Kenneth E. Sherman

Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection

BACKGROUND Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. METHODS We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. RESULTS Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). CONCLUSIONS In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).

Hepatitis C virus infection in USA: an estimate of true prevalence.

The recent National Health and Nutrition Examination Survey (NHANES) sampled only the civilian, non‐institutionalized population of USA and may have underestimated the prevalence of hepatitis C virus (HCV) in this country. We searched the database MEDLINE, the Bureau of Justice Statistics, Center for Medicare and Medicaid and individual states Department of Corrections for all epidemiological studies regarding the prevalence of HCV in populations not sampled by the NHANES survey namely the incarcerated, homeless, nursing home residents, hospitalized and those on active military duty. Because of their relatively low frequency in the NHANES sample, we also expanded our search to include healthcare workers and long‐term dialysis patients. Although included in the NHANES sample, we also performed searches on drug users (injection and non‐injection) and veterans to confirm the findings of the NHANES study. Based on the prevalence of studies identified meeting our inclusion criteria, our most conservative estimates state that there at least 142 761 homeless persons, 372 754 incarcerated persons and 6805 persons on active military duty unaccounted for in the NHANES survey. While the NHANES estimates of drug users (both injection and non‐injection) appear to be reasonable, the survey seems to have underestimated the number of HCV‐positive veterans. Our most conservative estimates suggest that there are at least 5.2 million persons living with HCV in USA today, approximately 1.9 million of whom were unaccounted for in the NHANES survey.

Principles for the Conservation of Wild Living Resources

We describe broadly applicable principles for the conservation of wild living resources and mechanisms for their implementation. These principles were engendered from three starting points. First, a set of principles for the conservation of wild living resources (Holt and Talbot 1978) required reexamination and updating. Second, those principles lacked mechanisms for implementation and consequently were not as effective as they might have been. Third, all conservation problems have scientific, economic, and social aspects, and although the mix may vary from problem to problem, all three aspects must be included in problem solving. We illustrate the derivation of, and amplify the meaning of, the principles, and discuss mechanisms for their implementation. The principles are: Principle I. Maintenance of healthy populations of wild living resources in perpetuity is inconsistent with unlimited growth of human consumption of and demand for those resources. Principle II. The goal of conservation should be to secure present and future options by maintaining biological diversity at genetic, species, population, and ecosystem levels; as a general rule neither the resource nor other components of the ecosystem should be perturbed beyond natural boundaries of variation. Principle III. Assessment of the possible ecological and sociological effects of resource use should precede both proposed use and proposed restriction or expansion of ongoing use of a resource. Principle IV. Regulation of the use of living resources must be based on understanding the structure and dynamics of the ecosystem of which the resource is a part and must take into account the ecological and sociological influences that directly and indirectly affect resource use. Principle V. The full range of knowledge and skills from the natural and social sciences must be brought to bear on conservation problems. Principle VI. Effective conservation requires understanding and taking account of the motives, interests, and values of all users and stakeholders, but not by simply averaging their positions. Principle VII. Effective conservation requires communication that is interactive, reciprocal, and continuous. Mechanisms for implementation of the principles are discussed.

Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1

BACKGROUND The combination of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection. Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 (HIV-1). METHODS This was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients, all of whom were coinfected with HIV-1. Previously untreated patients were randomly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a standard dose of 60 mg daily (with dose adjustment for concomitant antiretroviral medications) plus 400 mg of sofosbuvir daily. Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses. The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks. RESULTS Patients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised. CONCLUSIONS Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.).

Mechanism of indinavir-induced hyperbilirubinemia

Indinavir is a viral protease inhibitor used for the treatment of HIV infection. Unconjugated hyperbilirubinemia develops in up to 25% of patients receiving indinavir, prompting drug discontinuation and further clinical evaluation in some instances. We postulated that this side-effect is due to indinavir-mediated impairment of bilirubin UDP-glucuronosyltransferase (UGT) activity and would be most pronounced in individuals with reduced hepatic enzyme levels, as occurs in ≈10% of the population manifesting Gilberts syndrome. This hypothesis was tested in vitro, in the Gunn rat model of UGT deficiency, and in HIV-infected patients with and without the Gilberts polymorphism. Indinavir was found to competitively inhibit UGT enzymatic activity (KI = 183 μM) while concomitantly inducing hepatic bilirubin UGT mRNA and protein expression. Although oral indinavir increased plasma bilirubin levels in wild-type and heterozygous Gunn rats, the mean rise was significantly greater in the latter group of animals. Similarly, serum bilirubin increased by a mean of 0.34 mg/dl in indinavir-treated HIV patients lacking the Gilberts polymorphism versus 1.45 mg/dl in those who were either heterozygous or homozygous for the mutant allele. Whereas saquinavir also competitively inhibits UGT activity, this drug has not been associated with hyperbilirubinemia, most likely because of the higher KI (360 μM) and substantially lower therapeutic levels as compared with indinavir. Taken together, these findings indicate that elevations in serum-unconjugated bilirubin associated with indinavir treatment result from direct inhibition of bilirubin-conjugating activity.

Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial.

BACKGROUND Telaprevir (TVR) plus peginterferon-α2a (PEG-IFN-α2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-α2a-ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown. OBJECTIVE To assess the safety and efficacy of TVR plus PEG-IFN-α2a-ribavirin in patients with genotype 1 HCV and HIV-1 and to evaluate pharmacokinetics of TVR and antiretrovirals during coadministration. DESIGN Phase 2a, randomized, double-blind, placebo-controlled study. (ClinicalTrials.gov: NCT00983853). SETTING 16 international multicenter sites. PATIENTS 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment-naive and receiving 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-α2a-ribavirin or placebo plus PEG-IFN-α2a-ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-α2a-ribavirin. MEASUREMENTS HCV RNA concentrations. RESULTS Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-α2a-ribavirin during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-α2a-ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-α2a-ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-α2a-ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-α2a-ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-α2a-ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR. LIMITATION Small sample size and appreciable dropout rate. CONCLUSION In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-α2a-ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-α2a-ribavirin.

Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127

Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in subjects coinfected with HIV. Tenofovir disoproxil fumarate (TDF) and adefovir dipivoxil (ADV) are licensed for the treatment of HIV‐1 and HBV infection, respectively, but both have in vivo and in vitro activity against HBV. This study evaluated the anti‐HBV activity of TDF compared to ADV in HIV/HBV‐coinfected subjects. ACTG A5127 was a prospective randomized, double‐blind, placebo‐controlled trial of daily 10 mg of ADV versus 300 mg of TDF in subjects with HBV and HIV coinfection on stable ART, with serum HBV DNA ≥ 100,000 copies/mL, and plasma HIV‐1 RNA ≤ 10,000 copies/mL. This study closed early based on results of a prespecified interim review, as the primary noninferiority end point had been met without safety issues. Fifty‐two subjects were randomized. At baseline, 73% of subjects had a plasma HIV‐1 RNA < 50 copies/mL, 86% were HBeAg positive, 94% were 3TC resistant, median serum ALT was 52 IU/L, and 98% had compensated liver disease. The mean time‐weighted average change in serum HBV DNA from baseline to week 48 (DAVG48) was −4.44 log10 copies/mL for TDF and −3.21 log10 copies/mL for ADV. There was no difference in toxicity between the 2 treatment arms, with 11 subjects (5 ADV and 6 TDF) experiencing elevations of serum ALT on treatment. In conclusion, over 48 weeks, treatment with either ADV or TDF resulted in clinically important suppression of serum HBV DNA. Both drugs are safe and efficacious for patients coinfected with HBV and HIV. (HEPATOLOGY 2006;44:1110–1116.)

Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences†

An estimated 170 million persons are infected with the hepatitis C virus (HCV) worldwide. While hepatocytes are the major site of infection, a broad clinical spectrum of extrahepatic complications and diseases are associated with chronic HCV infection, highlighting the involvement of HCV in a variety of non‐hepatic pathogenic processes. There is a growing body of evidence to suggest that HCV can replicate efficiently in extrahepatic tissues and cell types, including peripheral blood mononuclear cells. Nonetheless, laboratory confirmation of HCV replication in extrahepatic sites is fraught with technical challenges, and in vitro systems to investigate extrahepatic replication of HCV are severely limited. Thus, future studies of extrahepatic replication should combine innovative in vitro assays with a prospective cohort design to maximize our understanding of this important phenomenon to the pathogenesis and treatment response rates of HCV. (HEPATOLOGY 2006;44:15–22.)

Chronic Active Hepatitis B Exacerbations in Human Immunodeficiency Virus-Infected Patients Following Development of Resistance to or Withdrawal of Lamivudine

Lamivudine is a nucleoside analog with activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Patients coinfected with HIV and HBV may have hepatitis flares when lamivudine therapy is discontinued or when resistance of HBV to lamivudine emerges. This retrospective, descriptive study conducted in three tertiary care medical centers describes patients coinfected with HIV type 1 and HBV who presented with a spectrum of clinical and subclinical hepatitic responses to lamivudine withdrawal or resistance. One patient had fulminant hepatic failure and a second patient had subclinical hepatitis when lamivudine therapy was discontinued and a more efficacious antiretroviral regimen was substituted. Three patients had flares of hepatitis after 13 to 18 months of lamivudine therapy. Lamivudine withdrawal or emergence of lamivudine-resistant mutants in patients coinfected with HIV and HBV may result in severe hepatitis. Clinicians caring for patients with coinfection with HIV and HBV should be aware of the possibility that a hepatitis B flare may occur in previously asymptomatic carrier patients.

Immune recovery is associated with persistent rise in hepatitis C virus RNA, infrequent liver test flares, and is not impaired by hepatitis C virus in co-infected subjects.

Objectives: The impact of highly active antiretroviral therapy (HAART) on hepatitis C virus (HCV) is unknown. We analysed changes in HCV RNA and the frequency of hepatotoxicity in co-infected patient enrolling in AIDS Clinical Trials Group trials, and determined whether HCV impairs successful immune reconstitution in these populations. Design/methods: In a prospective analysis of co-infected patients completing at least 16 weeks of HAART in four trials, and co-infected patients with available stored plasma from two other completed HAART trials, HCV RNA was measured at baseline and to week 48. A retrospective analysis of immune recovery in 40 HCV-RNA-positive and 129 HCV-RNA-negative patients from a single trial was performed. Results: Prospective analysis: 60 patients completed at least 16 weeks of HAART. The mean HCV-RNA level increased 0.35 log10 IU/ml at week 16 and 0.43 log10 IU/ml at week 48. When stratified by baseline CD4 cell count, subjects’ HCV-RNA levels increased 0.43 and 0.59 log10 IU/ml at weeks 16 and 48 for entry CD4 cell counts < 350 cells/mm3, but only 0.26 and 0.1 log10 IU/ml at weeks 16 and 48 for entry CD4 cell counts > 350 cells/mm3. Severe alanine aminotransferase elevations occurred in only 3.3%. Retrospective analysis: HCV co-infection had no effect on the overall mean CD4 cell increase at weeks 16 or 48 compared with uninfected controls. Conclusion: In HCV-co-infected patients undergoing HAART, immune recovery is associated with a persistent increase in HCV RNA, especially with baseline CD4 cell counts < 350 cells/mm3. HCV co-infection did not antagonize the CD4 cell response to HAART.