The introduction of oral direct-acting anti-viral (DAA) therapy has revolutionised the management of patients living with Hep C. Gilead Sciences, a biopharmaceutical company, recently announced the launch of fixed-dose co-formulation sofosbuvir (NS5B inhibitor) and velpatasvir (NS5A inhibitor).^2,4

In South Africa, co-formulation sofosbuvir-velpatasvir is indicated for the treatment of chronic Hep C, irrespective of genotype (see below) in treatment naïve or treatment-experienced patients aged ≥12-years, weighing at least 30kg without cirrhosis or with compensated and decompensated cirrhosis, in combination with ribavirin.⁵

Symptoms and diagnosis

According to the WHO, HCV infection can cause acute or chronic disease. Around 30% of patients living with acute Hep C clear the virus within six months of infection without any treatment.³

However, 70% of patients living with Hep C will develop chronic infection. Of those with chronic HCV infection, the risk of cirrhosis ranges from 15% to 30% within 20 years and between 10% to 20% of patients with cirrhosis will decompensate clinically within five years.^1,3

One of the challenges in the effective management of Hep C, is that symptoms are non-specific. Common symptoms include fatigue or malaise, intermittent right upper quadrant pain, joint pain, and a general feeling of being unwell with overall reduced quality of life(QoL).¹

The diagnosis of HCV infection is based on the detection of antibodies to recombinant HCV polypeptides and by assays for HCV RNA. Other baseline evaluations include testing for HIV, Hep B surface antigen, susceptibility to Hep A and Hep B virus infections, and screening for other underlying causes of liver disease such as autoimmune liver disease, haemochromatosis, and Wilson disease.¹ 

Before determining a Hep C treatment strategy, the next step is to stage the disease, utilising liver biopsy (gold standard) or approved imaging modalities with or without non-invasive biomarkers. Lastly, all of these patients should also undergo variceal screening and screening for hepatocellular carcinoma.¹

Genotypes

South Africa is a ‘pan-genotypic’ country with genotypes 1 to 5 being observed. However,genotype 1 and 5 are predominant with genotype 4 being detected with increasing frequency. Genotype 5a, first identified in South Africa, is a genotype unique to the country.⁷

Treatment

The goals of treatment are to eradicate the virus, delay fibrosis progression, alleviatesymptoms, prevent complications, minimise all-cause mortality, and  maximise QoL.¹

Before the development of oral DAAs, the mainstay of therapy was injectable pegylated interferon and ribavirin. In addition to only having a cure rate of 40%-60%, this form of treatment led to numerous adverse effects, including flu-like illness, haematological effects like neutropenia, thrombocytopenia, and severe anaemia and neurocognitive effects.¹

The first DAA was approved by the Food Drug Administration in 2011. DAAs work by interfering with the viral replication of HCV at different stages. The introduction of oral DAAs increased cure rates to between 90%-97% and eliminated the need for injectable agents.^1,4,6

A number of international guidelines including the 2019 South African National Department of Health, the 2019 American Association for the Study of Liver Diseases–Infectious Diseases Society of America (AASLD/IDSA) and the 2022 WHO updated guidelines recommend DAAs. Both the AASLD/IDSA and WHO guidelines recommend DAAs as first-line therapy.^7,8,9

Co-formulation simplify treatment

Evaluation of the efficacy and safety of sofosbuvir-velpatasvir was reported in different patient populations by a series of phase III clinical trials entitled ASTRAL.^10,11,12,13

In the Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection (ASTRAL 1) study, Feld et al (2015) showed that once-daily sofosbuvir–velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis.¹⁰

In the Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection (ASTRAL 2 and 3) study, Foster et al (2015) found that the rate of sustained virologic response in the sofosbuvir–velpatasvir group was 99% among patients with HCV genotype 2, which was superior to the rate of 94% in the sofosbuvir–ribavirin group. Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir–velpatasvir group was 95%, which was superior to the rate of 80% in the sofosbuvir–ribavirin group.¹¹

According to Curry et al (2015), as the population  infected with HCV infection ages, the number of patients with decompensated cirrhosis is expected to increase. In the Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis (ASTRAL 4) study, the team assessed the sustained virologic response at 12 weeks after the end of therapy in this patient population. Treatment with sofosbuvir–velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir–velpatasvir for 24 weeks resulted in high rates of sustained virologic response (SVR) in patients with HCV infection and decompensated cirrhosis.¹²

The primary endpoint of the Sofosbuvir and Velpatasvir for the Treatment of Hepatitis C Virus in Patients Coinfected With Human Immunodeficiency Virus Type 1: An Open-Label, Phase 3 Study (ASTRAL 5), conducted by Wyles et al (2017), was SVR 12 weeks after treatment. Sofosbuvir-velpatasvir for 12 weeks was safe and provided high rates of SVR 12 weeks after treatment in patients coinfected with HCV and HIV-1.¹³

Overcoming barriers to treatment step-up

High treatment cost, as well as availability and access to diagnostic and monitoring tests, are often cited as reasons for the lack of treatment step-up – particularly in low- and middle-income countries.¹⁴

The AIDS Clinical Trials Group A5360 Minimal Monitoring or MINMON trial was the first to examine the efficacy and safety of a simplified monitoring strategy to eliminate pre-treatment genotyping and to include people with evidence of compensated cirrhosis. The MINMON trial was a phase 4, open-label, single-arm trial conducted at 38 sites in Brazil, South Africa, Thailand, Uganda, and the United States.¹⁴

Participants had to be ≥18-years, with evidence of active HCV infection (HCV RNA >1000IU/mL), and HCV treatment-naïve. The trial also included participants living with compensated cirrhosis and HIV/HCV co-infection, but enrolment was capped.¹⁴

All participants (n=399) received a fixed dose combination of oral sofosbuvir (400mg) and velpatasvir (100mg) once daily for 12 weeks. The MINMON approach consisted of four components: (1) there was no pre-treatment genotyping, (2) the entire treatment course (84 tablets) was dispensed at entry, (3) there were no scheduled visits or laboratory monitoring,and (4) there were two points of remote contact, at week four for adherence and week 22, to schedule outcome assessment at week 24. Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72.¹⁴

The primary efficacy endpoint was SVR, defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation. The primary safety endpoint was serious adverse events.¹⁴

Overall, 95% of the participant who initiated treatment, had a SVR. SVR ranged from 92.4% in the United States to 100% in South Africa and Uganda. Among participants living with HIV, 94.6% achieved a SVR. Across genotypes, SVR ranged from 91.3% in genotype 3 to 100% for genotype 2. SVR was also 100% for genotypes 4, 5, 6 and 7.¹⁴  

According to the team, 4% of participants reported serious adverse events between treatment initiation and week 28, however none were treatment-related or led to treatment discontinuation or death.¹⁴

Another 4% had unplanned in-person visits between entry and week 22. The most common reasons were abnormal laboratory results at entry or non-adverse event-related clinical events.¹⁴

The authors concluded that sofosbuvir–velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case-finding strategies, this strategy could be crucial to the global elimination of Hep C.¹⁴

REFERENCES

1. Basit H, Tyagi I, Koirala J. Hepatitis C. [Updated 2022 Nov 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK430897/#!po=8.823531.
2. Sonderup MW, Gogela N, Nordien R, et al.  Direct-acting antiviral therapy for hepatitis C: The initial experience of the University of Cape Town/ Groote Schuur Hospital Liver Clinic, South Africa. SAMJ, 2020.
3. World Health Organization. Hepatitis C. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c
4. Dietz C, Maasoumy B. Direct-Acting Antiviral Agents for Hepatitis C Virus Infection—From Drug Discovery to Successful Implementation in Clinical Practice. Viruses, 2022.
5. PI Epclusa. https://www.gilead.com/-/media/files/pdfs/medicines/liver-disease/epclusa/epclusa_pi.pdf
6. Keikha M, Eslami M, Yousefi B, et al. HCV genotypes and their determinative role in hepatitis C treatment. Virus Dis, 2020.
7. ​South African National Department of Health. National Guidelines for the Management of Viral Hepatitis. https://www.knowledgehub.org.za/elibrary/national-guidelines-management-viral-hepatitis
8. ​AASLD-IDSA Hepatitis C Guidance Panel. Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Hepatology, 2020.
9. World Health Organization. WHO publishes updated guidance on hepatitis C infection – with new recommendations on treatment of adolescents and children, simplified service delivery and diagnostics. https://www.who.int/news/item/24-06-2022-WHO-publishes-updated-guidance-on-hepatitis-C-infection
10. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med, 2015.
11. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med, 2015.
12. Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med, 2015.
13. Wyles D, Bräu N, Kottilil S, et al. Sofosbuvir and Velpatasvir for the Treatment of Hepatitis C Virus in Patients Coinfected With Human Immunodeficiency Virus Type 1: An Open-Label, Phase 3 Study. Clin Infect Dis, 2017.
14. Solomon SS, Wagner-Cardoso S, Smeaton L, et al.  A minimal monitoring approach for the treatment of hepatitis C virus infection (ACTG A5360 [MINMON]): a phase 4, open-label, single-arm trial. Lancet Gastroenterol Hepatol, 2022.