Rising relapse rate in hepatitis C virus type 3a-infected patients against sofosbuvir and ribavirin combination therapy: a Pakistani experience

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Pakistan has the second highest prevalence of hepatitis C virus (HCV) in the world, and the severe rise in HCV-associated mortality is alarming 1. HCV genotype 3a, which is the most difficult to cure, continues to be the most prevalent subtype infecting people in Pakistan 2–4. The identification of innovative drug targets and inexpensive therapeutic agents remains a high priority in chronic HCV infection management. In the last few decades, the availability of highly effective interferon-free regimens for HCV treatment has been the only possible option for cure for a large number of chronic HCV patients. Failed response to antiviral therapy is one of the principal causes of mortality, and there is no prospective study that suggests a combination of drugs, salvage regimens, or retreatment options to overcome treatment failure in patients who have relapsed after a multidrug regimen 5. The majority of HCV-untreated patients experience liver cirrhosis, fibrosis, and hepatocellular carcinoma. Until 2014, interferon therapy was the standard of care; however, treatment failure, poor efficacy, and significant rise in relapse rate in interferon-treated patients necessitated the development of a novel interferon-free therapeutic approach. To this end, the advent of direct-acting antiviral drugs brought a revolutionary change to the management of HCV infection. Previous studies have shown excellent rates of sustained virological response (SVR), good safety, tolerability, and efficacy in HCV-infected patients treated with DAA drugs. SVRs reported in clinical trials with interferon-free regimens are consistently above 90% for the majority of HCV-infected patients 6–8.
Herein, we report a significantly higher rate of DAA relapse in HCV patients after completion of treatment with sofosbuvir (400 mg) and ribavirin for 24 weeks. A total of 285 treatment-naive HCV genotype 3a noncirrhotic patients who had received DAA therapy during 2014–2015 were recruited in the study. More than 90% patients attained SVR after the completion of 24 weeks of treatment with sofosbuvir and ribavirin. In 2017, all patients were screened again for HCV 2 years after the end of treatment to evaluate recurrence rate. Of the 285 sofosbuvir-based regimen-treated patients, 107 experienced HCV relapse (Fig. 1).
To date, we have very limited published data with regards to the response of DAA therapy in the Pakistani population, whereas the recurrence rate of this novel therapeutic approach has not been reported yet. According to previously published data, treatment with sofosbuvir plus ribavirin resulted in SVR in more than 90% of patients 9–11, whereas we found relapse rate of 37.5% (107/285) among HCV patients who were considered successfully treated with sofosbuvir-based regimen. Although accumulating evidence has shown durability and promising results with interferon-free regimen, our observation has raised a cause for concern. Failure of treatment against multidrug-resistant variants is the greatest challenge to the immediate future of HCV therapeutics. Healthcare professionals need to ponder over this unnoticed and alarming problem of DAA relapse. The nonresponsiveness to interferon therapy has been studied extensively, but the possible underlying cause responsible for DAA relapse is still unknown. Understanding the reasons behind this significant relapse is indispensable to finding the optimal treatment for HCV. There might be several possibilities behind this relapse. Few of these can be the adversity of liver condition due to the disease, overweight or obesity that may interfere with drug activity, age factor, high baseline viral load, and variation in response to drug from one population to another.
Although there is extensive and continuing effort to fight HCV, reports on relapse indicate the need for more rigorous and advanced research. This massive ratio of relapse is alarming and needs serious consideration of the scientific community.

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