Drug development strategies for salvage therapy: conflicts and solutions.
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Anti-HIV Agents↗
Biomedical subjects
Victor De Gruttola
Publications and source records attributed to Victor De Gruttola.
Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study.
BACKGROUND: Efavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment. METHODS: Adult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5, and MDR1 were characterized. RESULTS: The 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G-->T and CYP2C19 681G-->A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G-->A. CONCLUSIONS: Genetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Validation and discovery in Markov models of genetics data.
Markov models provide a natural framework for modeling cellular and molecular level changes over time. Kalbfleisch and Lawless propose using a Chi-squared statistic for assessing the appropriateness of assuming a first-order, homogeneous Markov process. While this statistic provides a global test of the Markov assumption, it does not permit identification of individual departures. We consider two approaches for discovering specific departures from the Markov assumption. First, we propose a diagnostic that tests whether the number of observed transitions out of a given state at a given time point is different than expected. Second, we construct statistics based on the number of observations in each state at each time point. In both cases, we construct multiple correlated statistics and testing is achieved through simulations. These approaches are applied to HIV genetics sequences measured over time.
Journal Article↗
Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection.
BACKGROUND: The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. METHODS: This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen. RESULTS: A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression. CONCLUSIONS: The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study.
Adult↗
Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection.
BACKGROUND: It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens. METHODS: In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir. RESULTS: A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21). CONCLUSIONS: There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice.
Adult↗
Cytomegalovirus (CMV) polymerase chain reaction profiles in individuals with advanced human immunodeficiency virus infection: relationship to CMV disease.
Cytomegalovirus (CMV) disease is a common complication of patients with advanced human immunodeficiency virus infection. The aim of the present study, based on a case-cohort design, was to determine the predictive value of follow-up and baseline qualitative plasma CMV polymerase chain reaction (PCR) values for CMV end-organ disease in 378 patients (158 who progressed to CMV end-organ disease and 220 who did not develop CMV disease). These patients are part of the full AIDS Clinical Trials Group 204 multinational study (1227 patients), a randomized, controlled trial that compared the effects of valacyclovir with those of acyclovir for CMV disease prevention. Baseline PCR positivity was a significant risk factor for CMV disease progression (relative risk [RR], 1.81; 95% confidence interval [CI], 1.09-3.00). In multivariate analyses, time-updated PCR positivity was strongly associated with progression to CMV end-organ disease (RR, 4.42; 95% CI, 2.87-6.81). Change in cumulative PCR status was informative for the risk of subsequent CMV disease.
AIDS-Related Opportunistic Infections↗
AIDS: prophecy and present reality.
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AIDS Serodiagnosis↗