HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct-acting antiviral regimens.

Multiple direct-acting antiviral (DAA)-based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post-treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

Accelerating drug development through collaboration: the Hepatitis C Drug Development Advisory Group.

Over the past decade, landmark collaboration between regulatory agencies, pharmaceutical companies, academia, and patient community representatives has enabled the development and approval of new hepatitis C virus (HCV) treatment regimens with unprecedented speed. By providing a neutral platform for cross-sector engagement, the Forum for Collaborative HIV Research's(1) HCV Drug Development Advisory Group played a critical role in fostering this collaboration and expediting drug development. The applicability of this model to other therapeutic areas should be explored.

Unusual distributions of body fat in AIDS patients: a review of adverse events reported to the Food and Drug Administration.

This report summarizes postmarketing adverse events reported to the Food and Drug Administration (FDA) that describe unusual or abnormal fat distribution in association with anti-retroviral therapies. Reports associated will protease inhibitors were compared to those associated with non-protease inhibitor antiretroviral therapies. The Spontaneous Reporting System (SRS) and Adverse Event Reporting System (AERS) of the FDA MEDWATCH post-marketing surveillance system served as the database. Four protease inhibitors (saquinavir, indinavir, nelfinavir, and ritonavir) and seven nonprotease inhibitors (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, and delavirdine) were searched for reports relating to: weight increase, unusual fat deposition, Cushing's syndrome, or Cushingoid appearance. Each drug was searched for its "life" from time of initial approval through a uniform database cutoff of March 18, 1998. A total of 62 cases of abnormal fat accumulation were reported in association with one or several of the four approved protease inhibitors compared to three cases reported in association with the seven non-protease inhibitor based therapies. Case descriptions varied, and included abdominal fat accumulation, breast enlargement, thick necks, buffalo humps, multiple lipomatous growths, Cushingoid features, centralized fat redistribution, and mesenteric, omental, and retroperitoneal fat accumulation. Some subjects switched or stopped their antiretroviral therapy, others underwent surgery to remove the fat, and many considered their symptoms disabling. The pathophysiologic mechanism for these events remains unclear and a causal link to a specific drug or drug class is uncertain. Patients and clinicians reporting to the MEDWATCH system, however, have clearly associated the development of abnormal body fat with protease inhibitors as opposed to other antiretroviral therapies.

The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs.

OBJECTIVES: To evaluate the utility of HIV RNA as an endpoint in antiretroviral efficacy studies. DESIGN: Data collected from antiretroviral efficacy trials were analyzed to explore relationships between clinical progression and the magnitude, nadir and duration of HIV RNA reductions. The proportion of patients suppressing HIV RNA below assay quantification, time to maximal virologic response, and loss of virologic response in relation to pretreatment characteristics were also analyzed. METHODS: Analyses were conducted using data from individual antiretoviral efficacy trials or groups of trials that studied similar types of drug regimens and used similar HIV RNA assays. Treatment regimens were pooled for most analyses. Clinical progression was defined as the occurrence of an AIDS-defining event (essentially Centers of Disease Control criteria) or death. RESULTS: Treatment-induced reductions in HIV RNA approximating total assay variability of about 0.5 log10 copies/ml were associated with decreases in the risk of clinical progression. Larger and more sustained reductions in HIV RNA were directly associated with lower risks for disease progression. Lower initial HIV RNA reductions were associated with more durable HIV RNA suppression. CONCLUSIONS: For antiretoviral efficacy studies, plasma HIV RNA is a suitable study endpoint that is likely to predict a decreased risk for AIDS progression and death. Because greater and more sustained reductions in HIV RNA appear to confer greater reductions in clinical risk, maintaining maximal suppression of plasma HIV RNA, particularly below the limits of assay quantification, appears to be a rigorous benchmark for assessing the efficacy of antiretroviral regimens.

Protease inhibitors for the treatment of human immunodeficiency virus infection.

The pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage and administration of protease inhibitors are reviewed. Protease inhibitors are a novel class of drugs used for the treatment of human immunodeficiency virus (HIV) infection. Saquinavir, ritonavir, indinavir, and nelfinavir have been approved in the United States; several other agents are under development. Protease inhibitors selectively block HIV protease, an enzyme involved in the later stages of HIV replication. Various pharmacokinetic differences exist among these agents, including differences in bioavailability, protein binding, and drug interactions. The drugs undergo extensive hepatic metabolism; dosage adjustments should be considered for patients with hepatic dysfunction. Clinical trials have shown protease inhibitors to be effective in reducing HIV RNA levels and increasing CD4+ lymphocyte counts. When protease inhibitors are used in combination with other antiretroviral agents, an additional beneficial effect on these markers occurs. Adverse effects of saquinavir and nelfinavir include mild gastrointestinal disturbances such as diarrhea. Ritonavir is less well tolerated because of gastrointestinal disturbances and circumoral and peripheral paresthesia. Indinavir has been associated with nephrolithiasis and asymptomatic hyperbilirubinemia. The development of resistance to protease inhibitors may be related to suboptimal dosages, noncompliance, or partial compliance. Protease inhibitors are potent and highly selective agents that block a critical step in HIV replication. They are effective and relatively well tolerated, but they are expensive, have extensive drug interaction profiles, and require careful compliance with the prescribed regimen.

Perceived parental behavior and the social desirability response set.

The purpose of the present study was to investigate the potential effects of the social desirability response set as a confounding variable in research involving self-report measures of perceived parental behavior. Scores on the Marlowe-Crowne Social Desirability Scale (M-C SDS) were correlated with each of the three factors on the Bronfenbrenner Parental Behavior Scale (BPB): (1) Loving, (2) Punishing, and (3) Demanding. Fifty-eight young adults participated in the study; the sample included roughly equal numbers of black and white subjects, male and female subjects, and college students and other community residents. Scores were analyzed by sex of subject and sex of parent as well as in combined groups. Significant correlations (p<.05, p<.01) were obtained from female subjects on BPB factors 2 and 3. Implications for the BPB's validity and suggestions for future research are discussed.