HIV for the Primary
Definition and Causes
Human immunodeficiency virus (HIV) is a retrovirus that infects primarily CD4+ T helper cells. Depletion of these cells causes progressive immunologic decline. When CD4+ T cell counts fall below 200 cells/mm3 or opportunistic infections occur, an infected patient is described as having the acquired immunodeficiency syndrome (AIDS).
Prevalence and Risk Factors
At the end of 2009, an estimated 780,000 people in the United States were living with HIV. The largest percentage was in those aged 45 to 49 years (20%), according to surveillance data published at the end of 2009, which were obtained from the 46 states that use name-based reporting. However, from 2007-2009, the largest percentage increases were seen among people aged 60 to 64 years. Among HIV-infected men in all age groups, 68% identified their risk behavior as men having sex with men (MSM), 13% reported a history of injection drug use (IDU), 8% reported both MSM and IDU, and 11% 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.1
The magnitude of the global HIV/AIDS epidemic vastly exceeds what is seen in the U.S. As of the end of 2011, 34 million people were estimated to be living with HIV/AIDS worldwide. Approximately 69% of those with the disease are in sub-Saharan Africa, where access to antiretroviral therapy is limited.2
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, 2 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 to result in slower disease progression than that caused by HIV-1.4
The human immunodeficiency viruses belong to the lentivirus subfamily of the RNA retroviruses. Like most retroviruses, the HIV genome consists of 3 structural genes, gag, pol, and env. The gag gene codes for viral capsid proteins, env for viral envelope proteins, and pol for proteins responsible for viral replication, including the RNA-dependent DNA polymerase known as reverse transcriptase. In addition, several other regulatory genes are present, including nef, rev, and tat.
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 a 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, myalgia, 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 Symptoms13
|Sign or Symptom||Frequency (%)|
|Nausea and vomiting||27|
|Myalgia or arthralgia||54|
|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, March 27, 2012. Available at 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 (Table 2).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.
Table 2: Indicator conditions in the 1993 AIDS surveillance case definition11
|Candidiasis of the esophagus, bronchi, trachea, or lungs|
|Cervical cancer, invasive|
|Cryptosporidiosis, chronic intestinal (>1-month duration)|
|Cytomegalovirus disease of any organ other than the liver, spleen, nodes|
|Herpes simplex with mucocutaneous ulcer >1-month duration, or bronchitis, pneumonitis, or esophagitis|
|Isosporiasis, chronic intestinal (>1 month duration)|
|Lymphoma, Burkitt’s, immunoblastic, or primary CNS involvement|
|Mycobacterium avium complex or M. kansasii, extrapulmonary|
|M. tuberculosis, any site|
|Pneumocystis jiroveci pneumonia|
|Pneumonia, recurrent bacterial (≥2 episodes in 1 year)|
|Progressive multifocal leukoencephalopathy|
|Salmonella septicemia, recurrent|
|Wasting syndrome caused by HIV|
AIDS, acquired immunodeficiency deficiency syndrome; CNS, central nervous system; HIV, human immunodeficiency virus.
A history of certain illnesses can also be suggestive of HIV infection. Infections such as active tuberculosis, recurrent community-acquired pneumonia, esophageal candidiasis, and either multidermatomal herpes zoster or zoster in younger adults should lead to HIV testing. Neoplastic diseases such as B-cell lymphoma, severe anal or cervical dysplasia, or invasive carcinoma and Kaposi sarcoma are indications for HIV testing, as is idiopathic dilated cardiomyopathy. The evaluation of fever of unknown origin or unexplained weight loss should always include an HIV test, even in older patients without identified risk factors.
Various findings on physical examination may suggest coexisting HIV infection. Examination of the skin can be particularly revealing. Seborrheic dermatitis or molluscum contagiosum are common in early disease, as is psoriasis. Oral candidiasis and oral hairy leukoplakia can be seen, typically with CD4+ counts <500 cells/mm3. Generalized lymphadenopathy is common. Recurrent or severe lesions of herpes simplex virus may be indicative of underlying HIV infection. Neurologic findings such as unexplained peripheral neuropathy or dementia are suggestive.
On laboratory evaluation, idiopathic thrombocytopenia, unexplained anemia, neutropenia, and/or leukopenia are frequent early clues to underlying HIV infection. An elevated total protein level or globulin fraction is also suggestive.
Since the recognition that HIV is the agent causing AIDS, many tests have been developed to aid in establishing the diagnosis of HIV infection and evaluating the stage of infection. However, only a few have application today for routine use.
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 HIV. ELISA is the initial screening test and has sensitivity and specificity >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 in 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 2 of the following 3 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
New fourth-generation assays that detect both HIV antibodies and the p24 antigen are now available in some labs. These tests would be beneficial during the window period of acute HIV infection. Additional diagnostic tests are available for use in specific circumstances. The diagnosis of HIV-2 infection requires an ELISA finding that will detect HIV-2 antibodies, followed by an HIV-2–specific Western blot test. Many currently available HIV ELISAs will detect antibodies to HIV-1 or HIV-2, and HIV-2–specific ELISAs are available. It is important to understand the test characteristics and a patient’s risk of HIV-2 infection─highest among immigrants from West Africa and in people with exposure to an individual at risk─before drawing conclusions based on test results.
Rapid testing systems allow the HIV assays to be run in 5 to 20 minutes. Negative rapid test assays can be considered negative unless there concern of acute HIV infection; however, all positive rapid assays must be confirmed by standard ELISA and Western Blot assays. Currently available U.S. Food and Drug Administration (FDA)-approved kits are available for blood, plasma, serum, and saliva specimens. These tests are particularly beneficial in the delivery room, emergency room, and after occupational exposures. Additionally, the availability of Clinical Laboratories Improvement Act-waived testing allows these assays to be run in the community, expanding access to testing. Home tests are available that allow patients to collect a blood sample after a finger stick, which is then sent anonymously for testing and a recently FDA approved Over-the-counter, in-home test kits can detect HIV-1 and HIV-2 infection, some can distinguish between the 2 viruses, and others can detect only samples positive for HIV-1 antibodies.
As with all diagnostic tests, the positive predictive value depends on the rate of disease in the population being screened. In low-prevalence populations, the likelihood that a positive ELISA result represents a false-positive result may exceed the likelihood of the test’s indicating true HIV infection.
Quantitative HIV Testing
Quantitative plasma HIV RNA (viral load) testing is most commonly used to measure response to antiviral therapy or to predict disease progression. Several methods of measuring viral load are commercially available, including viral RNA quantification by the polymerase chain reaction (PCR), branched-chain DNA assays, and nucleic acid sequence–based amplification. At present, the RNA PCR assay is most commonly used, but it should not be used for the diagnosis of HIV infection unless acute infection is a consideration. HIV-infected individuals can have undetectable viral loads in the absence of antiviral therapy, and the false-positive rate approaches 3%. When the clinician is concerned about acute HIV infection with a symptomatic patient and ELISA and Western blot test findings are negative or indeterminate, viral load testing can be helpful. With initial viremia, before the development of an immunologic response to the virus, the viral load is extremely high, often >100,000 copies/mL. Low viral loads (<15,000 copies/mL) with negative serologic studies may represent a false-positive RNA PCR result and the test should be repeated.12 Qualitative measurements of proviral DNA can also be useful for the detection of viremia before seroconversion.
Measurement of p24 antigenemia has also been used to detect HIV infection before seroconversion. On average, however, HIV DNA or RNA can be detected 2 to 3 days earlier than the p24 antigen. As a result, viral load testing has become the preferred method for the diagnosis of acute HIV infection. Studies of p24 antigen can be useful to help clarify confusing serologic or quantitative viral load results.
In summary, serologic testing is the gold standard for diagnosing HIV infection and should be performed on all patients in whom HIV infection is suspected. Viral load testing has no role in the diagnosis of established HIV infection. When suspicion of acute HIV infection is present, viral load testing can be performed, in addition to serologic studies. Negative serologic studies in the setting of a strongly positive viral load (>15,000 copies/mL) suggest acute HIV infection. These patients should be urgently referred to an HIV specialist; however, seroconversion must also be documented in the ensuing weeks to months. Indeterminate Western blot findings can present challenging management issues. At a minimum, the study should be repeated 6 months after the initial result to clarify whether the indeterminate findings were the result of ongoing seroconversion.
Appropriate treatment of the HIV-infected patient requires much more than consideration of antiretroviral therapy. The initial evaluation of such a patient should include a careful medical and social history, a medication history, including alternative and herbal supplements, and a thorough physical examination. The clinician should explore the patient’s knowledge of HIV, understanding of the course of disease, emotional well-being, and presence or absence of support systems. A discussion of safer sex practices and contraception is vital. Notification of sex partners should be discussed. Identification of a durable power of attorney and discussion of advanced directives are valuable early in the course of the disease.
Several baseline laboratory studies aid in establishing a treatment plan for the patient, choosing agents for antiretroviral therapy, and guiding prophylaxis (Table 3). HIV infection should be staged with a CD4+ count and HIV viral load measurement. Current guidelines suggest performing HIV resistance testing (HIV genotype) in all newly diagnosed patients, because acquisition of resistant virus is becoming more commonplace (6% to 16%).13 Recommended studies also include a complete blood cell count with differential and platelet counts, determination of electrolyte, blood urea nitrogen (BUN), creatinine, transaminase, and alkaline phosphatase levels, urinalysis, and serologies for hepatitis A, B, and C.13 Additional testing includes rapid plasma reagin or Venereal Disease Research Laboratory (VDRL) testing to assess for syphilis, Toxoplasma gondii IgG serology to assess past exposure, and determination of the glucose-6-phosphate dehydrogenase (G6PD) level.14 A purified protein derivative (PPD) test must be performed if not done within the past year, and exposure to any individuals with active tuberculosis must be assessed. An anergy panel is not necessary. Women should have a Pap smear performed every 6 months until 2 consecutive smears are negative, and then annually. Women with abnormal Pap smears should be referred for colposcopy. Annual ophthalmologic and dental visits are recommended. Consultation with a nutritionist experienced in HIV care and a social worker are beneficial.14
Table 3. Initial laboratory evaluation of the HIV-infected patient
|Complete blood count, including differential and platelets|
|Determination of levels of electrolytes, blood urea nitrogen, creatinine, transaminases, alkaline phosphate, glucose-6-phosphate dehydrogenase|
|Rapid plasma reagin (RPR) or VDRL testing|
|Toxoplasma gondii IgG determination|
|Hepatitis B and C serologies|
|Quantitative HIV RNA level|
|Purified protein derivative (PPD) test|
|Consider determination of cytomegalovirus IgG, hepatitis A IgG levels, baseline chest x-ray|
HIV, human immunodeficiency virus; IgG, immunoglobulin G; PPD, purified protein derivative; RNA, ribonucleic acid; VDRL, venereal disease research laboratory.
Preventive care is essential to treating the HIV-infected patient. Some infections can be minimized by avoiding uncooked and undercooked foods such as seafood, eggs, and meats, abstaining from drinking lake and river water, avoiding contact with cat litter boxes and animals with diarrhea, and institution of careful hand washing. The patient’s vaccination history should be carefully reviewed. All patients should receive the pneumococcal vaccine, updated every 3 to 6 years. The influenza vaccine is recommended, as is hepatitis B vaccination if the patient is seronegative. Although hepatitis A vaccination is indicated if the patient has existing hepatitis B or C, most clinicians favor vaccinating all seronegative individuals. Tetanus boosters are indicated every 10 years. At present, live vaccines are not recommended for patients with advanced disease. The safety of these vaccines (eg, varicella, measles-mumps-rubella, and yellow fever) early in the disease is unknown and should be considered on an individual basis. The inactivated vaccines for typhoid (Typhim Vi capsular polysaccharide vaccine, ViCPS) and polio should be administered when required rather than live vaccines.14
Patients with advanced HIV disease require prophylaxis to prevent opportunistic infections. With a CD4+ count <200 cells/mm3 (or CD4+ percentage <14), prophylaxis against PCP should be initiated promptly, because the incidence of disease approaches 20% per year in these patients in the absence of prophylaxis. The first-line agent is trimethoprim-sulfamethoxazole (TMP-SMX), 1 double-strength tablet daily. Dapsone, 100 mg/day, is recommended for patients who are TMP-SMX–intolerant and not G6PD-deficient. When the CD4+ count is <100 cells/mm3, patients with positive T. gondii IgG serologies require prophylaxis to prevent reactivation. Daily TMP-SMX is again the drug of choice. Patients receiving dapsone require the addition of pyrimethamine. Although Mycobacterium avium complex (MAC) prophylaxis is recommended at CD4+ counts <50 cells/mm3, initiation is never emergent, and active MAC disease should be ruled out before starting prophylaxis if the patient has any suggestive symptoms. The most common regimen is azithromycin, 1200 mg/week. More detailed information can be obtained from the U.S. Public Health Service and Infectious Disease Society of America guidelines for the prevention of opportunistic infections.14
Highly Active Antiretroviral Therapy
In the past decade, selection of highly active antiretroviral therapy (HAART) has become increasingly complex. Furthermore, textbook chapters often become obsolete almost as soon as they are printed as new classes and agents become available and recommendations for use change. Appropriate individualized selection of HAART should be left to an HIV specialist.
HAART therapy is now recommended for all HIV-infected individuals.13 Recent Department of Health and Human Services (DHHS) guidelines detail that the strength of the recommendation to initiate vary by the patient’s CD4+ cell count. However, there is no CD4+ cell count at which HAART is contraindicated. Initialization of HAART is strongly recommended in the setting of pregnancy, history of AIDS-defining illness, HIV-associated neuropathy, and HIV/ hepatitis B co-infection, regardless of CD4+ cell counts.
Current therapy should almost always include a minimum of 3 agents and often more, selected from among presently licensed drug classes: nucleoside nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, chemokine receptor antagonists, and integrase inhibitors. Recommended first-line regimens consist of: efavirenz (EFV)/ tenofovir (TDF)/emtricitabine (FTC), ritonavir-boosted atazanavir + TDF/ FTC, ritonavir-boosted darunavir + TDF/ FTC, raltegravir + TDF/ FTC.13 PIs are recommended to be prescribed in a boosted formulation, which means that low-dose ritonavir is added to an active PI, not for antiviral activity but as an inhibitor of the hepatic metabolism of the active agent. This increases the levels of the active drug, improving its potency and often allowing longer dosing intervals. Several alternative regimens are also available; in some instances, these regimens may be preferred when taking into consideration additional factors including comorbidities, other prescribed or over-the-counter medications, lifestyle, and family history.13
Once HAART is initiated, the goals of HAART are to reduce HIV-associated morbidity and prolong survival, restore immune function, suppress HIV viral load, and prevent HIV transmission. The suppression of HIV-1 RNA to below the limits of assay detections usually occurs within the first 12-24 weeks of therapy.13 The most critical and modifiable factor affecting success is patient adherence. Only 45% of patients taking 90% to 95% of the prescribed doses of antiretroviral medications will achieve viral suppression (<400 copies/mL) compared with 78% in those taking >95% of doses.15 Incomplete viral suppression leads to the development of drug resistance. Adherence to the antiviral regimen should be addressed at every visit with every physician in a detailed fashion, and the importance of careful adherence should be stressed. Once-daily dosing of many treatment regimens is now possible and changes in pill formulations have allowed more potent regimens to be prescribed with fewer total pills. Both pill burden and dosing frequency have been shown to correlate with adherence.
Side effects of the currently available antiretroviral agents are considerable, and the general practitioner should be aware of them (Table 4). Those that are the most common and potentially serious include cytopenia with zidovudine; pancreatitis with didanosine; peripheral neuropathy with didanosine and stavudine; hypersensitivity, including rash, fever, and risk of death with abacavir; Fanconi syndrome with tenofovir; rash with all NNRTIs; hepatitis with nevirapine; nephrolithiasis with indinavir; unconjugated hyperbilirubinemia with indinavir or atazanavir; and gastrointestinal toxicity, including diarrhea and nausea, with all protease inhibitors.
Table 4. Selected common adverse events caused by antiretroviral agents13
|Agent||Adverse Events Unique to Agent||Adverse Events Common Across Class|
|Nucleoside and Nucleotide Reverse Transcriptase Inhibitors||Lactic acidosis with hepatic steatosis (higher incidence with d4T), lipodystrophy*|
|Zidovudine (AZT, ZDV)||Anemia, neutropenia, myopathy|
|Didanosine (ddI)||Peripheral neuropathy, pancreatitis|
|Zalcitabine (ddC)||Peripheral neuropathy|
|Stavudine (d4T)||Peripheral neuropathy|
|Non-nucleoside Reverse Transcriptase Inhibitors||Rash|
|Fat misdistribution,* GI intolerance, hyperglycemia, lipid abnormalities|
|Indinavir||Nephrolithiasis, unconjugated hyperbilirubinemia|
|Enfuvirtide||Injection site reactions|
CNS, central nervous system; GI, gastrointestinal.
*The role of various antiretroviral agents in the development of lipodystrophy is not fully understood.
More recently appreciated are the metabolic abnormalities that can occur in patients taking HAART. Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia should be carefully monitored and treated (with attention to interactions between the protease inhibitors and many 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors). Additionally, studies have suggested an association between antiretroviral therapy use and increased relative risk of cardiovascular end points, such as myocardial infarction.16
In addition, significant drug interactions can occur between antiretroviral agents and commonly prescribed drugs that can lead to drug toxicities or reduction in levels of the drug or the antiretroviral agent, rendering them ineffective. For a complete listing of adverse effects, toxicities, and medication interactions, refer to the DHHS Antiretroviral Guidelines.13
The advent of HAART has improved mortality for HIV-infected patients who have access to these medications. In the U.S., deaths caused by AIDS declined sharply in 1996 and 1997, when protease inhibitors were first introduced. Among a cohort of adults with advanced HIV infection, death rates decreased from 29.4 per 100 person-years in 1995 to 8.8 per 100 person-years by 1997.17 Morbidity has declined as well, as measured by the incidence of opportunistic infection.17 Between 1994 and 1997, the incidence of PCP, MAC disease, and cytomegalovirus retinitis combined decreased by 83% (21.9 to 3.7 per 100 person-years). A study using a computer simulation of HIV disease has estimated that a total of 2,100,000 years of life were saved by prophylactic therapy and antiretroviral therapy between 1989 and 2003. The per-person survival gain attributed to HAART for HIV infection is estimated to be 180 months, or 9 times that of coronary artery bypass surgery.18 Current efforts are focused on improving ease of use and decreasing toxicity of HAART in hopes of enhancing the quality of life in those infected with HIV.
Prevention and Screening
Physicians must conduct a thorough, nonjudgmental assessment of risk factors for HIV infection. Persons at increased risk for HIV infection include those with a history of IDU, sexually transmitted diseases, including human papillomavirus, hemophilia, and receipt of blood products between 1977 and 1985. Men who have had sex with men, sex workers, and heterosexual persons with more than one partner since their last HIV test are also considered to be at high risk, as are the sexual partners of high-risk or HIV-infected persons. Mental illness and incarceration may serve as markers for high-risk behavior, as does a history of hepatitis B or C infection. Persons who consider themselves at risk should receive testing, even if risk behaviors are not disclosed. Past efforts have focused on testing individuals perceived to be at increased risk for HIV infection. The Centers for Disease Control and Prevention (CDC) has now recommended that all persons aged 13 to 64 be screened for HIV infection at least once, and that this should be done unless the patient declines testing (opt-out testing).19 Individuals at high risk should be screened more regularly and all pregnant women should be screened for HIV unless they choose to opt out of testing. Pre-exposure prophylaxis (PreP) has recently been approved by FDA for HIV-negative individuals in whom sexual transmission is poses a risk of HIV infection.20 Co-formulated HAART tenofovir/emtricitabine daily has been shown to reduce risk of HIV transmission in this population.
Considerations in Special Populations
Treatment of pregnant women poses special considerations. Antiretroviral therapy in pregnancy has been shown to dramatically decrease the risk of transmission to the child. Therapy with zidovudine in the third trimester, followed by IV infusion of zidovudine in labor and administration to the infant for the first 4 weeks of life, have been shown to lead to a 66% reduction in the risk of transmission of HIV to the infant.9 Currently, combination antiretroviral therapy during pregnancy is recommended. Delivery by cesarean section further reduces that risk, from approximately 8% to 2%. However, when the maternal viral load is reduced to <1000 copies/mL with HAART therapy, the likelihood of transmission to the fetus is <1%, regardless of vaginal or cesarean section delivery. Although counseling regarding the risks of antiretroviral medications to the fetus is necessary, the transmission benefits of antiretroviral therapy generally outweigh the risks of teratogenicity. Efavirenz is a pregnancy category D agent and should be avoided.21
Health care workers are at risk for contracting HIV infection through exposure to infectious body substances. Blood, cerebrospinal fluid, semen, and vaginal, peritoneal, synovial, pleural, and amniotic fluids, as well as tissue samples, can all transmit HIV, although nonbloody urine, saliva, tears, sweat, and vomitus cannot. Percutaneous exposures (needle sticks) carry a risk of transmission of 0.3%, whereas mucus membrane exposures (eg, a splash) transmit less virus and are less likely to lead to seroconversion (0.01% of the time). The risk of a percutaneous exposure is increased when blood is visible on the device causing the injury, when the device was in the source patient’s artery or vein, when the injury is deep, or when the source patient died within 60 days of the event. Retrospective data, animal data, and mother-to-child transmission data all suggest that immediate antiretroviral therapy after an exposure reduces the risk of HIV seroconversion in the exposed individual. Currently, administration of a 3-drug antiretroviral regimen is typically used.22 The postexposure regimen should be continued for 4 weeks if no toxicities occur and the first dose should be administered as soon as possible. Follow-up testing is recommended at 6 weeks, 3 months, and 6 months.8
- Acute HIV infection is associated with fever, rash, lymphadenopathy, and nonexudative pharyngitis. Up to 70% of seroconverters are symptomatic but are rarely diagnosed. The appropriate tests to establish the diagnosis are an HIV screening antibody test and HIV RNA by PCR assay.
- More than 250,000 people in the U.S. are infected with HIV but are unaware of the diagnosis. Current CDC guidelines recommend screening all individuals aged 13 to 64 years at least once in their lifetime. Testing should be conducted annually in those who engage in higher risk behavior. Consent for testing should be obtained using opt-out approaches.
- There is no CD4+ T cell count at which antiretroviral therapy is contraindicated.
- Currently recommended initial antiretroviral regimens include at least 3 different medications to suppress the virus.
- Combination antiretroviral therapy should be administered to HIV-positive pregnant women. It can reduce the risk of transmission of HIV to the fetus to <1%.
- PreP has been shown to reduce HIV transmission in HIV-negative people who are at risk of infection through sexual transmission.
- Cao Y, Qin L, Zhang L, et al. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332:201-208.
- 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.
- Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 1998;339:33-39.
- Mellors JW, Muñoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997;126:946-954.
- Mylonakis E, Paliou M, Lally M, et al. Laboratory testing for infection with the human immunodeficiency virus: Established and novel approaches. Am J Med 2000;109:568-576.
- Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338:853.
- Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000;133:21-30.
- UNAIDS. 2006 Report on the Global AIDS Epidemic, May 2006. Chapter 2, Overview of the global AIDS epidemic. Available at data.unaids.org/pub/GlobalReport/2006/2006_GR_CH02_en.pdf. (Accessed January 2, 2013).
- Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report. vol 17. Atlanta, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Available at www.cdc.gov/hiv/topics/surveillance/resources/reports/2005report/pdf/2005SurveillanceReport.pdf. (Accessed January 2, 2013).
- Pneumocystis pneumonia─Los Angeles. MMWR Morb Mortal Wkly Rep 1981;30:250-2.
- Markovitz DM. Infection with the human immunodeficiency virus type 2. Ann Intern Med 1993;118:211-8.
- Gelezuinas R, Greene W. Molecular Insights into HIV-1 infection and pathogenesis. In: Sande MA VP, ed. The Medical Management of AIDS. Philadelphia, PA: WB Saunders; 1999:23-39.
- Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997;126:946-54.
- Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332:201-8.
- Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54:1-17.
- Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1996;335:1621-9.
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