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Technology Guidance - Drug

Direct-acting antiviral agents for treating genotype 1 chronic hepatitis C Published on 1 October 2018

Guidance Recommendations
The Ministry of Health’s Drug Advisory Committee has recommended:
  • Sofosbuvir 400 mg/velpatasvir 100 mg tablet for treating genotype 1 chronic hepatitis C infection in treatment-naïve, or pegylated interferon plus ribavirin (PR)-experienced, or NS3/4A protease inhibitor (boceprevir, simeprevir, telaprevir)-experienced adults.
Sofosbuvir/velpatasvir should be used in line with the recommended treatment regimen and duration:
  • 12 weeks’ treatment of sofosbuvir/velpatasvir for patients with genotype 1 hepatitis C virus without cirrhosis or with compensated cirrhosis (Child-Pugh A)
  • 12 weeks’ treatment of sofosbuvir/velpatasvir in combination with ribavirin for patients with genotype 1 hepatitis C virus with decompensated cirrhosis (Child-Pugh B or C).
Sofosbuvir/velpatasvir should be prescribed by a specialist physician (gastroenterologist, hepatologist, or infectious disease specialist) with experience in the treatment of hepatitis C.

Subsidy status

Sofosbuvir 400mg/velpatasvir 100 mg tablet is recommended for inclusion on the Medication Assistance Fund (MAF), for the abovementioned indication.
A clinical checklist must be completed for all patients who are prescribed sofosbuvir/velpatasvir through MAF. Clinical outcome data will also be collected by MOH for each patient after they have completed their treatment course.
MAF assistance does not apply to other direct-acting antivirals (asunaprevir, ombitasvir/paritaprevir/ritonavir+dasabuvir, sofosbuvir/ledipasvir, elbasvir/grazoprevir and daclatasvir).

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Factors considered to inform the recommendations for subsidy

Technology evaluation

Point Item
1.1 The MOH Drug Advisory Committee (“the Committee”) considered the evidence presented for the technology evaluation of direct-acting antivirals (DAAs; ombitasvir/paritaprevir/ritonavir+dasabuvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, sofosbuvir/ledipasvir, asunaprevir and daclatasvir) for treating genotype 1 chronic hepatitis C. The Agency for Care Effectiveness conducted the evaluation in consultation with the MOH Hepatitis C Expert Working Group comprising senior healthcare professionals from the public healthcare institutions. The use of any DAA for treatment of other hepatitis C genotypes or for retreatment after DAA failure was outside the scope of this evaluation.
1.2 The evidence was used to inform the Committee’s deliberations around four core decision-making criteria:
  • Clinical need of patients and nature of the condition
  • Clinical effectiveness and safety of the technology
  • Cost-effectiveness (value for money) – the incremental benefit and cost of the technology compared to existing alternatives
  • Estimated annual technology cost and the number of patients likely to benefit from the technology
1.3 Additional factors, including social and value judgments, may also inform the Committee’s subsidy considerations.

Clinical need

Point Item
2.1 International clinical practice guidelines recommend DAAs to cure hepatitis C virus (HCV) infections, prevent progression to liver failure and liver cancer, and reduce mortality risk.
2.2 The Committee acknowledged that WHO has recommended DAAs as essential medicines, and local clinicians aim to align clinical practice with international treatment guidelines. However, because of high DAA treatment costs, patients can delay treatment until they have significant fibrosis (‘watch and wait’), or are treated with a combination of pegylated interferon (once weekly as a subcutaneous injection) plus twice-daily oral ribavirin (PR regimen) in local practice. The Committee understood PR to be associated with high treatment burden because of its long treatment duration (24 to 48 weeks), rigorous dosing requirements and significant side effects. PR is also contraindicated in some patients, such as those with decompensated cirrhosis (Child-Pugh B, or Child-Pugh C).
2.3 The Committee noted that HCV is divided into six distinct genotypes and the majority of the general population in Singapore with HCV are infected with genotype 1. The Committee noted that the true prevalence of hepatitis C was difficult to establish because many patients are asymptomatic and unaware of infection until severe symptoms present. However, based on expert opinion, there are more than 2,000 people with genotype 1 chronic hepatitis C requiring treatment.
2.4 The Committee agreed that there was a high clinical need to subsidise DAAs to align local patient care with international best practice for treating chronic hepatitis C, and reduce the prevalent viral load.

Clinical effectiveness and safety

Point Item
3.1 The Committee agreed that for DAAs, PR was the appropriate comparator. For patients with decompensated cirrhosis, best supportive care was considered the appropriate comparator. The DAA regimens were also compared with one other.
3.2 The Committee noted that most of the included DAA clinical studies were single-arm and did not compare directly with PR. Based on pooled estimates from in-house meta-analyses, the DAAs were associated with:
  • higher sustained virological response (SVR; cure) rates (96% [95% confidence interval 95 to 98%]) than those historically reported for PR (51% [95% CI 49 to 52%]);
  • lower rates of serious adverse events (3% [95% CI 2 to 4%]) than PR (7% [95% CI 7 to 7%]); and
  • lower rates of treatment discontinuation because of AEs (1% [95% CI 0 to 1%]) than PR (12%, 95% CI 11 to 14%).
3.3 The Committee noted that no head-to-head trials directly compared the DAAs with one other, and indirect comparisons were limited by the lack of a comparator arm in the single-arm studies to form connected trial networks. According to clinicians, DAA regimens that demonstrated SVR rates ≥90% could be considered clinically comparable. Based on available evidence, the Committee agreed that DAAs could be regarded as a class, as all had SVR rates ≥90%, with overlapping confidence intervals in the meta-analyses.


Point Item
4.1 Cost-effectiveness of DAA versus PR
The Committee noted that the in-house cost effectiveness analysis conducted for DAA versus PR showed that DAA was dominant over PR (i.e., DAA resulted in more quality adjusted life years gained at a lower cost). For patients with decompensated cirrhosis, DAA was associated with an incremental cost-effectiveness ratio (ICER) in the range of $15,000 to <$45,000 per quality-adjusted life-year (QALY) gained versus best supportive care.
4.2 Cost-minimisation among the DAAs
The Committee agreed that a cost-minimisation approach was appropriate in selecting the lowest-priced DAA for subsidy consideration in view of comparable clinical effectiveness and safety. It noted that the manufacturer of sofosbuvir/velpatasvir had offered the lowest price as part of their value-based pricing proposal (VBP). As a result, the Committee did not recommend the other DAAs (ombitasvir/paritaprevir/ritonavir+dasabuvir, asunaprevir, daclatasvir, sofosbuvir/ledipasvir, and elbasvir/grazoprevir) for subsidy given their higher cost prices compared with sofosbuvir/velpatasvir.

Estimated annual technology cost

Point Item
5.1 The Committee estimated about 1,372 people with genotype 1 chronic hepatitis C in Singapore would benefit from government assistance for sofosbuvir/velpatasvir if it were listed on the MAF. The annual cost impact was estimated at $1 to $3 million in the first year of listing on the MAF.

Additional considerations

Point Item
6.1 The Committee acknowledged that more patients may seek treatment if a DAA is listed on the MAF, and advised prescribing clinicians to explore a risk-based approach for prioritising patients needing treatment to manage capacity issues.
6.2 The Committee noted that improved treatment access and lower viral loads circulating in the local community could also lead to broader population benefits.


Point Item
7.1 Based on available evidence, the Committee recommended sofosbuvir 400 mg/velpatasvir 100 mg tablet be listed on the MAF for treating genotype 1 chronic hepatitis C given its favourable clinical and cost effectiveness, and the high clinical need for DAA treatment to ensure appropriate patient care.
Last Updated on 1 October 2018 Back to Top