Brittany E Yee; Nghia H Nguyen; Bing Zhang; Derek Lin; Philip Vutien; Carrie R Wong; Glen A Lutchman; Mindie H Nguyen
Discussion Only
In our primary analysis, we included five studies with a total of 20 014 patients (899 HCV-4; 12 033 HCV-1; and 7082 HCV-2/3). We observed pooled SVR rates of 53%, 44%, and 73% in patients with HCV-4, HCV-1 and HCV-2/3, respectively. While SVR rates with HCV-2/3 patients were significantly higher than HCV-4, we found no statistically significant difference between SVR rates with HCV-1 patients compared to HCV-4.
Prior guidelines from EASL in 2013[94] and AASLD in 2009[5] recommended dual therapy with PEG-IFN+RBV for HCV-4 carriers. Both societies' recommendations for response guided therapy combined recommendations for HCV-4 with HCV-1. Beginning in 2011, telaprevir and boceprevir were the first new direct-acting antivirals (DAA) licensed for use in HCV-1. Currently there are several other DAAs available, including sofosbuvir, simeprevir, sofosbuvir/ledipasvir, and paritaprevir/ritonavir/ombitasvir, which are approved for HCV-1 and HCV-4.[95–97] With shorter treatment duration and higher potency, triple therapy has significantly improved virological response rates for many HCV-infected individuals. However, this therapeutic option may remain elusive for patients in developing or under-resourced regions who lack access to DAAs. Therefore, dual therapy with PEG-IFN+RBV will likely remain the mainstay of treatment for many CHC patients in developing countries and is still a treatment option in the WHO guidelines.[98]
Although societies have grouped HCV-4 with HCV-1, there has been conflicting data as some studies showed a trend towards higher SVR rates in HCV-4 compared to HCV-1,[14,32] whereas other studies have not demonstrated any significant differences.[42,43,46] In our meta-analysis of studies directly comparing HCV-4 and HCV-1 patients, HCV-4 patients had significantly higher rates of RVR (OR 1.96, CI 1.64 to 2.35, p<0.001), but no statistically significant difference in SVR rates (53% vs 44%, OR 1.16 (CI 0.92 to 1.48, p=0.21)). Additionally, when compared to patients with HCV-2/3, patients with HCV-4 and HCV-1 both had lower rates of RVR, EVR and SVR.
Our findings are similar to results from large randomised controlled trials of PEG-IFN+RBV treatment.[8,9] However, the generalisability of these previous trials has been limited due to the paucity of HCV-4, which represented less than 41 patients or 3% of the total subjects randomised to treatment with PEG-IFN+RBV. In contrast, the current meta-analysis includes 899 HCV-4 patients from studies, which also provided comparison data for other treated genotype(s). To our knowledge, this is the first meta-analysis comparing virological response in HCV-4 to HCV-1 and HCV-2/3 patients treated with PEG-IFN+RBV. Subgroup analysis included only observational or non-randomised studies since no large RCTs with sufficient numbers of HCV-4, HCV-1 and/or HCV-2/3 patients have been performed. In the absence of any large RCTs comparing these genotypes, this meta-analysis provides the largest sample of HCV-4, HCV-1 and HCV-2/3 patients with a direct comparison of their SVR rates.
In the secondary analysis of treatment predictors, RVR rates were 39.3% in HCV-4, 24.8% in HCV-1 and 75.9% in HCV-2/3. Prior estimates of RVR in all genotypes have ranged widely: 15%–60% in HCV-4,[7,16,17,24,34,38,42–44,58,65,99] 20%–45% in HCV-1,[99–103] and 60%–95% in HCV-2/3,[99,101,102,104–107] which may be due in part to demographic or epidemiological factors as well as the distribution of advantageous IL28B phenotypes, which were not assessed by the studies included in this analysis. In direct comparison, RVR was favoured in HCV-2/3 over HCV-4, OR 4.85 (CI 3.40 to 6.94, p<0.001) and HCV-4 over HCV-1, OR 1.96 (CI 1.64 to 2.35, p<0.001), a finding previously reported in the current literature.
With both AASLD and EASL guidelines, EVR is especially important for response-guided therapy as failure to achieve EVR is used to recommend discontinuation of therapy at week 12 of therapy. In our study, overall EVR rates were 72.8% in HCV-4, 59.4% in HCV-1, and 91.4% in HCV-2/3. SVR rates in those who achieved EVR were 75.4% in HCV-4, 64% in HCV-1 and 85.2% in HCV-2/3. In contrast, SVR rates in those who did not reach EVR were 10% in HCV-4, 13.1% in HCV-1, and 22.3% in HCV-2/3. Failure to achieve EVR was a negative predictor of response to treatment for all genotypes.
As with HCV-1, lack of EVR is a good stopping rule for HCV-4 given the low SVR rate in those without EVR in the current meta-analysis and supports the societal recommendations that group HCV-4 with HCV-1. In addition, continuing therapy in HCV-4 patients who achieve EVR is also important as approximately three-quarter of HCV-4 patients treated with PEG-IFN+RBV achieved EVR and of those patients, three-quarters achieved SVR.
Although our meta-analysis is the first to quantitatively evaluate treatment predictors and outcomes in such a large population of patients with HCV-4, HCV-1, or HCV-2/3, this study was not without its limitations. Data on newer, all-oral regimens was not included. Additionally, only a small number of studies with a significant amount of heterogeneity were available for this analysis, which limited our ability to perform any additional subgroup analyses or detect publication bias. Our comprehensive literature search yielded only observational or non-randomised studies. Although randomised controlled trials are the reference standard, the studies included in this analysis may be more generalisable to routine clinic settings of heterogeneous patient populations.
In summary, in this meta-analysis of PEG-IFN+RBV treated patients, we observed a higher SVR rate in HCV-2/3 (~70%) and comparable SVR rates in HCV-4 (~50%) and HCV-1 (~45%). As in HCV-1, failure to achieve EVR may be a good stopping rule for patients with HCV-4. Considering the lower SVR rates in HCV-4 and HCV-1, HCV-4 patients infected with these genotypes may significantly benefit from the recently FDA-approved triple therapies, where available. In more resource limited regions, given the higher rate of RVR (39%) and EVR in HCV-4 patients (73%) compared to HCV-1 patients (25% and 59%, respectively) and high SVR in those with EVR (75%), a response-guided approach using PEG IFN+RBV is probably still a reasonable option for the majority of patients. As hepatitis C treatment rapidly evolves, future trials may benefit from use of more diverse patient populations to improve the representation of less common genotypes.
Read more....
BMJ Open Gastroenterology
Prior guidelines from EASL in 2013[94] and AASLD in 2009[5] recommended dual therapy with PEG-IFN+RBV for HCV-4 carriers. Both societies' recommendations for response guided therapy combined recommendations for HCV-4 with HCV-1. Beginning in 2011, telaprevir and boceprevir were the first new direct-acting antivirals (DAA) licensed for use in HCV-1. Currently there are several other DAAs available, including sofosbuvir, simeprevir, sofosbuvir/ledipasvir, and paritaprevir/ritonavir/ombitasvir, which are approved for HCV-1 and HCV-4.[95–97] With shorter treatment duration and higher potency, triple therapy has significantly improved virological response rates for many HCV-infected individuals. However, this therapeutic option may remain elusive for patients in developing or under-resourced regions who lack access to DAAs. Therefore, dual therapy with PEG-IFN+RBV will likely remain the mainstay of treatment for many CHC patients in developing countries and is still a treatment option in the WHO guidelines.[98]
Although societies have grouped HCV-4 with HCV-1, there has been conflicting data as some studies showed a trend towards higher SVR rates in HCV-4 compared to HCV-1,[14,32] whereas other studies have not demonstrated any significant differences.[42,43,46] In our meta-analysis of studies directly comparing HCV-4 and HCV-1 patients, HCV-4 patients had significantly higher rates of RVR (OR 1.96, CI 1.64 to 2.35, p<0.001), but no statistically significant difference in SVR rates (53% vs 44%, OR 1.16 (CI 0.92 to 1.48, p=0.21)). Additionally, when compared to patients with HCV-2/3, patients with HCV-4 and HCV-1 both had lower rates of RVR, EVR and SVR.
Our findings are similar to results from large randomised controlled trials of PEG-IFN+RBV treatment.[8,9] However, the generalisability of these previous trials has been limited due to the paucity of HCV-4, which represented less than 41 patients or 3% of the total subjects randomised to treatment with PEG-IFN+RBV. In contrast, the current meta-analysis includes 899 HCV-4 patients from studies, which also provided comparison data for other treated genotype(s). To our knowledge, this is the first meta-analysis comparing virological response in HCV-4 to HCV-1 and HCV-2/3 patients treated with PEG-IFN+RBV. Subgroup analysis included only observational or non-randomised studies since no large RCTs with sufficient numbers of HCV-4, HCV-1 and/or HCV-2/3 patients have been performed. In the absence of any large RCTs comparing these genotypes, this meta-analysis provides the largest sample of HCV-4, HCV-1 and HCV-2/3 patients with a direct comparison of their SVR rates.
In the secondary analysis of treatment predictors, RVR rates were 39.3% in HCV-4, 24.8% in HCV-1 and 75.9% in HCV-2/3. Prior estimates of RVR in all genotypes have ranged widely: 15%–60% in HCV-4,[7,16,17,24,34,38,42–44,58,65,99] 20%–45% in HCV-1,[99–103] and 60%–95% in HCV-2/3,[99,101,102,104–107] which may be due in part to demographic or epidemiological factors as well as the distribution of advantageous IL28B phenotypes, which were not assessed by the studies included in this analysis. In direct comparison, RVR was favoured in HCV-2/3 over HCV-4, OR 4.85 (CI 3.40 to 6.94, p<0.001) and HCV-4 over HCV-1, OR 1.96 (CI 1.64 to 2.35, p<0.001), a finding previously reported in the current literature.
With both AASLD and EASL guidelines, EVR is especially important for response-guided therapy as failure to achieve EVR is used to recommend discontinuation of therapy at week 12 of therapy. In our study, overall EVR rates were 72.8% in HCV-4, 59.4% in HCV-1, and 91.4% in HCV-2/3. SVR rates in those who achieved EVR were 75.4% in HCV-4, 64% in HCV-1 and 85.2% in HCV-2/3. In contrast, SVR rates in those who did not reach EVR were 10% in HCV-4, 13.1% in HCV-1, and 22.3% in HCV-2/3. Failure to achieve EVR was a negative predictor of response to treatment for all genotypes.
As with HCV-1, lack of EVR is a good stopping rule for HCV-4 given the low SVR rate in those without EVR in the current meta-analysis and supports the societal recommendations that group HCV-4 with HCV-1. In addition, continuing therapy in HCV-4 patients who achieve EVR is also important as approximately three-quarter of HCV-4 patients treated with PEG-IFN+RBV achieved EVR and of those patients, three-quarters achieved SVR.
Although our meta-analysis is the first to quantitatively evaluate treatment predictors and outcomes in such a large population of patients with HCV-4, HCV-1, or HCV-2/3, this study was not without its limitations. Data on newer, all-oral regimens was not included. Additionally, only a small number of studies with a significant amount of heterogeneity were available for this analysis, which limited our ability to perform any additional subgroup analyses or detect publication bias. Our comprehensive literature search yielded only observational or non-randomised studies. Although randomised controlled trials are the reference standard, the studies included in this analysis may be more generalisable to routine clinic settings of heterogeneous patient populations.
In summary, in this meta-analysis of PEG-IFN+RBV treated patients, we observed a higher SVR rate in HCV-2/3 (~70%) and comparable SVR rates in HCV-4 (~50%) and HCV-1 (~45%). As in HCV-1, failure to achieve EVR may be a good stopping rule for patients with HCV-4. Considering the lower SVR rates in HCV-4 and HCV-1, HCV-4 patients infected with these genotypes may significantly benefit from the recently FDA-approved triple therapies, where available. In more resource limited regions, given the higher rate of RVR (39%) and EVR in HCV-4 patients (73%) compared to HCV-1 patients (25% and 59%, respectively) and high SVR in those with EVR (75%), a response-guided approach using PEG IFN+RBV is probably still a reasonable option for the majority of patients. As hepatitis C treatment rapidly evolves, future trials may benefit from use of more diverse patient populations to improve the representation of less common genotypes.
Read more....
BMJ Open Gastroenterology
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