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Background & Aims Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. Methods Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. Results Of 177 patients, 169 (95.5%) were PI-naive. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. Conclusion Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. Lay summary Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. Clinical trial number NCT03092375 .

Multiple real-world studies have confirmed the safety and efficacy of hepatitis C (HCV) direct-acting antivirals (DAAs); however, few studies have provided data on long-term outcomes of patients without cirrhosis after achieving sustained virologic response (SVR).

Background & Aims Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. Methods We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. Results Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. Conclusions In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov , Number: NCT03092375 .

BACKGROUND & AIMS: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. METHODS: We collected data from the Hepatitis B Research Network—an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). RESULTS: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th–75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P

Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

To evaluate the change in premenstrual syndrome (PMS) symptoms in women with heavy periods who underwent endometrial ablation.The study used a prospective, single-arm cohort of adult women who were to undergo NovaSure endometrial ablation for heavy menses who also reported symptoms of PMS. A brief baseline survey was done to evaluate menstrual bleeding and baseline PMS symptoms, and two 30-day prospective validated measures of PMS were used. Follow-up surveys were sent at 4 to 6 months and included both the brief survey questions and the validated measures of PMS (Canadian Task Force classification II-3).Thirty-six women with heavy periods who were to undergo endometrial ablation had PMS symptoms and completed all surveys at baseline and follow-up. The mean age was 41.4 years, with a mean body mass index of 26.7. Most (27/36, 75%) had failed hormonal management. All measures of PMS showed significant improvement after endometrial ablation. Self-rating of PMS symptoms on a scale of 0 (none) to 10 (severe) improved from a baseline of 7.4 to a follow-up rating of 3.2 (p.05). The vast majority of women (35/36, 97%) reported improvement in PMS after undergoing endometrial ablation. Both validated measures of PMS, Daily Symptoms Report and Daily Record of Severity of Symptoms, showed statistically significant improvement in PMS symptoms.Women with heavy menses and associated PMS symptoms who undergo NovaSure endometrial ablation showed improvement in PMS symptoms, as well as reduced menstrual bleeding.

Background & Aims The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR. Methods A retrospective analysis of 1383 patients, encompassing genotypes 1–4, treated with peginterferon alfa-2a and ribavirin, was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis. Results RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1–4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97–7.52) for predicting SVR in multiple logistic regression analysis of these factors. Conclusions Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.

Background/Aims The aim of this study was to evaluate long term safety and antiviral activity of different doses of emtricitabine given once daily to patients chronically infected with hepatitis B. Methods Eligible patients were randomized in a double-blind, parallel study to evaluate 25, 100 or 200mg once daily doses of emtricitabine for 48 weeks. Patients were then followed for an additional 48 weeks on open-label 200mg emtricitabine. Serum HBV DNA, ALT, and hepatitis B serology were measured at regular intervals over the 2 years. Resistance surveillance was performed after 1 and 2 years on viremic samples, i.e. >4700copies/mL. Results Emtricitabine was well tolerated and produced a dose proportional antiviral response. After 2 years, 53% of the patients had serum HBV DNA ≤4700copies/mL, 33% seroconverted to anti-HBe and 85% had normal ALT. Eighteen percent of the patients who had received 200mg emtricitabine for 2 years developed resistance mutations. Conclusions Emtricitabine was well tolerated and demonstrated a potent antiviral response for up to 2 years in patients with chronic hepatitis B infection. Based on these data, 200mg emtricitabine once daily was chosen as the optimal dose for future hepatitis B studies.

Azathioprine is commonly prescribed for autoimmune hepatitis and inflammatory bowel disease. An acute gastroenteritis-like syndrome has been ascribed to azathioprine use, but chronic diarrhea has not. We report a patient with autoimmune hepatitis who developed severe small-bowel villus atrophy and chronic diarrhea after azathioprine was initiated (50 mg/day). We present a case report of a patient followed up prospectively. Duodenal mucosal histology and expression of brush border enzyme dipeptidyl peptidase IV and peptide transporter PepT1 messenger RNA levels were determined before and after azathioprine discontinuation. Chronic diarrhea developed several weeks after the initiation of azathioprine and resulted in micronutrient depletion and severe protein-calorie malnutrition, which was unresponsive to oral pancreatic enzyme therapy or a gluten-free diet. Severe malabsorption required parenteral nutrition support for longer than 1.5 years; this was complicated by unstable blood glucose control, acute calculous cholecystitis, catheter sepsis, and severe venous thrombosis. When the temporal association between azathioprine and diarrhea was identified, the drug was tapered while the patient consumed an unrestricted diet. Within 2 weeks after azathioprine was discontinued, diarrhea had completely resolved, and parenteral nutrition was discontinued. Mucosal biopsies obtained before and 4 months after azathioprine discontinuation showed complete reversal of severe duodenal villus atrophy and marked up-regulation of mucosal dipeptidyl peptidase IV and PepT1 messenger RNA. The patient has subsequently maintained normal liver function tests on low-dose prednisone alone, with normal stools and stable nutritional status for longer than 4 years. Azathioprine can induce severe small-bowel villus atrophy, diarrhea, and malabsorption that is reversible with drug discontinuation.

Major advances in the treatment of chronic hepatitis C have been made during the last decade. The use of PEG-IFN in combination with ribavirin undoubtedly will become the new standard of care for patients with chronic hepatitis C. For the first time there will soon be a choice of medications for which long-term benefit will be the rule rather than the exception, as sustained virologic response rates rise above 50%. As the data mature from clinical trials with these new agents, clinicians will be able to refine and expand the indications for their use, hone the predictors of sustained response, and develop new paradigms to optimize treatment for chronic hepatitis C.

Hepatitis C is the most common cause of liver disease in the dialysis patient. The prevalence of chronic hepatitis C determined by anti-HCV testing in this population ranges from 6% to 38%. Using second generation EIA assays, the prevalence of anti-HCV among patients participating in the 1997 National Surveillance of Dialysis Associated Diseases in the United States was 9.3%. Polymerase chain reaction testing for HCV RNA has shown that the prevalence of HCV infection can be as high as 20% to 30% of dialysis patients. The causes and source of infection in patients with chronic renal failure on hemodialysis are multiple. Before the introduction of routine screening of blood donors for anti-HCV, blood transfusions were an important risk factor for acquisition of hepatitis C. Other potential sources of infection include exposure to contaminated equipment and nosocomial routes such as patient-to-patient exposure. The risk of infection appears to correlate with the duration of hemodialysis and the number of transfusions. Interestingly, dialysate and buffers have been shown to be virus free even when used in hepatitis C infected patients. The natural history of chronic hepatitis C infection in patients with renal failure is not well characterized. Although persistent elevations in ALT levels occur in 12% to 50% of dialysis patients, the frequency of persistently normal ALT levels in HCV-infected dialysis patients appears to be higher than in HCV-infected patients without renal failure. Overt liver disease and liver failure rarely occur. The degree of inflammation in liver biopsies of renal failure patients is usually mild. Thus, progressive liver disease may be less common in patients with advanced renal disease but further studies are required to assess the true impact of hepatitis C infection in this high risk population. The impact of hepatitis C infection on morbidity and mortality of patients with end-stage renal disease remains poorly defined. Initial studies have failed to show a significant increase in mortality among HCV-infected hemodialysis or renal transplant patients within the first 5 years following transplantation. In contrast, recent studies with extended follow-up of renal transplant recipients suggest that hepatitis C infection may affect patient and graft survival during the second decade. Further studies are required to identify the mechanisms of infection of patients with end-stage renal disease and to define better treatment strategies for these patients before and after kidney transplantation.

Although knowledge of the molecular biology of the hepatitis C virus is rapidly evolving, current therapeutic strategies remain suboptimal for most patients with chronic hepatitis C. It is hoped that with information derived from virologic variables, therapy can be tailored to individual patients, offering them the greatest likelihood of response or preventing the unnecessary use of costly and occasionally unpleasant medications when treatment failure is deemed probable. Genotyping and quantitation of hepatitis C virus have provided great insights into the pathogenesis of chronic hepatitis C. Retrospective studies have demonstrated that hepatitis C virus genotyping and viral burden may play some role in disease progression and response to therapy. With the widespread availability of these tests, it is important to try to develop a rational plan for their use that will provide information in a manner that is both cost-effective and relevant to clinical decision making for the individual patient. At this point, the utility of measuring hepatitis C virus RNA levels and genotyping in making decisions about treatment regimens or monitoring therapy in daily clinical practice is continually evolving.

Rapidly evolving knowledge of the molecular biology of the hepatitis C virus (HCV) and the recognition that current therapeutic strategies are ineffective in most patients with chronic hepatitis C have fueled the search for methods to predict a favorable response to treatment. It is hoped that with information derived from demographic or virologic variables, therapy can be tailored to individual patients, offering them the greatest likelihood of response or, when treatment failure is deemed probable, preventing the unnecessary use of costly, occasionally unpleasant treatments. Genotyping of HCV and quantitation of viral load are virologic variables that have been evaluated as predictors of response to interferon therapy. Until recently, these tests were available only as research tools. However, most reference laboratories now offer some type of HCV RNA genotyping and quantitation, so that this information is readily available to gastroenterologists and patients. As we shall see, it is important to recognize the differences and limitations of the available HCV RNA assays within the context of clinical practice. The aim of this chapter will be to briefly review methodologies available for characterizing HCV RNA and to discuss their interpretation and clinical utility.

Background: Accurate quantitation of hepatitis C virus (HCV) RNA in serum may provide a means to predict disease course and response to interferon-alpha therapy. Several quantitative assays are commercially available, but none have been accepted as the gold standard. Methods and Results: The branched DNA quantitative hybridization assay (Quantiplex HCV 1.0, Chiron, Emeryville, CA) and a quantitative reverse transcription polymerase chain reaction (Amplicor HCV MONITOR, Roche Diagnostic Systems, Branchburg, NJ) were compared using a panel of 53 sera from patients with chronic hepatitis C. All sera contained HCV RNA of known genotype. Overall, there was a positive correlation between the results for the 41 sera that gave discrete values in both tests (r =.81, linear regression; P

Background & Aims: Glomerulonephritis is an uncommon complication of chronic hepatitis B virus (HBV) infection in adults. A high percentage of patients seem to have short-term response to interferon therapy with improvement of proteinuria. The aim of this study was to assess the long-term response of patients with HBV-related glomerulonephritis to interferon alfa therapy. Methods: All patients with chronic hepatitis B and glomerulonephritis who were treated with interferon alfa at the National Institutes of Health between 1985 and 1993 were assessed. Results: Of the 15 patients treated, 8 (53%) had a long-term serological response with sustained loss of serum hepatitis B e antigen and HBV DNA. After 1–7 years of follow-up, all 8 responders have normal serum aminotransferase levels and 5 are hepatitis B surface antigen negative. Seven of the responders also showed a gradual but marked improvement in proteinuria. In contrast, the 7 nonresponders continued to have evidence of active renal disease and 1 required long-term dialysis therapy. All 8 responders had membranous glomerulonephritis, whereas 4 of 7 nonresponders had membranoproliferative glomerulonephritis. Conclusions: Interferon alfa therapy resulted in long-term remission in liver disease in 8 of 15 patients with chronic hepatitis B and glomerulonephritis. This response was accompanied by significant improvement in markers of renal disease in the majority of patients.

Background & Aims T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). Methods We enrolled 200 adults with CHB who participated in the National Institutes of Health−supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Results Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3 + CD127 − regulatory T cells and CD4 + T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg) + than HBeAg − patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg + than HBeAg − patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. Conclusions HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell−based immune signatures for clinical phenotypes. These findings suggest additional T-cell−independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

LP08 SAFETY AND EFFICACY OF SOFOSBUVIR-CONTAINING REGIMENS IN HEPATITIS C INFECTED PATIENTS WITH REDUCED RENAL FUNCTION: REAL-WORLD EXPERIENCE FROM HCV-TARGET V. Saxena, F.M. Koraishy, M. Sise, J.K. Lim, R.T. Chung, A. Liapakis, D.R. Nelson, M. Schmidt, M.W. Fried, N. Terrault, and HCV-TARGET. University of California San Francisco, San Francisco, Saint Louis University School of Medicine, St. Louis, Massachusetts General Hospital, Boston, Yale University School of Medicine, New Haven, University of Florida, Gainesville, University of North Carolina, Chapel Hill, United States E-mail: varun.saxena@ucsf.edu

Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV.We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point.Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P.001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo.In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.

Body fluids from 14 patients with chronic hepatitis C were analyzed for the presence of hepatitis C viral RNA using the polymerase chain reaction. Nucleic acids were extracted from serum, saliva, and semen in guanidinium thiocyanate, subjected to reverse transcription, and then amplified by a double polymerase chain reaction technique using "nested" primers from the highly conserved 5′ non-coding region of the hepatitis C virus genome. Hepatitis C viral RNA was found in the serum of all patients in titers ranging between 10 −1 and 10 −3 . The hepatitis C viral genome was not detected in any saliva or semen sample. These findings suggest that body fluids of patients with chronic hepatitis C are rarely, if ever, contaminated with the hepatitis C virus. This may help to explain the infrequent transmission of this disease by sexual or close physical contact.

Recently developed drugs and innovative strategies for the treatment of chronic infection with genotype 1 hepatitis C virus (HCV) have become the standard of care. The protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are the first direct-acting antiviral (DAA) agents approved, and many more are being developed. These drugs substantially increased rates of sustained virologic response in treatment-naïve and -experienced patients, in conjunction with peginterferon and ribavirin (triple therapy), in phase 3 trials. The efficacy of triple therapy depends on appropriate selection of patients, although the population of patients that receive triple therapy could be expanded as the risk/benefit ratio improves. Attention to details that reflect the standard of care, such as appropriate dosing, anticipation of adverse effects, and strict adherence to stopping rules, will insure the success of these drugs and lead the way for new combination therapies.