Peter L. Anderson, Thomas N. Kakuda, and Courtney V. Fletcher
Infection with human immunodeficiency virus (HIV) occurs through three primary modes: sexual, parenteral, and perinatal. Sexual intercourse, primarily receptive anal and vaginal intercourse, is the most common method for transmission.
HIV infects cells expressing cluster of differentiation 4 (CD4) receptors, such as T-helper lymphocytes, monocytes, macrophages, dendritic cells, and brain microglia. Infection occurs via an interaction between glycoprotein 160 (gp160) on HIV with CD4 (primary interaction) and chemokine coreceptors (secondary interactions) present on the surfaces of these cells.
The hallmark of untreated HIV infection is profound CD4 T-lymphocyte depletion and severe immunosuppression that puts patients at significant risk for infectious diseases caused by opportunistic pathogens. Opportunistic infections (OIs) in settings without access to antiretroviral drugs are the chief cause of morbidity and mortality associated with HIV infection.
The current goal of ART is to achieve maximal and durable suppression of HIV replication, taken to be a level of HIV-RNA in plasma (viral load) less than the lower limit of quantitation. Another equally important outcome is an increase in CD4 lymphocytes because this closely correlates with the risk for developing OIs.
General principles for the management of OIs include preventing or reversing immunosuppression with antiretroviral therapy (ART), preventing exposure to pathogens, vaccination, prospective immunologic monitoring, primary chemoprophylaxis, treatment of acute episodes, secondary chemoprophylaxis, and discontinuation of such prophylaxes following ART and subsequent immune recovery.
Clinical use of antiretroviral agents is complicated by drug–drug interactions. Some interactions are beneficial and used purposely; others may be harmful, leading to dangerously elevated or inadequate drug concentrations. For these reasons, clinicians involved in the pharmacotherapy of HIV infection must exercise constant vigilance and maintain a current knowledge of drug interactions.
Current recommendations for the initial treatment of HIV advocate a minimum of three active antiretroviral agents from at least two drug classes. The typical regimen consists of two nucleoside/nucleotide analogs with either a protease inhibitor (PI; pharmacokinetically enhanced by coadministration with a CYP3A inhibitor), a nonnucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor (InSTI).
Inadequate suppression of viral replication allows HIV to select for antiretroviral-resistant HIV variants, a major factor limiting the ability of antiretroviral drugs to inhibit virus replication. Current recommendations for treating drug-resistant HIV include choosing at least two drugs (preferably three) to which the patient’s virus is susceptible. Susceptibility can be assessed using either (virtual) genotypic or phenotypic resistance testing.
The reduction of viral load with ART lowers the risk of transmission to others. Additionally, prophylaxis with antiretroviral agents in at-risk persons lowers HIV acquisition risk.
The longer life span conferred by antiretroviral treatment has given rise to other medical issues. First, a wide spectrum of complications associated with older age have become common, some of which are adverse effects from antiretroviral drugs. Second, hepatitis C virus (HCV) coinfection is an important cause of morbidity and mortality. Medical management of these contemporary HIV complications is constantly evolving.
Acquired immunodeficiency syndrome (AIDS) was first recognized in a cohort of young, previously healthy homosexual men with new-onset profound immunologic deficits, Pneumocystis carinii (now P. jirovecii) pneumonia (PCP), and/or Kaposi’s sarcoma. A retrovirus, human immunodeficiency virus type 1 (HIV-1), is the major cause of AIDS. A second retrovirus, HIV-2, also is recognized to cause AIDS, although it is less virulent, transmissible, and prevalent than HIV-1. These retroviruses are transmitted primarily by sexual contact and by contact with infected blood or blood products. Several risk behaviors for the acquisition of HIV infection have been identified in the United States, most notably the practice of anorectal intercourse and the sharing of blood-contaminated needles by injection-drug users. In many resource-limited countries, the majority of HIV transmission occurs via heterosexual intercourse and from childbearing women to their offspring. Initially, the medical management of HIV consisted of repeated treatments for opportunistic infections (OIs) and eventual palliative care. In the mid-1990s, a new era in the pharmacotherapy for HIV, known as combination antiretroviral therapy (ART), was born. ART consists of combinations of antiretroviral agents with different mechanisms of action that potently and durably suppress HIV replication, delay the onset of AIDS, reverse HIV-associated immunologic deficits, reduce HIV transmissions, and significantly prolong survival. Modern antiretroviral drugs and ART regimens have improved upon tolerability and efficacy. Unfortunately, therapeutic challenges remain in the ART era and include the need for continuous adherence to medication and care, drug–drug interactions, drug-resistant HIV, acute and long-term drug toxicities, and other complications associated with a prolonged life span. Progress has been made in the treatment access for this disease, but large numbers of HIV-infected persons remain outside of care. Antiretroviral drugs can prevent HIV acquisition in persons exposed to HIV, but they cannot cure established HIV infection, and no viable vaccine is available.
The epidemiologic characteristics of HIV infection differ according to geographic region and depend upon the mode of transmission, governmental prevention efforts and resources, and cultural factors.1,2
Infection with HIV occurs through three primary modes: sexual, parenteral, and perinatal. Sexual intercourse, primarily anal and vaginal intercourse, is the most common method for transmission. The probability of HIV transmission depends upon the type of sexual exposure. The highest risk appears to be from receptive anorectal intercourse at about 0.5% to 3% per sexual act.3 Transmission risk is lower for receptive vaginal or oral intercourse and each is lower for insertive versus receptive sex acts.4 Condom use reduces risk of transmission by approximately 20-fold.4 Other factors that affect the probability of infection include the stage of HIV disease and viral load in the index partner. For example, transmission is higher when the index partner has early or late HIV compared with asymptomatic HIV, as these disease stages are associated with higher viral loads.5 Individuals with genital ulcers or sexually transmitted diseases are at greater risk for contracting HIV. HIV incidence and prevalence are lower in cultures that advocate male circumcision, which is estimated to reduce risk of male acquisition of HIV during heterosexual intercourse by 60%.2,5 However, male circumcision may not have the same protective effects for receptive anal intercourse or for an uninfected partner.6 Casual contact with patients with AIDS or HIV infection is not a significant risk factor for HIV transmission.2
Prevention of sexual transmission has focused primarily on education that encourages abstinence (especially for adolescents), use of condoms, and reduction of high-risk behavior (anal intercourse or promiscuity with partners of unknown HIV status).1 Combination ART dramatically lowers viral replication and infectiousness, significantly reducing the risk of transmission to others.7 Chemoprophylaxis with antiretroviral drugs is also effective at preventing HIV acquisition.8–10 A combined approach has been advocated for optimal prevention. Prevention strategies under investigation include HIV vaccines and topical vaginal/rectal microbicides.11,12
Parenteral transmission of HIV broadly encompasses infections due to infected blood exposure from needle sticks, IV injection with used needles, receipt of blood products, and organ transplants. Use of contaminated needles or other injection-related paraphernalia by drug abusers has been the main cause of parenteral transmissions. The risk of HIV transmission from sharing needles is approximately 0.67% per episode.3 Prevention strategies include stopping drug abuse, obtaining needles from credible sources (e.g., pharmacies), never reusing any paraphernalia, using sterile procedures in all injecting activities, and safely disposing of used paraphernalia.4
Before widespread screening, HIV was readily transmitted in blood products.3 However, blood and tissue products in the healthcare system are now rigorously screened for HIV. The estimated risk for receiving tainted blood or blood products in the United States is approximately 1:2,000,000 and that for receiving a tainted tissue transplant is 1:55,000.13,14 Healthcare workers have a small but definite occupational risk of contracting HIV through accidental injury. Most cases of occupationally acquired HIV have been the result of a percutaneous needle stick injury, which carries an estimated 0.3% risk of transmitting HIV.15 Mucocutaneous exposures (e.g., tainted blood splash in eyes, mouth, nose) carries a transmission risk of approximately 0.09%.15 Significant risk factors for seroconversion with a needle stick include deep injury, injury with a device visibly contaminated with blood, and advanced HIV disease in the index patient (high viral load). The risk of transmission from an HIV-infected healthcare worker to a patient is extremely remote. Comprehensive medical guidelines, including antiretroviral drug prophylaxis, have been developed to minimize the hazard of HIV transmission for healthcare workers and for persons exposed by rape or other means.3,15
Perinatal infection, or vertical transmission, is the most common cause of pediatric HIV infection.16 Most infections occur during or near to the time of birth, although a fraction can occur in utero. The risk of mother-to-child transmission is approximately 25% in the absence of ART. Factors that increase the likelihood of vertical transmission include prolonged rupture of membranes, chorioamnionitis, genital infection during pregnancy, preterm delivery, vaginal delivery, birth weight less than 2.5 kg, illicit drug use during pregnancy, and high maternal viral load. Breast-feeding also can transmit HIV. The estimated frequency of breast milk transmission is approximately 4% to 16%, with the majority of infections developing within the first 6 months.17 High levels of virus in breast milk and in the mother are associated with higher risk of transmission.17 Formula feeding prevents breast milk transmission of HIV but may not improve mortality from other causes early in life in some settings.18 Whenever formula feeding is acceptable, feasible, affordable, sustainable, and safe, HIV-infected mothers are recommended not to breast-feed. A separate and comprehensive set of medical guidelines including antiretroviral drug prophylaxis have been developed to minimize the hazard of mother-to-child HIV transmission.16
Persons with HIV infection are broadly categorized as those living with HIV and those with an AIDS diagnosis. An AIDS diagnosis is made when the presence of HIV is laboratory-confirmed and the cluster of differentiation 4 (CD4; T-helper cell) count drops below 200 cells/mm3 (200 × 106/L) or after an AIDS indicator condition is diagnosed.19 Further distinctions regarding the stage of HIV and AIDS are given in the Revised Centers for Disease Control and Prevention (CDC) surveillance case definition (Table 103-1).19 In the United States, new HIV/AIDS cases are reported by healthcare providers to a public health department.20 The cumulative number of reported HIV/AIDS diagnoses in the United States is approximately 1.7 million; more than 550,000 persons have already died.21 The estimated prevalence of HIV infections including AIDS cases in the United States is about 1.2 million individuals. Each year the CDC estimates that 55,000 new cases of HIV infection occur in the United States.21,22 Approximately 20% of persons with HIV are unaware of their infection and approximately 50% of those who are aware of their infection are retained in care.22,23 Therefore, the majority of HIV-infected persons (∼60%) are not receiving ART regularly, which contributes to the ongoing transmission of HIV infection.23
TABLE 103-1 Surveillance Case Definition for HIV Infection among Adults and Adolescents (≥13 years)—United States, 2008
The epidemic in the United States initially was established in white men who have sex with men (MSM), and the prevalence of HIV in this population still is high.22 New trends in transmission include more cases in women (currently ∼25%) and African Americans and Hispanics, a proportion of whom are not well linked to appropriate prevention, care, and treatment services.21 Approximately half of new cases occur in African Americans (who make up only 12% of the general population), about one third in Caucasians, and less than one fourth in Hispanics.20 The main risk factor for transmission in women is heterosexual intercourse (∼80% of cases) and injection-drug use (∼20% of cases). For men the main risks are MSM (∼65%), heterosexual sex (∼15%), and injection-drug use (∼15%).24
The estimated number of individuals living with HIV/AIDS worldwide has stabilized at approximately 34 million persons. The new infection rate is declining.25 Approximately 2.7 million were infected in 2010, including 390,000 children, down from approximately 3.3 million new infections in 1998.25 About 1.8 million people succumbed to AIDS in 2010. Globally, the highest concentration of HIV/AIDS cases is in sub-Saharan Africa, where approximately 23 million people are infected. However, new infections rates in many sub-Saharan African countries have declined by approximately 25% since 1997.25Heterosexual transmission is the most common mode of transmission in sub-Saharan Africa and worldwide (85% of cases). Women in sub-Saharan Africa and resource-limited countries are at disproportionately high risk for acquiring HIV because of biological and cultural factors that foster HIV transmission, such as limited ability to refuse sex.1,25 Other important epidemiologic features of the HIV epidemic include growing prevalence in eastern Europe and central Asia (e.g., Russian Federation and Ukraine).25Injection-drug use is fueling these epidemics.
HIV is an enveloped single-stranded RNA virus and a member of the Lentivirinae (lenti, meaning “slow”) subfamily of retroviruses. Lentiviruses are characterized by their indolent infectious cycle. There are two related but distinct types of HIV: HIV-1 and HIV-2. HIV-2, found mostly in western Africa, consists of seven phylogenetic lineages designated as subtypes (clades) A through G. HIV-1 also can be categorized based on phylogeny.26 Three groups of HIV-1 are recognized: M (main or major), N (non-M, non-O), and O (outlier). A new HIV-1 virus was classified as group P (pending the identification of further cases).27 The nine subtypes of HIV-1 group M are identified as A through D, F through H, and J and K. Mixtures of subtypes are referred to as circulating recombinant forms (CRFs). Group M, subtype B, is primarily responsible for the epidemic in North America and western Europe.26
The accumulated evidence suggests that HIV in humans was the result of a cross-species transmission (zoonosis) from primates infected with simian immunodeficiency virus (SIV). Phylogenetic and geographic relationships suggest that HIV-2 arose from SIV that infects sooty mangabeys and HIV-1 group M and N arose from SIVcpz, a virus that infects chimpanzees (Pan troglodytes troglodytes). Groups O and P may have arisen from a SIV variant that infects wild gorillas. Cultural practices, such as preparation and eating of bush meat or keeping animals as pets, may have allowed the virus to jump from primates to humans. The earliest known human infection with HIV has been traced to central Africa in 1959, but cross-species transmissions probably date back to the early 1900s.28 Modern transportation, promiscuity, and drug abuse have caused the rapid spread of the virus within the United States and throughout the world.1,28 This chapter focuses on HIV-1 group M, which is the predominant strain likely to be encountered in the western world.
DETECTION OF HIV AND SURROGATE MARKERS OF DISEASE PROGRESSION
The preferred method for diagnosing HIV-1 infection is an enzyme-linked immunosorbent assay (ELISA), which detects antibodies against HIV-1.24 ELISA is both highly sensitive (>99%) and highly specific (>99%), but rare false-positive results can occur in multiparous women; recent recipients of hepatitis B, HIV, influenza, or rabies vaccine; patients with multiple blood transfusions, liver disease, and renal failure; or those undergoing chronic hemodialysis. False-negative results may occur and most commonly are attributed to new infection where antibody production is not yet adequate. An HIV-RNA test can detect viremia approximately 2 weeks prior to antibody production.29 The minimum time to develop antibodies is 3 to 4 weeks from initial exposure, with greater than 95% of individuals developing antibodies after 6 months. Convenient methods for obtaining an ELISA sample from blood or saliva have been developed, including a rapid (20 to 40 minutes) turnaround oral test marketed as a home kit.
Positive ELISA results are repeated in duplicate, and if one or both tests are reactive, a confirmatory test is performed for final diagnosis. Western blot is the most commonly used confirmatory test, although an indirect immunofluorescence assay is available. A reactive ELISA test and a positive confirmatory test indicate an established HIV infection. If the confirmatory test is indeterminate, the individual should be retested 4 weeks later.24
HIV testing is recommended when HIV infection is suspected because of symptoms and/or high-risk behavior. Additionally, the CDC now recommends routine HIV screening in all healthcare settings in persons 13 to 64 years, a new policy called “opt-out” testing.24 The policy states that consent for medical care will imply consent for HIV testing; however, the person must be informed of the test and can opt out of taking it. Because states may have different HIV consent laws, the local requirements for HIV testing should be consulted. The rationale for the opt-out strategy is to diagnose those who unknowingly carry HIV so as to improve their prognosis and reduce further transmission.
Once diagnosed, HIV disease is monitored primarily by two surrogate biomarkers, viral load and CD4 cell count.30 The viral load test quantifies the degree of viremia by measuring the number of copies of viral RNA (HIV RNA) in the plasma. Methods for determining HIV RNA include reverse-transcription polymerase chain reaction (RT-PCR), branched-chain DNA, transcription-mediated amplification, and nucleic acid sequence-based assay. RT-PCR is used more widely than the other techniques. Irrespective of the method used, viral load is reported as the number of viral RNA copies per milliliter of plasma. Each assay has its own lower limit of sensitivity to viral subtypes, and results can vary from one assay method to the other; therefore, it is recommended that the same assay method be used consistently within patients. Reductions in viral load often are reported in base 10 logarithm. For example, if a patient presents initially with a viral load of 100,000 copies/mL (105 copies/mL or 108 copies/L) and subsequently has a viral load of 10,000 copies/mL (104 copies/mL or 107 copies/L), the decrease in viral load is 1 log10. Given that HIV RNA varies within patients, a clinical response is generally considered when the decline in viral load is more than 0.5 log10.30 Viral load is a major prognostic factor for monitoring disease progression and the effects of treatment.
Because HIV attacks and leads to the destruction of cells bearing the CD4 receptor, the number of CD4 lymphocytes (T-helper cells) in the blood is a critical surrogate marker of disease progression. The normal adult CD4 lymphocyte count ranges from 500 to 1,600 cells/mm3, or 40% to 70% of total lymphocytes. CD4 counts in children are age dependent, with younger children having higher CD4 counts. The hallmark of HIV disease is depletion of CD4 cells and the associated development of OIs and malignancies.
Understanding the life cycle of HIV (Fig. 103-1) is necessary because the current strategies used for treatment of HIV target various points in this cycle. Once HIV enters the human body, the outer glycoprotein (gp160) on its surface, which is composed of two subunits (gp120 and gp41), has affinity for CD4 receptors, proteins present on the surface of T-helper lymphocytes, monocytes, macrophages, dendritic cells, and brain microglia.31 The gp120 subunit is responsible for CD4 binding. Once initial binding occurs, the intimate association of HIV with the cell is enhanced by further binding to chemokine coreceptors. The two major chemokine receptors used by HIV are Chemokine (C–C motif) receptor 5 (CCR5) and chemokine (C-X-C motif) receptor 4 (CXCR4). HIV isolates may contain a mixture of viruses that target one or the other of these coreceptors, and some viral strains may be dual-tropic (i.e., can use both coreceptors). The HIV strain that preferentially uses CCR5, R5 viruses, is macrophage-tropic and typically implicated in most cases of sexually transmitted HIV. Individuals with a common 32-base-pair deletion in the CCR5 gene are protected from progression of HIV disease, and those who are homozygous for the 32-base-pair deletion have a degree of resistance to acquisition of HIV-1.32,33 The HIV strain that targets CXCR4, designated X4 virus, is T-cell–tropic and often is predominant in the later stage of disease. Other chemokine coreceptors and galactosyl ceramide may also serve as a binding site for HIV. CD4 and coreceptor attachment of HIV to the cell promotes membrane fusion, which is mediated by gp41, and finally internalization of the viral genetic material and enzymes necessary for replication.
FIGURE 103-1 Life cycle of human immunodeficiency virus with potential targets where replication may be interrupted. Italicized compounds were in development at the time of this writing. (Reprinted with permission, Courtney V. Fletcher, 2012.)
After internalization, the viral protein shell surrounding the nucleic acid (capsid) is uncoated in preparation for replication.31 The genetic material of HIV is positive-sense single-stranded RNA; the virus must transcribe this RNA into DNA (transcription normally occurs from DNA to RNA; HIV works backward, hence the name retrovirus). To do so, HIV is equipped with the unique enzyme RNA-dependent DNA polymerase (reverse transcriptase). HIV reverse transcriptase first synthesizes a complementary strand of DNA using the viral RNA as a template. The RNA portion of this DNA–RNA hybrid is then partially removed by ribonuclease H (RNase H), allowing HIV reverse transcriptase to complete the synthesis of a double-stranded DNA molecule. The fidelity of HIV reverse transcriptase is poor, and many mistakes are made during the process. These errors in the final DNA product contribute to the rapid mutation of the virus, which enables the virus to evade the immune response (thus complicating vaccine development), and promotes the evolution of drug resistance during partially suppressive therapy. Following reverse transcription, the final double-stranded DNA product migrates into the nucleus and is integrated into the host cell chromosome by integrase, another enzyme unique to HIV.
The integration of HIV into the host chromosome is troublesome. Most notably, HIV can establish a persistent, latent infection, particularly in long-lived cells of the immune system such as memory T lymphocytes. The virus is effectively hidden in these cells, and this characteristic has greatly inhibited the ability to cure HIV infection. Second, random integration of HIV may cause cellular abnormalities and induce apoptosis.
After integration, HIV preferentially replicates in activated cells. Activation by antigens, cytokines, or other factors stimulates the cell to produce nuclear factor kappa B (NF-κ B), an enhancer-binding protein. NF-κ B normally regulates the expression of T-lymphocyte genes involved in growth but also can inadvertently activate replication of HIV. HIV encodes six regulatory and accessory proteins: Tat, Nef, Rev, Vpu, Vif, and Vpr, which enhance replication and inhibit innate immunity. For example, the Tat protein is a potent amplifier of HIV gene expression; it binds to a specific RNA sequence of HIV that initiates and stabilizes transcription elongation. Vif is a viral protein that binds human ABOBEC 3G, a cytidine deaminase that converts viral RNA cytosine to uracil and thereby provides innate cellular immunity.34Vpu inhibits tetherin, a human cellular membrane protein that prevents diffusion of virus particles after budding from infected cells, thereby allowing HIV to detach from the infected cell.35 Assembly of new virion particles occurs in a stepwise manner beginning with the coalescence of HIV proteins beneath the host cell lipid bilayer. The nucleocapsid subsequently is formed with viral single-stranded RNA and other components packaged inside. Once packaged, the virion then buds through the plasma membrane, acquiring the characteristics of the host lipid bilayer. After the virus buds, the maturation process begins. Within the virion, protease, another enzyme unique to HIV, begins cleaving a large precursor polypeptide (gag-pol) into functional proteins that are necessary to produce a complete virus. Without this enzyme, the virion is immature and unable to infect other cells.
The characteristics of viral replication and pathogenesis exhibit three general phases: acute, chronic, and terminal (AIDS).36,37 Initial rounds of HIV replication during acute infection take place largely in the mucosal CD4+ CCR5+ T cell pools in the gut resulting in a massive CD4 T-cell depletion in these tissues.36,37 Cells are destroyed by various mechanisms, including cell lysis from newly budding virions, cytotoxic T-lymphocyte–induced cell killing, and induction of apoptosis. Following this destruction of the mucosal CD4 T cell pool, which lasts for 2 to 3 weeks, a state of heightened immune activation ensues during the chronic infection phase, which can last for several years. The activated state is characterized by high levels of activation markers on circulating T cells and proinflammatory cytokines and may result from HIV antigen as well as translocation of microbial antigens from the T-cell depleted gut mucosa. Heightened activation enables further HIV replication and ultimately leads to continued depletion of CD4+ CCR5+ T cells. HIV-1 exhibits a very high turnover rate during this chronic phase, with an estimated 10 billion new viruses produced each day. More than 99% of these viruses are produced in newly infected activated cells. Nevertheless, the immune system is able to operate well enough during the chronic phase to prevent overt OIs that herald AIDS. Eventually, the depletion of CD4 cells and the continuous cellular activation leads to a final collapse of the immune system, or AIDS. HIV may use CXCR4 coreceptor during this last phase of infection and these viruses infect a broader range of CD4 cells (naïve and central-memory) speeding the disease progression. It is this unrelenting destruction of CD4 cells that causes the profoundly compromised immune system and AIDS.36,37
Clinical presentation of primary HIV infection varies, but most patients (40% to 90%) have an acute retroviral syndrome or mononucleosis-like illness (Table 103-2).38 Symptoms often last 2 weeks, and hospitalization may be required for 15% of patients. Primary infection is associated with a high viral load (>106 copies/mL [>109/L]) and a precipitous drop in CD4 cells. After several weeks an immune response is mounted, the amount of HIV RNA in plasma falls substantially, CD4 cells rebound slightly, and symptoms resolve gradually. However, as described above, this clinically latent period is not virologically latent because HIV replication is continuous (∼10 billion viruses per day) and immune system destruction is ongoing. A steady decrease in CD4 cells is the most measurable aspect of this immune system deterioration. Plasma viral load, on the other hand, will appear to have stabilized at a particular level or “set point.” The set point that is established correlates directly with the time to AIDS and morbidity. The Multicenter AIDS Cohort Study measured viral load in 181 HIV-positive men and followed them for as long as 11 years. The mortality rates within 5 years for those with a viral load below 4530 copies/mL (4.53 × 106/L) was 5% compared with 49% for those with a viral load above 36,270 copies/mL (36.27 × 106/L).39 Thus, a higher viral set point is associated with poorer prognosis. Not all individuals infected with HIV progress to AIDS—these so-called “long-term nonprogressors” may be infected with a defective virus (e.g., nef-deficient HIV) or may have an intrinsic ability to resist infection (e.g., CCR5 mutation).33
TABLE 103-2 Clinical Presentation of Primary Human Immunodeficiency Virus Infection in Adults
Most children born with HIV are asymptomatic. On physical examination, children often present with nonspecific signs, such as lymphadenopathy, hepatomegaly, splenomegaly, failure to thrive, weight loss or unexplained low birth weight (in prenatally exposed infants), and fever of unknown origin.40 Laboratory findings include anemia, hypergammaglobulinemia (primarily immunoglobulin [Ig] A and IgM), altered mononuclear cell function, and altered T-cell subset ratios. Of note, the normal range for CD4 cell counts in young children is much different from the range in adults (Table 103-3). Children have different susceptibility and/or exposures to OIs compared with adults.40Bacterial infections, including Streptococcus pneumoniae, Salmonella spp., and Mycobacterium tuberculosis, may be more prevalent in children with AIDS than in adults with the disease. Kaposi’s sarcoma is rare in children. Children with HIV infection may develop lymphocytic interstitial pneumonitis without evidence of P. jirovecii or other pathogens on lung biopsy. Some children (∼25%) will progress to AIDS rapidly within the first year of life. A presentation of serious OIs such as P. jirovecii pneumonia, encephalopathy, failure to thrive, and a precipitous drop in CD4 cells are common in these infants.40 The current CDC pediatric AIDS surveillance definition (see Table 103-3) excludes children with congenital or perinatally acquired cytomegalovirus or other identified causes of congenital immunodeficiency; laboratory-confirmed HIV-infection is required.19 General management of the HIV-infected child involves principles similar to those used for the adult: ART, treatment and prophylaxis of OIs, and supportive care.41,42
TABLE 103-3 Centers for Disease Control and Prevention 2008 Revised Classification System for Human Immunodeficiency Virus Infection in Children Younger Than 13 Years
The central goals of ART are to decrease morbidity and mortality, improve quality of life, restore and preserve immune function, and prevent further transmission. The most important and effective way to achieve these goals is maximal suppression of HIV replication, which is interpreted as plasma HIV RNA less than the lower limit of quantitation (i.e., undetectable; usually <50 copies/mL [<50 × 103/L]).30Such a profound reduction in HIV RNA is associated with reduced transmissions and long-term response to therapy (i.e., durability), as well as increases in CD4 lymphocytes that closely correlates with a reduced risk for developing OIs. While undetectable HIV RNA almost always corresponds with a rise in CD4 lymphocytes, some patients respond virologically or immunologically without the other.30
General Approach to Treatment
Prior to 1996, HIV infection was treated with one or two nucleoside analog reverse transcriptase inhibitors (NRTI), which were generally not effective at controlling viremia. Thus, the mainstay of treatment was pharmacologic management of OIs and palliative care. At that time, the prognosis for HIV infection was dire and most patients were disabled and eventually died. In 1995, HIV protease inhibitors (PIs) were introduced followed by NNRTIs, and a new paradigm in HIV treatment was born. Combinations of three active antiretroviral agents from two pharmacologic classes were shown to profoundly inhibit HIV replication to undetectable levels, prevent and reverse immune deficiency, and substantially decrease morbidity and mortality—constituting the ART era.43 At the same time, multiple other major medical advances were introduced, such as the discovery that HIV establishes a long-lived reservoir in chronically infected cells, and the viral load test (plasma HIV-RNA). With this backdrop of dramatic changes, in 1997 the National Institutes of Health Office of AIDS Research convened a panel to define the scientific principles that might serve as a guide for the clinical use of antiretroviral agents.44The 11 principles presented here are an amalgamation of knowledge of the life cycle of HIV, the consequences of HIV replication, clinical trials of antiretroviral agents, and scientific opinion. These foundational principles are still relevant today.
1. Ongoing HIV replication leads to immune system damage and progression to AIDS. HIV infection is always harmful, and true long-term survival free of clinically significant immune dysfunction is unusual.
2. Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4 cell destruction, whereas CD4 cell counts indicate the extent of HIV-induced immune damage already suffered. Regular periodic measurement of plasma HIV RNA levels and CD4 cell counts is necessary to determine the risk of disease progression in an HIV-infected individual and to determine when to initiate or modify antiretroviral treatment regimens.
3. Because rates of disease progression differ among individuals, treatment decisions should be individualized by level of risk indicated by plasma HIV RNA levels and CD4 cell counts.
4. Use of potent combination ART to suppress HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV replication should be the goal of therapy.
5. The most effective means for accomplishing durable suppression of HIV replication is simultaneous initiation of combinations of effective anti-HIV drugs with which the patient has not been treated previously and that are not cross-resistant with antiretroviral agents with which the patient has been treated previously.
6. Each of the antiretroviral drugs used in combination therapy regimens always should be used according to optimal schedules and dosages.
7. The available effective antiretroviral drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in ART increases future therapeutic constraints.
8. Women should receive optimal ART regardless of pregnancy status.
9. The same principles of ART apply to both HIV-infected children and adults, although treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations.
10. Persons with acute primary HIV infections should be treated with combination ART to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays.
11. HIV-infected persons, even those with viral loads below detectable limits, should be considered infectious and should be counseled to avoid sexual and drug-use behaviors that are associated with transmission or acquisition of HIV and other infectious pathogens.
The extent to which these 11 principles will continue to stand the test of time is unknown; new information on the pathogenesis and treatment of HIV accrues constantly. One continuing source of controversy is whether to treat patients with acute HIV infection. As of October 2012, 27 distinct antiretroviral compounds have been approved by the FDA; two (amprenavir and zalcitabine) have since been removed from the market. Table 103-4 presents the state of the art for treatment of HIV-infected individuals as of October 2012.30 Treatment is recommended for all HIV-infected persons with a CD4 lymphocyte count below 500 cells/mm3 (500 × 106/L). Many clinicians would also favor starting therapy in asymptomatic patients with CD4 counts above 500 cells/mm3 (500 × 106/L). Other indications for therapy at any CD4 count include pregnancy, history of AIDS-defining illness, HIV-associated nephropathy, or HIV/hepatitis B virus coinfection.
TABLE 103-4 Treatment of Human Immunodeficiency Virus Infection: Antiretroviral Regimens Recommended in Antiretroviral-Naïve Persons
Treatment of persons with acute primary HIV infection with combination ART to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays is controversial. Well-designed trials with clinical end points that define the long-term safety and efficacy of initiating combination ART during acute HIV infection are lacking. Theoretical benefits are decreasing the severity of acute disease; perhaps lowering the initial viral load set point, which affects progression rates; preserving immune function; and reducing the risk for viral transmission. However, these potential benefits must be weighed against the issues imposed by early intervention of chronic therapy, which may be many years ahead of normal initiation of therapy (discussed below).
The optimal time to initiate therapy in chronic HIV infection has been a matter of debate over the last 15 years. The challenges of life-long ART must be balanced against the higher relative risk of ongoing HIV transmissions and disease progression in asymptomatic HIV-infected individuals when ART is delayed. Randomized trials demonstrate that deaths and disease progression are higher if therapy is delayed until CD4 cells fall below 350 cells/mm3 (350 × 106/L).7,30,45 Epidemiological studies show significantly higher mortality if treatment is delayed in those with a CD4 count of 351 to 500 cells/mm3 (351 × 106to 500 × 106/L) or CD4 counts >500 cells/mm3 (>500 × 106/L) compared with deferring therapy until CD4 counts drop to lower levels.46 Other epidemiological studies show similar benefits in terms of the composite endpoint of disease progression and death for earlier initiation of therapy.47,48Together, these studies support early initiation of ART in patients who are ready and willing to commit to life-long treatment including an understanding of its risks and benefits and the need to maintain a high level of adherence. Healthcare professionals involved in the care of HIV-infected persons must consult the most current literature on the principles and strategies for therapy. Better patient outcomes are demonstrated when clinicians have significant HIV expertise. An excellent source for information on treatment guidelines, which is regularly updated, is available at www.AIDSinfo.NIH.gov. Additional guidelines and electronic resources for HIV clinicians are provided in reference 24.
The precise time to start therapy is controversial. Early in the ART era, the mantra was “hit early and hit hard,” with hopes that the drugs would be well tolerated and the virus could be eradicated. When it became clear that treatment was long term and that these earlier drugs had potential long-term side effects, the mantra changed to a drug-sparing paradigm where therapy was initiated as late as possible. Newer agents have improved upon tolerability, but lack long-term safety data. The benefits of early therapy include preventing the known detriments of unchecked viral replication, including irreversible immune damage and increased likelihood of viral transmission. The potential risks of initiating combination ART include the lifestyle demands of continuous therapy, drug toxicities, and development of antiretroviral drug resistance.
Conceptually the four primary methods of therapeutic intervention against HIV are direct inhibition of chronic viral replication or prevention of HIV acquisition including as virucidal topical formulations (chemicals that destroy intact viruses) to prevent HIV infection, vaccination to stimulate a more effective immune response, and restoration of the immune system with immunomodulators; the latter three approaches are mostly investigational. Several approaches for an HIV vaccine are in development, including whole killed virus, subunit and peptide vaccination, recombinant live vector, and naked DNA delivery. A randomized placebo controlled trial demonstrated a modest 30% reduction in HIV transmission in a modified-intention to treat analysis of ALVAC-HIV plus AIDSVAX vaccine in 16,402 volunteers.49 The modified analysis excluded subjects who were found to be HIV-infected prior to randomization. However, the efficacy difference was not significant in the per-protocol analysis. Therefore, the findings must be considered tentative until more definitive data become available. Overall, progress has been slow for the vaccine field. Genetic variability in HIV and a nascent understanding of the role of the immune system in suppressing viral replication are significant barriers to the development of an effective HIV vaccine with long-lasting and protective immunity. Immunomodulators, such as aldesleukin (interleukin-2), provide mild benefits in terms of increased CD4 cells; however, aldesleukin is also associated with significant toxicities and no apparent clinical benefit.50Additional immunotherapies are in earlier phases of study. Topical virucidal or antiretroviral drug formulations for use vaginally or rectally to prevent sexual transmission of HIV are in various phases of development. Vaginal application of tenofovir 1% gel before and after intercourse reduced HIV infection by 39% in women.12 However, another study showed that daily tenofovir 1% gel vaginally did not reduce HIV acquisition, indicating that additional trials will be needed before licensing decisions are made.
Direct inhibition of viral replication with combinations of potent antiretroviral agents has been the most clinically successful strategy. Four general classes of drugs are used today: entry inhibitors, reverse transcriptase inhibitors, InSTIs, and HIV PIs (Table 103-5).30 Reverse transcriptase inhibitors consist of two classes: those that are chemical derivatives of purine- and pyrimidine-based nucleosides and nucleotides (nucleoside/nucleotide reverse transcriptase inhibitors [NRTIs]) and those that are not (nonnucleoside reverse transcriptase inhibitors [NNRTIs]). NRTIs include the thymidine analogs stavudine (d4T) and zidovudine (AZT or ZDV); the deoxycytidine analogs emtricitabine (FTC) and lamivudine (3TC); the deoxyguanosine analog abacavir sulfate (ABC); and the deoxyadenosine analogs of which didanosine (ddI) is an inosine derivative and tenofovir disoproxil fumarate (TDF) is a deoxyadenosine-monophosphate nucleotide analog (a nucleotide is a nucleoside with one or more phosphates). Note that drug abbreviations are provided here and below for reference, but their use is discouraged because they may lead to prescribing or administration errors. As a class, the NRTIs require phosphorylation to the 5’-triphosphate moiety to become pharmacologically active. Intracellular phosphorylation occurs by cytoplasmic or mitochondrial kinases and phosphotransferases (not viral kinases). The 5’-triphosphate moiety acts in two ways: (a) it competes with endogenous deoxyribonucleotides for the catalytic site of reverse transcriptase, and (b) it prematurely terminates DNA elongation, if taken up and incorporated, as it lacks the requisite 3’-hydroxyl for sugar-phosphate linking.42 Although NRTI triphosphates (or diphosphate for tenofovir) are specific for HIV reverse transcriptase, their adverse effects may be caused in part by inhibition of mitochondrial DNA or RNA synthesis.51 Toxicities include peripheral neuropathy, pancreatitis, lipoatrophy (subcutaneous fat loss), myopathy, anemia, and rarely life-threatening lactic acidosis with fatty liver.52 Use of stavudine and didanosine has declined in favor of more tolerable NRTIs (e.g., emtricitabine, lamivudine, and tenofovir).30 Emtricitabine, lamivudine, and tenofovir are active against hepatitis B virus, and a combination of these agents should be used in HIV–hepatitis B coinfected patients. With some exceptions (e.g., abacavir), NRTIs are mainly eliminated by the kidney and dose adjustments are required for renal insufficiency (and abacavir should not be used in advanced hepatic impairment). Resistance has been reported for all NRTIs, including cross-resistance within the class as multiple and/or specific mutations accrue.53
TABLE 103-5 Selected Pharmacologic Characteristics of Antiretroviral Compounds
NNRTIs are a chemically heterogeneous group of agents that bind noncompetitively to reverse transcriptase adjacent to the catalytic site. Unlike NRTIs, NNRTIs do not require intracellular activation, do not compete against endogenous deoxyribonucleotides, and do not have potent antiviral activity against HIV-2. Given the different site of binding to reverse transcriptase, NNRTIs can be used with NRTIs effectively. Available NNRTIs include delavirdine (DLV), efavirenz (EFV), etravirine (ETR), nevirapine (NVP), and rilpivirine (RPV).30 As a class, the NNRTIs are generally associated with rash and elevated liver function tests, including life-threatening cases rarely, particularly for nevirapine.51 NNRTIs tend to have long plasma half-lives and are mainly cleared by liver and/or gut-mediated metabolism through the cytochrome P450 (CYP) enzyme system, and caution should be used for those with advanced hepatic insufficiency (nevirapine should not be used in moderate or advanced hepatic insufficiency). NNRTI can be perpetrators of drug–drug interactions associated with CYP metabolism. The NNRTIs are unique in that a single mutation is needed to confer high-level cross-resistance for the class (except etravirine), which has been termed a low-genetic barrier to resistance.53
The HIV PIs include atazanavir (ATV), darunavir (DRV), fosamprenavir (FPV), indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), ritonavir (RTV), saquinavir (SQV), and tipranavir (TPV). HIV PIs competitively inhibit the cleavage of the gag-pol polyprotein, which is a crucial step in the viral maturation process, thereby resulting in the production of immature, noninfectious virions. HIV PIs are generally associated with GI distress and metabolic changes, such as increased lipids, insulin insensitivity, and changes in body fat distribution.52 HIV PIs are cleared by liver- and gut-mediated metabolism (mainly CYP3A), and dose adjustments may be required in hepatic insufficiency (tipranavir/ritonavir should not be used in moderate to severe hepatic insufficiency). HIV PIs are almost always used with low doses of ritonavir (or potentially cobicistat in the future), i.e., CYP3A inhibitors, to increase the plasma concentrations of the HIV PI of interest. CYP3A-mediated drug interactions with concomitant medications are important considerations for PIs. Resistance to the HIV PIs generally requires the buildup of multiple mutations, termed a high-genetic barrier. Multiple mutations can lead to cross-resistance.53
There are currently two types of entry inhibitors: fusion inhibitors and CCR5 antagonists. Enfuvirtide (ENF) is the only fusion inhibitor available at this time. Enfuvirtide is a synthetic 36-amino-acid peptide that binds gp41, which inhibits envelope fusion of HIV-1 with the target cell, but does not have activity against HIV-2. Because of the peptide nature of enfuvirtide, oral delivery is impossible, and subcutaneous injection is the preferred route of administration. Injection-site reactions (pain, erythema, nodules) are the most common adverse effect, nearing 100% incidence. Enfuvirtide is cleared via protein catabolism and amino acid recycling. Enfuvirtide appears to have a low genetic barrier to resistance.53 Maraviroc is a CCR5 antagonist. Unlike the other available anti-retrovirals that interact with a viral target, CCR5 antagonists block a human receptor. The long-term consequences of blocking CCR5 are unknown but may include increased susceptibility to infection by flaviviruses (e.g., West Nile virus and tickborne encephalitis virus).54 One advantage of targeting a human receptor is that resistance to CCR5 antagonists may be more difficult to develop. Because CCR5 antagonists are only effective against R5 virus and not X4 virus, a viral tropism assay must be performed prior to using a CCR5 antagonist. Maraviroc is a CYP3A and P-glycoprotein substrate and is therefore susceptible to drug-drug interactions and caution should be used in those with advanced hepatic insufficiency. Resistance mutations have been identified for enfuvirtide, but assays for maraviroc resistance have not been developed other than the R5 versus X4 tropism test.
Raltegravir (RAL) and elvitegravir (EVG) are approved InSTI, and dolutegravir is in late development. InSTI bind to HIV integrase while it is in a specific complex with viral DNA. As a result, viral DNA cannot become incorporated into the human genome and cellular enzymes degrade unincorporated viral DNA. Alternatively, recombination and repair mechanisms may form long-terminal repeat (LTR) circular DNA from the unincorporated viral DNA. Raltegravir and dolutegravir are primarily glucuronidated by UGT1A1 and are not susceptible to CYP-mediated drug interactions. Elvitegravir is extensively metabolized by CYP3A and is co-formulated with cobicistat, a potent CYP3A inhibitor, to optimize drug exposure and enable once daily dosing. Cobicistat, which is devoid of antiretroviral activity, is also being studied as a pharmacokinetic enhancer of HIV PIs. InSTI should be used with caution in advanced hepatic insufficiency. Updated dosing recommendations for hepatic and renal insufficiency for all antiretroviral drugs are included in the Department of Health and Human Services Guidelines.30 Multiple mutations have been identified conferring resistance to InSTI including cross-resistance as mutations accrue. Dolutegravir was designed to be active against raltegravir and elvitegravir resistant strains.
Novel antiviral agents in the classes listed above and novel agents in new drug classes that exploit other steps in the HIV life cycle (see Fig. 103-1) are in development, with a focus on long-lasting activity and/or high activity against drug-resistant virus.55
The anti-herpes and anti-hepatitis B antivirals acyclovir, foscarnet, entecavir, and adefovir exhibit modest anti-HIV activity.56,57 If these antivirals are used in HIV-infected patients, it should be with suppressive ART therapy.
Medical use of antiretroviral agents is complicated by clinically significant drug–drug interactions that can occur with many of these agents.30,58 Some interactions are beneficial and used purposely (e.g., ritonavir and cobicistat); others may be harmful, leading to dangerously elevated or inadequate drug concentrations. Clinicians involved in the pharmacotherapy of HIV must understand the mechanistic basis for these interactions and maintain a current knowledge of drug interactions for these reasons.
Many clinically significant antiretroviral-associated drug interactions involve CYP3A-mediated metabolism and clearance. The HIV PIs, except nelfinavir, the NNRTIs delavirdine, etravirine, and rilpivirine, the CCR5 antagonist maraviroc, and the InSTI elvitegravir are metabolized by CYP3A. In general, efavirenz, etravirine and nevirapine are inducers of CYP3A, whereas delavirdine and the PIs inhibit CYP3A. Ritonavir is a potent inhibitor of CYP3A-mediated metabolism and is now used almost exclusively at lower doses as a pharmacokinetic enhancer of other HIV PIs. Darunavir, lopinavir, saquinavir, and tipranavir must be taken with ritonavir to achieve optimal plasma concentrations. Atazanavir, fosamprenavir, and indinavir are also primarily used with ritonavir for the same reason. Nelfinavir is not effectively boosted by ritonavir given its CYP2C19-mediated metabolism. Cobicistat, which is an analog of ritonavir without antiretroviral activity, is also a potent inhibitor of CYP3A activity and is under study as a booster of HIV-PIs. Many potential concomitant drugs on the market are also metabolized by CYP3A and therefore susceptible to clinically relevant drug interactions with HIV PIs, NNRTIs, and cobicistat.30,58 Agents with narrow therapeutic indices and/or that exhibit major changes in pharmacokinetics with CYP3A inhibition are most important in this regard. Examples include, but are not limited to, simvastatin, lovastatin, corticosteroids (including inhaled and intranasal), ergot derivatives, oral hormonal contraceptives, hepatitis C PIs (boceprevir/telaprevir), and some antiarrhythmics. The drug interaction potential of antimycobacterium agents, specifically the rifamycins, are particularly relevant given the high potential for such infections in HIV-infected patients.58 Rifampin, a potent inducer of CYP3A metabolism and conjugation enzymes, is contraindicated with use of most HIV PIs, etravirine, rilpivirine, and maraviroc because concentrations are reduced substantially even with ritonavir enhancement. Raltegravir dose should be doubled in the presence of rifampin; efavirenz is an alternative agent. Ritonavir enhancement generally allows coadministration of HIV PIs with rifabutin.58 In such cases, the rifabutin dose will require adjustment given its CYP3A-mediated clearance.
The herbal product St. John’s wort (Hypericum perforatum) is a potent inducer of metabolism and is contraindicated with PIs, NNRTIs, and maraviroc.30 It must be stressed that the pharmacology of CYP3A interactions may be complicated by simultaneous induction/inhibition of drug transporter-mediated (e.g., P-glycoprotein) clearance and/or other phase I or phase II enzymes. Furthermore, some antiretroviral drugs require acidic environments for optimal absorption creating interactions with antacids, particularly proton-pump inhibitors (e.g., atazanavir, rilpivirine). Clinicians who treat HIV must stay abreast of antiretroviral drug interaction data. Websites are available that catalog and regularly update HIV drug-interaction information (http://www.hiv-druginteractions.org/), and the Department of Health and Human Services guidelines for antiretroviral use provide, and regularly update, excellent summaries of known clinically relevant drug interactions.30,58
NRTIs are not metabolized by CYP3A, but other drug interaction considerations are important. Generally, NRTIs of the same nucleobase should not be coadministered. For example, zidovudine and stavudine are both thymidine analogs and phosphorylated by the same cellular enzymes. Antagonism occurs between these two drugs both in vitro and in vivo; thus, the two should never be given together. Similarly, deoxycytidine analogs should not be coadministered. The deoxyadenosine analogs didanosine and tenofovir exhibit a plasma drug interaction whereby didanosine concentrations are significantly increased.30Furthermore, the two adenosine analogs are less effective together compared with other recommended NRTI regimens and there is concern for CD4 lymphotoxicity, a troubling effect that appears unique to this NRTI combination. Coadministration of didanosine and tenofovir is not recommended.30
Landmarks in the Evolution of Antiretroviral Therapy
ART has undergone major changes over the past decades. Illustrating these changes is important for a thorough understanding of current treatment strategies. The fundamental landmarks in the use of antiretroviral agents are as follows:
1. An early study demonstrated that zidovudine monotherapy confers a survival benefit in persons who have AIDS.59 This study showed that a single drug provided moderate clinical benefit.
2. Further investigation showed that combination regimens of two NRTIs (e.g., zidovudine and didanosine or zalcitabine) were superior to zidovudine monotherapy in immunologic and virologic parameters, particularly in patients with no previous ART, and conferred a superior survival benefit.60 This established that NRTI monotherapy was inferior to dual NRTI therapy.
3. A pivotal study showed that dual NRTI therapy was inferior to triple therapy consisting of 2 NRTIs and the HIV PI indinavir.61 Use of triple therapy with combinations of two NRTIs with NNRTIs or HIV PIs was associated with a durable response as well as significantly reduced incidence of OIs and improved survival, thus establishing the current paradigm of ART.62
4. Evolution of triple-therapy regimens utilizing boosted HIV PIs, co-formulations, new drug classes, and better tolerated agents showed improvements in convenience, tolerability, safety, and virologic efficacy, all helping usher in the current era of ART.63,64
Taken together, the pivotal studies described above established that HIV should not be treated with single or dual NRTIs. Current recommendations for initial treatment of HIV infection advocate a minimum of three active antiretroviral agents: tenofovir disoproxil fumarate (TDF) plus emtricitabine with either a ritonavir-enhanced PI (darunavir or atazanavir), the NNRTI efavirenz, or the InSTI, raltegravir.30 Multiple alternative regimens are also safe and effective, but have one or two disadvantages compared with the preferred regimens such as lack of long-term follow-up, weaker virologic responses with high viral loads, lower tolerability, or greater risk of long-term toxicities such as subcutaneous fat loss. Preferred and alternative antiretroviral regimens are listed in Table 103-4.30 The World Health Organization (WHO) also updated its treatment recommendations for resource-limited settings. The main updates to the WHO guidelines are the recommendation to treat at higher CD4 count thresholds (350 cell/mm3 [350 × 106/L]) and not to include stavudine as initial therapy, due to elevated risk of mitochondrial toxicity.65
The simplest definition of adherence is the patient’s ability to take medication as directed. Variable adherence to ART is common, and a leading cause of therapeutic failure.66 Factors associated with poor adherence include major psychiatric illnesses, active substance abuse, unstable social circumstances, adverse events, and poor adherence with clinic visits.30 Studies consistently show that average adherence rates range from 60% to 80% for both HIV PI and NNRTI-based regimens including 30% of subjects who miss >7 consecutive days of dosing.67–69 The odds of persistent or breakthrough viremia are several-fold higher in patients with adherence below 60% to 80%, and the risk mounts with longer dosing “holidays”.67–69 As clinicians, it is critical to establish a relationship of trust with the patient and to communicate to the patient the importance of proper medication taking. Education should be aimed at understanding the disease process, monitoring, and goals of therapy. An individual’s “readiness” to take medications should be clearly established before any treatment is initiated.30 Help from caregivers, friends, and/or family members should be leveraged by the patient because social and psychological support are among the most important factors that influence adherence in this patient population.
Based on clinical trial data, approximately 70% to 90% of patients will achieve undetectable viral loads with modern ART regimens. The preferred NRTI combination, TDF plus emtricitabine, has demonstrated virologic and tolerability advantages compared with zidovudine/lamivudine and abacavir/lamivudine.70 An open-labeled trial of 517 antiretroviral naive patients randomized to TDF-emtricitabine versus zidovudine–lamivudine both with efavirenz demonstrated that significantly more patients in the TDF-emtricitabine arm achieved less than 400 copies/mL (400 × 103/L) at 48 weeks (84%) compared with patients randomized to zidovudine–lamivudine (73%).70 Part of this difference was attributed to more patients discontinuing zidovudine–lamivudine due to adverse events compared with TDF–emtricitabine. Subcutaneous fat loss and lipid elevations were also higher in the zidovudine–lamivudine group through 48 weeks. Another randomized study compared abacavir–lamivudine to TDF–emtricitabine in a blinded manner in combination with either efavirenz or atazanavir/ritonavir (open labeled) in 1858 antiretroviral naïve adults. Among subjects with >100,000 copies/mL (>100 × 106/L) of plasma HIV-RNA at screening, those randomized to abacavir–lamivudine experienced twice the virologic failure rate and significantly more adverse events compared with those randomized to TDF-emtricitabine.71 However, other studies have also evaluated virologic efficacy and safety of abacavir–lamivudine in subjects with >100,000 copies/mL (>100 × 106/L) at baseline and have found high rates of efficacy and safety regardless of baseline viral load.72
Large, randomized, controlled trials have compared TDF–emtricitabine based regimens and demonstrated comparable potency for raltegravir versus efavirenz,73 and atazanavir/ritonavir versus lopinavir/ritonavir,74 and increased potency for darunavir/ritonavir over lopinavir/ritonavir.75 Lopinavir/ritonavir was less tolerable than atazanavir/ritonavir and darunavir/ritonavir in terms of GI distress.74,75These studies established the preferred initial regimens for HIV infection listed above. Trials of new combinations such as coformulated elivitegravir–cobicistat–tenofovir disproxil fumarate–emtrictabine versus preferred regimens demonstrate comparable safety and efficacy over 48 weeks, but lack longer-term follow-up compared with the preferred regimens above.76 Recommended preferred regimens are continuously updated as longer-term follow-up data accrue. Patients with sustained undetectable HIV-RNA taking out-of-date drug regimens may be candidates to simplify to one of the preferred regimens or a more desirable alternative regimen based on past treatment history and other variables. Simplified regimens should continue to include three active drugs. If abacavir is to be used in any regimen, a test for the presence of human leukocyte antigen (HLA)-B*5701 should be done as its presence has been strongly correlated with the development of abacavir hypersensitivity. Should this test be positive, an abacavir allergy should be added to the patient’s chart and abacavir should not be used in the patient. Similarly, a tropism test is required prior to using maraviroc to establish that the patient’s virus uses the CCR5 coreceptor.30
Regimen failure is commonly associated with antiretroviral resistance, and testing for such resistance is a useful clinical tool.53 The two types of resistance tests available are phenotype and genotype. A phenotype test determines the concentration of antiretroviral agent necessary to inhibit 50% (IC50) replication of the patient’s viral isolate (inhibitory concentration of 50% [IC50]) in a recombinant in vitro viral assay. Results usually are expressed as a fold change in susceptibility (IC50) compared with a wild-type laboratory strain virus. Generally, the fold-change in IC50 increases as HIV accumulates additional mutations that confer resistance to a particular drug. However, a single mutation may confer a very high fold-change in IC50 for some drugs (e.g., lamivudine, emtricitabine, efavirenz, nevirapine) rendering them ineffective after a single mutation. Although small-to-moderate increases in the fold change suggests reduced susceptibility to that antiretroviral agent, resistance may not be absolute, and partial susceptibility may remain. Theoretically, drug concentrations may be increased to overcome reduced susceptibility. The strengths of phenotypic testing is to provide resistance information for complex mutation patterns, but it is also associated with higher cost, limited number of commercial providers, and slower turnaround time for results. Genotyping assesses genetic mutations and associated codon changes in gp41, reverse transcriptase, integrase or protease in the patient’s virus and compares it with the wild-type sequence. Mutations, when present, are listed by the wild-type amino acid followed by the position in the protein or enzyme and end with the mutation found in the patient’s virus. For example, a common mutation caused by lamivudine and emtricitabine is the M184V mutation: a substitution of valine (V) for methionine (M) at the 184 position of reverse transcriptase. Mutations can confer varying degrees of antiretroviral drug resistance and in some cases, weighting algorithms have been developed to predict the relative impact of mutation combinations on antiretroviral activity. Algorithms have also been developed to predict a phenotype from a genotype test (i.e., virtual phenotype). Not all mutations, however, are only detrimental—for example, while M184V confers significant resistance to lamivudine and emtricitabine, it is also associated with a less fit virus.77 New genetic mutations are discovered occasionally and are catalogued and maintained on websites (e.g., www.iasusa.org/resistance_mutations). Interpretation of genotypes resistance tests is complex; therefore, the reader is encouraged to obtain expert advice and consult the most recent guidelines on HIV resistance testing.53
Treatment of Special Populations
Several considerations are relevant to the treatment of pregnant women, including the health of the mother, prevention of HIV transmission to the fetus, potential for teratogenicity, and dosing issues based on pharmacokinetic changes during pregnancy. Treatment recommendations should be consulted to address the specific requirements for HIV-infected pregnant women and the prevention of vertical transmission.16 Generally, pregnant women should be treated as would nonpregnant women, with some exceptions. In general, efavirenz should be avoided when possible in pregnant women during the first trimester or in women trying to conceive because of potential teratogenicity. Drugs that cross the placental barrier should be included such as, abacavir, emtricitabine, lamivudine, tenofovir, or zidovudine. IV zidovudine is recommended intrapartum depending on the mother’s viral load, based on early studies demonstrating clear prophylactic effectiveness as well as extensive familiarity with the side effect profile.16 Infants also receive zidovudine (± several doses of nevirapine) prophylaxis for 6 weeks after birth. Lopinavir–ritonavir has also been studied extensively in pregnant women, and is recommended in this population. Currently, HIV transmission rates have been reduced to <0.5% for women who are treated with ART and when zidovudine prophylaxis is used.16
In resource-limited settings or when HIV infection is detected very close to delivery, an abbreviated course of zidovudine with a single dose of nevirapine also can reduce transmission substantially. In these cases, a 7-day course of zidovudine–lamivudine is given to the mother intrapartum and postpartum to reduce the substantial risk of nevirapine resistance due to its low genetic barrier to resistance and the long decay half-life leading to prolonged suboptimal concentrations.78 Zidovudine (± nevirapine) is also recommended in the infant. If breast-feeding is necessary because alternatives are not safe or feasible, extended nevirapine prophylaxis in the infant significantly lowers the risk of HIV transmission from the mother.79
In addition to fetal and infant chemoprophylaxis, protection of healthcare workers from accidental exposure to HIV and in cases of rape or high-risk postcoital and postinjection drug-use episodes are important concerns. The CDC has issued guidelines governing antiretroviral treatment of occupational and other high-risk HIV exposures.3,15 These guidelines should be consulted for updates as the knowledge in this field evolves. The principles of the guidelines are to grade the exposure risk and treat as soon as possible after high-risk exposures to prevent HIV infection. The makeup of the treatment depends upon the risk. Postexposure prophylaxis (PEP) with a triple-drug regimen consisting of two NRTIs and a boosted-PI is recommended for percutaneous blood exposure involving significant risk (e.g., large-bore needle, visible blood from patients with advanced AIDS). Two NRTIs may be offered to the healthcare worker with lower risk of exposure, such as cases involving superficial exposures to the mucous membrane or broken skin. Urine, saliva, nasal secretions, stool, and sputum are not considered infectious unless visibly contaminated with blood. The optimal duration of treatment is unknown, but at least 4 weeks of therapy is advocated. Treatment ideally should be initiated within 1 to 2 hours of exposure, but treatment is recommended up to 72 hours postexposure. Expert consultation is needed when exposure to drug-resistant virus is suspected or confirmed, but this should not delay initiation of PEP.3,15
Preexposure prophylaxis (PrEP) using the antiretroviral drugs emtricitabine and TDF was recently approved for preventing sexual HIV acquisition. The approach involves adding tenofovir disoproxil fumarate–emtricitabine to traditional prevention strategies (e.g., condoms) in HIV-negative persons at high risk of HIV acquisition to prevent infection if HIV-exposed PrEP is effective in MSM, sero-discordant couples, and at-risk heterosexual men and women.8,10,80 The key considerations to maximize PrEP effectiveness are to document an HIV-negative test prior to initiating PrEP, to monitor for HIV infection and renal function regularly, and to promote adherence and the continued use of safe sex practices.
EVALUATION OF THERAPEUTIC OUTCOMES
Two laboratory tests are used to evaluate response to ART: the plasma HIV RNA and the CD4 count.30 These tests should be established at baseline, along with hematology, chemistries, and serologies for coinfections. A HIV resistance test is recommended upon entry into care. After therapy is initiated, patients are generally monitored at 3-month intervals until HIV-RNA reaches undetectable levels. An assessment at 2 to 8 weeks is warranted to document early response. Monitoring may be increased to every 6 months in stabilized patients. The two main indications for a change in therapy are significant toxicity and treatment failure. Should a single agent be responsible for an intolerable side effect, that agent often can be singly changed out of the regimen, for example, the patient who experiences intolerable CNS disturbances during initiation of efavirenz can switch to a boosted PI without changing the dual NRTI backbone. Caution must be exercised when drugs in the regimen have overlapping toxicities, which makes changing a single agent problematic. Serious and life-threatening toxicities warrant cessation of the whole regimen before deciding upon a subsequent therapy.
As a general guide, the following events indicate treatment failure and should prompt consideration for changing therapy:
1. Less than 1 log10 reduction in HIV RNA 1 to 4 weeks after initiation of therapy or a failure to achieve less than 200 copies/mL (200 × 103/L) by 24 weeks or less than 50 copies/mL (50 × 103/L) by 48 weeks.
2. After HIV RNA suppression, repeated detection of HIV-RNA.
3. Clinical disease progression, usually the development of a new OI.
The most important measure of therapeutic failure is suboptimal suppression of viral replication. Many reasons may underlie suboptimal suppression of viral replication such as nonadherence to medication, development of drug resistance, intolerance to one or more medications, adverse drug–drug or drug–food interactions, or pharmacokinetic–pharmacodynamic variability.30 In cases of suboptimal suppression of viral replication, these potential causes should be investigated and addressed, if possible. As a general rule, drug resistance develops for regimens that do not maximally suppress HIV replication. Drug resistance testing is recommended while the patient is undergoing the failing regimen or within 4 weeks after stopping the regimen as long as the HIV RNA count is greater than 500 copies/mL (500 × 103/L), which is the threshold for resistance assays (∼500 to 1000 copies/mL [∼500 × 103 to 1000 × 103/L]).53 Virus may revert to wild-type if more than 4 to 6 weeks has elapsed between regimen discontinuation and the resistance test. Most clinicians use the genotype assay because it is less expensive and results typically are available sooner compared with the phenotype assay. Resistance results usually require expert interpretation. Treating patients with drug-resistant HIV utilizes the same general treatment approaches described for initial therapy above. Patients should be treated with at least two (preferably three) fully active antiretroviral drugs based on medication history, resistance tests, and new mechanistic drug classes (e.g., maraviroc and raltegravir). The goal of therapy is to suppress HIV-RNA to <50 copies/mL (<50 × 103/L). In cases when <50 copies/mL (<50 × 103/L) cannot be attained, maintenance on the regimen is preferred over drug discontinuation so as to prevent rapid immunological and clinical decline.
The two newest PIs darunavir and tipranavir and the NNRTI, etravirine, have demonstrated activity in persons with multidrug-resistant HIV in controlled clinical trials.30 The drugs in the newer drug classes, raltegravir, maraviroc, and enfuvirtide, are also active against NRTI-, NNRTI-, and PI-resistant viruses in highly treatment experienced patients in controlled trials.
Previous strategies for therapeutic failure have proven largely ineffective, including drug holidays, structured or strategic treatment interruptions, and structured intermittent therapy. The overall premise of these strategies was similar: stop all antiretrovirals and allow the patient time off medication. Reinitiation of therapy was intended to reestablish control of viral replication, as wild-type virus would be expected to predominate, although the resistant virus is likely archived in long-lived cells. A landmark clinical trial tested the hypothesis that episodic ART guided by the CD4 count would lower morbidity and mortality, including that associated with drug toxicity compared with continuous therapy.81 However, the patients randomized to episodic therapy (drug-sparing) experienced significantly increased risk of opportunistic disease or death from any cause, including non-AIDS causes.82 Most morbidity and mortality were consequences of lowering the CD4 count and increasing the viral load, but increased drug-related toxicity was also observed. This and other studies have established that viral replication is damaging to the immune system and end organs and drug-sparing approaches are generally not advocated. Finally, it is important to consider the implications of stopping all drugs simultaneously for regimens containing drugs with short half-lives (e.g., zidovudine) as well as drugs with long half-lives (e.g., efavirenz and nevirapine). The result may be functional monotherapy for the drug with the longest half-life once the shorter half-life drugs are cleared, which can lead to resistance mutations especially for drugs with low genetic barriers (e.g., NNRTIs).83 At this time, the optimal time sequence for staggered component discontinuation has not been determined.
There is a compelling theoretical rationale for therapeutic drug monitoring in the experienced patient, but this approach is currently controversial. Drug susceptibility is founded on the premise that increasing drug concentration corresponds with stronger inhibition of replication up to a maximal effectiveness. This principle holds for drug-resistant variants, except higher drug concentrations are needed for the same levels of inhibition. Therefore, drug concentration monitoring could guide dose adjustments needed to attain the higher target drug concentrations required for optimal viral inhibition. Currently, therapeutic drug monitoring is suggested as a consideration for patients with multidrug-resistant HIV as well as in other select clinical situations. However, limitations to therapeutic drug monitoring include the lack of established target concentrations, intrapatient pharmacokinetic variability, lack of randomized clinical trials proving benefit or cost effectiveness, and few analytical laboratories and experts available for interpretation. Most antiretrovirals are not suitably formulated for minor dose adjustments.
COMPLICATIONS OF HIV INFECTION AND AIDS
In the pre-ART era, the major therapeutic focus was prevention and treatment of OIs associated with uncontrolled HIV replication and a steady decline in CD4 cells.43 Uncontrolled HIV is an insidious disease; persons infected often present with OIs, a consequence of the weakened immune system rather than HIV per se. Most OIs are caused by organisms that are common in the environment and often represent the reactivation of quiescent, hidden infections common in the population. The probability of developing specific OIs is closely related to CD4 count thresholds (Fig. 103-2). These CD4 thresholds serve as a basis for initiating primary OI chemoprevention.
FIGURE 103-2 Natural history of opportunistic infections associatbed with human immunodeficiency virus infection. (Reprinted with permission, © Courtney V. Fletcher, 2009.)
In the ART era, the main principle in the management of OIs is treating HIV infection to enable CD4 cell recovery and maintenance above safe levels.58 Additional important principles regarding management of OIs are as follows:
1. Prevent exposure to opportunistic pathogens
2. Vaccinations to prevent first-episode disease (consult HIV-specific guidelines)
3. Primary chemoprophylaxis at certain CD4 thresholds to prevent first-episode disease
4. Treat emergent OI
5. Secondary chemoprophylaxis to prevent disease recurrence
6. Discontinuation of certain prophylaxes with sustained ART-associated immune recovery
Several considerations are required for the patient who presents with an OI and is simultaneously diagnosed with HIV and who thus needs both OI and ART treatment.58 Immediate initiation of ART is indicated for OIs that respond to CD4 recovery, such as cryptosporidiosis, progressive multifocal leukoencephalopathy, and Kaposi’s sarcoma. However, for other OIs such as cryptococcal meningitis, tuberculosis, Mycobacterium avium complex (MAC), and PCP, several potential problems complicate the timing of when to initiate ART relative to OI therapy. First, drug–drug interactions and the complexity of adhering to concomitant regimens can be daunting. Second, potentially overlapping drug toxicities can limit the options for clinicians trying to stop specific drugs thought to be eliciting the toxicity event. Third, an immune reconstitution syndrome (IRIS) has been associated with initiation of ART in the presence of underlying OIs. IRIS is generally characterized by fever and worsening of OI manifestations in the first few months after ART, and the reaction may take weeks to months to resolve.58,84 Risk factors for IRIS are a low CD4 count, a rapid virologic response to ART, and a high antigenic burden.85 An ART-associated rapid-onset immune reconstitution against the smoldering OI infection is thought to be the mechanism of IRIS. Treatment of IRIS is supportive, but may also include interruption of ART or antiinflammatory drugs.84,85
The AIDS Clinical Trials A5164 study compared immediate versus deferred ART in subjects treated for an acute OI (63% PCP, 12% Cryptococcal meningitis, and 12% bacterial infections). Subjects had advanced HIV infection with an average CD4 count of 29 cells/mm3 (29 × 106/L) and viral load >100,000 copies/mL (>100 × 106/L). Subjects with tuberculosis were excluded. The immediate ART arm (N = 141) initiated ART within 12 days after OI treatment was started versus within 45 days for the deferred ART arm (N = 141). The rate of AIDS progression or death was significantly greater in the deferred ART arm compared with early ART arm (14% vs. 24%).86 Other studies have demonstrated similar mortality improvements when initiating ART within 2 weeks of tuberculosis therapy compared with delaying ART by 8 to 12 weeks, particularly in those with low CD4 cell counts.87–89 However, early ART in patients with cryptococcal meningitis may increase mortality risk compared with beginning ART after the completion of antifungal therapy.90,91 Expert consultation should be used in the management of ART initiation in patients with OIs.
The three major OIs (PCP, MAC, and cytomegalovirus retinitis) all have decreased substantially in incidence with the advent of ART.43,58 Furthermore, primary and secondary chemoprophylaxes for OIs have contributed to the same decreases. Nevertheless, opportunistic diseases continue to be complications of HIV disease and occur at low CD4 lymphocyte counts in patients who are unaware of their HIV infection, or who have not responded to ART therapy or OI prophylaxis because of adherence issues or inadequate engagement with the healthcare system.58
The spectrum of OIs observed in HIV-infected individuals and recommended first-line regimens for treatment are given in Table 103-6. Recommended therapies for primary prophylaxis are given in Table 103-7.58 These lists of recommendations are not as extensive as in the published guidelines, which include multiple additional alternatives and cover other less common OIs.58 The following brief discussion of PCP provides an overview of the epidemiology, diagnosis, clinical manifestations, and results of treatment and serves as an illustration for the principles discussed earlier.
TABLE 103-6 Therapies for Common Opportunistic Pathogens in HIV-Infected Individuals
TABLE 103-7 Therapies for Prophylaxis of Select First-Episode Opportunistic Diseases in Adults and Adolescents
Pneumocystis Jirovecii Pneumonia
Pneumocystis jirovecii (carinii) pneumonia (PCP) has been and continues to be the most common life-threatening OI in patients with AIDS.92 P. jirovecii was formerly named P. carinii; the name change was made to distinguish the organism that infects humans (P. jirovecii) from the strain that infects rodents (P. carinii). The acronym PCP is still used today. Early in the AIDS epidemic 80% of patients experienced PCP at some point during their lifetime.58,93 Although the incidence of PCP has fallen substantially since the advent of ART and effective prophylaxis for PCP, it still occurs in persons unaware of their HIV infection, and breakthrough PCP can occur in those with variable adherence to ART and/or prophylaxis.58
P. jirovecii is a fungus that has protozoan characteristics as well.92,93 Exposure to P. jirovecii is widespread; two thirds of the population have developed serum antibodies by age 2 to 4 years.58 The organism appears to reside without consequence in humans unless the host becomes immunologically impaired.94 Disease associated with immunosuppression probably occurs from both new acquisition and reactivation. Ninety percent of PCP cases in AIDS patients occurred in those with CD4 counts less than 200 cells/mm3 (200 × 106/L).58 Other risk factors include oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and high plasma HIV RNA. Past episodes of PCP increase risk for future episodes, which provides the basis for secondary chemoprophylaxis, as described below.58
The presentation of PCP in AIDS often is insidious.58,92 Characteristic symptoms include fever and dyspnea. Clinical signs are tachypnea with or without rales or rhonchi and a nonproductive or mildly productive cough occurring over a period of weeks, although more fulminant presentations can occur. Chest radiographs may show florid or subtle infiltrates but occasionally are normal. Infiltrates usually are interstitial and bilateral, however. Arterial blood gases may show minimal hypoxia (PaO2 80 to 95 mm Hg [10.6 to 12.6 kPa]) but in more advanced disease may be markedly abnormal. The diagnosis of PCP usually is made by identification of the organism in induced sputum or in specimens obtained from bronchoalveolar lavage. Less commonly, transbronchial or open lung biopsy is used to locate the organism. Diagnostic PCR tests are available in some institutions.92
Untreated PCP has a mortality rate of nearly 100%. Several potential treatments are available for PCP, but the treatment of choice is trimethoprim–sulfamethoxazole (or cotrimoxazole), which is associated with a response rate of 60% to 100%.58 Parenteral pentamidine is equally efficacious but significantly more toxic. Trimethoprim–sulfamethoxazole is also the regimen of choice for primary and secondary prophylaxis of PCP in patients with and without HIV.58,92
When used for treatment of PCP, the dose of trimethoprim–sulfamethoxazole is 15 to 20 mg/kg/day (based on the trimethoprim component) as three to four divided doses.58,92 Treatment duration typically is 21 days but also must be based on clinical response. Trimethoprim–sulfamethoxazole usually is initiated by the IV route, although oral therapy may suffice in mildly ill and reliable outpatients or for completion of a course of therapy after a response has been achieved with IV administration. Patients with moderate-to-severe PCP should be treated with corticosteroids as soon as possible after starting PCP therapy and certainly within 72 hours, in order to blunt the deterioration seen just after initiation of PCP therapy. Alternative regimens include pentamidine for moderate-to-severe disease and dapsone with trimethoprim, primaquine with clindamycin, and atovaquone for mild-to-moderate PCP.58 Early initiation of ART is also generally recommended as long as there are no contraindications.86
Adverse reactions to trimethoprim–sulfamethoxazole and pentamidine are common, occurring in 20% to 85% of patients in this setting.58 The more common adverse reactions seen with trimethoprim–sulfamethoxazole are rash (rarely including Stevens–Johnson syndrome), fever, leukopenia, elevated serum transaminase levels, and thrombocytopenia. The incidence of these adverse reactions is higher in HIV-infected individuals than in those not infected with HIV. Mild rashes should be watched closely for progression to more severe reactions but are not an absolute contraindication to continuing therapy.58This highlights the need for thoughtful consideration of ART components because of overlapping toxicities with some antiretrovirals such as abacavir and nevirapine, which also are associated with rash and hypersensitivity, including life-threatening cases. For pentamidine, side effects are pronounced and include hypotension, tachycardia, nausea, vomiting, severe hypoglycemia or hyperglycemia, pancreatitis, irreversible diabetes mellitus, elevated serum transaminase levels, nephrotoxicity, leukopenia, and cardiac arrhythmias. Some of these reactions appear to be related to the infusion rate (e.g., hypotension and tachycardia) and can be minimized by infusing pentamidine over 1 hour or more.93 Dosage modification or pharmacokinetic monitoring can reduce the toxicity of both pentamidine and trimethoprim–sulfamethoxazole.95 Dose reduction of pentamidine from 4 to 3 mg/kg/day appears to be successful in minimizing further rises in serum creatinine levels.93 Maintenance of serum trimethoprim concentrations between 5 and 8 mcg/mL (mg/L; 17 to 28 μmol/L) may help to prevent severe myelosuppression.95 Early addition of adjunctive corticosteroid therapy to anti-PCP regimens decreases the risk of respiratory failure and improves survival in patients with AIDS and moderate-to-severe PCP (PaO2 ≤70 mm Hg [≤ 9.3 kPa] or alveolar–arterial gradient ≥35 mm Hg [≥ 4.7 kPa]).58,92 The adverse effects associated with corticosteroid therapy in these patients were minimal, primarily an increased incidence of herpetic lesions, although some concerns exist about the potential for reactivation of tuberculosis or cytomegalovirus and/or long-term effects on bones.93,96
Prevention of PCP is clearly a preferable treatment strategy. Primary prophylaxis is recommended for any HIV-infected person who has a CD4 lymphocyte count less than 200 cells/mm3 (200 × 106/L) (or CD4 percentage of total lymphocytes <14%) or a history of oropharyngeal candidiasis.58,92 Secondary PCP prophylaxis is recommended for all HIV-infected individuals who have had a previous episode of PCP.
Trimethoprim–sulfamethoxazole is the most effective and least expensive agent and is the preferred therapy for both primary and secondary prophylaxis of PCP in adults and adolescents.58,92 It also appears to confer cross-protection against toxoplasmosis and many bacterial infections. The recommended dose in adults and adolescents is one double-strength tablet daily, although other regimens, such as one double-strength tablet thrice weekly or one single-strength tablet daily and gradual dose escalation using liquid trimethoprim–sulfamethoxazole, have been used in an attempt to reduce the incidence of adverse reactions and improve compliance. Alternative prophylactic regimens are available if trimethoprim–sulfamethoxazole cannot be tolerated.
In the ART era, the profound reduction in HIV replication and restoration in CD4 cell count to levels rarely associated with the development of OIs provides a basis for the discontinuation of primary and secondary prophylaxis.58For PCP, primary prophylaxis should be discontinued in patients receiving and responding to ART who have a CD4 cell count greater than 200 cells/mm3 (200 × 106/L) sustained for at least 3 months, but should be reinstated if the CD4 count drops to less than 200 cells/mm3 (200 × 106/L). The same criteria apply for both discontinuation and reinitiation of secondary prophylaxis of PCP. However, continued secondary prophylaxis should be considered when the original PCP episode occurred at a CD4 count greater than 200 cells/mm3 (200 × 106/L).58
In summary, comprehensive recommendations are available for management of PCP and other OIs in the context of HIV infection including prevention and treatment.58 Readers are advised that data continue to emerge on new OI therapies, the safety of stopping primary and secondary prophylaxis, as well as criteria for when to restart secondary prophylaxes. The most current guidelines always should be consulted. Similar OI guidelines have been developed and are updated regularly that are specific to children.41
Complications in the ART Era
As with any medication, adverse reactions occur with antiretroviral agents that can range from life-threatening to minor intolerances. Characteristic side effects for each antiretroviral agent are listed in Table 103-5. A comprehensive discussion of all the adverse effects during ART is beyond the scope of this chapter, but can be found in various other sources.30,51,52 The purpose of this section is to highlight certain medical issues that have emerged in the ART era as HIV-infected patients live longer and are exposed to antiretroviral drugs for many years.
A broad spectrum of complications usually associated with aging appear to occur earlier in HIV-infected patients in the ART era.82,97 These complications include osteoporosis and osteopenia, renal insufficiency, metabolic syndrome, neurocognitive decline, atherosclerotic disease, frailty, and malignancy. The cause of the early manifestation of these complications is not entirely clear, but evidence suggests that immune-damage or dysregulation (e.g., a state of persistent heightened cellular activation) and ongoing viral replication play a role, as well as adverse events from antiretroviral medications.82,96
While contemporary ART has reduced the incidence of some HIV-related cancers such as Kaposi’s sarcoma and non-Hodgkin’s lymphoma, other non-AIDS-related malignancies plague HIV-infected individuals at significantly elevated rates such as Hodgkin’s lymphoma and anal, lung, skin, and hepato-carcinoma.98 Part, but not all, of this increased risk in HIV-infected patients may be attributed to elevated exposures to human papillomavirus (anal cancer), smoking (lung carcinoma), and chronic hepatitis B and/or C coinfection (liver cancer). Some concern has been raised that antiretroviral drugs may contribute directly to these increased cancer rates, as some agents have caused cancers in laboratory animals as well as genotoxicity in vitro.16 However, studies have shown similar cancer rates in organ transplant recipients with medication-induced immunosuppression, which suggests that it is the impairment to the immune system associated with HIV-infection that is driving much of these higher cancer rates.99 While the approach to treatment of AIDS-related malignancies in HIV-infected patients is similar to that in non-HIV-infected patients, treatment is complicated by drug–drug interactions that may exist between the antiretrovirals and the oncolytics.98
Antiretroviral drugs may contribute to several complications. Tenofovir has been associated with renal proximal tubulopathy (including rare cases of Fanconi’s syndrome and renal failure) as well as osteopenia.100 PIs and zidovudine–lamivudine have also been associated with osteopenia, although the precise mechanism for these effects is not clear.101,102 Relationships exist between PIs, efavirenz, and the thymidine analog NRTIs and dyslipidemia (increased triglycerides and low-density lipoproteins [LDL] and decreased high-density lipoproteins [HDL]), abnormal glucose homeostasis (insulin resistance and impaired glucose tolerance), body fat abnormalities (lipoatrophy of the face and extremities and central lipoaccumulation), and lactic acidosis with hepatosteatosis (all the NRTIs).103,104 These metabolic abnormalities may occur in combination. Notably, some of the same abnormalities are also associated with the HIV infection itself, such as hypertriglyceridemia and insulin resistance.103 Distinguishing the contribution of disease versus drug and ascertaining whether one abnormality precipitates the development of other abnormalities is difficult.97,104,105 Various mechanistic hypotheses have been put forward, including NRTI-induced mitochondrial toxicity, and PI/NNRTI interactions with various cellular processes, such as glucose uptake, altered apolipoprotein degradation or synthesis, adipocyte differentiation, and lipolysis.103,105 Some agents within these classes are less associated with these complications including atazanavir for the PIs, nevirapine for NNRTIs, and lamivudine, emtricitabine, tenofovir, and abacavir for the NRTIs.103 Early evidence also suggests that raltegravir and maraviroc are less associated with metabolic complications as well.73,106
Metabolic complications create several challenges and concerns. First, the metabolic abnormalities may increase the risk of adverse cardiovascular events, and some evidence gives credence to this concern.107A large observational prospective cohort study of 23,468 HIV-infected patients applied the Framingham cardiovascular risk algorithm and compared the estimated cardiovascular event rate with the actual event rate.108 The algorithm takes into account known risk factors, many of which are associated with ART, such as diabetes and dyslipidemia as well as sex, age, smoking, and blood pressure. The estimated event rate paralleled the actual event rate, and both increased with years on ART. This finding suggests that increased cardiovascular risk can be explained by conventional risk factors, which are aggravated by ART. Therefore, the metabolic abnormalities precipitated by ART and HIV should be treated as cardiovascular disease risk factors and may warrant medical intervention. Finally, some observational studies have found an association between myocardial infarction and abacavir and didanosine use.107,109However, these associations for abacavir have not been duplicated when evaluating data from randomized controlled trials, indicating the need for additional study.110
A second concern and challenge is how to manage the changes in body fat distribution.111 Preferred agents such as tenofovir, emtricitabine, efavirenz, darunavir, atazanavir, and raltegravir are less associated with lipoatrophy compared with older agents such as stavudine, zidovudine, and indinavir. However, all therapies appear to be associated with visceral abdominal adiposity.111 Controlled trials of antiretroviral substitution have demonstrated that patients randomized to switch away from stavudine to either abacavir or tenofovir have had small gains in subcutaneous fat.112 Small controlled studies have demonstrated modest but inconsistent gains in subcutaneous fat with thiazolidinedione therapy.113 Central fat accumulation is difficult to treat. Lifestyle changes, such as reducing calorie intake and increasing aerobic exercise, should be the first-line approach. Metformin reduces central fat accumulation, but lean body mass and subcutaneous fat may exhibit unwanted declines.113 Tesamorelin, a growth hormone releasing analog was approved to safely reduce central adiposity, although a drawback is that visceral fat returns within months of discontinuation.111 Unfortunately, both lipoatrophy and fat accumulation eventually may lead to reconstructive surgery strategies in severe or refractory cases. The best management of body fat changes is prevention through initiation of preferred regimens less likely to cause such changes (see current recommendations for initial therapy).30
ART-associated hyperlipidemia can create several therapeutic challenges. Antiretroviral substitution studies have shown lipid improvements after switching away from older PIs to either NNRTIs or atazanavir, but direct pharmacologic intervention may be required.113 Elevated LDL may respond to β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy. However, serious concerns exist regarding drug–drug interactions between PIs and statins, especially for lovastatin and simvastatin.30,113 The plasma area under the concentration–time curve of these statins can be increased >10-fold and may increase the risk for rhabdomyolysis. Generally, fluvastatin, pitavistatin, and pravastatin are recommended as alternatives. Atorvastatin or rosuvastatin should be used with caution30 including initiation with low doses with careful monitoring. Other HIV-specific recommendations exist for lifestyle modifications, and the use of fibrates, niacin, and/or fish oil for isolated hypertriglyceridemia.111 Current guidelines should always be consulted, as new information regarding the special concerns and challenges associated with HIV lipodystrophy continue to accrue.
Many HIV-infected patients are coinfected with hepatitis C (HCV), which poses another challenge in the ART-era. HIV–HCV coinfection is common because of the shared blood–borne route of transmission.114,115Approximately 30% of HIV-infected patients in the United States have HIV–HCV (approximately 300,000 individuals). Up to 90% of injection–drug users and 90% of hemophiliacs with HIV are coinfected with HCV.114 HIV worsens the prognosis of HCV by reducing the chance of HCV clearance and accelerating HCV progression. After acute HCV infection, approximately 20% of patients without HIV will clear HCV compared with only 5% to 10% of those who also have HIV. With chronic HCV infection, progression to fibrosis, cirrhosis, and liver failure is several-fold faster in HIV–HCV patients versus HCV-monoinfected patients.115 For these reasons, ART is recommended for HIV–HCV coinfected patients.
A challenge in HIV–HCV patients is the potential for liver toxicity to ART. Coinfected patients have several-fold higher risk of ART-associated transaminase elevations versus patients infected with HIV but not HCV.114,115Nevirapine and full-dose ritonavir appear to carry the highest risk of transaminase elevations, whereas stavudine has been linked with steatosis. Ritonavir-boosted PIs generally do not carry the same elevated risk as full-dose ritonavir with the exception of tipranavir–ritonavir, which is associated with risk of clinical hepatitis and hepatic decompensation in those with HCV or hepatitis B infections. Stavudine and didanosine are generally not recommended in combination with HCV therapy owing to risk of mitochondrial toxicity including noncirrhotic portal hypertension for didanosine.114,115 Other than these examples, the general threat of major liver toxicity is low overall, and this concern should not dissuade the use of ART in HIV–HCV-coinfected persons given the known benefits of therapy.30,114,115
HCV therapy should be offered to HIV–HCV coinfected patients according to HCV guidelines, although beginning when CD4 cell counts are above 200 cells/mm3 (200 × 106/L) is preferable. A significant consideration is potential drug–drug interactions between ART and HCV therapies. In addition to the considerations listed above, severe anemia is possible when zidovudine is used with ribavirin and interferon.114,115 This appears to be a pharmacodynamic interaction, as zidovudine reduces red blood cell output and ribavirin causes hemolysis. Zidovudine should be avoided when possible.114,115Concomitant HCV PIs, boceprevir or telaprevir, with HIV PIs results in a bi-way interaction resulting in reduced concentrations of both drug classes. These interactions were not predicted based on the known pharmacology of these drugs, underscoring the need to study drug–drug interactions prospectively. Drug interactions were not observed between boceprevir or telaprevir with raltegravir, suggesting that raltegravir-based therapy may be a good choice for concomitant therapy. It is likely that the list of drug–drug interactions among HIV and HCV medications will grow as more HCV therapies become available underscoring the importance for consulting the most current literature when managing HIV–HCV coinfection.
A great number of considerations go into choosing the optimal drug regimen for a given patient. A resistance test is generally recommended when the patient enters HIV care, as resistant virus is transmitted in 6% to 16% of new infections. Resistance results should help guide therapy. Other considerations include avoidance of PIs in patients taking contraindicated concomitant medications such as rifampin (efavirenz would be an alternative), avoidance of tenofovir in patients with preexisting renal dysfunction (abacavir would be an alternative), and avoidance of efavirenz in women of childbearing age trying to conceive or not using stable and reliable contraception (PIs would be an alternative). Several once-daily fixed-dose combination formulations are available, which enhances convenience by minimizing the number of tablets or capsules required per dose. Many antiretroviral regimens have important requirements for dosing relative to a meal to optimize absorption.30 Several factors contribute to whether the patient will mount a durable response to initial therapy, including adherence, pharmacologic effectiveness, and convenience/tolerability.
This work was supported by Grants UO1 AI84735 and AI68636, R01AI093319, and PO1 AI074340 from the National Institute of Allergy and Infectious Disease.
Thomas Kakuda is an employee of Janssen Pharmaceuticals, LLC, a Johnson & Johnson company and a stock holder of Johnson & Johnson.
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