John Hinkle

Severe Hepatotoxicity Associated with Nevirapine Use in HIV-Infected Subjects

Human immunodeficiency virus (HIV)-infected South African patients (n=468) received blinded lamivudine or emtricitabine, stavudine, and either nevirapine or efavirenz (based on screening viral load). Baseline characteristics were analyzed in univariate and multivariate regression, to identify risk factors for hepatotoxicity (grade 3 or greater increase in serum aminotransferase levels). The occurrence of early hepatotoxicity was 17% in the nevirapine group and 0% in the efavirenz group and was balanced between the lamivudine and emtricitabine arms. Two subjects died of hepatic failure. Independent risk factors were body-mass index (BMI) <18.5, female sex, serum albumin level <35 g/L, mean corpuscular volume >85 fL, plasma HIV-1 RNA load <20,000 copies/mL, aspartate aminotransferase level <75 IU/L, and lactate dehydrogenase level <164 IU/L. The use of nevirapine in female patients with a low BMI should be discouraged.

Pharmacogenetics of Nevirapine-Associated Hepatotoxicity: An Adult AIDS Clinical Trials Group Collaboration

Associations have been reported between an MDR1 variant and responses to nonnucleoside reverse-transcriptase inhibitors. We explored associations between MDR1, CYP2B6, and CYP3A polymorphisms and nevirapine hepatotoxicity. Among participants in a randomized study in South Africa (FTC-302), MDR1 3435C-->T was significantly associated with decreased risk of hepatotoxicity (risk ratio, 0.30; P=.016).

Bioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen.

Objective:Efavirenz (EFV; 600 mg), emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) are preferred agents for treatment of HIV-1 infection in adults. This study evaluated the pharmacokinetics (PK) and bioequivalence of an investigational coformulation of EFV/FTC/TDF (test) single-tablet regimen compared with the commercially available individual dosage forms (EFV+FTC+TDF; reference treatment) in healthy subjects. Methods:Subjects were randomized to 1 of 2 treatment sequences (test→reference or reference→test) in an open-label crossover study design. Study drug was administered under fasted conditions, and serial blood samples were obtained over 504 hours after oral administration of each treatment. Formulation bioequivalence was assessed in accordance with the US Food and Drug Administration bioequivalence criteria. Results:Forty-eight subjects were enrolled, and 45 completed the study, with all study treatments being generally well tolerated. For EFV (n = 44), the geometric mean ratios (90% confidence interval [CI]) for maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) were 99.9 (93.4 to 107), 95.7 (90.5 to 101), and 95.2 (88.9 to 102), respectively. For FTC (n = 45), the geometric mean ratios (90% CI) for Cmax, AUC0-last, and AUCinf were 88.8 (84.0 to 93.9), 98.0 (94.9 to 101), and 98.0 (94.9 to 101), respectively. For tenofovir (n = 45), the geometric mean ratios (90% CI) for Cmax, AUC0-last, and AUCinf were 91.5 (84.6 to 98.8), 99.3 (91.0 to 108), and 100 (93.2 to 108), respectively. Conclusions:The coformulation of EFV/FTC/TDF is bioequivalent to administration of its individual components.

Associations between HLA-DRB1*0102, HLA-B*5801, and hepatotoxicity during initiation of nevirapine-containing regimens in South Africa.

A three-drug regimen comprising nevirapine plus two nucleoside reverse transcriptase inhibitors is frequently prescribed for HIV-1 infection worldwide. Unfortunately, drug hypersensitivity which can include severe hepatotoxicity during the initial weeks of therapy with nevirapine, particularly when initiated in women with >250 CD4+ T cells/mm3, have prompted changes in prescribing guidelines. Although isolated non-severe skin rash associated with nevirapine may be managed conservatively, the major treatment-limiting side effect of nevirapine is a drug hypersensitivity syndrome comprising fever, skin rash and/or hepatitis. This affects as many as 5% of those starting the drug. Various HLA class I and II alleles have been associated with nevirapine rash and/or hepatitis across different populations [1–6]. A population based study from Western Australia first identified an association between HLA-DRB1*0101 and nevirapine-associated hepatitis among patients with ≥25% CD4+ T cells [1]. This work was complemented by ex vivo studies suggesting a CD4 T cell-dependent process. Associations were subsequently identified between various HLA class I alleles such as HLA-B*1402 and HLA-Cw8 and nevirapine hypersensitivity in Sardinian [2] and Japanese [3] populations. A case control study in a Thai population identified an association between HLA-B*3505 and nevirapine-associated rash or hypersensitivity [4]. Further analyses from Western Australia confirmed the original association between HLA-DRB1*0101 and ≥25% CD4 T cells, and identified an association between HLA-B*3501 and nevirapine-associated rash, suggesting that phenotype was particularly important for defining specific HLA associations [5]. Only in the presence of hepatitis was HLA-DRB1*0101 associated with rash, while HLA-B*3501 was associated with rash regardless of hepatitis [5]. A retrospective analysis involving 76 sites in 11 countries (none in Africa) enrolled 276 cases who had experienced severe rash and/or hepatitis within 8 weeks of nevirapine initiation, and 587 nevirapine-tolerant controls [6]. Based on two digit HLA typing, that study associated HLA-DRB1*01 with hepatitis in whites, both HLA-B*35 and HLA-Cw*04 with rash in Asians, and HLA-Cw*04 alone with rash in Whites and Blacks. Furthermore, CYP2B6 slow metabolizer genotype was associated with rash but not hepatotoxicity. The above studies suggest that diverse genetic, immunological and drug metabolism pathways contribute to nevirapine hypersensitivity syndromes, and that associations may differ by specific toxicity phenotype and population. Data from Africa, where HIV prevalence and nevirapine use is high have been scant. Herein we used data and specimens previously collected during a clinical trial in South Africa to characterize relationships between HLA I and II alleles and nevirapine hepatotoxicity.

Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir.

Objective:To evaluate the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (EVG/r) and the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV), didanosine (ddI), stavudine (d4T), or abacavir (ABC) upon coadministration. Methods:In 3 studies, healthy subjects were administered a single dose of ddI, d4T, or ABC, or multiple doses of ZDV, followed by multiple doses of EVG/r alone and together with an NRTI; pharmacokinetics (PK) of EVG and NRTIs were evaluated after individual administration and coadministration. Lack of PK alteration bounds (90% confidence intervals [CI]) for the NRTIs were based on the lack of PK-based dose adjustments per prescribing information. Results:Twenty-four of 28, 32/32, and 24/26 subjects completed the ZDV-EVG/r, ddI/d4T-EVG/r, and ABC-EVG/r studies, respectively. All study drugs were well tolerated and no serious adverse events were noted. The PK of ZDV, its glucuronide (G-ZDV), d4T, ABC, and EVG were within the lack of PK alteration 90% CI bounds upon coadministration. Exposures of ddI were modestly (∼15%) lower, but these changes are unlikely to be clinically meaningful. Conclusions:There are no clinically relevant drug interactions between EVG/r and the NRTIs zidovudine, didanosine, stavudine, or abacavir. These agents can be coadministered without dose adjustment.

Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir.

Objective:Elvitegravir (EVG) is in phase 3 development in combination with ritonavir (RTV)-boosted protease inhibitors in treatment-experienced, HIV-infected patients. Two studies evaluated pharmacokinetic (PK) interactions among EVG and RTV-boosted tipranavir (TPV/r) or darunavir (DRV/r). Methods:Healthy volunteers received EVG/r alone (study 1: 200/100 mg once daily; study 2: 125/100 mg once daily), TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) alone, and EVG (200 or 125 mg as applicable) added to TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) in a randomized crossover design, with assessment of steady-state PK for EVG, TPV, DRV, and RTV. Safety was assessed by clinical monitoring. Studies were powered to conclude lack of an interaction if the 90% confidence interval for the geometric mean ratios of the AUCtau and Cmax for EVG, TPV, and DRV were within predefined no-effect boundaries. Trough concentrations were also assessed. Results:No subjects discontinued for adverse events during treatment with EVG/r alone. On coadministration, AUCtau and Cmax of EVG and TPV and EVG and DRV were within prespecified no-effect boundaries versus treatment alone; trough concentrations were also not substantially altered. Conclusions:The PK of EVG and TPV or DRV were not altered after coadministration of EVG with TPV/r or DRV/r. EVG PK was similar with varied RTV doses of 100 mg once daily, 100 mg twice daily, or 200 mg twice daily. EVG can be added to TPV/r or DRV/r regimens without dose adjustment.

Long-term safety and efficacy results of once-daily emtricitabine-based highly active antiretroviral therapy regimens in human immunodeficiency virus-infected pediatric subjects.

OBJECTIVES. The purpose of this work was to obtain long-term safety and efficacy data for antiretroviral regimens containing emtricitabine in HIV-infected pediatric subjects and confirm that a pediatric dose of 6 mg/kg once daily would provide steady-state emtricitabine concentrations comparable to those observed in adults given 200 mg of emtricitabine once daily. PATIENTS AND METHODS. HIV-infected subjects between 3 months and 16 years of age were enrolled, including 71 antiretroviral-naïve subjects and 45 antiretroviral-experienced subjects. Naive subjects received emtricitabine plus stavudine plus lopinavir or ritonavir. Experienced subjects replaced the lamivudine in their existing regimens with emtricitabine. Tolerance, safety, disease progression, and virologic and immunologic responses were evaluated. RESULTS. The Kaplan-Meier probability of persistent virologic response in the intent-to-treat population through week 164 at ≤400 copies per mL and ≤50 copies per mL was 74% and 62%, respectively. Three subjects (3%) discontinued the study for adverse events, 8 (7%) for virologic failure, and 1 died through a median follow-up of 164 weeks. The annualized incidence rate of grade 3 to 4 adverse events and grade 3 to 4 laboratory abnormalities was 6% and 3%, respectively. The annualized incidence rate of serious adverse events was 9%, with 1% attributed as related to emtricitabine. Genotypic analysis showed the emergence of the M184V mutation in 4 of the 15 subjects who experienced virologic failure through week 164. Pharmacokinetic evaluation demonstrated plasma drug exposures in these children comparable to adults receiving the approved dose of 200 mg once daily. CONCLUSIONS. These results demonstrate the safety and efficacy of emtricitabine in pediatric patients. They also support that the safety and efficacy profile of emtricitabine in children is similar to that demonstrated in adults.

Absorption and safety of serum-derived bovine immunoglobulin/protein isolate in healthy adults

Purpose Previous studies have shown that oral administration of bovine immunoglobulin protein preparations is safe and provides nutritional and intestinal health benefits. The purpose of this study was to evaluate the plasma amino acid response following a single dose of serum-derived bovine immunoglobulin/protein isolate (SBI) and whether bovine immunoglobulin G (IgG) is present in stool or in blood following multiple doses of SBI in healthy volunteers. Methods A total of 42 healthy adults were administered a single dose of placebo or SBI at one of three doses (5 g, 10 g, or 20 g) in blinded fashion and then continued on SBI (2.5 g, 5 g, or 10 g) twice daily (BID) for an additional 2 weeks. Serial blood samples were collected for amino acid analysis following a single dose of placebo or SBI. Stool and blood samples were collected to assess bovine IgG levels. Results The area under the curve from time 0 minute to 180 minutes for essential and total amino acids as well as tryptophan increased following ingestion of 5 g, 10 g, or 20 g of SBI, with a significant difference between placebo and all doses of SBI (p<0.05) for essential amino acids and tryptophan but only the 10 g and 20 g doses for total amino acids. Bovine IgG was detected in the stool following multiple doses of SBI. No quantifiable levels of bovine IgG were determined in plasma samples 90 minutes following administration of a single dose or multiple doses of SBI. Conclusion Oral administration of SBI leads to increases in plasma essential amino acids during transit through the gastrointestinal tract and is safe at levels as high as 20 g/day.

Evaluation of oral serum-derived bovine immunoglobulins in HIV-infected patients with chronic idiopathic diarrhea

Objectives To evaluate serum-derived bovine immunoglobulin/protein isolate (SBI) for safety and impact on gastrointestinal (GI) symptoms in HIV patients with chronic idiopathic diarrhea. Methods A multi-center trial comprised of a double-blind, placebo (PBO)-controlled lead-in phase, (participants received PBO or SBI at 2.5 or 5.0 g BID for 4 weeks) followed by a 20-week, PBO-free phase (SBI at either 2.5 or 5.0 g BID). Participants included HIV-infected patients who were virologically suppressed with a history of chronic idiopathic diarrhea, defined as > 3 loose stools per day for ≥ 3 months without an identifiable cause. Safety was evaluated by monitoring adverse events (AEs) and clinical laboratory testing. Health status and changes in GI symptoms were assessed using validated questionnaires. Results SBI was well tolerated by the 103 participants with only 2 withdrawals due to AEs potentially associated with SBI. Mean number of daily unformed stools decreased from about 4 at baseline to less than 2 by week 4 for all study groups. Improvements in several other GI symptoms were also reported. Comparison of the PBO group to SBI groups showed no significant differences, although both SBI cohorts reported significantly improved health status scores. GI symptom improvements were maintained throughout the 20-week PBO-free phase. Conclusions Oral SBI is safe and well tolerated at the doses studied in HIV patients with chronic diarrhea. No conclusions could be drawn regarding impact on GI symptoms. Additional studies are ongoing to examine the biological and immunologic effects of SBI in virologically suppressed HIV-infected patients.