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HIV/AIDS 

HIV/AIDS

Chapter:
HIV/AIDS
Author(s):

Graz A. Luzzi

, T.E.A. Peto

, P. Goulder

, and C. P. Conlon

DOI:
10.1093/med/9780199204854.003.070523_update_001

Update:

Epidemiology—updated HIV prevalence data and world distribution figure.

Diagnosis—new recommendations on HIV testing in higher prevalence areas.

Primary HIV infection—use of fourth-generation HIV tests; summary of results of the SPARTAC trial on antiretroviral treatment (ART) in primary HIV infection.

HIV and TB—new information on timing of initiation of ART in patients presenting with HIV-associated tuberculosis.

Primary cerebral lymphoma—updated section on treatment and prognosis.

Non-AIDS-defining cancers—new detailed section replaces former section on other tumours in AIDS.

HIV-associated nephropathy—detailed updating.

HIV/HCV coinfection—comment on new HCV protease inhibitors.

Management of HIV infection and prognosis—inclusion of new data on long-term prognosis; management of HIV-negative sexual partners.

Antiretroviral therapy—inclusion of new drugs;–updated recommendations on when to start ART and reference to the START study.

Bone metabolism—comment on osteoporosis, bone fracture risk, and contributing factors.

Prophylaxis of major opportunistic infections in HIV—table updated.

Prevention of HIV transmission—new discussion on risk of sexual transmission in patients on ART; updated information on vaginal microbicides and pre-exposure prophylaxis.

Updated on 31 May 2012. The previous version of this content can be found here.
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date: 28 April 2017

Since its discovery in 1983, the human immunodeficiency virus (HIV) has been associated with a global pandemic that has affected more than 60 million people and caused more than 30 million deaths. The highest prevalence rates are in sub-Saharan Africa and other parts of the developing world. The impact of HIV in some African countries has been sufficient to reverse population growth and reduce life expectancy into the mid thirties, although HIV incidence has recently declined in some of these high-prevalence countries. However, there are large-scale epidemics of HIV elsewhere, e.g. India, the Russian Federation, and eastern Europe.

Transmission

Worldwide, the principal mode of transmission is heterosexual intercourse. Other risk factors for acquisition of HIV include unprotected sex between men, injecting drug use, transfusion of contaminated blood products, and mother-to-child transmission.

Cellular biology

HIV-1 (derived from a simian immunodeficiency virus in the chimpanzee) and HIV-2 (animal reservoir the sooty mangabey monkey) belong to the lentivirus subfamily of retroviruses. The viral genes in infectious particles are carried as RNA, but upon infection of the host cell, reverse transcriptase catalyses the synthesis of a double-stranded DNA viral genome that is inserted into the chromosomal DNA of the infected cell by viral integrase.

Genomic structure—HIV has only nine genes: (1) gag—encoding the core proteins p17, p24, and p15; (2) pol—encoding the enzymes protease, reverse transcriptase, and integrase; (3) env—encoding envelope glycoproteins (gp120 and gp41); (4) two major regulatory genes—tat and rev—encoding proteins that are not assembled into the virus but are essential for replication in the cell; (5) four accessory genes, whose functions are not clearly understood.

HIV receptors and cellular tropism—CD4 is the cell surface receptor for HIV, which binds to it via gp120; gp41 is then thought to effect membrane fusion. However, another cellular component or coreceptor is required, and different substrains of HIV (even those isolated from the same patient) exhibit specific tropisms for different cell types in culture, dependent on the ability of each particular substrain to bind to particular chemokine receptor family coreceptors.

Knowledge of the cell biology of HIV has facilitated the development of pharmacological agents that have transformed the disease from a uniformly fatal illness to a chronic condition in those countries able to provide antiretroviral treatment.

Diagnostic tests and screening

Reliable tests that detect HIV antibodies and antigen are used for diagnosis and screening. In all countries, many HIV-infected people are unaware of their infection, increasing the risk of sexual and perinatal transmission and requiring the development of targeted screening programmes.

Clinical features

Primary HIV infection—a few weeks after acquisition of HIV, many people develop a nonspecific influenza-like illness (seroconversion illness/acute retroviral syndrome), with a transient macular or maculopapular rash affecting the upper body. Rarely, there are neurological complications and severe immunodeficiency with secondary opportunistic infections. Most do not seek medical help, and whether treatment of primary HIV infection with antiretroviral drugs would improve long term prognosis is not known.

Clinical latency—following primary infection (symptomatic or asymptomatic) a period of clinical latency follows, typically lasting 8 to 10 years before development of further illness. The infected person is asymptomatic, but some have persistent generalized lymphadenopathy, and they may develop minor opportunistic conditions affecting the skin and mucous membranes, e.g. viral warts, oropharyngeal candidiasis, oral hairy leucoplakia.

Progression to symptomatic HIV disease (AIDS)—the value of making a distinction between AIDS and HIV infection at other stages is questionable, especially in industrialized countries: it is more useful to consider progressive HIV disease as a continuous spectrum. Complications of late-stage HIV disease include (1) opportunistic infections—e.g. pneumocystis pneumonia, oesophageal candidiasis, cerebral toxoplasmosis, and cytomegalovirus retinitis; (2) opportunistic tumours—e.g. Kaposi’s sarcoma and non-Hodgkin’s lymphoma; and (3) direct HIV effects—e.g. HIV encephalopathy/dementia.

Clinical management and prognosis

CD4+ T- lymphocyte count (CD4 count) and plasma HIV-1 viral load are the two laboratory markers with the best prognostic value. (1) CD4 count—this is an indicator of HIV-related immune impairment, with decline to below 200/mm3 associated with the risk of life-threatening opportunistic infection; antiretroviral treatment is currently considered when it has fallen to around 350/mm3. (2) Viral load—quantitative estimation of HIV RNA in the blood plasma adds additional prognostic information before starting antiretroviral treatment, and is useful in monitoring the effectiveness of therapy, which aims to maintain suppression of viral RNA at undetectable levels (<40 copies/ml). The choice of initial antiretroviral regimen should take into account the results of baseline genotypic resistance testing.

Prognosis—the outlook for people with HIV infection in well-resourced countries was transformed in the late 1990s by the advent of highly active antiretroviral therapy (HAART), but access to antiretroviral drugs continues to be difficult in less-developed countries (see Chapter 7.5.24).

Drug regimen—more than 20 agents are now available: a minimum of 3, drawn from at least 2 drug classes, is required for effective treatment. Initial regimens usually include (1) a backbone of two nucleoside analogues (inhibitors of HIV reverse transcriptase), e.g. tenofovir and emtricitabine or abacavir and lamivudine with either (2) a non-nucleoside reverse transcriptase inhibitor (NNRTI), e.g. efavirenz or nevirapine, (3) a boosted protease inhibitor, e.g. lopinavir and ritonavir or atazanavir and ritonavir. Factors considered when selecting the initial antiretroviral combination include potential drug interactions with other medications, presence of renal or hepatic dysfunction, likelihood of pregnancy, and the presence of cardiovascular risk factors. An important development has been the availability of simplified regimens involving small numbers of coformulated tablets taken once or twice daily. Adherence to treatment and avoidance of suboptimal therapy (such as regimens involving fewer than three active agents, or use of agents in the presence of HIV mutations conferring resistance) are important in avoiding treatment failure.

Other drugs for HIV—(1) New agents in established drug classes—these have activity against HIV despite mutations conferring resistance to other drugs in the class, e.g. etravirine (a NNRTI), and tipranavir and darunavir (protease inhibitors); (2) fusion entry inhibitors; (3) CCR5 receptor antagonists (e.g. maraviroc); and (4) integrase inhibitors (e.g. raltegravir). The role of these newer agents in HIV therapy is being determined in clinical trials.

Adverse reactions to antiretroviral drugs—these are relatively common and include. (1) Short-term reactions—gastrointestinal disturbances, rashes, and neuropsychiatric reactions may require early adjustments to the treatment regimen. (2) Longer-term reactions—metabolic complications include (a) mitochondrial toxicity; (b) disturbances of lipid and glucose metabolism associated with a risk of cardiovascular disease including myocardial infarction—the absolute risk is small but requires consideration in patients with pre-existing cardiovascular risk factors; (c) renal impairment, e.g. with tenofovir; (d) metabolic bone disese. (3) Paradoxical reactions—called immune reconstitution syndromes, these occur in up to 20% of patients starting treatment and include new or worsening inflammatory symptoms, especially in patients who have opportunistic infections such as tuberculosis, Mycobacterium avium infection, cryptococcal meningitis, and cytomegalovirus retinitis.

Co-infections involving HIV and tuberculosis, hepatitis B or hepatitis C are common and require specialized treatment.

Prevention

Strategies to raise awareness and provide education, and promote risk reduction, underpin HIV control programmes worldwide. Control of coexistent sexually transmitted genital ulcers and other genital infections reduces HIV transmission. Mother-to-child transmission can be reduced to below 1% if antiretroviral treatment is administered to the mother during pregnancy, delivery is by planned caesarean section (vaginal delivery may be an option if HIV viral load is below the detection threshold), and breastfeeding is avoided. Despite decades of research, an effective HIV vaccine is not available.

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