Oral Direct-acting Antiviral Regimens Research Articles

Hepatitis C Virus in the Elderly in the Direct-Acting Antiviral Era: from Diagnosis to Cure.

Purpose of reviewHepatitis C (HCV) is the most common cause of viral hepatitis in elderly individuals. This patient population previously experienced suboptimal outcomes with interferon-based regimens. Unfortunately, patients aged 65 years and older were underrepresented in phase 2 and 3 clinical trials with newer direct acting antiviral (DAA) therapies. Since the advent of second-generation DAA in 2013, numerous robust real-world experiences highlighting the efficacy and safety of DAA in the elderly have been published. This review article summarizes the cascade of care for hepatitis C from diagnosis to cure from an evidence-based perspective of the aging population.Recent findingIn a large study from the Veterans Affairs Healthcare System, the overall sustained virologic response (SVR) of 15,884 patients treated with DAA regimens was 91.2%. These newer therapies remained highly effective in the subset of patients aged 65 years and older with SVR rates above 90%. A Spanish National Registry reported outcomes in patients ≥ 65 years old treated for HCV with oral DAA regimens over a 2-year period. The overall SVR was 94% in the study of 1252 subjects.SummaryCurrent real-world data imply DAA treatment regimens remain highly effective and safe in elderly patients when compared to the general population.

Short Course of Treatment for Hepatitis C in Adolescents

Source: El-Khayat H, Kamal EM, Yakoot M, et al. Effectiveness of 8-week sofosbuvir/ledipasvir in the adolescent chronic hepatitis C-infected patients. Eur J Gastroenterol Hepatol. 2019; 31(8): 1004– 1009; doi: 10.1097/MEG.0000000000001360Investigators from multiple institutions in Egypt conducted a randomized trial assessing the efficacy and safety of sofosbuvir/ledipasvir (SOF/LVD) for 8 weeks, compared to 12 weeks, for treatment of genotype 4 hepatitis C virus (HCV) infection in adolescents 12–17 years old. Study patients were randomized to a single daily dose of a combination of SOF 400 mg and LVD 90 mg for either 8 or 12 weeks. At baseline, participants underwent a FibroScan to assess liver fibrosis using a standardized classification system. Laboratory screening was conducted at baseline and throughout the 12-week study period to measure HCV RNA and assess for possible adverse events; study participants reported adverse events. The primary study outcome was the sustained virologic response (SVR) rate, defined as undetectable HCV RNA at week 12. Secondary outcomes included SVR rates at 4 weeks and adverse events.A total of 157 patients were enrolled in the study: 73 were randomized to 8 weeks of SOF/LVD treatment and 84 to 12 weeks of treatment. The mean age of study patients was 14 years, the mean (standard deviation) HCV RNA at baseline was 5.80 (0.17) IU/L, and 68% had no to mild liver fibrosis at baseline. The source of HCV infection was considered to be perinatal infection in 73% of patients, surgical or dental procedures in 10%, and unknown in 17%. Patient characteristics were similar in the 2 treatment groups.The SVR rate at 12 weeks was 98.6% (95% CI, 93%–100%) for those treated for 8 weeks and 97.6% (95% CI, 96%–100%) for patients treated for 12 weeks. SVR rates at 4 weeks were 63% and 58%, respectively, for adolescents in the 8-week and 12-week treatment groups. Adverse events were reported by 7% of those in the 8-week group, including fatigue (2 patients), and headache, epigastric tenderness, and nausea in 1 patient each. Among patients randomized to 12 weeks of treatment, 8.3% reported an adverse event, including fatigue (1 patient), epigastric tenderness (1 patient), diarrhea (2 patients), nausea (1 patient), and rash (2 patients). Laboratory screening did not reveal any significant adverse events.The authors conclude that 8 weeks of SOF/LVD is as effective as 12 weeks of treatment in adolescents with HCV infection.Dr Rosenthal has disclosed the following financial relationships relevant to this commentary: Research grant support from Gilead, AbbVie, and Merck. This commentary does contain a discussion of an unapproved/investigative use of a commercial product/device.With the advent of highly effective direct-acting antiviral (DAA) drugs for HCV therapy, chronic HCV infection is no longer the leading indication in adults requiring liver transplant.1 Although therapies for HCV in children lag behind the regimens approved in adults, all oral DAA regimens in children are also now approved by the US Food and Drug Administration (FDA) and available.2 Regimens are so effective that cure can be anticipated in 8–12 weeks of therapy. The current investigators found that an 8-week course of SOF/LVD therapy was as effective and safe as the classic 12-week course in curing adolescents of genotype 4 HCV.In the United States, approximately 75% of chronic HCV infections are caused by HCV genotype 1; 15%–20% by genotype 2 or 3; and <5% by genotypes 4, 5, or 6.3 The FDA has approved 12-week combination SOF/LVD for the treatment of pediatric patients ≥12 years of age who weigh at least 35 kg and have HCV genotype 1 infection; they can be treatment naive without cirrhosis or with compensated cirrhosis or treatment experienced without cirrhosis.4 The FDA also approved its use for 12 weeks of therapy in adolescents with genotypes 4, 5, or 6 who are treatment naive or who are treatment experienced without cirrhosis or with compensated cirrhosis.4 In treatment-experienced adolescents with genotype 1 HCV and compensated cirrhosis, therapy should consist of 24 weeks of SOF/LVD. If SOF/LVD is used, 2 warnings need to be heeded.4 Patients with HCV and hepatitis B virus coinfection need to be monitored for hepatitis B virus reactivation and hepatitis flare during HCV treatment and posttreatment follow-up. Coadministration of amiodarone with SOF/LVD is not recommended because serious bradycardia with symptoms may occur.4DAA therapies for HCV infection are approved for use in adolescents. Regimens are effective and safe.At first glance, it would appear that therapy for HCV infection is solely within the purview of gastroenterologists. Pediatricians, however, can ensure that HCV screening is performed in patients at high risk, such as children of mothers who are HCV positive, and that potentially hepatotoxic agents (eg, alcohol) are avoided in those with HCV infection. (See AAP Grand Rounds. 2019;41[4]:45.5)

Similar Sustained Virologic Response in Real-World and Clinical Trial Studies of Hepatitis C/Human Immunodeficiency Virus Coinfection

Clinical trials evaluating efficacy of direct-acting antiviral (DAA) therapies demonstrate sustained virologic response (SVR) rates greater than 90% in patients infected with hepatitis C (HCV) and human immunodeficiency virus (HIV). However, generalizability of this data to real-world coinfected populations is unknown. We aim to compare efficacy data from clinical trials to effectiveness data of real-world observational studies that evaluate oral interferon-free HCV treatment regimens in patients infected with HIV and HCV. We included English-language studies on PubMed and MEDLINE databases from inception until October 2017. Eight clinical trials and 11 observational studies reporting on efficacy data and effectiveness data, respectively, of interferon-free oral DAA regimens in HCV/HIV coinfected patients, were included. Of patients in the eight clinical trials evaluated, 93.1% (1218/1308) achieved SVR12; of the 11 real-world observational studies, 90.8% (2269/2499) achieved SVR12. Relative risk between those treated in clinical trials versus observational studies was 0.98. Patients with genotype 1 infection, African-American patients, cirrhotic patients, and patients with prior HCV treatment experience had similar rates of SVR in real-world and clinical trial cohorts. SVR among real-world HCV/HIV coinfected populations treated with DAA regimens is similar to SVR of patients studied in clinical trials. Historically negative predictors of achieving SVR during the era of interferon-based treatments, such as those with cirrhosis, prior HCV treatment failure, GT1 infection, and African-American race, are not associated with a significantly lower SVR in real-world populations treated with various DAA regimens.

Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review.

Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection. To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection. MEDLINE and EMBASE from inception through 1 November 2016. 42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs. Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently. Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child-Turcotte-Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without. Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling. Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis. Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711).