About HIV : How is HIV Disease Treated?

While there is still no cure for HIV, new drugs are dramatically prolonging the lives of many HIV-positive people and making them feel healthy. For some, however, the drugs have side effects that may prevent their use. For others, the drugs simply do not work. Also, the long-term effectiveness of new drugs is relatively unknown.

Therapy should be initiated with antiretroviral drugs before the onset of symptoms, and must be maintained as long as possible to continue suppression of viral replication. Although monotherapy with any of the antiretroviral agents can increase CD4+ lymphocyte count, the clinical benefit of such therapy is limited, largely because of the development of viral resistance. Strategies of antiretroviral therapy have evolved to prevent or delay the development of viral resistance. Combination antiretroviral therapy has been shown to have superior effectiveness in controlling viral replication and in limiting the emergence of resistant virus. These effects translate into greater clinical benefit through reduced risk of HIV progression and death. Although none of the treatment options currently available offer a cure, they can significantly prolong the survival of the infected individual.

A system has been designed to provide accurate counts of helper T lymphocytes for guiding the use of antiretroviral chemotherapy in HIV infection. The system, called immunocytometry, employs labeled monoclonal antibodies developed for surface receptors on the T lymphocytes and, utilizing flow cytometry, accurately groups and counts them by their attached, labeled antibodies. The surface receptors on helper T lymphocytes (T4 lymphocytes) combine with the CD4 monoclonal antibody. The receptor is labeled the CD4 receptor and the cells are designated as CD4+ T lymphocytes. Similarly, the receptors on the suppressor or cytotoxic T lymphocytes (T8 lymphocytes) are labeled by the CD8 monoclonal antibody. Immunocytometry can be used to identify a range of cells in the circulating blood using appropriately labeled monoclonal antibodies.

At present, guidelines for beginning antiretroviral therapy in asymptomatically infected individuals are based on plasma HIV RNA levels (plasma viral load) and the CD4+ lymphocyte count. Viral load is the essential determinant in the decision to initiate therapy in these cases and is measured using the FDA approved RT-PCR assay (Roche). Viral load measurements along with CD4+ T cell counts and evaluation of clinical status should be performed at the beginning of therapy and every 3-4 months thereafter. Symptomatic individuals should be started on therapy as soon as possible regardless of CD4+ lymphocyte count or plasma HIV level and followed in the same manner as asymptomatic patients. In most patients adherence to a regimen of potent antiretroviral therapy results in a large decrease (>10 fold) in viral load during the first 4 weeks. If a decrease of this magnitude is not seen following initiation of therapy, patient adherence should be assessed and such factors as malabsorption ruled out. A change in drug regimen may be necessary. At present a minimally significant change in plasma viremia during therapy is considered to be a 3-fold increase or decrease. A significant decrease in CD4+ T lymphocyte count is a drop of >30% from baseline in absolute cell numbers. Discordance between trends in CD4+ T cell numbers and plasma HIV RNA levels can occur and complicate decisions regarding antiretroviral therapy. This may be due to factors that affect plasma HIV RNA testing. In such cases expert consultation should be considered.

Triple drug therapy i.e., highly active antiretroviral therapy (HAART) including one of several protease inhibitors with two of the nucleoside analogue type inhibitors is the current choice for initiating therapy for all patients unless otherwise contraindicated. Since these drugs must be taken on a rigid schedule, the patient's lifestyle should be taken into account. Other treatment options include non-nucleoside inhibitors such as nevirapine plus a protease inhibitor. Patients should be monitored every 3 to 4 months for plasma viral load, CD4+ T lymphocyte levels, and clinical status. Changes in therapy are often necessary either because of toxicity due to one or more of the drugs or treatment failure. Treatment failure can be due to poor compliance with the treatment schedule or because of viral resistance to one or more of the drugs. The latter is illustrated either by increasing levels of plasma viral load, falling CD4+ lymphocyte counts, or the patient's clinical decline. The initiation of new therapeutic regimens is guided, in part, by resistance testing of the patient's viral isolates and the patient's treatment history. The specific combination of antiretroviral therapy selected for such patients must take into account many factors. These include specific side effects, dosing schedules, interactions between different medications, and history of previous antiretroviral therapy.

Antiretroviral agents

Nucleoside Analogues. Nucleoside analogue reverse transcriptase inhibitors (NRTIs) were the first class of agents shown to be effective in the treatment of HIV infection. The target enzyme for this group of drugs is the HIV reverse transcriptase, an RNA-dependent DNA polymerase. Six NRTIs are currently licensed in the United States: zidovudine (AZT), didanosine (ddI), zalcitibine (ddC), stavudine (d4T), lamivudine (3TC), and abacivir.

Nonnucleoside Reverse Transcriptate Inhibitors. Nonnucleocide reverse transcriptate inhibitors (NNRTIs) noncompetively inhibit HIV reverse transcriptatst by binding to a site distant from the enzyme's active site. Three NNRTIs are currently available in the United States: nevirapine, delavirdine, and efavirenz.

Protease Inhibitors. Protease inhibitors (PIs) prevent maturation of virus protein by competively inhibiting HIV protease, an enzyme essential for viral protein cleavage. When this enzyme is blocked, incomplete, noninfectious virus particles are produced by the cell.

Recommendations for antiretroviral treatment continue to evolve with the development of new medications and additional data from clinical trials. At present there are five PIs approved for use, their generic names are; amprenavir, indinavir, nelfenavir, ritanavir, and saquinavir. Gastrointestinal upsets of varying degrees are common to all of them but other adverse reactions and toxicities as well as interactions with other drugs differ. Perhaps the most widely known adverse event which can occur during treatment with PIs is the development of lipodystrophy syndrome, a cosmetically undesirable redistribution of body fat. Although this has been seen in individuals not receiving treatment with PIs, its association with these drugs has been a cause for concern among HIV patients.

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