Health & Medical hepatitis

The New Paradigm of Hepatitis C Therapy

The New Paradigm of Hepatitis C Therapy

Current Evolution of All-Oral Therapies for HCV

Arrays of IFN-free regimens for treating HCV are currently in the later stages of clinical development. At scientific meetings, data have been presented from phase 2 and 3 studies of various all-oral regimens. The results of individual studies will not be described in great detail here but are summarized in Table 1. The more promising regimens have the following characteristics: a strong safety profile, SVR rates approaching or even exceeding 90%, minimal pill burden and minimal potential for drug–drug interactions.

Several major conclusions and predictions regarding the future of all-oral therapies were discussed. A reasonable anticipation is that a genotype-specific, all-oral therapy for HCV genotypes 2 and 3 with sofosbuvir and ribavirin will be available by 2014. By 2015, genotype-1-specific therapies should follow, and these will comprise any of three regimens currently under development by AbbVie Pharmaceuticals, Bristol-Myers Squibb and Gilead Sciences (Table 1). True pangenotypic regimens will probably not be available until 2016 or 2017 and will require development of pangenotypic NS5A inhibitors and protease inhibitors that can be combined with each other and with nucleotide polymerase inhibitors. Some of these combinations are in phase 1 or early phase 2 studies across multiple genotypes.

Another major area of discussion was whether pretreatment and on-treatment predictors of response, including those used for PEG-IFN, can help predict response to all-oral therapies. Although there is evidence that many of these factors still predict response to relatively weak interferon-sparing regimens, more potent regimens, with SVR rates >90%, readily overcome the traditional obstacles seen with PEG-IFN. For example, in phase 2 studies of the Abbott multidrug regimen or sofosbuvir plus simeprevir or daclatasvir, prior interferon response was not strongly related to response to all-oral treatment. In fact, interferon null responders did just as well as naïve patients and had SVR rates in the 90% range. It is increasingly apparent that regimens consisting of potent agents that individually or cumulatively impose a high barrier to resistance attenuate or eliminate factors such as 1a/1b subtype, IL28B status, viral load, race, metabolic syndrome, obesity and age as major determinants of response. In addition, with potent directly acting antiviral combinations, nearly all patients are negative within 4 weeks, which means the traditional strategy of using virologic response at week 4 or 12 to determine the duration of treatment may be moot. The presence of cirrhosis, which often excludes patients from early phase trials, may yet be a differentiating factor in SVR rates, but this remains to be further determined for genotype 1, and as with other factors, presence of cirrhosis can probably be overcome by a sufficiently potent regimen or longer treatment duration. In studies of sofosbuvir and RBV in patients with HCV genotypes 2 or 3, cirrhosis was a significant negative predictor of response for treatment-naïve patients with HCV genotype 3 and for prior treatment-failure patients with either genotype 2 or 3, but these studies only included 1 potent directly acting antiviral. The effect of portal hypertension and hepatocellular dysfunction (Child's class B and C) on SVR in patients with more advanced liver disease remains an area requiring additional investigation.

The final major questions for discussion encompassed the need for RBV and duration of therapy, which are in some ways connected. As with the pretreatment predictors, ribavirin use and treatment duration appear to matter with relatively weak regimens but may not with sufficiently potent combinations. In studies of the polymerase inhibitor sofosbuvir with either the NS5A inhibitor daclatasvir or the protease inhibitor simeprevir, SVR rates were independent of RBV use. However, in a study combining the protease inhibitor faldaprevir and the non-nucleoside polymerase inhibitor deleobuvir, omitting RBV resulted in a marked reduction in efficacy in genotype 1a patients. And for HCV genotype 1a patients in the phase 2 AVIATOR trial, the removal of RBV from a regimen containing the ritonavir-boosted protease inhibitor ABT-450/r, the NS5A inhibitor ABT-267 and the non-nucleoside polymerase inhibitor ABT-333 resulted in a 10% loss of efficacy. The optimal duration of therapy remains unknown, but with potent regimens, 12 weeks is probably the maximum required for most patients (with the potential exception for patients with advanced cirrhosis). Eight-week treatment regimens can be explored, although this may result in a moderate (~10%) reduction in SVR depending on the regimen.

For regimens containing only direct-acting antivirals, one could imagine a scenario where more potentially difficult-to-treat patients are distinguished from a potentially more easily treatable population. Difficult-to-treat patients may be best served by undergoing an individualized regimen under the care of a specialist. Individualized therapy could be based upon HCV genotype, fibrosis stage, comorbidities, concomitant medications or prior directly acting antiviral drug exposure. Populations of patients who may require individualized therapy but for whom evidence-based treatment data are limited include those with cirrhosis, including decompensated cirrhosis, HIV coinfection, renal failure, an organ transplant or other conditions resulting in being immunocompromised. In the future, it is possible that the population of HCV positive individuals with F0-2 histology will undergo treatment without further stratification such as via HCV genotype or IL28B polymorphisms, because SVR rates will likely be in the 90% range.

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