Decision-making table, PICO question on how to treat

Web Annex 2Decision-making table, PICO question on how to treat

Acknowledgement

The World Health Organization (WHO) wishes to express its appreciation to the following individuals, who contributed to the development of this annex: Marc Bulterys, WHO, Geneva, Switzerland; Roger Chou, Oregon Health and Science University, Portland, United States of America (USA); Judith van Holten, WHO, Geneva, Switzerland; and Yvan Hutin, WHO, Geneva, Switzerland.

PICO question 2. Which combination of antiviral therapies is the preferred treatment option for persons with chronic hepatitis C infection?

A. Background

1): WHO estimated that 71 million persons were living with chronic HCV infection in 2015, accounting for 1% of the global population.

2): The global response to viral hepatitis entered a new phase in 2015, when the United Nations (UN) General Assembly adopted the 2030 Agenda for Sustainable Development, which called on the international community to combat hepatitis. The following year, the World Health Assembly adopted WHO’s first “Global Health Sector Strategy on viral hepatitis” with elimination by 2030 as its overarching vision.

3): There is good scientific evidence that eliminating viral hepatitis is technically feasible (2017 WHO Global hepatitis report). For hepatitis C, the targets are to reduce HCV incidence by 90% and HCV-related mortality by 65% by 2030.

4): In April 2016, WHO issued updated Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection. The 2016 Guidelines included the recommendation that direct-acting antiviral (DAA) regimens be used for the treatment of persons with chronic HCV infection. All oral DAA options have demonstrated efficacy comparable or superior to pegylated interferon and ribavirin, with far less adverse events, shorter duration of treatment and greater patient acceptability. The 2016 Guideline Development Group (GDG) acknowledged that in specific subpopulations, most notably patients infected with HCV genotype 3 with cirrhosis, there was a lack of evidence to support all-oral DAAs over interferon-based therapies. There was also a lack of evidence to make conclusive recommendations for (the less frequent) treatment of infection with genotypes 5 and 6.

5): Since that time, newer DAAs, including pangenotypic drug combinations, have been developed and new evidence from clinical trials has been published. Several pangenotypic DAA regimens have recently been approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

6): In view of this, WHO is reviewing its hepatitis C guidelines to address recommendations for the newer, pangenotypic DAA regimens. These regimens could facilitate more rapid treatment expansion worldwide. Pangenotypic DAA regimens are optimal for resource-limited settings, as they simplify diagnosis (i.e. no need for expensive genotyping), drug procurement and delivery, and reduce prescribing and dispensing errors.

7): The focus of this PICO 2 is to develop a set of recommendations as to which pangenotypic DAA regimen is (are) the preferred option(s) to treat persons with chronic HCV infection. The recommendations take into consideration: efficacy, safety, cost, access/availability, drug interactions and acceptability (as evaluated by duration of regimen, number of doses/day, sideeffects), as well as genotype distribution. In addition, specific considerations of persons with HIV/HCV coinfection, cirrhosis and those with severe renal impairment will be addressed.

Systematic reviews of evidence have been conducted to inform these elements.

POPULATION: adults and children over the age of 12 and/or above 35 kg in weight with chronic hepatitis C infection

INTERVENTION: combination DAA therapy

COMPARISON: current WHO-recommended DAA therapy

OUTCOMES: rate of sustained virological response (SVR) at 12 weeks (SVR12), decompensated liver disease, hepatocellular carcinoma, all-cause mortality, treatment-related adverse events leading to discontinuation of therapy

SETTING: primarily for lower- and middle-income countries (LMIC)

PERSPECTIVE: public health approach

Table

All comers: all patients, no subgroup stratification; may include patients with cirrhosis, HIV coinfection Genotype mixed/unspecified: where outcomes were not available by genotype or presented by genotype groupings; if ≥1 patient with a non-common (more...)

H. Draft Recommendation

WHO recommends the use of pangenotypic DAA regimens for the treatment of persons with chronic HCV infection aged 18 years and above.

I. RATIONALE for recommendation

Potential clinical benefits of pangenotypic regimens are similar to those of non-pangenotypic regimens
However, pangenotypic regimens remove the need for genotyping
Cost reduction (genotyping is very expensive)
Simplification of medicine procurement and supply chains
Simplified treatment scheme which can reduces lost to follow up

J. STRENGTH of recommendation

Conditional

K. Implementation Considerations

Countries need to plan for the transition to the use of pangenotypic regimens Speed of transition depends on prevalence of HCV infection, the distribution of HCV genotypes and how effective the current regimen is in treating HCV infection with these genotypes

L. Research Gaps

Data on efficacy and safety of pangenotypic regimens are required in specific populations, including those with severe renal impairment, persons under the age of 18 and pregnant women.
Investigate predictive factors for selecting persons who could be treated for a shorter period of time
Cost-effectiveness data of pangenotypic regimens in LMICs
Establish the clinical importance of drug resistance
Data on treatment failure and the relation with rare genotypes and resistence

Table

Summary of judgements.

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World Health Organization, Geneva

NLM Citation

Guidelines for the Care and Treatment of Persons Diagnosed with Chronic Hepatitis C Virus Infection [Internet]. Geneva: World Health Organization; 2018 Jul. Web Annex 2, Decision-making table, PICO question on how to treat.

		2016	2017
B. SUMMARY AND QUALITY OF EVIDENCE A systematic review was performed to compare the safety and efficacy of DAA regimens for the treatment of HCV infection. This included the following pangenotypic regimens: sofosbuvir + velpatasvir, glecaprevir + pibrentasvir, sofosbuvir + velpatasvir + voxilaprevir. In addition, other DAA regimens recommended by WHO (2016 Guidelines) were included in the systematic review. In specific instances, drug combinations including ribavirin were also included. The tables below demonstrate the pooled SVR12 rates for the regimens of highest interest (by genotypes 1–6). Subgroups of special interest include (a) patients with cirrhosis; and (b) patients with HIV coinfection. More details are available in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tables included in the annex. Pooled safety outcomes are also provided as follows: (1) mortality (during the follow-up period in the trial); (2) adverse events leading to discontinuation of treatment (DAEs); and (3) serious adverse events (SAEs). Definitions All comers: all patients, no subgroup stratification; may include patients with cirrhosis, HIV coinfection Genotype mixed/unspecified: where outcomes were not available by genotype or presented by genotype groupings; if ≥1 patient with a non-common genotype Naive: no prior HCV treatment Experienced: any prior HCV treatment (for nearly all trials, this was interferon-based) Naive and experienced: where outcomes not reported by treatment experience or where treatment experience unclear; does not include outcomes that are reported for treatment-naive and treatmentexperienced patients separately				□ High x Moderate □Low □ Very low


Summary of the evidence: The systematic review demonstrates that oral therapy with DAAs is generally associated with high (>90%) SVR12 rates in HCV patients infected with all genotypes (1–6). In treatment-naive patients infected with genotypes 1–6 treated with a DAA, the pooled SVR rates were all higher than 90%. Similar results were observed in treatment-experienced patients, where DAA therapies reached SVR rates of 90% or higher. SAEs were relatively low (usually <5%) across all genotypes in HCVinfected patients treated with DAAs. No major differences were observed between treatment-naive and treatment experienced patients. The safety profiles of all the DAA-recommended regimens appear favourable. Discontinuation rates due to adverse events (DAEs) were generally higher for patients with cirrhosis (approximately 2%). All pangenotypic DAAs (sofosbuvir + velpatasvir, glecaprevir + pibrentasvir, sofosbuvir + velpatasvir + voxilaprevir) showed similar SVR12 rates. SAEs and DAEs also were comparable between the pangenotypic DAAs and ledipasvir + sofosbuvir. The safety and efficacy of sofosbuvir in combination with daclatasvir (SOF/DAC) for 12 weeks has been studied in clinical trials involving patients infected with HCV genotypes 1–4. When adding unpublished trial data provided to WHO by Médecins Sans Frontières (MSF), it appears SOF/DAC has high SVR12 rates for all genotypes, including 5 and 6. Patients with compensated cirrhosis (treatment naive and/or experienced) have high rates of SVR12 with all three pan-genotypic DAA regimens (sofosbuvir + velpatasvir, glecaprevir + pibrentasvir, sofosbuvir + velpatasvir + voxilaprevir). However, SVR12 rates are generally lower for patients with (harder-to-treat) genotype 3. For the triple DAA combination, sofosbuvir + velpatasvir + voxilaprevir, there are very limited data in treatment-naive patients. A general consensus is to preserve this regimen for patients who have failed previous DAA treatment (in line with recommendations currently being formulated by the American Association for the Study of Liver Diseases (AASLD)Infectious Diseases Society of America/(IDSA) and European Association for the Study of the Liver (EASL) professional societies). Patients with HIV coinfection also achieve high SVR12 rates (>95%) with sofosbuvir + velpatasvir and glecaprevir + pibrentasvir. Additional subgroup data will be available for discussion at the GDG meeting. Based on the available evidence, we propose the following DRAFT RECOMMENDATIONS: (to be discussed at the GDG meeting) WHO recommends the use of pangenotypic regimens with high efficacy.

C. HARMS/BENEFITS Benefits of the use of pangenotypic regimens All oral pangenotypic regimens have been shown to be highly effective and safe. Pangenotypic regimens remove the need for costly genotyping before the start of treatment. The use of pangenotypic regimens has the potential to simplify treatment decisions, medicine procurement and supply chains, which is especially relevant in lower-middle-income countries (LMICs). Harms of the use of pangenotypic regimens Pangenotypic DAAs have only recently been approved by at least one stringent regulatory authority. There may be a possibility of rare sideeffects that were not detected during clinical trials.				x Benefits clearly outweigh harms □ Benefits and harms are balanced □ Potential harms clearly outweigh potential benefits Are the desirable anticipated effects large? x No □ Probably □ Uncertain □ Yes □ Varies
D. ACCEPTABILITY, VALUES AND PREFERENCES Four studies were identified that assessed patient preferences related to HCV treatment. From these studies, the most important patient outcome was overall efficacy (likelihood of cure) followed by risk of adverse events. The safety profiles of all the DA- recommended regimens are favourable and the likelihood of cure (SVR12) is high across all genotypes for the pangenotypic drug regimen(s) under consideration. Thus, we believe this treatment is highly acceptable to most patients. Survey of people living with HCV infection An online survey (100 respondents) found that nearly all respondents living with HCV infection favour a “treat all” policy with DAAs and are advocating for universal access to treatment. No specific concerns were raised about pangenotypic DAA regimens. Survey of health-care workers An online feasibility survey among health-care providers (111 respondents) found that health-care workers highly value “cure” (i.e. high SVR) for their patients. Health-care workers express a strong preference for simplified patient management algorithms and simplified treatment choices. Perspective of national programme managers Cure leads to progress towards HCV elimination goals. Decision-makers express a preference for simplified treatment decisions and for strategies that represent cost-effective use of the limited resources available.				x No major variability □ Major variability Is the option acceptable to key stakeholders? □ No □ Probably □ Uncertain □ Yes x Varies
E. EQUITY, ETHICS AND HUMAN RIGHT IMPLICATIONS Will the recommendation raise questions around equity? Treatment with pangenotypic DAAs would reduce practical obstacles by simplifying patient management (e.g. no need for genotyping; only one regimen for procurement and dispensing), which can be resource- and time-intensive. This would lead to a broader offer of treatment that would likely reduce inequities. Are there ethical implications to this recommendation? There are no direct ethical implications from the choice of optimal DAA regimen (pangenotypic compared with non-pangenotypic) as long as they are highly effective and safe.				□ Less equitable x More equitable
F. RESOURCE USE AND FINANCIAL IMPLICATIONS Patients in more than 100 lower and middle-income countries can benefit from low-cost generic formulations of daclatasvir, sofosbuvir, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir, under voluntary licensing (VL) agreements signed between innovator companies and companies that manufacture generic medicines. Pangenotypic regimens are optimal for resource-limited settings, as they simplify diagnosis (i.e. no need for genotyping), procurement and delivery. This also translates in substantially reduced costs of laboratory testing (as in most settings, genotyping costs over $150 per patient). The SOF–VEL combination appears slightly more effective than SOF–LDV/DCL (see evidence tables) but is still costlier in many settings. Based on data from India, with the above assumptions, SOF–VEL appears cost effective (compared with SOF–LDV/DCL) with an incremental cost–effectiveness ratio of ~US$ 900–1000 per qualityadjusted life year (QALY) gained for those without cirrhosis and of ~US$ 1700–1850 per QALY gained for those with cirrhosis. For SOF–VEL to be cost-neutral compared to the SOF–LDV/DCL, the price of SOF–VEL will need to be below US$ 145 for each 4 weeks of treatment (unpublished data from India, personal communication, Rakesh Aggarwal). For glecaprevir plus pibrentasvir (G/P), the originator company has not yet decided on its access strategy; WHO has been told the company is considering several options for access. For the time being, the combination is registered in the USA and a number of highincome countries only. The price in the USA for an 8-week course of treatment is $26 000.				Are the resources required small? □ No □ Probably □ Uncertain □ Yes x Varies
G. FEASIBILITY AND CONSTRAINTS TO IMPLEMENTATION The first oral DAA has been approved since 2013 and more than 1 million HCV-infected patients have already been successfully treated worldwide. However, with the exception of Egypt, most of the DAA treatments have been provided in high-income countries (WHO Global report on access to hepatitis C treatment: focus on overcoming barriers, October 2016). Treatment with pangenotypic DAA regimens may remove several key barriers to rapid treatment scale up (including the need for genotyping before the start of treatment) and simplify treatment decisions. RELEVANCE TO DIFFERENT SETTINGS/POPULATIONS Are any major barriers expected for the implementation of this recommendation? Will this recommendation be most relevant for particular settings (e.g. endemicity)? The recommendations in this DM table are most relevant for lower-middleincome countries (LMICs) with access to generic DAAs. Currently, over 110 countries have access to at least one generic DAA. As treatment is scaled up, ensuring the quality of supply is of great importance. As of September 2017, the WHO programme has prequalified daclatasvir from the innovator company and generic sofosbuvir made by the Indian company, Mylan. None of the other generic DAAs that are currently on the market are approved by a stringent regulatory authority or WHO prequalified. This is likely to change soon as a number of generic and innovator products are fairly advanced in the process of WHO prequalification. This will facilitate procurement of generic treatment by international as well as domestic programmes. Availability of WHO-prequalified generic DAAs The number of generic versions of DAAs has increased between mid-2015 and September 2017. The following charts show this increase and also the current status of WHO prequalification. Prices reported by companies producing generic DAAs The prices reported in 2017 are compared with those listed in the October 2016 Global report on access to hepatitis C treatment. Some companies did not provide prices for both years. Highlighted in the table below are those prices that have been confirmed by companies. These prices are for a 28-day supply (or per bottle); thus, one has to multiply by three to obtain the price for a 12-week DAA treatment regimen.				Is the option feasible to implement? □ No x Probably □ Uncertain □ Yes □ Varies
SOF	Hetero	80
SOF	Gilead	300	250
SOF	Beximco		106
SOF	Galenica		343,01
SOF	Incepta	197	210
SOF	Mylan		70
SOF	Natco	199
SOF	Pharco	85	70,5
SOF	Pharma 5	300	274
SOF	Richmond	500,5
SOF	Strides	300	40
SOF/VEL	Incepta		350
SOF/VEL	Mylan		150
SOF/VEL	Strides		130
DCV	Beximco		92
DCV	Galenica		171,51
DCV	Incepta		140
DCV	Mylan		35
DCV	Natco	70
DCV	Pharma 5	306,8	143
DCV	Pharco
SOF/LDV	Gilead	400	300
SOF/LDV	Beximco		364
SOF/LDV	Incepta	352,2	350
SOF/LDV	Mylan		100
SOF/LDV	Natco	250
SOF/LDV	Strides	400	100
The table and graphs show that prices for generic DAA have continued to decline between September 2016 and September 2017. Prices for the generic, pangenotypic SOF–VEL regimen are still somewhat higher than for the older DAA drug combinations. However, it is believed these prices will decline further as the market matures. Prices remain high in high-income countries and those middle-income countries that do not have access to generic formulations (i.e. outside VL territories), those with a high burden and/or highly affected key populations such as Argentina, Brazil and China.

Summary of judgements

	Judgement
Problem	No	Probably no	Probably yes	yes	varies
Certainty of evidence	Very low	Low	Moderate	High
Balance of benefits and harms	Potential harms clearly outweigh potential benefits	Benefits and harms are balanced	Benefits clearly outweigh harm
Large desirable effects	No	Uncertain	Probably	Yes	Varies
Are required resources small?	No	Uncertain	Probably	Yes	Varies
Equity	Less equitable	More equitable
Acceptability	No	Uncertain	Probably	Yes	Varies
Feasibility	No	Uncertain	Probably	Yes	Varies