HIV for the Primary Care Physician
PREVALENCE AND RISK FACTORS
At the end of 2005, an estimated 1,200,000 million persons in the United States were living with HIV, AIDS, or both, with approximately 25% of those unaware of their HIV infection.1 According to surveillance data at the end of 2004 obtained from the 35 areas that use name-based reporting, 73% of cases were in males. Almost 50% of infected persons were black non-Hispanic, despite representing only 14% of the U.S. population, 37% were white non-Hispanic, and almost 18% were Hispanic. Among infected men, 60% identified their risk behavior as men having sex with men (MSM), 19% reported a history of injection drug use (IDU), 7% admitted to both MSM and IDU, and 13% reported heterosexual contact as their route of HIV exposure. Of HIV-infected women, 71% identified heterosexual sex as their HIV exposure, and 27% had IDU as a risk factor. Once a predominant mode of transmission, receipt of blood products accounted for less than 2% of cases of HIV/AIDS.2
The magnitude of the global HIV/AIDS epidemic vastly exceeds that in the United States. As of the end of 2005, more than 38,600,000 people were estimated to be living with HIV/AIDS. In 2005, 4,100,000 people were newly infected with HIV and 2,800,00 deaths were estimated to have occurred from AIDS. Almost 75% of those with the disease are living in sub-Saharan Africa, where access to antiretroviral therapy is limited.1
PATHOPHYSIOLOGY AND NATURAL HISTORY
HIV infection was first described in 1981 when an epidemic of Pneumocystis jiroveci (formerly identified as Pneumocystis carinii) pneumonia (PCP) was noted in homosexual men.3 In 1984, HIV was identified as the causative agent of AIDS. Subsequently, two genetic types of HIV were identified. The predominant type worldwide is HIV type 1 (HIV-1). HIV-1 is further subdivided into subtypes (also called clades), designated A through K (collectively referred to as group M), N, and O. More than 98% of HIV-1 infections in the United States are caused by subtype B. HIV type 2 (HIV-2) is found in West Africa, particularly Guinea-Bissau, Gambia, and Senegal, as well as in France, Portugal, Angola, and Mozambique. Disease caused by HIV-2 appears to be less readily transmissible and results in slower disease progression than that caused by HIV-1.4
Most commonly, transmission of the virus occurs after a breach in the integument or mucous membranes. HIV infection occurs when the envelope subunit gp120 binds the human CD4+ T cell receptor found primarily on lymphocytes and monocyte-derived macrophages. In addition, binding also requires the presence on the host cell of the chemokine receptor CCR5 or CXCR4. The viral envelope then fuses with the host cell, allowing release of the viral core into the host cell. Viral DNA is synthesized by reverse transcriptase and incorporated into the host genome by the protein integrase. Once the viral gene products are transcribed and assembled, the HIV protease mediates packaging of new virions for release into serum to propagate the infection.5
Over time, infected persons have a progressive loss of CD4+ lymphocytes, although in the early stages of infection, this is not associated with increased immunosuppression. The rate of CD4 cell loss is variable and depends on viral and host factors. On average, infected persons lose 40 to 80 CD4 cells/mm3/year.6 A subset of patients progress rapidly; however, 5% of infected persons, known as long-term nonprogressors, will have little or no progression of clinical disease or decline in CD4+ counts over 10 years, even without antiretroviral therapy.7
Transmission of the virus occurs through exposure to infected body fluids, including blood, semen, and vaginal fluid. The most common modes of transmission are sexual contact (male-male or heterosexual sex), parenteral exposure to blood and blood products, and vertical transmission during pregnancy. The magnitude of risk depends on the exposure and degree of viremia of the source. For example, the risk of HIV transmission from a known HIV-positive source from receptive anal intercourse is 0.1% to 0.3%, whereas receptive vaginal intercourse carries a risk per episode of 0.08% to 0.2%. A percutaneous exposure from a needlestick injury or IDU results in transmission 0.3% or 0.67% of the time, respectively.8 The risk of vertical transmission from mother to fetus without any preventive therapy is approximately 25%.9 The efficiency of transmission increases with greater degrees of viremia in the source patient and the presence of concurrent sexually transmitted diseases.
SIGNS AND SYMPTOMS
Acute HIV Infection
In an estimated 40% to 90% of individuals, HIV seroconversion is associated with a clinical syndrome known as acute or primary HIV infection, or the acute retroviral syndrome. In one prospective study, among those with symptoms at the time of seroconversion, 95% sought medical care. Nevertheless, acute HIV infection is rarely diagnosed, partly because the symptoms are protean. The onset of illness is between 2 and 6 weeks after viral transmission and is believed to correlate with peak viremia, often in excess of 1 million viral copies/mL. Fever (mean, 38.9° C), rash, lymphadenopathy, and nonexudative pharyngitis are each present in at least 70% of individuals (Table 1). Most often, the rash is reminiscent of a viral exanthem with erythematous maculopapular lesions on the face and trunk, although many types of lesions have been described. Headache with or without cerebrospinal fluid pleocytosis, myalgias, and gastrointestinal symptoms are also common. Although present in only 5% to 20% of patients, oral or genital ulcers can be an important diagnostic clue. Laboratory abnormalities, specifically leukopenia, thrombocytopenia, and elevated transaminase levels, are not uncommon. Opportunistic infections such as mucocutaneous candidiasis and PCP may manifest during acute HIV infection as a result of transient but dramatic CD4+ cell count depletion caused by the high level of viremia.
Table 1 Acute HIV Infection: Frequency of Associated Signs and Symptoms
| Sign or Symptom | Frequency (%) |
|---|---|
| Fever | 96 |
| Headache | 32 |
| Lymphadenopathy | 74 |
| Nausea and vomiting | 27 |
| Pharyngitis | 70 |
| Hepatosplenomegaly | 14 |
| Rash | 70 |
| Weight loss | 13 |
| Myalgia or arthralgia | 54 |
| Thrush | 12 |
| Diarrhea | 32 |
| Neurologic symptoms | 12 |
| Oral or genital ulcers | 5-20 |
Adapted from Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents, December 1, 2007. Available at http://www.aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
The symptoms of acute HIV infection are self limited and most likely correlate with viremia. After reaching high levels, the viral load declines to a steady state or set point, and the CD4+ count recovers. HIV-1–specific cytotoxic T lymphocytes are present in high titer and appear to play an important role in controlling viral replication. The magnitude of the viral set point and the severity of initial symptoms predict disease progression. Recognition of this syndrome has obvious implications for public health. Whether early antiretroviral treatment changes an individual’s disease course remains unclear.10 Diagnosis is discussed below.
Chronic HIV Infection
Various historical details, findings on physical examination, and laboratory abnormalities should prompt testing to identify persons with established HIV infection. As expected, these findings are more prominent in patients with more advanced disease. Often, the initial diagnosis of HIV infection is made when the patient develops an AIDS indicator condition (Box 1).11 However, the astute clinician can often detect signs and symptoms of HIV infection earlier in the course of disease, allowing access to appropriate therapy and prophylaxis before significant illness develops.
Box 1 Indicator Conditions in the 1993 AIDS Surveillance Case Definition
Adapted from Centers for Disease Control and Prevention: 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992;41(RR-17):1-19.
DIAGNOSIS
Serologic Tests
The principal tests for the diagnosis of HIV-1 infection are the HIV enzyme-linked immunosorbent assay (ELISA) and the confirmatory Western blot test. Both detect host antibodies to the HIV virus. ELISA is the initial screening test and has a sensitivity and specificity greater than 99%. A false-negative ELISA result occurs most commonly when the test is performed in a newly infected patient before an antibody response has developed (the window period). Most patients have a positive ELISA finding 10 to 14 days after infection, although seroconversion may be delayed in some. False-negative results occur rarely in patients with late-stage disease and in those with subtype N or O HIV-1 infection. False-positive results occur in various settings, including patients with autoimmune diseases, multiparity, and liver disease, as well as recipients of multiple transfusions, hemodialysis, and vaccinations.12 An isolated positive ELISA finding should never be considered evidence of HIV infection, and clinicians should counsel patients accordingly.
The confirmatory study for a persistently positive ELISA finding is the Western blot test, which detects antibodies to specific HIV proteins. A positive study is defined as one in which bands are present in two of the following three proteins: the envelope proteins gp41 and gp120/160 and the viral capsid protein p24. A negative Western blot test result has no positive bands, but a study with any positive bands that do not meet the above criteria is considered indeterminate. Of patients with persistently positive ELISA results, 4% to 20% have indeterminate Western blot test findings. Indeterminate findings may occur during the window period between infection and seroconversion. Alternatively, other conditions such as autoimmune disease can lead to an indeterminate study. Western blot tests have a reported specificity of 97.8%; therefore, false-positive results can occur. Patients with both false-positive ELISA and false-positive Western blot test results are rare (6 to 7 in 1,000,000 tests).12
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