PACTG 1039 (VERSION 10) A PHASE III RANDOMIZED TRIAL OF THE SAFETY AND ANTIR

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The current approach to antiretroviral therapy in pregnancy has had a dramatic effect on the risk of maternal to child transmission of HIV. In women whose viral load at the time of delivery is less than 1000 copies/mL, transmission rates are in the 1-2% range, regardless of the treatment regimen applied to achieve such a viral load. Public Health Service (PHS) guidelines for the treatment of non-pregnant, asymptomatic, chronically HIV-infected adults suggest that antiretroviral treatment be withheld until a viral load of 55,000 copies/mL or greater is reached, or CD4+ cell counts fall below 350 cells/mL. Once therapy is initiated, a regimen containing three or four drugs from usually at least two classes of antiretrovirals is recommended to maximize response, minimize the likelihood of development of viral resistance and optimize therapeutic durability. Important issues that must be considered when providing treatment to pregnant women who intend to discontinue treatment postpartum include: 1. Reduction of the risk of maternal to child transmission of HIV to the lowest attainable level 2. Minimization of the risk of fetal toxicity 3. Minimization of maternal drug side effects 4. Preservation of therapeutic options for the mother for the future 5. Minimization of the likelihood of developing resistance to antiretrovirals used during pregnancy and in the future. At present, the optimum means to attain these goals are unknown. PACTG P1022 was designed to compare a PI containing regimen (ZDV/3TC/Nelfinavir) to a protease inhibitor (PI)-sparing regimen (ZDV/3TC/Nevirapine) in women who initiate treatment during pregnancy. However, the study was discontinued because of significant adverse events in several of the subjects in the nevirapine arm of the study. Triple nucleoside regimens have been studied by several investigators as first line treatment for HIV-1 infected adults. One recent large study showed similar responses to treatment in subjects receiving regimens consisting of stavudine and didanosine plus indinavir or nevirapine or lamivudine. After 48 weeks of therapy there was no significant difference in the number of subjects with viral loads less than 500 copies/mL (57%, 58.4% and 58.7% respectively). Abacavir is a potent NRTI. It has been widely used in combination with zidovudine and lamivudine as Trizivir as proposed in the present study. Studies have shown that this NRTI combination is an effective and safe treatment regimen in both antiretroviral naive and antiretroviral experienced patients. In the first of these studies, subjects received either abacavir/lamivudine/zidovudine or indinavir/lamivudine/zidovudine. After 48 weeks of therapy an equivalent suppression of viral replication was seen in patients whose initial viral load was less than 100,000 copies/mL. A viral load less than 400 copies/mL was obtained in 51% of subjects in each group. In subjects with initial viral loads greater than 100,000 copies/mL a greater response was seen in subjects receiving indinavir. There were no differences in CD4+ cell counts between the two treatment arms. These studies support the use of Trizivir in suitable patients (viral load less than 100,000 copies/mL). Experience of Trizivir in pregnancy is somewhat limited although a growing number of clinicians are using this combination in suitable patients. There have been 527 cases of abacavir use in pregnancy reported to the Antiretroviral Pregnancy Registry as of the 31 January 2004 report. A recent study showed excellent suppression of viral load, no perinatal transmission of HIV and minimal side effects in 30 treated mother-infant pairs. Additional experience with Trizivir use in 10 pregnant women supports these findings, with viral suppression to less than 400 copies in 9/10 patients and no perinatal transmission. Abacavir therapy is associated with a small risk of idiosyncratic hypersensitivity which may be life threatening. The risk of this in pregnancy is, as yet, unquantified. PACTG P1039 will address some of these issues. The present study is limited to women with initial viral loads less than 55,000 copies/mL and CD4+ cell counts greater than 350. We expect to see an equivalent response to therapy with equal efficacy in both treatment arms based on published data in non pregnant adults meeting the same criteria. Although the NNRTI efavirenz is considered by many to be an important component to initial treatment, its potential toxicity to the fetus makes it a drug to be avoided during pregnancy. Protease inhibitors are considered by many experts as first line treatment for individuals initiating antiretroviral therapy. During pregnancy a combination of zidovudine, lamivudine and a PI has demonstrated efficacy in reducing mother-to-infant HIV transmission to less than 2%. Lopinavir/ritonavir (Kaletra) is a potent protease inhibitor that has demonstrated efficacy in the treatment of HIV- infected adults and is currently recommended by the Public Health Guidelines Committee as the preferred PI of choice when instituting antiretroviral therapy. Protease inhibitors have the documented side effects of glucose intolerance and altered lipid metabolism. The impact of such alterations in metabolism on maternal, fetal and newborn health have been little explored and may have far reaching implications for the future health of offspring exposed to this drug in utero.