Cost‐effectiveness of sofosbuvir for the treatment of chronic hepatitis C‐infected patients

The efficacy of treatment for hepatitis C genotype 1 infection has significantly improved with the introduction of first‐generation protease inhibitors. However, there remains a need for effective treatments for patients infected with other genotypes, for nonresponders and patients unsuitable for interferon. Sofosbuvir is the first nucleotide polymerase inhibitor with pan‐genotypic activity. Sofosbuvir‐based regimens have resulted in >90% sustained virological response across treatment‐naïve genotype 1–6 patients in five phase III clinical trials of sofosbuvir administered with ribavirin or pegylated interferon and ribavirin. This analysis evaluates the cost‐effectiveness of sofosbuvir within the current licensed indication, for genotype 1–6 in the UK. A Markov model followed a cohort of 10 000 patients over lifetime, with approximately 20% initiating treatment for compensated cirrhosis. Sofosbuvir‐regimens were compared to telaprevir, boceprevir, pegylated interferon and ribavirin, or no treatment. Costs and outcomes were discounted at 3.5%. The cost perspective utilized costs applicable to the National Health Service in the UK. Sofosbuvir proved to be cost‐effective in most patient populations with incremental cost‐effectiveness ratios (ICERs) at £11 836/QALY and £7292/QALY against telaprevir and boceprevir, respectively. In genotype 3, sofosbuvir had a weighted ICER of £18 761/QALY. Sofosbuvir‐based regimens are a cost‐effective option for the majority of hepatitis C‐infected patients in the United Kingdom although the incremental cost‐effectiveness varies by genotype and regimen. Sofosbuvir and ribavirin is an alternative regimen for patients unsuitable for interferon.     

Cost‐effectiveness of sofosbuvir in the treatment of patients with hepatitis C

In France, 190 306 patients were suffering from chronic hepatitis C in 2012. These patients have a decreased life expectancy and are susceptible to complications associated with chronic hepatitis. Current treatments are poorly tolerated and their effectiveness varies depending on the genotype of the virus. Sofosbuvir, a new class of treatment, has demonstrated in five phase III trials sustained viral response (SVR) rates of over 90% across genotypes, higher than current treatments and has a tolerance profile similar to placebo. The objective was to determine the cost‐effectiveness of using sofosbuvir in the treatment of chronic HCV infection. A Markov model was used to compare treatment strategies with and without sofosbuvir. The model simulated the natural history of HCV infection. SVR rates were based on data from clinical trials. Utilities associated with different stages of disease were based on data from the literature. French direct medical costs were used. Price for sofosbuvir was the price used in the early access program for severe fibrosis stages. The incremental cost–effectiveness ratio for sofosbuvir versus current reference treatments was € 16 278/QALY and varied from 40 000 €/QALY for F0 stages to 12 080 €/QALY for F4 stages. The sensitivity analyses carried out confirmed the robustness of this result. Sofosbuvir is a cost‐effective treatment option for patients with hepatitis C.     

Real‐world safety and effectiveness of ledipasvir/sofosbuvir for the treatment of chronic hepatitis C virus genotype 1 in Japan

As patients with chronic hepatitis C virus (HCV) tend to be older and/or have advanced liver disease in Japan, real‐world data are needed to evaluate safe and effective treatment options. The study aim was to assess safety and effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in a real‐world cohort of Japanese patients with HCV genotype (GT) 1 infection overall and by patient subgroups: elderly, compensated cirrhotic, advanced fibrotic and those with hepatocellular carcinoma (HCC). A large prospective observational study was conducted, enrolling adult patients treated for HCV GT1 infection with LDV/SOF at clinical sites across Japan. Patients were observed for safety outcomes during and 4 weeks after treatment, and for sustained virologic response at 12‐weeks post‐treatment (SVR12). Incidence rates (IRs) of adverse drug reactions (ADRs) and serious ADRs (SADRs) and SVR12 rates were assessed overall and by subgroups. ADR and SADR IRs were low (2.26 and 0.17 per 100 person‐months, respectively) and did not significantly differ in elderly patients or those with presence of compensated cirrhosis, worsening fibrosis or HCC. SVR12 rates were high overall (98.5%) and across subgroups investigated (≥94%), including patients who were elderly (98.2%), treatment‐experienced (97.6%), advanced fibrotic (≥95.8%), had existing NS5A resistance‐associated substitutions reported pre‐treatment (95.0%), compensated cirrhosis (95.7%), HCC (94.0%) and other chronic liver diseases (96.1%). In this large, real‐world observational study of Japanese patients with HCV GT1 infection, LDV/SOF treatment resulted in low incidence of adverse events, with high real‐world effectiveness, even among patients with potentially higher risks of adverse safety outcomes and treatment failure.     

The optimal timing of hepatitis C therapy in liver transplant‐eligible patients: Cost‐effectiveness analysis of new opportunities

Different strategies of DAAs treatment are currently possible both pre‐ and postliver transplantation (LT). Clinical and economic consequences of these strategies still need to be adequately investigated; this study aims at assessing their cost‐effectiveness. A decision analytical model was created to simulate the progression of HCV‐infected patients listed for decompensated cirrhosis (DCC) or for hepatocellular carcinoma (HCC). Three DAAs treatment strategies were compared: (i) a 12‐week course of DAAs prior to transplantation (PRE‐LT), (ii) a 4‐week course of DAAs starting at the time of transplantation (PERI‐LT) and (iii) a 12‐week course of DAAs administered at disease recurrence (POST‐LT). The population was substratified according to HCC presence and, in those without HCC, according to the MELD score at listing. Data on DAAs effectiveness were estimated using a cohort of patients still followed by 11 transplant centres of the European Liver and Intestine Transplant Association and by data available in the literature. In this study, PRE‐LT treatment strategy was dominant for DCC patients with MELD<16 and cost‐effective for those with MELD16‐20, while POST‐LT strategy emerged as cost‐effective for DCC patients with MELD>20 and for those with HCC. Sensitivity analyses confirmed PRE‐LT as the cost‐effective strategy for patients with MELD≤20. In conclusion, PRE‐LT treatment is cost‐effective for patients with MELD≤20 without HCC, while treatments after LT are cost‐effective in cirrhotic patients with MELD>20 and in those with HCC. It is worth reminding, though, that the final choice of a specific regimen at the patient level will have to be personalized based on clinical, social and transplant‐related factors.     

Cost‐effectiveness analyses of anti‐hepatitis C virus treatments using quality of life scoring among patients with chronic liver disease in Hiroshima prefecture,Japan

Aim

We estimated the cost‐effectiveness of direct‐acting antiviral treatment (DAA) compared to triple therapy (simeprevir, pegylated interferon‐α [Peg‐IFN], and ribavirin [RBV]) (scenario 1), Peg‐IFN + RBV (scenario 2), and non‐antiviral therapy (scenario 3).

Methods

Cost‐effectiveness was evaluated as incremental cost‐effectiveness ratios (ICERs) using direct costs and indirect costs, which included loss of wages during the patient's lifetime due to early death caused by viral hepatitis infection. Quality of life (QOL) scores were determined by EQ‐5D‐3L questionnaire survey on 200 HCV patients in Hiroshima.

Results

The QOL scores for chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma were estimated as 0.871, 0.774, and 0.780, respectively. The follow‐up period that the ICER of scenario 1 becomes shortest (cost <¥6 million) was 25 years after treatment in men and women who started treatment at the age of 20–60. In contrast, those of scenarios 2 and 3 was 10 years after treatment in patients who started treatment at age <80 years. Based on the sensitivity analysis in scenario 1, the most significant factor affecting the value of ICER is the QOL score after sustained virologic response (SVR), followed by the SVR rate of DAA or follow‐up period.

Conclusions

Direct‐acting antiviral treatment was estimated to be cost‐effective from 10 to 25 years after treatment, depending on the SVR rate of the drugs and the age of onset of treatment. In order to increase the cost‐effectiveness of DAA treatment, measures or effort to improve the QOL score of patients after SVR are necessary.     

Sofosbuvir plus ribavirin in treatment‐naïve patients with chronic hepatitis C virus genotype 1 or 3 infection in India

Until 2014, pegylated interferon plus ribavirin was the recommended standard of care for the treatment of chronic hepatitis C virus (HCV) infection in India. This open‐label phase 3b study, conducted across 14 sites in India between 31 March 2014 and 30 November 2015, evaluated the efficacy and safety of sofosbuvir plus ribavirin therapy among treatment‐naïve patients with chronic genotype 1 or 3 HCV infection. A total of 117 patients with genotype 1 or 3 HCV infection were randomized 1:1 to receive sofosbuvir 400 mg and weight‐based ribavirin (1000 or 1200 mg) daily for 16 or 24 weeks. Among those with genotype 1 infection, the primary efficacy endpoint of sustained virologic response at 12 weeks post‐treatment (SVR12) was reported in 90% (95% confidence intervals [CI], 73‐98) and 96% (95% CI, 82‐100) of patients following 16 and 24 weeks of treatment, respectively. For patients with genotype 3 infection, SVR12 rates were 100% (95% CI, 88‐100) and 93% (95% CI, 78‐99) after 16 and 24 weeks of therapy, respectively. Adverse events, most of which were mild or moderate in severity, occurred in 69% and 57% of patients receiving 16 and 24 weeks of treatment, respectively. The most common treatment‐emergent adverse events were asthenia, headache and cough. Only one patient in the 24‐week group discontinued treatment with sofosbuvir during this study. Overall, sofosbuvir plus ribavirin therapy achieved SVR12 rates ≥90% and was well tolerated among treatment‐naïve patients with chronic genotype 1 or 3 HCV infection in India.     

Community‐based real‐world treatment outcomes of sofosbuvir/ledipasvir in Asians with chronic hepatitis C virus genotype 6 in the United States

Sofosbuvir/ledipasvir (SOF/LDV) is the first all‐oral ribavirin‐free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real‐world outcomes of this regimen are lacking. We aim to evaluate real‐world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community‐based real‐world cohort of Asian chronic HCV genotype 6 patients treated with all‐oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.     

Real‐world effectiveness of glecaprevir/pibrentasvir and ledipasvir/sofosbuvir for mixed genotype hepatitis C infection: A multicenter pooled analysis in Taiwan

Data on direct‐acting antiviral agent (DAA) treatment for mixed genotype hepatitis C virus (HCV) infection are scant. This study examined the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) and ledipasvir/sofosbuvir (LDV/SOF) for mixed HCV genotype infection in a real‐world setting in Taiwan. We analysed the data from all patients with mixed HCV genotype infections treated with GLE/PIB or LDV/SOF from 2017 to 2019 in three Chang Gung Memorial Hospitals in Taiwan. The primary treatment outcome was sustained virologic response 12 weeks after treatment cessation (SVR12). Adverse events (AEs) were also evaluated. A total of 5190 HCV patients received DAA treatment during this time period. Among them, 116 patients (2.2%) had mixed infections of any 2 or 3 genotypes of 1a, 1b, 2, 3 and 6. Fifty‐four patients received GLE/PIB and 62 received LDV/SOF. SVR12 rates for LDV/SOF vs GLE/PIB therapy were 96.6% (56/58) vs 100% (51/51) by the per‐protocol analysis and 90.3% (56/62) vs 94.4% (51/54) by the evaluable population analysis. Two patients with 1b + 6 and 1b + 2 genotype infections in the LDV/SOF group had relapse. Evaluating the GLE/PIB vs LDV/SOF groups for the most common AEs revealed pruritus (16.7% vs 4.8%), abdominal discomfort (5.6% vs 8%) and fatigue (5.6% vs 4.8%). One patient with AE‐related treatment discontinuation presented with liver decompensation after 4‐week GLE/PIB therapy. DAA‐related significant laboratory abnormalities occurred in two patients with >3× elevated bilirubin level in the GLE/PIB group. GLE/PIB and LDV/SOF are well tolerated and achieve high SVR12 rates for patients with mixed HCV genotype infection.     

Treatment failure may lead to accelerated fibrosis progression in patients with chronic hepatitis C

Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon‐based therapy. We aimed to investigate long‐term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty‐three patients had TF, and 62 patients were treatment‐naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥2 stage increase in fibrosis during follow‐up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma‐glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01–1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81–19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon‐based CHC treatment may lead to accelerated FPR in the long‐term compared with the natural course.     

Low recurrence rate of hepatocellular carcinoma following ledipasvir and sofosbuvir treatment in a real‐world chronic hepatitis C patients cohort

The aims of the present study were to evaluate the efficacy and tolerability of ledipasvir/sofosbuvir (LDV/SOF) with or without ribavirin in the treatment of chronic hepatitis C (CHC) in patients with advanced liver disease and to analyse whether the use of LDV/SOF treatment is associated with a new occurrence of hepatocellular carcinoma (HCC) during and after LDV/SOF treatment. The Turkish Early Access Program provided LDV/SOF treatment to a total of 200 eligible CHC patients with advanced liver disease. The median follow‐up period was 22 months. All patients were Caucasian, 84% were infected with genotype 1b, and 24% had a liver transplantation before treatment. The sustained virological response (SVR12) was 86.0% with ITT analysis. SVR12 was similar among patients with Child‐Pugh classes A, B and C disease and transplant recipients. From baseline to SVR12, serum ALT level and MELD score were significantly improved (P < 0.001). LDV/SOF treatment was generally well tolerated. Only one patient developed a new diagnosed HCC. Seventeen of the 35 patients, who had a history of previous HCC, developed HCC recurrence during the LDV/SOF treatment or by a median follow‐up of 6 months after treatment. HCC recurrence was less commonly observed in patients who received curative treatment for HCC compared with those patients who received noncurative treatment (P = 0.007). In conclusion, LDV/SOF with or without ribavirin is an effective and tolerable treatment in CHC patients with advanced liver disease. Eradication is associated with improvements in liver function and a reduced risk of developing a new occurrence of HCC.