Background

In April 2014, WHO issued its Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C Infection. These guidelines included recommendations for the use of pegylated interferon plus ribavirin, telaprevir, boceprevir, sofosbuvir, and simeprevir. Since that time, three new medicines have been approved by at least one stringent regulatory authority (SRA) (e.g. US FDA). In addition, new evidences from clinical trials and observational cohorts have been published using all oral therapy with DAA (Direct Acting Antivirals). In view of this, WHO is updating its guidelines to include recommendations for these new therapies.

The focus of this PICO is to develop a set of recommendations as to which regimen is (are) the preferred option(s) to treat persons with chronic HCV infection. The recommendations would take into consideration: efficacy, safety, price, availability, drug interactions, and acceptability (as evaluated by duration of regimen, number of doses/day, side effects) as well as genotype distribution. Systematic reviews of evidence will be conducted to inform these elements. The results of the systematic review would be entered into a network meta-analysis in order to provide comparisons of individual regimens for which there are no (or few) head-to-head comparisons. A cost-effectiveness model would be used to identify cost thresholds for cost-effectiveness in various settings.

PICO 1

Population: Adults and Children with chronic HCV infection

Intervention: combination of direct-acting anti-viral therapy with or without ribavirin therapy

Comparison: pegylated interferon and ribavirin therapy with or without DAA or other DAA

Outcomes: Rate of SVR, decompensated liver disease, hepatocellular carcinoma, all-cause mortality, and treatment-related adverse events leading to discontinuation of therapy, Quality of life, resource use, cost-effectiveness.

Method

We will commission systematic reviews of clinical trials of approved medicines that were approved by at least one stringent regulatory authority by January 2015.

Relative efficacy and safety: Since there are few head-to-head comparisons of these medicines, we will commission a network meta-analysis to provide indirect evidence of the relative efficacy of the combinations.

Resource considerations: In view of the high cost of these medicines, resource consideration and equity-of-access will be also important factors in making recommendations. Price of medicines will be obtained from WHO Global Price Reporting Mechanism and other sources. Regarding availability, pharmaceutical companies will be contacted to ask in which countries their medicine has been registered. We will commission an external group to develop a health-economics model that will assess the budget impact of these medicines. To make the recommendations on preferred regimens, a decision-making framework will be used. The Guidelines Development Group will be asked to agree on a framework, but it is likely to include elements such as:

-

Efficacy (rate of SVR)

-

Safety (rate of adverse effect)

-

Price

-

Availability

-

Accessibility

-

Duration of treatment

-

Drug interaction

-

Number of tablets

-

Cost-effectiveness

Study type/limits

We will assess the results of drug-registration clinical trials, any other published articles (including observational cohort data), abstracts presented at annual meetings of major gastroenterological societies such as Digestive Diseases Week (DDW), American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL). We will also include data submitted by the originator companies to the FDA and EMA as part of drug registration applications.

For this systematic review, results will be stratified by: (However, It is unlikely that any data will be available for many of these factors)

• Population: adults and children
• Genotype: type 1 (1a, 1b), type 2, type 3, type 4, type 5 and type 6
• Fibrosis stage: cirrhosis and non-cirrhosis
• Naïve vs previously treated by interferon therapy
• HIV-infected vs not infected

The evidence that will be summarized through the systematic reviews and other analysies will be used to inform all the treatment-related recommendations that will emanate from the Guidelines Development Group meeting.