Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir.

BACKGROUND & AIMS: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin. METHODS: We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients. RESULTS: In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n = 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12. CONCLUSIONS: The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection.

Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery.

BACKGROUND: DNA vaccines have been very poorly immunogenic in humans but have been an effective priming modality in prime-boost regimens. Methods to increase the immunogenicity of DNA vaccines are needed. METHODS: HIV Vaccine Trials Network (HVTN) studies 070 and 080 were multicenter, randomized, clinical trials. The human immunodeficiency virus type 1 (HIV-1) PENNVAX®-B DNA vaccine (PV) is a mixture of 3 expression plasmids encoding HIV-1 Clade B Env, Gag, and Pol. The interleukin 12 (IL-12) DNA plasmid expresses human IL-12 proteins p35 and p40. Study subjects were healthy HIV-1-uninfected adults 18-50 years old. Four intramuscular vaccinations were given in HVTN 070, and 3 intramuscular vaccinations were followed by electroporation in HVTN 080. Cellular immune responses were measured by intracellular cytokine staining after stimulation with HIV-1 peptide pools. RESULTS: Vaccination was safe and well tolerated. Administration of PV plus IL-12 with electroporation had a significant dose-sparing effect and provided immunogenicity superior to that observed in the trial without electroporation, despite fewer vaccinations. A total of 71.4% of individuals vaccinated with PV plus IL-12 plasmid with electroporation developed either a CD4(+) or CD8(+) T-cell response after the second vaccination, and 88.9% developed a CD4(+) or CD8(+) T-cell response after the third vaccination. CONCLUSIONS: Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans.

Cobicistat-containing antiretroviral regimens are not recommended during pregnancy: viewpoint.

: Product labels for cobicistat with atazanavir or darunavir, and for elvitegravir/cobicistat/emtricitabine/tenofovir (alafenamide or disoproxil fumarate) were recently updated to state that these products are not recommended for initiation during pregnancy, and an alternative regimen is recommended for those who become pregnant during therapy with these products. Herein, we present the rationale for these recommendations, which are based on studies in pregnant women evaluating the pharmacokinetics and antiviral activity of darunavir/cobicistat or elvitegravir/cobicistat-containing antiretroviral regimens. In these studies, mean steady-state minimum concentrations in the second and third trimester versus postpartum of cobicistat, darunavir, and elvitegravir were reduced by 61-83%, 89-92%, and 82-86%, respectively. In the absence of data with atazanavir/cobicistat, we leveraged the available data with darunavir/cobicistat and elvitegravir/cobicistat to make recommendations for atazanavir/cobicistat. Darunavir/ritonavir and atazanavir/ritonavir remain viable treatment options for pregnant women.

Assessing a drug for an eradicated human disease: US Food and Drug Administration review of tecovirimat for the treatment of smallpox.

The development and ultimate approval of tecovirimat for the antiviral treatment of smallpox, a disease that has been eradicated from the world for nearly 40 years, required a unique regulatory approach based on the US Food and Drug Administration's Animal Rule. We summarise the regulatory pathway and describe the challenges involved.

Effects of Sorbitol on the Pharmacokinetics of Lamivudine Solution and the FDA's Decision to Increase the Dose of Lamivudine Solution for Pediatric Patients.

The article by Adkison et al. described sorbitol effects on lamivudine exposures. The results indicate a plausible mechanism for lower lamivudine exposures in pediatric patients receiving the solution formulation with concomitant medications containing sorbitol. In this commentary, we discuss lower lamivudine exposures in pediatric patients receiving the solution formulation, the impact of sorbitol on lamivudine exposures, and the US Food and Drug Administration's (FDA's) decision to increase the dose of the lamivudine solution for all pediatric patients.

US FDA Perspective on Elbasvir/Grazoprevir Treatment for Patients with Chronic Hepatitis C Virus Genotype 1 or 4 Infection.

Elbasvir/grazoprevir demonstrated high sustained virologic response rates 12 weeks after the end of treatment (SVR12) across five clinical trials in subjects infected with chronic hepatitis C virus (HCV) genotype 1, including those with advanced chronic kidney disease (CKD), and GT4. Despite favorable results overall, the US Food and Drug Administration (FDA) encountered challenging regulatory issues due to the limitations of clinical trial data in certain subpopulations. In GT1a-infected subjects, baseline NS5A resistance-associated polymorphisms emerged as the strongest baseline characteristic associated with diminished SVR12 rates following 12 weeks of elbasvir/grazoprevir treatment. The decision for recommending 16 weeks of elbasvir/grazoprevir + ribavirin in this population and for extrapolating these recommendations to patients with advanced CKD was based on benefit-versus-risk analyses using the available data. Conversely, FDA had insufficient data to define a specific elbasvir/grazoprevir treatment regimen for GT1a-infected subjects with baseline NS5A resistance-associated polymorphisms who failed prior treatment with pegylated interferon + ribavirin (PR) and either boceprevir, simeprevir, or telaprevir. For GT4 PR-experienced patients, leveraging of data in related populations and additional pooled analyses were employed to support labeling for elbasvir/grazoprevir. This article describes FDA's rationale for labeling determinations in situations where limited data made these decisions challenging.

Does an increase in serum creatinine always reflect renal injury? The case of Stribild®

Single tablet, once-daily HIV treatment regimens offer patient convenience, the potential for increased adherence, and fewer patient-related dosing errors[1] . Stribild® (manufactured and marketed by Gilead Sciences; referred to as "applicant" in this report), a 4-drug fixed-dose combination (FDC) tablet, is approved for the treatment of HIV-1 infection in treatment-naïve adult patients. Stribild® contains elvitegravir (an integrase strand transfer inhibitor), cobicistat (an inhibitor of cytochrome P450 enzymes), and the nucleoside/nucleotide reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF).

Intentions to use preexposure prophylaxis among current phase 2B preventive HIV-1 vaccine efficacy trial participants.

In November 2010, the iPrEx study reported that preexposure prophylaxis (PrEP) with daily tenofovir disoproxil fumarate/emtricitabine reduced HIV infections by 44% among men who have sex with men and subsequent trials corroborated efficacy among heterosexual men and women. During regularly scheduled follow-up visits from January to March 2011, participants in an ongoing phase 2b vaccine efficacy trial completed an anonymous Web survey about PrEP. Among 376 respondents, 17% reported they were very likely to use PrEP in the next year. Nonwhite participants were more likely to use PrEP. Among those with some level of interest, intent to use PrEP was greatest if the drug were available through the clinical trial or health insurance. Most (91%) believed taking PrEP would not change their willingness to stay in the vaccine trial and few thought it would affect recruitment. As key stakeholders, currently enrolled trial participants can offer vital input about emerging prevention technologies that may affect the design of future HIV vaccine and nonvaccine prevention trials.