4Recommendations

Balance of benefits versus harms of treating all HCV-infected persons

Values and preferences

Four studies were identified that assessed patient preferences related to HCV treatment (97-100). The most important patient-relevant outcome was overall treatment efficacy followed by risk of adverse events. Of 112 people living with HCV infection who responded to an online feasibility survey carried out by WHO, nearly all favoured a Treat All policy and advocated for universal access to treatment for all those with HCV infection (see Web annex 7).

While there is clear support for a Treat All policy among people living with HCV infection, 18% of respondents expressed some concern about acceptability among HCV-infected persons without fibrosis or with mild fibrosis. This finding underscores the need for careful messaging to help HCV-infected persons understand the benefits of early treatment.

Health-care workers highly value cure for persons with HCV infection and expressed a preference for simplified patient management algorithms.

Programme managers understand that cure of more individuals through a Treat All policy will lead to progress towards elimination, and that simplifying the staging step with the use of serum biomarkers facilitates implementation and task-sharing (88–90, 101). Programme managers expressed a preference for strategies that represent cost-effective use of the resources available. Therefore, they would benefit from cost–effectiveness analyses that describe the relation between the cost incurred in the short term versus the savings in the future because of prevented sequelae of HCV infection and onward transmission (102, 103).

Feasibility and acceptability

An online feasibility survey among 145 health-care providers indicated that 45% of respondents already had a Treat All policy at their place of work. Nearly all perceived it as feasible and desirable (see Web annex 7).

Experience from HIV suggests that widening treatment access is feasible. In September 2015, WHO released guidance recommending Treat All for HIV-positive individuals (8). By the end of 2017, more than 70% of LMICs and almost all HICs had adopted the Treat All policy, demonstrating a high level of acceptability of this recommendation by policy-makers (104). Despite initial concerns about health system capacity to meet the demands of a Treat All approach, no major increase in medication stock-outs or other essential supplies have been reported during this period.

Equity and human rights

Therapeutic guidelines that restrict an individual’s access to HCV treatment when cure rates are high and adverse events are rare raise ethical challenges (105). Many HCV-infected persons from groups that are marginalized or stigmatized such as PWID, MSM, prisoners or migrants have poor access to health care. Progress towards a Treat All approach with equity in access regardless of age, risk group or stage of disease would help overcome some of the obstacles to access among these populations. Concerns that mandatory or coercive approaches might be used among highly affected marginalized populations highlight the importance of adequate information, informed consent, appropriate health worker training and rights-based legal frameworks to facilitate access.

Resource considerations

DAAs are cost effective or cost-saving. In general, in many countries, DAAs are cost effective or cost-saving for the large majority of subgroups (defined in terms of prior treatment experience, fibrosis stage and HCV genotype). Most published cost–effectiveness analyses do not include HCV transmission or the risk of reinfection. This omission may result in underestimating or overestimating the benefits of treatment (75).

Expanding treatment to the general population is cost effective. When applying country-specific willingness-to-pay thresholds, several studies from HICs and Egypt reported that expanding treatment in the general population is cost effective, though it may require substantial short-term payments to cover the cost of treatment. The cost–effectiveness of treatment expansion for individuals above 65 years of age with mild fibrosis is highly sensitive to treatment price and, in some settings, where prices remain relatively high, may not be cost effective (75).

Treating PWID along with provision of harm reduction interventions is cost effective. It is generally cost effective to treat HCV-infected PWID, but cost-effectiveness is influenced by the potential for preventing new infections and by the risk of reinfection. Some studies also estimate that intensified case-finding in this group is cost effective along with treatment scale up, that treatment of all PWID was cost effective compared to delaying treatment until progression to a later stage of fibrosis, and that treatment can be cost effective even in a declining epidemic. However, in settings with a high burden of HCV infection among PWID, the cost–effectiveness of preventing onward transmission via treatment is diminished by the high probability of reinfection in case of inadequate access to harm reduction programmes. This underscores the need for concurrent, high-coverage HCV prevention interventions with highly effective and cost-effective harm reduction programmes (75).

Treating incarcerated individuals is cost effective. Studies from the United States of America (USA), Australia and the United Kingdom (UK) reported that it is generally cost effective to treat incarcerated individuals who are HCV infected (3). Testing upon entry to prisons can be cost effective if there is linkage to treatment that can be completed in prison or after release through continuity of care. Similar to the findings in PWID communities, concurrent investments in HCV prevention programmes complement investments in HCV treatment and make HCV treatment more cost effective by reducing the probability of reinfection (75).

Budget implications. While DAAs are cost effective and/or cost-saving for the treatment of HCV infection, the short-term budget implications will depend on (i) the price of the medications and (ii) the size of the population to be treated (the latter being also affected by testing and linkage activities in the population). On the one hand, treating all will increase the budget impact. On the other hand, the Treat All policy should lead to price reductions as it will increase the volume of medicines purchased (see section 6.7 on Strategies for more efficient procurement and supply management of medicines and diagnostics and Table 6.2). To finance the treatment of all persons with HCV through a universal health coverage approach, a two-step approach is proposed.

• Improving efficiencies and reducing costs. This can be done through the choice of high-impact interventions, simplified management and price reduction strategies for key commodities, including medicines, and improved service delivery, as has been demonstrated for other infectious diseases (106). The calculation for cost–effectiveness may be used to back-calculate the pricing level that DAAs should reach to be cost effective or cost-saving within a horizon that has been defined by those that finance the health sector (e.g. health insurance, national social security scheme, Ministry of Health); see the hepatitis C calculator (http://www.hepccalculator.org/).
• Identifying innovative financing solutions. This can be done through both external and domestic funding, and innovative and fair budget allocation (107).

Evidence that pangenotypic DAAs are effective in HCV infection

A WHO-commissioned systematic review identified 142 clinical studies that evaluated the safety and efficacy of various FDA- and EMA-approved DAA regimens. These included sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, sofosbuvir/daclatasvir, daclatasvir/asunaprevir, elbasvir/grazoprevir, ledipasvir/ sofosbuvir, paritaprevir/ritonavir/ombitasvir/dasabuvir, sofosbuvir/velpatasvir/ voxilaprevir, sofosbuvir/daclatasvir/ribavirin, sofosbuvir/ribavirin. The complete evidence summaries for each of the regimens can be found in Web annex 3.1, 3.2 and 8, with a short summary below.

Pangenotypic DAAs in HCV-infected adults without cirrhosis

Pangenotypic DAAs in HCV-infected adults with compensated cirrhosis

TABLE 4.2

Current available pangenotypic DAAs for the treatment of HCV-infected persons with compensated cirrhosis.

Safety of pangenotypic DAAs

Treatment discontinuation due to adverse events was very low in persons without and with cirrhosis in the regimens discussed above (<1%). Similar results were observed in treatment-naive and treatment-experienced persons (see Web annex 3.1 Tables 58–60, page 58).

Balance of benefits and harms

The use of pangenotypic regimens removes the need for genotyping. This simplifies medicine procurement and supply chains, may reduce costs and loss to follow up after diagnosis. Potential harms include the development of rare long-term side-effects of these recently approved medicines, which may not have been identified during post-marketing surveillance, and the potential overtreatment of persons treated with sofosbuvir/daclatasvir if persons are treated for 24 weeks in the absence of genotyping.

Values and preferences and acceptability

Four identified studies investigated the preferences of HCV-infected persons regarding HCV treatment regimens. For persons infected with HCV, the likelihood of a cure and the lack of adverse events are the most important considerations related to treatment regimens, though factors such as a shorter (e.g. 8-week) course of treatment were also valued (97-100). Therefore, use of pangenotypic regimens would be acceptable.

Resource considerations

The resources required to administer HCV therapy can be broadly divided into health system costs (e.g. laboratory and personnel) and the price of medicines. Treating persons with pangenotypic DAAs incurs fewer health system costs as it removes expensive genotyping, which requires specialist laboratories and personnel, saving up to US$ 200 per test in LMICs. The Guidelines Development Group recognizes, however, that access to pangenotypic DAA regimens remains limited in many LMICs (see Chapter 6, Table 6.2). Prices for sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are still higher than the older DAA combinations, but it is expected that prices will substantially decrease as the volume of use increases and access policies for HCV-infected persons living in LMICs are optimized.

Feasibility

The WHO progress report on access to hepatitis C treatment points to the feasibility of widening access to HCV treatment with the use of pangenotypic DAAs (4).

Equity

Simplifying the care pathway by using pangenotypic regimens could improve equity and help improve access to populations that currently do not have access to HCV treatment.

What treatment to use

Adolescents (12–17 years)

The regulatory approval by the FDA and EMA in April and June 2017, respectively, of the use of a fixed-dose combination of sofosbuvir/ledipasvir for genotype 1-infected adolescents aged 12–17 years old or weighing ≥35 kg, and sofosbuvir/ ribavirin for those infected with HCV genotype 2 or 3 was based on the extensive data in adults of high rates of cure and low rates of toxicity, and two studies of pharmacokinetics, efficacy and safety in adolescents (118, 119). In one study, 100 genotype 1 HCV-infected treatment-naive and -experienced adolescents were treated with sofosbuvir/ledispasvir as a single tablet once daily for 12 weeks (118). The SVR was 98% with good tolerability. A second study evaluated the use of sofosbuvir and weight-based ribavirin for 12 weeks in 52 adolescents with genotype 2 or 3 infection (119). SVR rates were 100% (13/13) in genotype 2 and 97% (38/39) in persons with genotype 3. No serious adverse effects leading to treatment discontinuation or significant abnormalities in laboratory results were reported. This study also reported an improvement in health-related quality of life following SVR (122), particularly in social functioning and school performance domains.

Children (6–12 years)

Currently, the only licensed, approved treatment option for children younger than 12 years is pegylated-interferon α-2a or -2b injections with twice-daily ribavirin tablets, for 24 to 48 weeks depending on the HCV genotype (109-117). In genotype 1, the SVR of pegylated-interferon/ribavirin is suboptimal compared to DAAs; and only 52% in those with HCV genotype 1 and 4, but 89% in genotypes 2 and 3 (109–111, 114). Pegylated-interferon and ribavirin are associated with significant side-effects, and potentially irreversible post-therapy side-effects, such as thyroid disease, type 1 diabetes, ophthalmological complications and growth impairment (112, 114, 123–127). None of the DAAs are approved yet for use in children aged less than 12 years. There are two ongoing studies of half-dose sofosbuvir/ledipasvir in 90 treatment-naive or -experienced children aged 6 to 12 years infected with HCV genotypes 1, 3 and 4, and sofosbuvir plus ribavirin in children aged 6 to 12 years (120).

Balance of benefits and harms

Among the Guidelines Development Group there was consensus that the overall goal of treatment in adolescence and childhood is to prevent HCV-associated liver damage and extrahepatic manifestations, together with the potential to achieve an HCV-free generation through earlier treatment.

Treat adolescents ≥12 years or weighing at least 35 kg (without cirrhosis or with only compensated cirrhosis) with sofosbuvir/ledipasvir and sofosbuvir/ribavirin

The Guidelines Development Group recommended that all chronically HCV infected adolescents should be offered treatment with the current FDA- and EMA-approved regimens of sofosbuvir/ledipasvir and sofosbuvir/ribavirin. Data on DAA therapy in HCV-infected adolescents is limited. The recommendation was based on both indirect evidence from adult treatment studies (discussed in Chapter 4.2, see Web annexes 3.1 and 3.2) and two published trials in adolescents (118, 119) of specific recommended regimens (sofosbuvir/ledipasvir and sofosbuvir/ribavirin) used for regulatory approval by the EMA and FDA that showed high efficacy and safety rates and pharmacokinetic equivalence. A systematic review and metaanalysis comparing DAAs with pegylated-interferon in adolescents (128) also confirmed higher efficacy and tolerability of oral short-course DAA treatments when compared to interferon therapy in adolescents and children. This recommendation was therefore strong despite the low quality of evidence specific to adolescents.

The Guidelines Development Group recognized that the recommended regimens had limitations.

1. These regimens are not pangenotypic and therefore genotyping will still be required. Pangenotypic DAA regimens would be preferable in settings with a range of genoptypes. DAAs under evaluation in adolescents include sofosbuvir/ velpatasvir, sofosbuvir/daclatasvir and glecaprevir/pibrentasvir.
2. There remains limited data on treatment in those with cirrhosis, but recommendations include those with compensated cirrhosis. In those who are treatment experienced and with compensated cirrhosis, treatment for 24 weeks is recommended.
3. Use of a ribavirin-based regimen requires haematological monitoring. Ribavirin is also teratogenic and contraindicated in pregnancy. This is important as adolescents are more likely to have unplanned pregnancies. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy, as well as in partners of HCV-infected men who are taking ribavirin therapy.
4. Sofosbuvir with ribavirin is a suboptimal regimen for persons with genotype 3 infection, especially if they have cirrhosis. The Guidelines Development Group noted that the EMA indicates that sofosbuvir/ledipasvir can be considered for use in some persons infected with genotype 3, and so a potential off-label use of sofosbuvir/ledipasvir plus ribavirin is a possible option for adolescents with genotype 3 HCV infection.

Values and preferences and acceptability

Curative, short-course (e.g. 12-week) oral DAA treatment is highly acceptable to adolescents and children, as well as their parents or caregivers (80), because of the likelihood of a cure, and minimal side-effects compared to interferon injections. Cure will enable adolescents and children to live free of a socially stigmatizing infection.

Resource considerations

Treatment of adolescents (and in the future children <12 years) may avoid the higher costs associated with treating adults with advanced liver disease and related complications. Deferring treatment until children reach 12 years and can be treated with DAAs (or until approval of DAAs in younger children), has the potential to reduce costs, as interferon is more expensive.

Equity

The approval of DAAs for use in adolescents is a major opportunity to advance treatment access and cure to a vulnerable group that will benefit from early treatment.