Abstract
In India, hepatitis C virus (HCV) infection is treated with sofosbuvir in combination with NS5A inhibitor (Daclatasvir, Ledipasvir, or Velpatasvir). A small proportion of them fail to achieve sustained virological response at 12 weeks (SVR12) and need retreatment. Triple-drug combination (Sofosbuvir/Velpatasvir/Voxilaprevir) is one of the options for retreatment. Here we describe a patient with cirrhosis and genotype 3a infection who was successfully treated with a triple-drug combination after relapse with two courses of Sofosbuvir-containing regimens.
Keywords: hepatitis c virus, voxilaprevir, velpatasvir, sofosbuvir, resistance associated variant, hepatitis C retreatment
Abbreviations: DAA, Direct-Acting Antiviral drugs; HCV, Hepatitis C virus
In recent years, the treatment of the hepatitis C virus (HCV) has witnessed a marked revolution. In the present era, HCV is given treatment with orally administered direct acting antiviral (DAAs) drugs that are highly effective and safe. Each of these DAAs acts against a specific viral protein and are accordingly grouped into three classes—NS5B inhibitors (Sofosbuvir), NS5A inhibitors (Daclatasvir, Ledipasvir, Velpatasvir), and NS3/4 protease inhibitors. Sofosbuvir, an NS5B inhibitor, is the most widely used DAA and forms the backbone of DAA-based HCV treatment.
A small proportion of those with cirrhosis fail to clear viremia (nonresponse), or viremia reappears (relapse) in them after stopping the treatment. In those who have failed treatment with Sofosbuvir-containing regimens, the options for the retreatment are limited. Triple-drug combination of Sofosbuvir, Velpatasvir, and Voxilaprevir (NS3/4 protease inhibitor) for 12 weeks is one of the regimens used for retreatment.1 Here, we report the successful use of triple-drug combination in a cirrhotic patient with genotype 3 infection who had a relapse with two courses of sofosbuvir-based HCV treatment.
Case
A 72-year-old lady was detected to have an anti-HCV antibody test positive. She had received a blood transfusion 28 years ago for obstetrical reasons. She never had ascites, pedal edema, hepatic encephalopathy, or variceal bleed and tested negative for hepatitis B virus (HBV) and human immunodeficiency virus.2 Her associated illnesses of diabetes, hypertension, and atrial fibrillation were well controlled with medications.
On evaluation, her platelet count was 100 thousand/mm3, serum albumin of 3.3 gm/dL, liver stiffness 19.8 Kilopascal, small shrunken liver without portal vein thrombosis or hepatocellular carcinoma. Endoscopic examination showed unbled small esophageal varices. The virological evaluation revealed an HCV viral load of 122,767 IU/mL, and the genotype was 3a.
She failed to achieve sustained virological response at 12 weeks after stopping the DAA (SVR12) with two courses of Sofosbuvir-containing anti-HCV treatment, i.e, Sofosbuvir/Velpatasvir for 12 weeks and sofosbuvir/daclatasvir/ribavirin for 24 weeks. Subsequently, she successfully achieved SVR12 with the triple-drug combination of Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi®) for 12 weeks. The use of ribavirin was avoided with triple drugs because she poorly tolerated ribavirin during her second course of DAA. All the three SVR12 results were confirmed with repeat testing in a fresh specimen before restarting the next course of DAA. The HCV RNA was tested twice with COBAS AmpliPrep/COBAS TaqMan HCV quantitative Test, v2.0 (Roche, Branchburg, NJ, USA), with the lower limit of detection of 15 IU/mL. The details of the anti-HCV treatment and virological response are summarized in Table 1.
Table 1.
Laboratory Investigations, Treatment Details, and Virological Response With Three Courses of Anti-HCV Treatment.
| Time period | 1st regimen |
2nd regimen |
3rd regimen |
|---|---|---|---|
| May 2017–July 2017 | January 2019–June 2019 | September 2020–November 2020 | |
| Platelet | 100 | 97 | 100 |
| TSB | 1.4 | 1.0 | 0.7 |
| Albumin | 3.44 | 3.6 | 3.9 |
| INR | 1.74 | 2.08 | 1.9 |
| Creatinine | 0.8 | 1.0 | 0.8 |
| CTP class (score) | CTP-A (6/15) | CTP-A (6/15) | CTP-A (6/15) |
| Liver stiffness | 22 | – | 19.8 |
| APRI | 2.4 | 2.5 | 2.7 |
| FIB-4 | 3.5 | 4.3 | 4.4 |
| Treatment regimen | Sofosbuvir 400 mg/d Velpatasvir 100 mg/d |
Sofosbuvir 400 mg/d Daclatasvir 100 mg/d Ribavirin 800 mg/d |
Sofosbuvir 400 mg/d Velpatasvir 100 mg/d Voxilaprevir 100 mg/d |
| Treatment duration | 12 weeks | 24 weeks | 12 weeks |
| HCV RNA | 122,767 | 275,053 | 428,000 |
| RVR4 | Undetectable | Undetectable | Undetectable |
| ETR | Undetectable | Undetectable | Undetectable |
| SVR12 | 275,053 | 428,000 | Undetectable |
RVR4, quantitative HCV RNA after 4 weeks of anti-HCV treatment; ETR, quantitative HCV RNA at the end of planned 12 or 24 weeks of anti-HCV treatment; SVR12, quantitative HCV RNA after 12 weeks of completion of anti-HCV treatment.
Written informed consent was taken from the patient for publication.
Discussion
The advent of DAAs has revolutionized HCV treatment and has led to the decentralization of HCV treatment services from tertiary care hospital-based treatment to the remotely placed healthcare center. Among the entire armamentarium of DAAs, India has access to Sofosbuvir, Daclatasvir, Ledipasvir, and Velpatasvir only. Sofosbuvir stays as the backbone of HCV treatment in India and is administered in combination with either of the other three DAAs.
The success of HCV treatment is partially reduced by the presence of cirrhosis and genotype 3 infection.3 India has an estimated burden of nearly nine million viremic population.4 In India, genotype 3 is the most prevalent HCV genotype (∼65%), followed by genotype 1 (∼30%). In India, sofosbuvir-based HCV treatment regimens have achieved an SVR12 rate of >90–95% in low-risk5,6 and high-risk populations.7,8
HCV treatment could fail because of factors related to the drug, host, or the virus.9 The combination of a high multiplication rate and a poor proof-reading mechanism of replication enzyme results in numerous quasi-species. A few of them carry specific nucleotide substitution in the viral genome, which are known as resistance-associated variants (RAV).10 Such RAVs may be present either naturally or develop due to selection pressure during DAA use. Among those with prior exposure to NS5A and NS5B inhibitors, RAVs are much more common in NS5A regions.11 The most commonly identified RAV in NS5A region are Y93H and A30K. Due to limited resources, we have not tested for the presence of RAV in our patient.
There is no widely accepted guideline for the retreatment of those who have previously relapsed to Sofosbuvir-containing DAA regimen. We have limited treatment options for retreatment, and most of the second-line drugs are not available in India. In the lack of newer DAAs in India for retreatment, it is common to retreat with a combination of the following approaches—change of NS5A inhibitor, prolongation of treatment duration, and addition of ribavirin. The results of limited experiences, available with such retreatment strategies, has shown better results for non-3 genotype as compared to genotype 3 infections.12 A combination of Sofosbuvir/Velpatasvir/Vvoxilaprevir is widely used for HCV retreatment and has shown 96–98% SVR12 in non-3 genotype and genotype-3 retreatment.13 The serum drug level of Voxilaprevir may be elevated up to 300–500% in patients with advanced cirrhosis, and hence, its use is approved only for those with either no cirrhosis or with CTP-A cirrhosis.14
Here, we reported the first experience of using a triple-drug combination in a genotype-3 cirrhotic patient who had earlier failed two complete courses of Sofosbuvir-containing DAA regimens. We need a collective effort, in the form of a multicentric HCV retreatment registry, to gather more data and define the most effective, acceptable, affordable, and pragmatic approach for HCV retreatment in our country.
CRediT authorship contribution statement
Prachi Tiwari: Data collection, Writing - original draft. Harshita Katiyar: Data collection, Writing - original draft. Praveer Rai: Conceptualization, planning, Data collection, Writing - review & editing, Approval of final version. Amit Goel: Conceptualization, planning, Writing - review & editing, Approval of final version.
Conflicts of interest
The authors have none to declare.
Acknowledgement
None.
Source of funding
The Fellowship of Miss Harshita Katiyar was supported by Indian Council of Medical Research by extramural research grant no VIR/18/2018/ECD-I.
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