Chronic hepatitis C genotype 1 treatment roadmap for resource constrained settings

Abstract

Aim: To use existing hepatitis C virus (HCV) antiviral therapies as access to new treatments is limited.

Methods: A PubMed search for randomised control trials or meta-analysis related to response-guided therapy of HCV genotype 1 patients was undertaken using pegylated interferon and ribavirin (PR), boceprevir (B) and telaprevir (T) and lead-in where response-guided therapy at TW4(TW4), 8(TW8), 10(TW10), or 12(TW12) based on HCVRNA(+) or HCVRNA(-). Studies presented at major conferences were also used. Where necessary, a post-hoc analysis was performed. A response-guided management roadmap was created based on sustained virological response (SVR).

Results: Starting with PR, those with HCVRNA(-) at TW4 have > 86% SVR, while those are HCVRNA(+) have 34%-41.7% SVR. HCVRNA(-) TW4 patients can have 24 wk PR if HCVRNA < 400000 IU/mL. Alternatively, 28 wk BPR has similar SVR. If HCVRNA(+) at TW4, 72 wk PR leads to 53% SVR, hence BPR is a better option, and if HCVRNA(-) by TW8, 28 wk therapy is sufficient. If HCVRNA(+) at TW8, then HCVRNA should be checked at TW10 and TW12. By TW12, HCVRNA ≥ 100 IU/mL activates the stopping rule. This roadmap is applicable for treatment-naïve, treatment failures and cirrhotic patients. Validation from an Asia Pacific early access boceprevir program confirmed the findings that HCVRNA(-) at TW4, or TW8 conferred > 80% SVR, leading to the "80-80" rule.

Conclusion: Using a roadmap based on HCVRNA(-) at TW4 or TW8 (the "80-80" rule), high SVR can be achieved, and guide the best choices for treatment, and also reduces drug exposure in poor responders.

Keywords: Boceprevir; Chronic hepatitis C; Cirrhosis; Partial responder; Peginterferon; Response-guided therapy; Ribavirin; Sustained virological response; Telaprevir; hepatitis C virus RNA.

Figure 1

Treatment week 4 (A), hepatitis C virus RNA negative (B) and hepatitis C virus RNA positive (C). A: All patients eligible for PR therapy regardless of whether they are treatment naïve, previous treatment failures or cirrhotics. Patients who achieve RVR after 4 wk lead-in either have detectable or undetectable HCVRNA. Those with undetectable HCVRNA have SVR > 86% while those with detectable HCVRNA have SVR 34%-41.7%; B: These patients have a high possibility of SVR so PR therapy can be shortened to 24 wk if they have baseline viral load < 400000 IU/mL). If they do not have good baseline predictors, therapy can also be shortened by addition of boceprevir (4 wk lead-in, 24 wk boceprevir + PR). If they also have IL28B CC genotype, telaprevir and PR can be used for 12 wk as well. Alternatively, they can continue on to 48 wk PR; C: These patients have a low possibility of SVR (41.7%) hence the alternative is to extend PR to 72 wk (53% SVR) or to add boceprevir (61%-66% SVR). TW: Treatment week; HCV: Hepatitis C virus; PR: Pegylated interferon and ribavirin; SVR: Sustained virological response.

Figure 2

Treatment week 8 (A) and treatment week 8 to week 24 (B). A: These patients regardless of the treatment week 4 responses have a high possibility of SVR if they are HCVRNA negative (SVR > 87%) and are eligible for shortened therapy but if they are HCVRNA positive, then SVR rates are low, 35%-41.7%; B: After addition of boceprevir, with undetectable HCVRNA, these patients are eligible for shortened therapy (4 wk lead-in, 24 wk boceprevir +PR). However if they are HCVRNA positive then HCVRNA at weeks 10 and 12 are useful to guide therapy. Those who are HCVRNA ≥ 100 IU/mL at week 12 or have detectable HCVRNA at week 24 fulfill the stopping rules. ¹Not eligible for shortened therapy - should complete 32 wk BPR ± 12 wk PR or complete 44 wk BPR. HCV: Hepatitis C virus; PR: Pegylated interferon and ribavirin; SVR: Sustained virological response.

Figure 3

Roadmap for GT1 hepatitis C virus (A), Roadmap for GT1 hepatitis C virus and new direct acting antivirals (B) and the “80-80” Rule (C). A: Full roadmap showing timepoints, predicted SVR based on undetectable HCVRNA at timepoints, and alternative choices at each timepoint. ¹Not eligible for shortened therapy - should complete 32 wk BPR ± 12 wk PR or complete 44 wk BPR; B: Modification of the roadmap showing that new DAAs can be considered at Treatment week (TW)4 or TW8 if HCVRNA is positive; C: Main points of the roadmap showing that if HCVRNA is negative at TW4 (on PR) or 8 (on BPR) then there is > 80% SVR. If HCVRNA is positive at week 4, then there is 41.7% SVR if 48 wk PR is continued, but at week 8, if HCVRNA is positive while on BPR then the possibility of SVR is 35%-41.2%. HCV: Hepatitis C virus; PR: Pegylated interferon and ribavirin; SVR: Sustained virological response.