Direct-Acting Antiviral Therapy for Patients with Chronic Hepatitis C Infection and Decompensated Cirrhosis.

Patients with chronic hepatitis C virus (HCV) infection and decompensated cirrhosis are an important population for antiviral therapy yet under-represented in clinical trials. HCV direct-acting antiviral (DAA) therapies, unlike interferon-containing regimens, can be safely utilized in decompensated patients. Per guidelines from the American Association for the Study of Liver Diseases (AASLD), therapy of choice in HCV and decompensated cirrhosis is sofosbuvir, an HCV polymerase inhibitor, combined with a replication complex inhibitor (NS5A inhibitor) with or without ribavirin. Combination therapy with a HCV protease inhibitor and an NS5A inhibitor is effective in this population but is specifically not recommended in AASLD guidelines due to safety concerns. Important risk factors for further decompensation during DAA therapy are serum albumin < 3.5 g/dL, MELD (Model for End-Stage Liver Disease) score > 14, or HCV genotype 3 infection. Although sustained virologic response (SVR) is achieved less often in patients with decompensated vs compensated cirrhosis, in clinical studies response rates are > 80%. Both Child-Turcotte-Pugh Class at baseline and viral genotype can affect these response rates. Achieving SVR lowers risk of mortality, but to a lesser extent than in individuals with compensated cirrhosis. Likewise, treating patients for HCV infection along with successful treatment for hepatocellular carcinoma improves risks of both liver-related and overall mortality. In fewer than one third of cases, treating transplant-eligible, HCV-infected patients pre-transplant enables their delisting from transplant wait lists.

Efficacy of Glecaprevir and Pibrentasvir in Patients With Genotype 1 Hepatitis C Virus Infection With Treatment Failure After NS5A Inhibitor Plus Sofosbuvir Therapy.

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.

The combination of simeprevir and sofosbuvir is more effective than that of peginterferon, ribavirin, and sofosbuvir for patients with hepatitis C-related Child's class A cirrhosis.

BACKGROUND & AIMS: The efficacy and safety of interferon-free regimens for the treatment of chronic hepatitis C virus (HCV) infections require further evaluation and comparison with those of interferon-containing regimens. We compared a regimen of peginterferon, ribavirin, and sofosbuvir with a regimen of simeprevir and sofosbuvir in patients with HCV infection and unfavorable treatment features. METHODS: We performed a prospective open-label study of 82 patients with chronic HCV genotype 1a infection and Child's grade A cirrhosis enrolled from 2 clinics at a single center in Atlanta, Georgia, from December 2013 through January 2014. Fifty patients (61%) had not responded to treatment with peginterferon and ribavirin (null responders), and 32 (39%) were therapy naive; 39 (48%) were African American. Subjects were assigned randomly to groups given simeprevir (150 mg/day) and sofosbuvir (400 mg/day) (n = 58 in the final analysis) or peginterferon alfa 2b (1.5 mcg/kg/wk), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day) (n = 24 in the final analysis). Both regimens were given for 12 weeks. The primary trial end point was the proportion of patients with undetectable HCV-RNA levels 12 weeks after therapy completion (SVR12). RESULTS: A significantly greater percentage of patients (93%) given simeprevir and sofosbuvir achieved an SVR12 than those given the interferon-containing regimen (75%) (P = .02). Patients given the interferon-containing regimen had a significantly higher rate of virologic relapse than patients given simeprevir and sofosbuvir (P = .009), as well as worse self-reported outcomes and more side effects. Quality-of-life scores were higher in patients with SVR12 than those without, regardless of treatment regimen. CONCLUSIONS: In a prospective study of patients with chronic HCV genotype 1a infection and cirrhosis (48% African American and 61% prior null responders), a 12-week regimen of simeprevir and sofosbuvir produced a significantly higher rate of SVR12 and was better tolerated, with a lower viral relapse rate, than a 12-week regimen of peginterferon, ribavirin, and sofosbuvir. Clinicaltrials.gov no: NCT021683615.

Hepatitis C genotype 1 virus with low viral load and rapid virologic response to peginterferon/ribavirin obviates a protease inhibitor.

UNLABELLED: The new standard of care for treatment-naïve patients with hepatitis C virus (HCV) genotype 1 includes triple therapy with peginterferon, ribavirin, and a protease inhibitor. However, patients who achieve a rapid virologic response after 4 weeks of peginterferon and ribavirin therapy are likely to achieve a sustained virologic response (SVR), and we hypothesized that protease inhibitor therapy may be unnecessary in these patients. Treatment-naïve, noncirrhosis patients infected with genotype-1 HCV and a low viral load at baseline were considered for inclusion (n = 233). After 4 weeks of lead-in therapy with peginterferon α-2b and ribavirin, 101 patients (48%) had a rapid virologic response (defined as undetectable levels of hepatitis C virus RNA at 4 weeks) and were eligible to participate. Patients were randomized 1:1 to 20 weeks of additional therapy with peginterferon α-2b and ribavirin (double therapy) or to 24 weeks of peginterferon α-2b, ribavirin, and boceprevir (triple therapy). There was no significant difference in rates of SVR-12 in patients treated with double versus triple therapy. This similarity persisted regardless of viral subtype (genotype 1a or 1b), interleukin (IL)-28b genotype (CC or non-CC), or ethnicity (African American versus non-Hispanic white). CONCLUSION: Protease inhibitor therapy could be obviated in genotype 1-infected treatment-naïve patients with low viral load at baseline who achieve undetectable viremia after 4 weeks of peginterferon/ribavirin.

Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more.

Sustained virologic response (SVR) is defined as aviremia 24 weeks after completion of antiviral therapy for chronic hepatitis C virus (HCV) infection. In analyses of SVR durability, the incidence of late relapse is extremely low (<1%). Histologic regression of both necroinflammation and fibrosis has been demonstrated in paired liver biopsy samples in SVR-achieving patients. More noteworthy is the sustained responder's favorable prognosis even with baseline cirrhosis; despite mostly retrospective analyses, relative to nonresponders or to those untreated, patients with SVR have significantly fewer liver-related complications, less hepatocellular carcinoma, and fewer liver-related deaths. Although HCV is associated with insulin resistance, successful eradication of HCV appears to reduce the risk of impaired fasting glucose and diabetes development. In summary, chronic HCV infection is curable with SVR attainment, and with cure comes improved liver histology and more favorable clinical outcomes, in comparison with patients who do not achieve the same therapeutic milestone.

Coordinated evolution among hepatitis C virus genomic sites is coupled to host factors and resistance to interferon.

Machine-learning methods in the form of Bayesian networks (BN), linear projection (LP) and self-organizing tree (SOT) models were used to explore association among polymorphic sites within the HVR1 and NS5a regions of the HCV genome, host demographic factors (ethnicity, gender and age) and response to the combined interferon (IFN) and ribavirin (RBV) therapy. The BN models predicted therapy outcomes, gender and ethnicity with accuracy of 90%, 90% and 88.9%, respectively. The LP and SOT models strongly confirmed associations of the HVR1 and NS5A structures with response to therapy and demographic host factors identified by BN. The data indicate host specificity of HCV evolution and suggest the application of these models to predict outcomes of IFN/RBV therapy.

The IL-28 genotype: how it will affect the care of patients with hepatitis C virus infection.

The hypothesis that host genetics play an essential role in the ability not only to clear acute hepatitis C infection but also to achieve sustained virologic response (SVR) to interferon (IFN)-based therapy has been proved with the recent discovery of two single-nucleotide polymorphisms on chromosome 19. Variants in the minor allele rs8099917 and the proximate polymorphism rs12979860, 3 kb upstream of the interleukin (IL)-28B gene, which encodes the endogenous antiviral cytokine IFN-λ, are associated with SVR and with natural viral clearance. The disparate frequencies of these alleles in ethnic groups worldwide may well explain differing rates of SVR among them. The test for one of these polymorphisms is now commercially available and can serve as a powerful predictor of a patient's chance of achieving SVR. Perhaps more importantly, the test can help the clinician personally tailor the duration and even the type of therapy that is most appropriate for an individual patient, newly or chronically infected with the hepatitis C virus.

Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1-infected slow responders.

UNLABELLED: In hepatitis C virus (HCV) genotype 1 infection, the duration of interferon-based therapy is a critical determinant in achieving sustained virologic response (SVR). Slow or late responders to peginterferon and ribavirin may benefit from an extended treatment course. We sought to determine if therapy extension could improve response rates in a United States population of slow responders. Slow response was defined by achieving at least a 2-log decrement in HCV RNA from baseline, yet having detectable HCV RNA at 12 weeks and undetectable HCV RNA at 24 weeks (polymerase chain reaction, TaqMan, Roche; detection limit 10 IU/mL). Patients were treatment-naïve, chronically infected genotype 1-infected slow responders to 1.5 mug/kg/week of peginterferon-alpha2b and 800-1400 mg/day of ribavirin and were randomly assigned 1:1 to complete a total of 48 or 72 weeks of therapy. Dose reductions and treatment discontinuations for adverse events or laboratory abnormalities were similar between the 2 treatment arms. End-of-treatment response rates were similar in the 72-week group compared with those in the 48-week group (48% versus 45%; P value not significant). Overall, the rate of SVR was superior in patients treated for 72 weeks versus 48 weeks (38% versus 18%, respectively; P = 0.026). CONCLUSION: Extending the treatment duration from 48 weeks to 72 weeks in genotype 1-infected patients with slow virologic response to peginterferon-alpha2b and weight-based ribavirin significantly improves SVR rates. Treatment extension does not seem to increase the rate of dose reduction or therapy discontinuation.

Extended-therapy duration for chronic hepatitis C, genotype 1: the long and the short of it.

With pegylated interferon and ribavirin, more than half of all chronically-infected hepatitis C patients can achieve a sustained virologic response; however, patients with genotype 1 infections and those with other poor prognostic factors have relatively inferior treatment response rates. Since new therapies are still years away from approval, it is incumbent upon providers to maximize the therapeutic efficacy of today's treatment. The later the virus is undetectable in serum during treatment, the less likely it will be eradicated. Patients with a delayed or slow virologic response to therapy (at least a 2-log(10) decrease in baseline hepatitis C RNA yet detectable viremia at 12 wk of therapy and undetectable virus 12 wk subsequently) may, therefore, benefit from an extended therapy course beyond one of standard duration. Although higher rates of treatment discontinuation may plague this approach, 72 wk of treatment for genotype 1-infected slow-responders may improve response rates and diminish relapse rates relative to those of 48 wk. Based on data from both viral kinetic and clinical studies, therapy prolongation in slow responders may be a reasonable strategy to improve response rates in these treatment-refractory patients.

Review article: novel antivirals for hepatitis C-sofosbuvir/velpatasvir/voxilaprevir, glecaprevir/pibrentasvir.

BACKGROUND: In 2017, the hepatitis C treatment regimens sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) and glecaprevir/pibrentasvir (G/P) received approval from the U.S. Food and Drug Administration. Although both SOF/VEL/VOX (NS5B polymerase inhibitor/NS5A inhibitor/NS3/4A protease inhibitor) and G/P (NS3/4A protease inhibitor/NS5A inhibitor) are pangenotypic regimens, they are indicated for distinct subsets of patients with hepatitis C. AIM: To compare and contrast available safety and efficacy data for SOF/VEL/VOX and G/P and outline their clinical utility. METHODS: For each of the regimens, this review outlines the indications, safety information, and the major clinical studies in which SOF/VEL/VOX and G/P were evaluated. RESULTS: SOF/VEL/VOX is positioned as a salvage regimen for patients previously treated with NS5A inhibitors and for genotype 1a- and 3-infected patients who had failed other sofosbuvir-containing regimens. G/P is the first pangenotypic regimen with an 8-week duration for treatment-naïve, non-cirrhotic patients, and it is indicated for patients with any genotype who have advanced kidney disease, including those on dialysis. CONCLUSION: The addition of SOF/VEL/VOX and G/P to existing hepatitis C treatment options will expand the number of patients who are eligible for and responsive to treatment, thus increasing the possibility of eliminating hepatitis C as a public health issue.

Hepatitis C virus infection in African Americans.

Hepatitis C is more prevalent among African Americans than among persons of any other racial group in the United States. However, comparatively little data are available on the natural history and treatment of hepatitis C in this population. Compared with white persons, African American persons have a lower rate of viral clearance and, consequently, a higher rate of chronic hepatitis C. Nonetheless, African American persons may have a lower rate of fibrosis progression than do white persons. African American persons with hepatitis C-related cirrhosis have higher rates of both hepatocellular carcinoma and liver cancer-related mortality than do white persons with hepatitis C-related cirrhosis. In nearly all treatment trials that enrolled a significant proportion of African American subjects, such patients had inferior treatment responses, compared with those of white subjects. The prevalence of infection with hepatitis C virus genotype 1 is higher among African American patients than white patients, although this difference does not account for a greatly dissimilar response to therapy. Some of the postulated mechanisms for these disparate treatment responses and natural histories of infection are also reviewed.

Increased Mitochondrial Genetic Diversity in Persons Infected With Hepatitis C Virus.

BACKGROUND & AIMS: The host genetic environment contributes significantly to the outcomes of hepatitis C virus (HCV) infection and therapy response, but little is known about any effects of HCV infection on the host beyond any changes related to adaptive immune responses. HCV persistence is associated strongly with mitochondrial dysfunction, with liver mitochondrial DNA (mtDNA) genetic diversity linked to disease progression. METHODS: We evaluated the genetic diversity of 2 mtDNA genomic regions (hypervariable segments 1 and 2) obtained from sera of 116 persons using next-generation sequencing. RESULTS: Results were as follows: (1) the average diversity among cases with seronegative acute HCV infection was 4.2 times higher than among uninfected controls; (2) the diversity level among cases with chronic HCV infection was 96.1 times higher than among uninfected controls; and (3) the diversity was 23.1 times higher among chronic than acute cases. In 2 patients who were followed up during combined interferon and ribavirin therapy, mtDNA nucleotide diversity decreased dramatically after the completion of therapy in both patients: by 100% in patient A after 54 days and by 70.51% in patient B after 76 days. CONCLUSIONS: HCV infection strongly affects mtDNA genetic diversity. A rapid decrease in mtDNA genetic diversity observed after therapy-induced HCV clearance suggests that the effect is reversible, emphasizing dynamic genetic relationships between HCV and mitochondria. The level of mtDNA nucleotide diversity can be used to discriminate recent from past infections, which should facilitate the detection of recent transmission events and thus help identify modes of transmission.