Wednesday, January 11, 2017

Full Text/Original Article Sofosbuvir-based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt

Alimentary Pharmacology & Therapeutics
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Original Article Sofosbuvir-based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt
Authors A. Elsharkawy, R. Fouad, W. El Akel, M. El Raziky, M. Hassany, G. Shiha, M. Said, I. Motawea, T. El Demerdash, S. Seif, A. Gaballah, Y. El Shazly, M. A. M. Makhlouf, I. Waked, A. O. Abdelaziz, A. Yosry, M. El Serafy, M. Thursz, W. Doss, G. Esmat
First published: 9 January 2017
Full publication history DOI: 10.1111/apt.13923

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Chronic hepatitis C virus infection is one of the most important health problems in Egypt. The Ministry of Health's National Treatment Programme introduced sofosbuvir-based therapy in October 2014.

To assess the clinical effectiveness and predictors of response to SOF-based treatment regimens, either dual therapy, with SOF/ribavirin (RBV) for 6 months or triple therapy with SOF/peg-IFN-alfa-2a/RBV for 3 months, in a cohort of patients treated in National Treatment Programme affiliated centres in Egypt.

Between October 2014 and end of 2014, patients who were eligible for treatment were classified according to their eligibility for interferon therapy: Group 1 (interferon eligible) were treated with triple therapy for 12 weeks and Group 2 (interferon ineligible) were treated with dual therapy for 24 weeks. Difficult to treat patients included those with F3-F4 on Metavir score, Fib-4 >3.25, albumin ≤3.5, total Bilirubin >1.2 mg/dL, INR >1.2 and platelet count <150 000 mm3.

Twelve weeks post-treatment data were available on 14 409 patients; 8742 in group 1 and 5667 in group 2. In group 1, the sustained virological response at week 12 (SVR12) was 94% and in group 2 the SVR12 was 78.7%. Multivariate logistic regression analysis in which treatment failure is the dependent variable was done. Male gender, being a difficult to treat patient and previous interferon therapy were significant predictors of nonresponse in both treatment groups.

Results of sofosbuvir-based therapies in Egypt achieved similar rates of SVR12 as seen in phase III efficacy studies.

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Continuous efforts from the National committee of control of viral hepatitis and the Ministry of Health ensured that Sofosbuvir became available in 2014 at prices appropriate for the scale of the epidemic of HCV and for the economic situation in Egypt. Nevertheless, due to the large number of patients with HCV in Egypt, the high cost and the limited amounts of drugs available, it was not possible to treat all patients immediately and the decision was made to start with those patients who had advanced liver fibrosis (F3-F4) as recommended by EASL 2014[9] and AASLD 2015.[12] Our results therefore reflect the severity of liver disease in this cohort of patients.

HCV genotype4 was previously considered a difficult to treat genotype. Using Peg-IFN/RIB as standard of care for 48 weeks SVR24 rates which were higher than in genotype 1 but substantially lower than those seen in patients with genotype 2 and 3 patients. Overall, SVR rates for genotype 4 in Egypt and the Middle East were about 60–69%.[13-15]

SOF-based therapies are the novel standard of care with high anti-viral activity, broad genotypic coverage and a high barrier to resistance.[16, 17] In genotype 4 infected patients SVR12 rates for triple therapy with SOF/PEG-IFN/RBV were 96%[8] in clinical trials. There is substantially less data on treatment outcomes for genotype 4 infected patients using dual therapy with SOF/RBV for 24 weeks. Doss et al., 2015 reported SVR 12 rate of 78% for cirrhotic patients and 93% in patients without cirrhosis.[18]

Treatment outcomes in the real world do not necessarily follow those seen in efficacy trials used for licensing new treatments. However, in HCV a number of recent publications from real world cohorts have reported SVR12 rates in the same order of magnitude as those seen in pivotal trials.[19, 20] The real world cohorts arising from centres in the USA and Europe are dominated by patients infected with genotypes 1a and 1b and to a lesser extent genotype 3. In contrast genotype 4 infection dominates in Egypt and this is the first large scale real world cohort to be reported. It is reassuring to note that the SVR12 results achieved in patients who completed follow-up were in the same order of magnitude as those seen in clinical trials. Our results using the triple therapy regimen were very close to the results of the phase 2 trials (Photon and Atomic) using the same drugs.[7, 21] Furthermore, in the triple therapy group the SVR12 rates were equal to that reported in the phase 3 NEUTRINO trial with predominantly genotype 1 or 4 HCV infection.[16]

In the phase 2 trials (QUANTUM and ELECTRON) using SOF/RBV dual therapy, SVR12 rates were 56% and 88% respectively. Extending the treatment duration to 24 week as in our study showed no obvious benefit in a subgroup of patients in the QUANTUM and NIH SPARE studies.[22, 23] The difference between our results and these trials may be attributed to different genotypes and the absence of treatment-experienced patients in previous trials.[22, 23]

Results of the FUSION trial that used the same duration (24 weeks) in genotypes 2 and 3 led to significant improvement of SVR from 56–73%.[24]

Doss et al., 2015 suggested that SOF/RBV for either 12 or 24 weeks is successful in treating treatment-naïve and treatment-experienced Egyptian patients with genotype 4 HCV. The rate of SVR12 was higher in the group receiving 24 weeks (90%) vs. 12 weeks (77%) of therapy with 17% cirrhotic at baseline.[18] The low number of cirrhotic patients in their study would possibly explain the difference.

By multivariate regression analysis and as reported in other studies,[16, 18, 25] liver cirrhosis evidenced by any of criteria we included for the group of ‘difficult to treat’ was a predictor of nonresponse in our population. A European study on 60 subjects of Egyptian ancestry with HCV genotype 4 including both treatment naïve or treatment-experienced patients compared SVR rates with either 12 or 24 weeks of treatment with SOF/RBV.[26] As reported in this study, they reported that treatment-naïve patients had higher SVR rates than the treatment-experienced patients.

The main limitation of this study is the low rate of follow-up. Only 72.2% of the 28 142 patients who commenced therapy were followed up to completion of treatment and only 51.2% were followed up to 12 weeks after the end of therapy when the outcome of treatment can be judged. It is not possible to estimate the treatment success rate in patients who were not followed up but it is reasonable to assume that it may not be as high as the rates seen in patients who were fully adherent to the monitoring regimen.

Sofosbuvir-based therapies whether triple or dual show higher rates of SVR compared to that of the previously used SOC. However, it is not possible to assess treatment effectiveness comprehensively as the rate of loss to follow-up is high. There is still a need for further novel DAA s based therapy to have better response rates especially in patients with advanced fibrosis.

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