Harrisons Manual of Medicine, 18th Ed.

CHAPTER 114. HIV Infection and AIDS

DEFINITION

AIDS was originally defined empirically by the Centers for Disease Control and Prevention (CDC) as “the presence of a reliably diagnosed disease that is at least moderately indicative of an underlying defect in cell-mediated immunity.” Following the recognition of the causative virus, HIV, and the development of sensitive and specific tests for HIV infection, the definition of AIDS has undergone substantial revision. The current surveillance definition categorizes HIV-infected persons on the basis of clinical conditions associated with HIV infection and CD4+ T lymphocyte counts (Tables 189-1, and 189-2, pp. 1506 and 1507, in HPIM-18). From a practical standpoint, the clinician should view HIV disease as a spectrum of disorders ranging from primary infection, with or without the acute HIV syndrome, to the asymptomatic infected state, to advanced disease.

ETIOLOGY AND TRANSMISSION

AIDS is caused by infection with the human retroviruses HIV-1 or -2. HIV-1 is the most common cause worldwide. These viruses are passed through sexual contact; through transfusion of contaminated blood or blood products; through sharing of contaminated needles and syringes among injection drug users; intrapartum or perinatally from mother to infant; or via breast milk. There is no evidence that the virus can be passed through casual or family contact or by insects such as mosquitoes. There is a definite, though small, occupational risk of infection for health care workers and laboratory personnel who work with HIV-infected specimens. The risk of transmission of HIV from an infected health care worker to his or her pts through invasive procedures is extremely low.

EPIDEMIOLOGY

As of January 1, 2010, an estimated 1,108,611 cumulative cases of AIDS had been diagnosed in the United States; there have been approximately 600,000 deaths due to AIDS. However, the death rate from AIDS has decreased substantially in the past 10 years primarily due to the increased use of potent antiretroviral drugs. As of January 1, 2010, an estimated 1.1 million HIV-infected persons were living in the United States; approximately 21% of these individuals are unaware that they are infected. An estimated 56,000 individuals are newly infected each year in the United States; this figure has remained stable for at least 15 years (Fig. 189-12, p. 1518, in HPIM-18). Among adults and adolescents newly diagnosed with HIV infection in 2009, ~76% were men and ~24% were women. Of new HIV/AIDS diagnoses among men, ~75% were due to male-to-male sexual contact, ~14% to heterosexual contact, and ~8% to injection drug use. Among women, ~85% were due to heterosexual contact and ~15% to injection drug use (Figs. 189-13 and 189-14, p. 1519, in HPIM-18). HIV infection/AIDS is a global pandemic, especially in developing countries. At the end of 2009, the estimated number of cases of HIV infection worldwide was ~33.3 million, two-thirds of which were in sub-Saharan Africa; ~50% of cases were in women and 2.5 million were in children. In 2009 there were 2.6 million new HIV infections worldwide and 1.8 million deaths (Fig. 189-10, p. 1517, in HPIM-18).

PATHOPHYSIOLOGY AND IMMUNOPATHOGENESIS

The hallmark of HIV disease is a profound immunodeficiency resulting from a progressive quantitative and qualitative deficiency of the subset of T lymphocytes referred to as helper T cells. This subset of T cells is defined phenotypically by the expression on the cell surface of the CD4 molecule, which serves as the primary cellular receptor for HIV. A co-receptor must be present with CD4 for efficient entry of HIV-1 into target cells. The two major co-receptors for HIV-1 are the chemokine receptors CCR5 and CXCR4. The CD4+ T lymphocyte and CD4+ monocyte lineage are the principal cellular targets of HIV.

Primary Infection

Following initial transmission, the virus infects CD4+ cells, probably T lymphocytes, monocytes, or bone marrow–derived dendritic cells. Both during this initial stage and later in infection, the lymphoid system is a major site for the establishment and propagation of HIV infection. The gut-associated lymphoid tissue (GALT) plays a major role in the establishment of infection and in the early depletion of memory CD4+ T cells.

Essentially all pts undergo a viremic stage during primary infection; in some pts this is associated with the “acute retroviral syndrome,” a mononucleosis-like illness (see below). This phase is important in disseminating virus to lymphoid and other organs throughout the body, and it is ultimately contained partially by the development of an HIV-specific immune response.

Establishment of Chronic and Persistent Infection

Despite the robust immune response that is mounted following primary infection, the virus is not cleared from the body. Instead, a chronic infection develops that persists for a median time of 10 years before the untreated pt becomes clinically ill. During this period of what appears to be clinical latency, the number of CD4+ T cells gradually declines, but few, if any, clinical signs and symptoms may be evident. However, active viral replication can almost always be detected by measurable plasma viremia and the demonstration of virus replication in lymphoid tissue. The level of steady-state viremia (referred to as the viral set point) at ~6 months to 1 year post-infection has important prognostic implications for the progression of HIV disease; individuals with a low viral set point at 6 months to 1 year after infection progress to AIDS more slowly than do those whose set point is very high at this time (Fig. 189-22, p. 1524, in HPIM-18).

Advanced HIV Disease

In untreated pts or in pts in whom therapy has not controlled viral replication (see below), after some period of time (often years), CD4+ T cell counts will fall below a critical level (~200/μL) and pts become highly susceptible to opportunistic disease. The presence of a CD4+ T cell count of <200/μL or an AIDS-defining opportunistic disease establishes a diagnosis of AIDS. Control of plasma viremia by effective antiretroviral therapy, particularly maintaining the plasma viral load consistently at <50 copies of RNA per mL, even in individuals with low CD4+ T cell counts, has dramatically increased survival in these pts, including those whose CD4+ T cell counts may not increase significantly as a result of therapy.

IMMUNE ABNORMALITIES IN HIV DISEASE

A broad range of immune abnormalities has been documented in HIV-infected pts, resulting in varying degrees of immunodeficiency. These include both quantitative and qualitative defects in lymphocytes, and qualitative defects in monocyte/macrophage and natural killer (NK) cell function. Autoimmune phenomena also have been observed in HIV-infected individuals.

IMMUNE RESPONSE TO HIV INFECTION

Both humoral and cellular immune responses to HIV develop soon after primary infection (see summary in Table 189-6, p. 1535, and Fig. 189-26, p. 1536, in HPIM-18). Humoral responses include antibodies with HIV binding and neutralizing activity, as well as antibodies participating in antibody-dependent cellular cytotoxicity (ADCC). Cellular immune responses include the generation of HIV-specific CD4+ and CD8+ T lymphocytes, as well as NK cells and mononuclear cells mediating ADCC. CD8+ T lymphocytes may also suppress HIV replication in a noncytolytic, non-MHC-restricted manner. This effect is mediated by soluble factors such as the CC-chemokines RANTES, MIP-1α, and MIP-1β. For the most part, the natural immune response to HIV is not adequate. Broadly reacting neutralizing antibodies against HIV are not easily generated in infected individuals, and eradication of the virus from infected individuals by naturally occurring immune responses has not been reported.

DIAGNOSIS OF HIV INFECTION

Laboratory diagnosis of HIV infection depends on the demonstration of anti-HIV antibodies and/or the detection of HIV or one of its components.

The standard screening test for HIV infection is the detection of anti-HIV antibodies using an enzyme immunoassay (EIA). This test is highly sensitive (>99.5%) and is quite specific. Most commercial EIA kits are able to detect antibodies to both HIV-1 and -2. Western blot is the most commonly used confirmatory test and detects antibodies to HIV antigens of specific molecular weights. Antibodies to HIV begin to appear within 2 weeks of infection, and the period of time between initial infection and the development of detectable antibodies is rarely >3 months. The HIV p24 antigen can be measured using an EIA-type capture assay. Plasma p24 antigen levels rise during the first few weeks following infection, prior to the appearance of anti-HIV antibodies. A guideline for the use of these serologic tests in the diagnosis of HIV infection is depicted in Fig. 114-1.

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FIGURE 114-1 Algorithm for the use of serologic tests in the diagnosis of HIV-1 or HIV-2 infection. *Stable indeterminate Western blot 4–6 weeks later makes HIV infection unlikely. However, it should be repeated twice at 3-month intervals to rule out HIV infection. Alternatively, one may test for HIV-1 p24 antigen or HIV RNA. EIA, enzyme immunoassay.

HIV can be cultured directly from tissue, peripheral blood cells, or plasma, but this is most commonly done in a research setting. HIV genetic material can be detected using reverse transcriptase PCR (RT-PCR), branched DNA (bDNA), or nucleic acid sequence–based assay (NASBA). These tests are useful in pts with a positive or indeterminate EIA and an indeterminate Western blot. They turn positive early in infection and will usually be positive in pts in whom serologic testing may be unreliable (such as those with hypogammaglobulinemia).

LABORATORY MONITORING OF PTS WITH HIV INFECTION

Measurement of the CD4+ T cell count and level of plasma HIV RNA are important parts of the routine evaluation and monitoring of HIV-infected individuals. The CD4+ T cell count is a generally accepted indicator of the immunologic competence of the pt with HIV infection, and there is a close relationship between the CD4+ T cell count and the clinical manifestations of AIDS (Fig. 189-32, p. 1541, in HPIM-18). Pts with CD4+ T cell counts <200/μL are at higher risk of infection with Pneumocystis jiroveci. Once the count declines to <50/μL, pts are also at higher risk for developing CMV disease and infection with Mycobacterium avium intracellulare. Pts should have their CD4+ T cell count measured at the time of diagnosis and every 3–6 months thereafter. (Measurements may be done more frequently in pts with declining counts.) According to DHHS practice guidelines, a CD4+ T cell count <500/μL is a clear indication to initiate antiretroviral therapy. While the CD4+ T cell count provides information on the current immunologic status of the pt, the HIV RNA level predicts what will happen to the CD4+ T cell count in the near future. Measurements of plasma HIV RNA levels should be made at the time of HIV diagnosis and every 3–4 months thereafter in the untreated pt. Measurement of plasma HIV RNA is also useful in making therapeutic decisions about antiretroviral therapy (see below). Following the initiation of therapy or any change in therapy, HIV RNA levels should be monitored approximately every 4 weeks until the effectiveness of the therapeutic regimen is determined by the development of a new steady-state level of HIV RNA. During therapy, levels of HIV RNA should be monitored every 3–6 months to evaluate the continuing effectiveness of therapy.

The sensitivity of an individual’s HIV virus(es) to different antiretroviral agents can be tested by either genotypic or phenotypic assays. In the hands of experts, the use of resistance testing to select a new antiretroviral regimen in pts failing their current regimen leads to a ~0.5-log greater decline in viral load compared with the efficacy of regimens selected solely on the basis of drug history. HIV resistance testing may also be of value in selecting an initial treatment regimen in geographic areas with a high prevalence of baseline resistance.

CLINICAL MANIFESTATIONS OF HIV INFECTION

A complete discussion is beyond the scope of this chapter. The major clinical features of the various stages of HIV infection are summarized below (see also Chap. 189, HPIM-18).

Acute HIV (Retroviral) Syndrome

Approximately 50–70% of infected individuals experience an acute syndrome following primary infection. The acute syndrome follows infection by 3–6 weeks. It can have multiple clinical features (Table 114-1), lasts 1–2 weeks, and resolves spontaneously as an immune response to HIV develops and the viral load diminishes from its peak levels. Most pts will then enter a phase of clinical latency, although an occasional pt will experience rapidly progressive immunologic and clinical deterioration.

TABLE 114-1 CLINICAL FINDINGS IN THE ACUTE HIV SYNDROME

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Asymptomatic Infection

The length of time between HIV infection and development of disease in untreated individuals varies greatly, but the median is estimated to be 10 years. HIV disease with active viral replication usually progresses during this asymptomatic period, and CD4+ T cell counts fall. The rate of disease progression is directly correlated with plasma HIV RNA levels. Pts with high levels of HIV RNA progress to symptomatic disease faster than do those with low levels of HIV RNA.

Symptomatic Disease

Symptoms of HIV disease can develop at any time during the course of HIV infection. In general, the spectrum of illness changes as the CD4+ T cell count declines. The more severe and life-threatening complications of HIV infection occur in pts with CD4+ T cell counts <200/μL. Overall, the clinical spectrum of HIV disease is constantly changing as pts live longer and new and better approaches to treatment and prophylaxis of opportunistic infections are developed. In addition, a variety of neurologic, cardiovascular, renal, metabolic, and hepatic problems are increasingly seen in pts with HIV infection and may be a direct consequence of HIV infection. The key element to treating symptomatic complications of HIV disease, whether primary or secondary, is achieving good control of HIV replication through the use of combination antiretroviral therapy and instituting primary and secondary prophylaxis as indicated. Major clinical syndromes seen in the symptomatic stage of HIV infection are summarized below.

• Persistent generalized lymphadenopathy: Palpable adenopathy at two or more extrainguinal sites that persists for >3 months without explanation other than HIV infection. Many pts will go on to disease progression.

• Constitutional symptoms: Fever persisting for >1 month, involuntary weight loss of >10% of baseline, diarrhea for >1 month in absence of explainable cause.

• Neurologic disease: Most common is HIV-associated neurocognitive disease (HAND); other neurologic complications include opportunistic infections, primary CNS lymphoma, CNS Kaposi’s sarcoma, aseptic meningitis, myelopathy, peripheral neuropathy, and myopathy.

• Secondary infectious diseases: Common secondary infectious agents include P. jiroveci (pneumonia), CMV (chorioretinitis, colitis, pneumonitis, adrenalitis), Candida albicans (oral thrush, esophagitis), M. avium intracellulare(localized or disseminated infection), M. tuberculosis (pulmonary or disseminated), Cryptococcus neoformans (meningitis, disseminated disease), Toxoplasma gondii (encephalitis, intracerebral mass lesion), herpes simplex virus (severe mucocutaneous lesions, esophagitis), diarrhea due to Cryptosporidium spp. or Isospora belli (diarrhea), JC virus (progressive multifocal leukoencephalopathy), bacterial pathogens (pneumonia, sinusitis, skin).

• Secondary neoplasms: Kaposi’s sarcoma (cutaneous and visceral, more fulminant course than in non-HIV-infected pts), lymphoma (primarily B cell, may be CNS or systemic).

• Other diseases: A variety of organ-specific syndromes can be seen in HIV-infected pts, either as primary manifestations of the HIV infection or as complications of treatment. Diseases commonly associated with aging are also seen with an increased frequency in pts with HIV infection.

TREATMENT HIV Infection (See also Chap. 189, HPIM-18)

General principles of pt management include counseling, psychosocial support, and screening for infections and other conditions and require comprehensive knowledge of the disease processes associated with HIV infection.

ANTIRETROVIRAL THERAPY (SEE Table 114-2) The cornerstone of medical management of HIV infection is combination antiretroviral therapy, or cART. Suppression of HIV replication is an important component in prolonging life as well as in improving the quality of life of pts with HIV infection. However, several important questions related to the treatment of HIV disease lack definitive answers. Among them are questions regarding when antiretroviral therapy should be started, what the best cART regimen is, when a given regimen should be changed, and which drugs in a regimen should be changed when a change is made. The drugs that are currently licensed for the treatment of HIV infection are listed in Table 114-2. These drugs fall into four main categories: those that inhibit the viral reverse transcriptase enzyme, those that inhibit the viral protease enzyme, those that inhibit viral entry, and those that inhibit the viral integrase. There are numerous drug-drug interactions that must be taken into consideration when using these medications.

TABLE 114-2 ANTIRETROVIRAL DRUGS COMMONLY USED IN THE TREATMENT OF HIV INFECTION

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Nucleoside/Nucleotide Analogues These agents act by causing premature DNA-chain termination during the reverse transcription of viral RNA to proviral DNA and should be used in combination with other antiretroviral agents. The most common usage is together with another nucleoside/nucleotide analogue and a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor (see below).

Nonnucleoside Reverse Transcriptase Inhibitors These agents interfere with the function of HIV-1 reverse transcriptase by binding to regions outside the active site and causing conformational changes in the enzyme that render it inactive. These agents are very potent; however, when they are used as monotherapy, they result in the rapid emergence of drug-resistant mutants. Five members of this class, nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine are currently available for clinical use. These drugs are licensed for use in combination with other antiretrovirals.

Protease Inhibitors These drugs are potent and selective inhibitors of the HIV-1 protease enzyme and are active in the nanomolar range. Unfortunately, as in the case of the nonnucleoside reverse transcriptase inhibitors, this potency is accompanied by the rapid emergence of resistant isolates when these drugs are used as monotherapy. Thus, the protease inhibitors should be used only in combination with other antiretroviral drugs.

HIV Entry Inhibitors These agents act by interfering with the binding of HIV to its receptor or co-receptor or by interfering with the process of fusion. A variety of small molecules that bind to HIV-1 co-receptors are currently in clinical trials. The first drugs in this class to be licensed are the fusion inhibitor enfuvirtide and the entry inhibitor maraviroc.

HIV Integrase Inhibitors These drugs interfere with the integration of proviral DNA into the host cell genome. The first agent in this class, raltegravir, was approved in 2007 for use in treatment-experienced pts.

CHOICE OF ANTIRETROVIRAL TREATMENT STRATEGY The large number of available antiretroviral agents makes the subject of antiretroviral therapy one of the more complicated in the management of HIV-infected pts.

The principles of therapy for HIV infection have been articulated by a panel sponsored by the U.S. Department of Health and Human Services (Table 114-3). Treatment decisions must take into account the fact that one is dealing with a chronic infection and that complete eradication of HIV infection has not been achieved with currently available cART regimens. Thus, therapeutic decisions must take into account the balance between risks and benefits. At present a reasonable course of action is to initiate antiretroviral therapy in anyone with the acute HIV syndrome; pts with symptomatic disease; pts with evidence of renal disease; pts with asymptomatic infection and CD4+ counts <500/μL; and pts with hepatitis B infection when hepatitis B treatment is indicated, to avoid development of resistant strains of HIV. In addition, one may wish to administer a 4-week course of therapy to uninfected individuals immediately following a high-risk exposure to HIV (see below). Some experts favor treating all pts with HIV infection with cART while awaiting the results of randomized, controlled trials.

TABLE 114-3 PRINCIPLES OF THERAPY OF HIV INFECTION

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When the decision to initiate therapy is made, the physician must decide which drugs to use in the initial regimen. The two options for initial therapy most commonly in use today are (1) two nucleoside/nucleotide analogues (one of which is usually tenofovir or abacavir, and the other of which is usually lamivudine or emtricitabine) combined with a protease inhibitor; or (2) two nucleoside/nucleotide analogues and a nonnucleoside reverse transcriptase inhibitor. There are no clear data at present on which to base a distinction between these two approaches. Following the initiation of therapy, one should expect a 1-log (tenfold) reduction in plasma HIV RNA within 1–2 months; eventually a decline in plasma HIV RNA to <50 copies/mL; and a rise in CD4+ T cell count of 100–150/μL during the first year. Failure to achieve and maintain an HIV RNA level <50 copies/mL is an indication to consider a change in therapy. Other reasons for changing therapy are listed in Table 114-4. When changing therapy because of treatment failure, it is important to attempt to provide a regimen with at least two new drugs. In the pt in whom a change is made for reasons of drug toxicity, a simple replacement of one drug is reasonable.

TABLE 114-4 INDICATIONS FOR CHANGING ANTIRETROVIRAL THERAPY IN PTS WITH HIV INFECTIONa

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Treatment of Secondary Infections and Neoplasms Specific for each infection and neoplasm (see Chap. 189, in HPIM-18).

Prophylaxis against Secondary Infections

(See also Table 189-10, pp. 1544–1546, in HPIM-18)

Primary prophylaxis is clearly indicated for P. jiroveci pneumonia (especially when CD4+ T cell counts fall to <200 cells/μL), for M. avium complex infections in pts with CD4+ T cell counts <50 cells/μL, and for M. tuberculosisinfections in pts with a positive PPD or anergy if at high risk of TB. Vaccination with the influenza and pneumococcal polysaccharide vaccines is generally recommended for all pts and may need to be repeated in pts with CD4+ T cell counts <200/μL when their counts increase to >200/μL (Table 189-10, pp. 1544–1546, in HPIM-18). Secondary prophylaxis, when available, is indicated for virtually every infection experienced by HIV-infected pts until they have significant immunologic recovery.

HIV AND THE HEALTH CARE WORKER

There is a small but definite risk to health care workers of acquiring HIV infection via needle stick exposures, large mucosal surface exposures, or exposure of open wounds to HIV-infected secretions or blood products. The risk of HIV transmission after a skin puncture by an object contaminated with blood from a person with documented HIV infection is ~0.3%, compared with a 20–30% risk for hepatitis B infection from a similar incident. Postexposure prophylaxis appears to be effective in decreasing the likelihood of acquisition of infection through accidental exposure in the health care setting. In this regard, a U.S. Public Health Service working group has recommended that chemoprophylaxis be given as soon as possible after occupational exposure. While the precise regimen remains a subject of debate, the U.S. Public Health Service guidelines recommend (1) a combination of two nucleoside analogue reverse transcriptase inhibitors given for 4 weeks for routine exposures, or (2) a combination of two nucleoside analogue reverse transcriptase inhibitors plus a third drug given for 4 weeks for high-risk or otherwise complicated exposures. Most clinicians administer the latter regimen in all cases in which a decision to treat is made. Regardless of which regimen is used, treatment should be initiated as soon as possible after exposure.

Prevention of exposure is the best strategy and includes following universal precautions and proper handling of needles and other potentially contaminated objects.

Transmission of TB is another potential risk for all health care workers, including those dealing with HIV-infected pts. All workers should know their PPD status, which should be checked yearly.

VACCINES

A recent clinical trial conducted in Thailand demonstrated moderate (31% effective) protection against acquisition of HIV infection. However, this modest degree of efficacy does not justify deployment of the vaccine; active investigation continues in the pursuit of a safe and effective vaccine against HIV.

PREVENTION

Education, counseling, and behavior modification along with the consistent and correct use of condoms in risk situations remain the cornerstones of HIV prevention efforts. Avoidance of shared needle use by IDUs is critical. If possible, breast-feeding should be avoided by HIV-positive women, as the virus can be transmitted to infants via this route. In societies where withholding of breast-feeding is not feasible, treatment of the mother, if possible, greatly decreases the chances of transmission. Recent studies have demonstrated the important role of medically supervised adult male circumcision in the prevention of acquisition of heterosexually transmitted HIV infection. In addition, antiretroviral-containing vaginal gels, as well as pre-exposure prophylaxis in men who have sex with men and in heterosexual men and women practicing risk behavior, have proved to be effective means of prevention when the regimens are adhered to. Finally, treatment of the HIV-infected partner in heterosexual discordant couples has proved highly effective in preventing transmission of HIV to the uninfected partner.

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For a more detailed discussion, see Fauci AS, Lane HC: Human Immunodeficiency Virus Disease: AIDS and Related Disorders, Chap. 189, p. 1506, in HPIM-18.