Hepatitis C treatment in the era of directly acting antivirals: an encouraging scenario

Introduction

The prevalence of hepatitis C (HCV) infection in India has been estimated to be approximately 1.3% in the general population. ¹ Though treatment with earlier interferon-based regimens was difficult, the introduction of directly acting antivirals (DAA) has revolutionised the treatment of hepatitis. In India, sofosbuvir was launched on the market in March 2015, ¹ while ledipasvir and daclatasvir became available from January 2016. ² Availability of generics of these medications has led to substantial reduction in costs of treatment. ³

The present study sought to determine the spectrum of HCV-related liver disease and its response to treatment using generic DAAs.

Materials and methods

Ours is a retrospective analysis of data from a cohort of adult patients (aged >18 years) with HCV infection collected prospectively from June 2015 to December 2019. Patients with hepatocellular carcinoma, co-infection with hepatitis B, HIV and those with incomplete data were excluded. The data analysed included the severity of liver disease, treatment offered and response rates. The diagnosis of cirrhosis and chronic hepatitis was based on clinical presentation, upper gastrointestinal endoscopy for evidence of oesophageal varices, biochemical and radiological investigations including abdominal ultrasound, transient elastography and/or computed tomography. The severity of liver disease was assessed using the Child Turcotte Pugh (CTP) and Model for End Stage Liver Disease (MELD) scores.

Treatment was initiated in those with CTP class A disease immediately and in class B after initial optimisation. DAA treatment was avoided in those with CTP class C or with a MELD score >20.

HCV viral genotype and viral load (ribonucleic acid, Cobas Taqman PCR) was assessed for all patients before starting treatment. The primary aim was to determine the efficacy in terms of a sustained virological response (SVR) at 12 weeks after starting DAAs. Virologic failure or non-response (detectable HCV RNA at end of treatment), rebound (>1 log10 14; IU/mL increase in HCV RNA from nadir while on treatment); breakthrough (detectable HCV RNA on treatment after previously being undetectable) or relapse (HCV RNA undetectable at end of treatment, then becoming detectable during follow-up) were the other endpoints.

The data were tabulated in a Microsoft Excel spreadsheet. Statistical analysis was done using median, range, frequency and proportions. A P value <0.05 was considered significant.

Results

A total of 106 patients (84 men; median age = 55 years; age range = 22–80 years) were included in the study. Eleven patients (10.4%) had received prior treatment with interferon-based regimens but did not attain SVR. Twelve (11.3%) had end-stage renal disease and were on maintenance haemodialysis. Eight (7.5%) had thalassemia major on regular blood transfusions (Table 1).

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Table 1.

Details of study cohort.

Outcome	Sustained virological response (n = 101)	Worsening of liver disease (n = 3)	Lost to follow-up (n = 2)	Total (n = 106)
Males	80 (95.2)	2 (2.3)	2 (2.3)	84
Co-morbid states	–	–	–	–
Chronic renal failure	12 (100)	–	–	12
Thalassaemia	8 (100)	–	–	8
Others (hypothyroidism, diabetes  mellitus and hypertension)	16 (89)	–	2 (11)	18
Prior history of treatment	10 (90.9)	–	1 (9.1)	11
Genotypes	–	–	–	–
1	38 (95)	1 (2.5)	1 (2.5)	40
3	53 (94.6)	2 (3.6)	1 (1.8)	56
4	8 (100)	–	–	8
6	2 (100)	–	–	2
Severity of liver disease	–	–	–	–
Chronic hepatitis	55 (98.2)	–	1 (1.8)	56
CTP A cirrhosis	35 (97.2)	–	1 (2.8)	36
CTP B cirrhosis	11 (78.6)	3 (21.4)	–	14

The frequencies of various HCV genotypes were: type 1 (n = 40, 37.7%); type 3 (n = 57, 53.7%); type 4 (n = 8, 7.5%); and type 6 (n = 2, 1.9%). The median HCV RNA viral load was 7.25 × 10⁵IU/mL (range = 920–10⁸IU/mL).

The various regimes used for treatment are shown in Figure 1. SVR was documented in 101 (95.3%) cases. Two cases were lost to follow-up. Three patients with CTP B cirrhosis (median MELD 16) had worsening of liver disease on treatment with sofosbuvir, ribavirin and ledipasvir/daclatasvir, which was subsequently discontinued. Of these, two were men. Their genotypes included two cases of type 3 and one of type 1. OPEN IN VIEWER

Discussion

Our study highlights that DAA treatment shows excellent response rates. The introduction of sofosbuvir in India at a relatively affordable price (USD 250–300 per month) made treatment of HCV infection simpler and has replaced the use of pegylated interferon. Concern has been the poorer response of genotype 3 and non-availability of many of the DAAs recommended by other guidelines. ¹ Studies, however, in adult Indian thalassaemic patients have shown that generic DAAs are safe and effective with 100% SVR. The requirement of blood products rises significantly during the course of treatment but normalises after completion of therapy. Moreover, it has been noted that serum ferritin levels fall significantly during and after treatment. The presence of other co-morbidities, such as diabetes, splenectomy or iron overload, does not adversely affect the outcome. ⁴ The safety and efficacy of sofosbuvir regimes has been documented in end-stage renal disease, including those patients with severe liver dysfunction.^5,6 These two subgroups of patients also responded well to treatment.

Appropriate timing of DAA therapy in patients with cirrhosis, especially decompensated cirrhosis, is important. Though improvement in hepatic function and quality of life is noted in numerous patients with liver disease, patients with a MELD score >20 should be transplanted first and then treated for HCV infection afterwards. Patients with a MELD score <15 should be readily treated, while in those with scores of 15–20, treatment should be individualised. ⁷

As our response rate was high across genotypes and drug regimes, it was not possible to determine the predictors of non-response to DAAs.

In our study, only three patients with advanced cirrhosis and median MELD score >15 deteriorated on starting DAA forcing the drugs to be discontinued.

Decentralised use of generic drugs in the Punjab hepatitis C care programme aims to eliminate viral hepatitis C by 2030. ⁸

Ours is a single-centre study and details of adverse effects of treatment of blood transfusion requirement and hospitalisation are not available. Despite these shortcomings, our data confirm the remarkable efficacy of generic DAA treatment for HCV.