas others progress to significant immunodeficiency within 2 years. The strongest predictor of disease progression is the set point HIV RNA level after the acute HIV episode.206,207 For example, patients with an HIV RNA level below 10,000 copies/ml have less than a 40% chance of progressing to AIDS within 10 years, compared with a greater than 90% chance of progression for patients with an HIV RNA level above 100,000 copies/ml.206,208 Considerable variation in disease progression also exists within each HIV RNA stratum, however.209 Some patients with low HIV RNA levels fit the category of so-called long-term nonprogressors, whose decline in CD4+ T cell levels is much slower than average and who preserve immune function for years—in some cases, for 20 years or more—without needing HAART.

Fortunately, HAART has fundamentally altered the grim prognosis for most HIV-infected patients and has transformed AIDS from a fatal disease to a treatable chronic one. Before the development of HAART, the estimated median time from the appearance of an AIDS-defining condition to death was approximately 1.5 years. HAART has extended this to 14 years—and even this figure may underestimate survival in patients using current drug regimens who strictly adhere to their treatment protocols.13 Patients who adhere to their drug regimens have a potential life expectancy similar to that of uninfected persons, especially when HAART is started at higher CD4+ T cell counts. A study with an HIV-infected population and a very similar uninfected comparator population reported equivalent survival when HAART was started with a CD4+ T cell count above 350/mm3.210 The best predictor of long-term survival now is successful virologic suppression with HAART.211,212Thus, the importance of adherence cannot be overemphasized. Currently, treatment cohorts report approximately 80% virologic suppression 1 year after initiation of HAART.213


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Editors: Dale, David C.; Federman, Daniel D.