Veronica Miller

Hepatitis C virus drug resistance-associated substitutions: State of the art summary.

Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon‐free, all‐oral combinations of direct‐acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct‐acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors’ trials as a tool to inform the HCV drug development field. (Hepatology 2015;62:1623–1632)

Recommendations for standardized nomenclature and definitions of viral response in trials of hepatitis C virus investigational agents

Outdated virological response terms used at key trial timepoints in clinical trials with first‐generation direct‐acting antivirals plus pegylated interferon and ribavirin have failed to keep pace with hepatitis C virus (HCV) drug development. A more intuitive and flexible nomenclature capable of adapting to continuing advances in HCV drug development is needed. Assistance in standardization of the field was provided by members of the Hepatitis C Virus Drug Development Advisory Group, a project of the Forum for Collaborative HIV Research with participation from the American Association for the Study of Liver Diseases, European Association for the of the liver, and the Infectious Diseases Society of America. Our proposed descriptive, virological response nomenclature for key decision points in trials (with and without lead‐in treatment) is based on an assay‐specified lower limit of quantitation cutoff. This allows responses to be categorized as either quantifiable or unquantifiable HCV RNA, with unquantifiable responses further divided based on whether target HCV RNA was detected or not detected. The unified reporting recommendations will facilitate interpretation of results across clinical trials and validation of new response‐guided timepoints. As time‐critical treatment parameters are shortened in HCV trials, the proposed nomenclature will greatly simplify and facilitate future adaptations of virological response terms. Our proposed nomenclature will also be helpful in developing treatment guidelines for use in clinical practice. (HEPATOLOGY 2012;56:2398–2403)

Sequence and phenotypic analysis for resistance monitoring in hepatitis C virus drug development: recommendations from the HCV DRAG.

ANN D. KWONG,* ISABEL NAJERA, JILL BECHTEL, SCOTT BOWDEN, JOSEPH FITZGIBBON, PATRICK HARRINGTON, DALE KEMPF,** TARA L. KIEFFER,* DIANA KOLETZKI, GEORGE KUKOLJ, SHARLENE LIM, TAMI PILOT–MATIAS,** KAI LIN, NINA MANI, HONGMEI MO,*** JULES O’REAR, MICHAEL OTTO, NEIL PARKIN, JEAN–MICHEL PAWLOTSKY, CHRIS PETROPOULOS, GASTON PICCHIO, ROBERT RALSTON,**** JACQUELINE D. REEVES, ROBERT T. SCHOOLEY, SCOTT SEIWERT, DAVID STANDRING, LIEVEN STUYVER, JAMES SULLIVAN,* VERONICA MILLER, under the auspices of the Forum or Collaborative Human Immunodeficiency Virus Research and on behalf of the HCV Drug Development Advisory Group HCV DRAG), for the Sequence Analysis Working Group (SAWG) and Phenotype Analysis Working Group (PAWG)

Adverse Outcome Analyses of Observational Data: Assessing Cardiovascular Risk in HIV Disease

Clinical decisions are ideally based on randomized trials but must often rely on observational data analyses, which are less straightforward and more influenced by methodology. The authors, from a series of expert roundtables convened by the Forum for Collaborative HIV Research on the use of observational studies to assess cardiovascular disease risk in human immunodeficiency virus infection, recommend that clinicians who review or interpret epidemiological publications consider 7 key statistical issues: (1) clear explanation of confounding and adjustment; (2) handling and impact of missing data; (3) consistency and clinical relevance of outcome measurements and covariate risk factors; (4) multivariate modeling techniques including time-dependent variables; (5) how multiple testing is addressed; (6) distinction between statistical and clinical significance; and (7) need for confirmation from independent databases. Recommendations to permit better understanding of potential methodological limitations include both responsible public access to de-identified source data, where permitted, and exploration of novel statistical methods.

HIV and HCV infection in the United States: Whom and How to Test

In the United States, of the 1.1 million persons infected with human immunodeficiency virus (HIV) and the 2.7 million infected with hepatitis C virus (HCV), approximately 16% and 50%, respectively, are unaware of their infection. Highly effective treatments have turned both diseases into manageable conditions, and in the case of hepatitis C, a disease that can be cured. Early diagnosis is imperative so that infected persons can take measures to stay healthy, get into care, benefit from therapy, and reduce the risk of transmission. In this report, we review current recommendations provided by the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force on whom to screen for HIV and HCV infections, and recommendations from the CDC, the Association of Public Health Laboratories, and the Clinical and Laboratory Standards Institute on how to test for these infections.

HIV and Hepatitis C Virus Infection in the United States: Whom and How to Test

In the United States, of the 1.1 million persons infected with human immunodeficiency virus (HIV) and the 2.7 million infected with hepatitis C virus (HCV), approximately 16% and 50%, respectively, are unaware of their infection. Highly effective treatments have turned both diseases into manageable conditions, and in the case of hepatitis C, a disease that can be cured. Early diagnosis is imperative so that infected persons can take measures to stay healthy, get into care, benefit from therapy, and reduce the risk of transmission. In this report, we review current recommendations provided by the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force on whom to screen for HIV and HCV infections, and recommendations from the CDC, the Association of Public Health Laboratories, and the Clinical and Laboratory Standards Institute on how to test for these infections.

Beneficial impact of antiretroviral therapy on non-AIDS mortality.

likely due to non-AIDS causes (than AIDS cause The remarkable impact of HAART on HIV-associated mortality has been amply demonstrated [1–5]. Treatment guidelines across the world reflect emergent information regarding benefits of earlier treatment initiation, including reduced AIDS-associated mortality and reduction of the risk of HIV transmission [6,7]. However, non-AIDS conditions as cause of death have become increasingly apparent with the decline of AIDS-related mortality [8,9]. A critical question is whether HAART reduces non-AIDS mortality among HIV-infected persons to levels observed in HIV-uninfected populations.

Regulatory Science and Drug Approval for Alcoholic and Nonalcoholic Steatohepatitis

lcoholic hepatitis (AH) and nonalcoholic steatoheApatitis (NASH) are 2 major causes of liver-related morbidity and mortality. While AH is a major cause of liver-related hospitalizations, NASH is projected to surpass hepatitis C virus infection as the leading etiology of endstage liver disease requiring liver transplantation. NASH is also the leading etiology driving the burden of hepatocellular cancer. Despite their obvious public health relevance, there are currently no drugs approved for either condition. Therefore, there is a need to consider the barriers that have contributed to this situation and the potential pathways to overcome such barriers to bring effective therapies for these conditions to afflicted individuals (Table 1).

Use of Viral Load as a Surrogate Marker in Clinical Studies of Cytomegalovirus in Solid Organ Transplantation: A Systematic Review and Meta-analysis

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

Sequencing of Hepatitis C Virus for Detection of Resistance to Direct-Acting Antiviral Therapy: A Systematic Review

The significance of the clinical impact of direct‐acting antiviral (DAA) resistance‐associated substitutions (RASs) in hepatitis C virus (HCV) on treatment failure is unclear. No standardized methods or guidelines for detection of DAA RASs in HCV exist. To facilitate further evaluations of the impact of DAA RASs in HCV, we conducted a systematic review of RAS sequencing protocols, compiled a comprehensive public library of sequencing primers, and provided expert guidance on the most appropriate methods to screen and identify RASs. The development of standardized RAS sequencing protocols is complicated due to a high genetic variability and the need for genotype‐ and subtype‐specific protocols for multiple regions. We have identified several limitations of the available methods and have highlighted areas requiring further research and development. The development, validation, and sharing of standardized methods for all genotypes and subtypes should be a priority. (Hepatology Communications 2017;1:379–390)