" Management of the Patient with HIV Disease
Surendra K. Sharma, MD, PhD
Tamilarasu Kadhiravan, MD
This article was published in: Rakel RE, Bope ET. Conn’s Current Therapy 2008. Section 2: The Infectious Diseases. Management of the Patient with HIV Disease, p. 47-61.
PII S0011-5029(07)00151-4
Introduction
AIDS was described initially in the United States in 1981 among several case clusters of previously healthy young men who had sex with men, presenting with unusual infections such as Pneumocystis jiroveci pneumonia (PCP), mucosal candidiasis, disseminated cytomegalovirus (CMV) disease, and Kaposi’s sarcoma. The cause of AIDS remained elusive then, leading to several speculations. A few years later, amid much controversy, the causative agent was established as HIV, which has a predilection to infect and destroy the immune effector cells, primarily the CD4+ T lymphocytes. The discovery of HIV led to the development of definitive diagnostic tests that unearthed, to everyone’s dismay, a widespread, hitherto invisible, smoldering pandemic in evolution.
EpidemiologySince the beginning of the epidemic, approximately 25 million people have died of AIDS worldwide, making it one of the most devastating epidemics of all times. An estimated 40 million people are living with HIV/AIDS globally, including 17.5 million women and 2.3 million children younger than 15 years. In 2005 alone, an estimated 5 million people were newly infected, and approximately 3 million people died because of AIDS. More than half of the burden of HIV/AIDS is borne by sub-Saharan Africa, particularly the southern African nations. In countries such as Botswana, South Africa, Zimbabwe, Swaziland, and Namibia, the prevalence of HIV infection among expectant mothers is consistently in excess of 20%.
North America accounts for approximately 1.2 million people living with HIV/AIDS, most of them in the United States. Every year, more than 35,000 new cases are reported in the United States. Blacks and Hispanics are disproportionately represented among them, and pediatric AIDS accounts for approximately 1% of the cases. With the widespread implementation of preventive measures, a marginal but significant fall in HIV infection rates was observed for the first time among non-Hispanic blacks and injection drug users.
The Causative AgentHIV is an enveloped single-stranded RNA virus (family, Retroviridae; subfamily, Lentivirinae). Embedded in its envelope are glycoprotein spikes (gp120, gp41) that are crucial for binding with the host cell surface receptors, such as CD4, CCR5, and CXCR4, and subsequent entry into the host cell. HIV is a retrovirus that elaborates the enzyme reverse transcriptase. It enables transcription of genomic RNA to proviral DNA for integration into the host cell DNA. Host cells that bear CD4+ (helper T cells, macrophages, etc.) are the main targets of HIV infection. There are two human immunodeficiency viruses: HIV-1 and HIV-2. Compelling genetic evidence suggests that they originated from the simian immunodeficiency viruses, of the chimpanzee (SIVcpz) and the sooty mangabey monkeys (SIVsm), respectively, in Africa several decades back. HIV-1 is global in distribution, whereas HIV-2 is confined mainly to western Africa. HIV-2 infection is less effectively transmitted and results in lower levels of viremia and slower disease progression compared with HIV-1.
Isolates of HIV-1 across the globe exhibit marked genetic heterogeneity and are classified into three groups (M, O, and N) and several clades. Clade C is the most common form worldwide. In North America and Europe, clade B is the predominant subtype. Genetic recombination among co-circulating clades often occurs, and such a recombinant subtype AE is the most prevalent form in Southeast Asia. Clade AE viruses are transmitted more effectively by the heterosexual route than the clade B virus. The genetic heterogeneity of HIV has to be taken into consideration in the development and evaluation of HIV vaccines.
Modes of TransmissionTransmission of HIV occurs through contact with the body fluids of a HIV-infected person. The routes of transmission are sexual, both male-to-male as well as heterosexual contact; mother-to-child; transfusion of HIV-tainted blood and blood products; injection drug use; and occupational exposure in health care and laboratory workers. No evidence suggests that HIV is transmitted by casual contact and insect bites. Heterosexual transmission is the most prevalent route of HIV transmission worldwide, especially in developing countries. In the United States, male-to-male sexual contact is the most common route of transmission; however, the proportion of cases caused by heterosexual transmission is steadily increasing.
The average risk of HIV transmission per coital act in sero-discordant heterosexual couples is approximately 0.1%. Several factors, such as the presence of other sexually transmitted infections (ulcerative as well as nonulcerative) and higher viral load, increase the risk of transmission; condom use and male circumcision considerably reduce the risk. Female-to-male transmission is less effective than male-to-female transmission. Commercial sex is associated with a higher risk of transmission of approximately 5% to 10%. Receptive anal intercourse is associated with a higher risk of transmission as compared with vaginal intercourse. Even though the risk of transmission by oral sex is very low, it should not be considered completely safe.
Mother-to-child transmission of infection can occur during pregnancy, during delivery, or by breastfeeding. More than half of the transmissions occur intrapartum, mediated by direct contact of infant mucosa with HIV-laden maternal blood, amniotic fluid, and cervical/vaginal secretions. Placental microtransfusion also plays a role. High maternal plasma viremia, prolonged rupture of membranes, and chorioamnionitis increase the risk of mother-to-child transmission, whereas cesarean delivery and use of peripartum antiretroviral prophylaxis decrease the risk markedly.
With the implementation of mandatory testing practices, transmission through infected blood and blood products is almost eliminated in the developed world. However, despite using the highly sensitive nucleic acid-based tests, given the enormous number of transfusions in clinical practice, the risk of transfusion-transmitted HIV infection cannot be overlooked. It is estimated that each year 16 infectious donations are available for transfusion in the United States.
Although injection drug use is responsible for approximately 20% of HIV transmission in the United States, it is the driving force behind the HIV epidemic in Southeast Asian countries and China. Apart from direct transmission through sharing of contaminated needles and other paraphernalia, injection drug use also promotes risk-taking behavior and unsafe sexual practices. In developing countries, unsafe injections administered at health care facilities are a potential, but underappreciated, route of HIV transmission. Occupational transmission occurs through percutaneous needle stick injuries and after mucous membrane or nonintact skin exposure to infected body fluids. The risk of HIV infection following a contaminated needle stick injury is approximately 0.3% and is approximately 0.09% following mucous membrane exposure.
Pathogenesis and Natural History of HIV InfectionFollowing infection, HIV localizes to the lymphoid organs of the body, where it productively infects the CD4+ helper T lymphocytes in the milieu provided by the dendritic cells and subsequently spills over into the circulation. In the absence of an immune response, this results in intense viremia in the early weeks following primary infection. During this phase, extensive dissemination of the virus occurs throughout the body. In approximately 50% to 70% of individuals, this might become clinically manifest as a self-limited, mononucleosis-like illness known as “acute HIV syndrome” (Table 1). Soon, with the elaboration of HIV-specific cell-mediated as well as humoral immune responses, viremia is brought under control albeit incompletely. A balance thus is struck between the opposing influences of viremia and the host immune response, establishing the viral load around a relatively low, stable level known as the virologic setpoint. The virologic setpoint is one of the important determinants of the pace of subsequent disease progression. Even if the viremia gets suppressed to below-detectable limits, despite the disease being clinically silent, active viral replication occurs throughout the course of HIV disease."
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