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.

Clinical evaluation of the nelfinavir-rifabutin interaction in patients with tuberculosis and human immunodeficiency virus infection.

STUDY OBJECTIVE: To characterize the bidirectional interaction between twice-daily nelfinavir and twice-weekly rifabutin and isoniazid in patients with tuberculosis and human immunodeficiency virus (HIV) infection. DESIGN: Prospective cohort study. SETTING: Three clinical research centers. PATIENTS: Seven patients with HIV-related tuberculosis. INTERVENTION: Rifabutin 300 mg and isoniazid 15 mg/kg (maximum dose 900 mg) twice/week were administered for at least 2 weeks during the continuation phase of tuberculosis treatment. Antiretroviral therapy with nelfinavir 1250 mg twice/day and two nucleoside reverse transcriptase inhibitors was then added. MEASUREMENTS AND MAIN RESULTS: Patients underwent blood sampling for pharmacokinetic analysis during the continuation phase of tuberculosis therapy and after a median of 21 days after the addition of antiretroviral treatment. When rifabutin was coadministered with nelfinavir, its area under the concentration-time curve from 0-21 hours (AUC(0-21)) increased 22% (geometric mean 5.01 microg.hr/ml [90% confidence interval (CI) 3.25-7.71] with nelfinavir vs 4.10 microg.hr/ml [90% CI 3.18-5.27] without nelfinavir; geometric mean ratio 1.22 [90% CI 0.78-1.92]). Also, the AUC(0-21) for the active metabolite, desacetylrifabutin, increased significantly (geometric mean ratio 3.46, 90% CI 1.84-6.47, p=0.009). In the presence of rifabutin, the pharmacokinetic parameters of nelfinavir and its principal metabolite M8 were similar to those of patients not taking rifabutin. No drug interaction between nelfinavir and isoniazid was detected. CONCLUSIONS: Coadministration of rifabutin and isoniazid without dosage adjustment during twice-weekly tuberculosis therapy with nelfinavir-based antiretroviral therapy resulted in rifabutin exposures within the acceptable ranges for safety and efficacy. Therefore, this combination is an appropriate option for the simultaneous treatment of tuberculosis and HIV infection when tuberculosis therapy is given twice weekly.

Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C.

OBJECTIVES: To determine the incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients with known stage of liver fibrosis. METHODS: All HIV/HCV-coinfected patients were monitored for a period of 12 months after starting nelfinavir-containing regimens and, with an available liver biopsy, were included in a retrospective study. RESULTS: A total of 82 patients were included in the study. Nine (10.9%) HIV/HCV-coinfected patients showed an episode of severe hepatotoxicity during the study period. Eight (9.8%) individuals showed grade 3 or 4 change in levels of serum alanine aminotransferase and one subject presented with an event of decompensated liver cirrhosis. Six (18.2%) of 33 patients with advanced liver fibrosis and three (6%) of 49 individuals without advanced liver fibrosis showed an episode of severe hepatotoxicity (P = 0.1). In the multivariate analysis, only nevirapine use during nelfinavir therapy [adjusted odds ratio (AOR) 8.9; 95% confidence interval (CI), 1.4-54.1; P = 0.01] was independently associated with risk of development of severe liver toxicity. CONCLUSIONS: The incidence of severe hepatotoxicity of nelfinavir-containing regimens is low among HIV/HCV-coinfected patients with known stage of liver fibrosis. In addition, our findings show that concomitant nevirapine use is associated with an increased risk of severe hepatotoxicity in these subjects. Likewise, the proportion of severe liver toxicity tended to be higher in individuals with advanced liver fibrosis.