Acquired Immunodeficiency Syndrome

Epidemiology

Infection is spread mostly through sexual transmission. Until the mid-1990s, male-to-male sexual transmission dominated in the developed countries. Now, heterosexual activity is the major route of transmission globally, including many developed countries. Intravenous drug abuse is another common cause of disease transmission. Perinatal transmission from an infected mother to her offspring can occur in utero. Transmission can also occur during delivery or through breastfeeding. Finally, transmission to health care workers can occur, usually as the result of a needlestick injury. The rate of seroconversion to HIV after a needlestick injury is about 0.3%, depending on the viral load; this is about 10 to 100 times less than that with hepatitis C or B. Before the availability of a serologic test for HIV antibody, large numbers of patients, including those with hemophilia, were exposed to the virus through transfusion of infected blood products.

HIV/AIDS remains a global epidemic, with over 35 million people estimated to have the infection in 2016. Although the number of patients with newly diagnosed HIV infection appears to be declining in the United States, HIV disproportionately affects certain segments of the population, including intravenous drug users, commercial sex workers, people living in poverty, and men who have sex with men. In 2017, the number of new diagnoses of HIV infection was 11.8 per 100,000 population in the United States. The annual rate of infections classified as stage 3 (AIDS) in 2017 was 5.4 per 100,000 population in the United States.

Diagnosis

HIV infection can be diagnosed on the basis of the presence of antibody to viral antigens or direct detection of HIV or one of its components. Antibodies to HIV generally occur in the circulation 3–12 weeks after infection. The antibodies do not control the infection or prevent its sequelae. Diagnosis of HIV infection is usually made by performing an immunoassay, and many experts then recommend that a positive result be confirmed with a Western blot test. ^, However, the Centers for Disease Control and Prevention (CDC) recommendations currently indicate that a positive result on a fourth-generation assay, confirmed with a second HIV-1 or HIV-2 specific immunoassay, is adequate for diagnosis. Some strains of HIV are not detected on enzyme-linked immunosorbent assay (ELISA). Nevertheless, ELISA is almost 100% sensitive, albeit not 100% specific, so false-positive results can occur. The virus can also be cultured from blood, semen, and solid tissues, but only rarely from saliva and tears. In the eye, the virus has been found in the cornea, vitreous, and retina. Rapid tests for HIV are now commercially available, although testing algorithms for these tests are still being assessed.

HIV Disease

An acute retroviral syndrome occurs in approximately one-half to three-quarters of patients, usually 3 to 6 weeks after HIV infection. Typically, fever, rash, myalgias, headache, or gastrointestinal symptoms develop. The CD4+ count is reduced, and many patients have elevated liver enzyme levels. Without treatment, CD4+ counts decline by about 75 cells/μL/year. The time from initial infection to the development of a disease that meets the definition of AIDS is about 10 years. Respiratory diseases, including acute bronchitis, pneumonia, and sinusitis, are prevalent during all stages of the disease. AIDS is the most severe manifestation of HIV infection and occurs at a point at which the immune system is so impaired by the infection that opportunistic infections, such as Pneumocystis jirovecii, Cryptococcus neoformans, and cytomegalovirus (CMV) infections and oral candidiasis, and unusual malignant processes, such as Kaposi sarcoma, can emerge. ^, A type of encephalopathy is also caused by direct HIV infection of the brain. Fortunately, effective prophylactic regimens have significantly decreased the occurrence of many of these secondary infections, such as Pneumocystis pneumonia. Recommendations on the management of opportunistic infections in patients with HIV infection are evolving rapidly, and guidelines can be found online.

Progression of HIV disease is related to the CD4+ lymphocyte count. The amount of HIV-1 viral RNA predicts the course of HIV disease, specifically, how rapidly the disease is likely to progress. Persons with HIV loads greater than 30,000 copies/mL have an 80% likelihood of AIDS developing within 6 years. In contrast, those with HIV loads less than 500 copies/mL have a 5.4% chance of development of AIDS. CD4+ lymphocyte counts are good predictors for the development of specific clinical manifestations of the disease, particularly opportunistic infections. For example, most cases of P. jirovecii pneumonia occur when CD4+ counts fall to less than 200 cells/μL. Typically, CMV retinitis occurs when CD4+ counts are less than 50 cells/μL.

HIV Therapy

The discovery and widespread use of combination antiretroviral therapy (cART) has profoundly improved patient outcomes and survival in persons with HIV. Historically, there was debate on when to start ART for HIV disease. The decision regarding initiation of treatment was based on symptoms, HIV-1 RNA level, and CD4+ count. The potential benefit of ART must be based on the risks of therapy and the impact on quality of life with adherence to a strict therapeutic regimen, which is required to avoid drug resistance. Some clinicians only begin treatment when the CD4+ count drops to less than 350 cells/μL or if symptoms are present. The rapidity of the decline in CD4+ count and HIV load are other factors in the decision regarding when to start therapy. However, studies have suggested that the benefits of prompt initiation of ART outweigh the risks of treatment regardless of CD4+ T-cell count. ^, The benefit of prompt initiation of ART applies to both infected persons and their uninfected sexual partners.

When therapy is started, a highly active regimen consisting of a combination of antiretroviral agents should be employed to maximize efficacy and minimize resistance. The goal of therapy is to suppress plasma HIV-1 RNA to below detectable limits by using a sensitive assay. All regimens should combine drugs with synergistic antiviral activity. Four classes of anti-HIV therapy are currently available: (1) viral reverse transcriptase enzyme inhibitors (nucleoside and nucleotide reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors); (2) viral protease enzyme inhibitors (protease inhibitors); (3) viral integrase enzyme inhibitors (integrase inhibitors); and (4) drugs that interfere with viral entry into the cell (fusion inhibitors and CCR5 antagonists). Box 12.1 lists the currently available antiretroviral agents. Combinations of these agents have also been approved by regulatory authorities, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and are available commercially.