Maintenance therapy after combination therapy

study of maintenance therapy of HIV infection (after an initial response to combination therapy) showed that suppression of plasma HIV RNA was better sustained with a combination of indinavir, zidovudine, and lamivudine than either indinavir alone or zidovudine and lamvudine (17). A similar study also found that three-drug therapy (zidovu-dine, lamivudine, and indinavir) was more effective than two-drug maintenance therapy (zidovudine plus lamivudine or zidovudine plus indinavir) in sustaining a reduced viral load in HIV-1-infected patients after three months of induction therapy (18).

These studies and others have led to the current therapeutic approach to HIV, which involves HAART. These treatment guidelines suggest early and aggressive drug therapy with three antiretroviral drugs from different classes of drugs. In previously untreated patients, this approach is expected to reduce the plasma HIV virus levels to levels below the limits of detection (19). However, studies have shown that even with effective HAART therapy and unde-tectable plasma HIV virus levels, virus is still present in lymph nodes, semen, or possibly elsewhere. Furtado et al. (20) showed that despite treatment with potent antiretroviral drugs and suppression of plasma HIV-1 RNA, HIV transcription was actively present in peripheral blood mononuclear cells. Zhang et al. (21) found that several HIV-1-infected men on HAART therapy continued to have virus present in seminal cells, which may still allow for sexual transmission of the virus. Moreover, combination antiretrovirals appear to suppress HIV-1 replication in some, but not all, patients (22).

Regardless of these dilemmas, the leading problem with HAART therapy is its cost and availability. With the extremely high expense of daily combination treatment (i.e., $15,000 to $20,000 per year), more than 95% of the 46 million HIV-infected people worldwide cannot afford it. Further progress in the battle against HIV will require a more economic and accessible means of treatment that can reach the population in the developing world.

Prophylactic antiretroviral drugs. Another advance in the treatment of HIV is the potential to administer prophylactic antiretroviral drugs to exposed individuals in order to decrease the risk of acquiring infection. Although large-scale, placebo-controlled clinical trials are not logistically possible, one study has found that zidovudine prophylaxis reduced HIV seroconversion after percutaneous exposure (23,24). Current basic recommendations for postexposure prophylaxis (PEP) include a four-week regimen of zidovudine and lamivudine, begun as soon as possible after exposure (25). For occupational HIV exposure with additional risk for transmission (e.g., higher virus titers or larger blood exposure), indinavir or nelfi-navir is added to the basic regimen.

Zidovudine chemoprophylaxis is also effective in the reduction of perinatal transmission, in some studies decreasing the risk of vertical transmission from mother to child by 66 to nearly 70% (26,27). This regimen consists of daily oral zidovudine given during the last six weeks of pregnancy, followed by intravenous zidovudine during labor (28). Thereafter, the newborn is given oral zidovudine for the first six weeks of life. Implementation of this regimen in the United States and Europe has dropped the rate of perinatal transmission to 6% or less (29). However, the high expense of treatment is cost-prohibitive for developing countries. Three recent studies have evaluated the efficacy of short-term zidovudine in decreasing the risk of HIV-1 perinatal transmission. The trial regimens generally consisted of oral zidovudine given during the last four weeks of pregnancy, some with additional doses during labor. Results revealed a 37 to 38% decrease in vertical transmission of HIV-1 in subjects who breastfed (30,31). In a similar study without breastfeeding, the reduction in the rate of transmission was 50% (32). While a shorter course of zidovudine is considerably cheaper, ($50 for the shorter course vs. $800 for the longer course), the cost of therapy remains too high for most developing countries. Musoke et al. (33) found that a single dose of nevirapine administered to HIV-positive women during labor and another dose given to their infants during the first week of life may be a safe and well-tolerated treatment that is helpful in reducing perinatal transmission of HIV. This treatment would be a low-cost and accessible alternative for poor and developing countries with high rates of HIV infection and limited funds for treatment.

Guidelines for therapy. The National Institutes of Health has defined general principles for the therapy of HIV (34). Both plasma HIV RNA levels (viral load) and CD4+ T cell counts should be followed for monitoring of response to treatment. The combination of these values has been determined to be a more accurate assessment of prognosis (35). In addition, they are a useful tool in determining the efficacy of antiretro-viral treatment while the patient is awaiting clinical response. CD4+ counts indicate the extent of immune system damage and the risk for opportunistic infections. Although HIV RNA levels are more predictive of the risk for disease progression, CD4+ counts are a more accurate measurement of the effect of antiretroviral therapy.

HIV RNA levels should begin to decline within days of effective treatment and ideally should progressively fall to below the limits of detection within eight weeks, although complete suppression is seen in a maximum of only 60-80% of previously untreated patients. A more realistic eight-week target is a one-log reduction of the viral load. Rebound of viral load levels during consistent treatment may indicate resistant HIV variants and may likely require changes in the current antiretroviral regimen. It should be noted that if one of the drugs in the antiretroviral regimen must be stopped, they all should be stopped and that a single-drug substitution can be made only if the patient's viral load is completely suppressed.

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