Published online Sep 21, 2016. doi: 10.3748/WJG.v22.i35.8050
Second-generation direct-acting-antiviral hepatitis C virus treatment: Efficacy, safety, and predictors of SVR12
Christoph R Werner, Julia M Schwarz, Daniel P Egetemeyr, Robert Beck, Nisar P Malek, Ulrich M Lauer, Christoph P Berg
Abstract
AIM
To gather data on the antiviral efficacy and safety of second generation direct acting antiviral (DAA) treatment with respect to sustained virological response (SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this setting.
AIM
To gather data on the antiviral efficacy and safety of second generation direct acting antiviral (DAA) treatment with respect to sustained virological response (SVR) 12 wk after conclusion of treatment, and to determine predictors of SVR12 in this setting.
METHODS
Two hundred and sixty patients treated with SOF combination partners PR (n = 51), R (n = 10), SMV (n = 30), DCV (n = 81), LDV (n = 73), or 3D (n = 15). 144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were post-liver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3.
Two hundred and sixty patients treated with SOF combination partners PR (n = 51), R (n = 10), SMV (n = 30), DCV (n = 81), LDV (n = 73), or 3D (n = 15). 144/260 were pre-treated, 89/260 had liver cirrhosis, 56/260 had portal hypertension with platelets < 100/nL, 25/260 had a MELD score ≥ 10 and 17/260 were post-liver transplantation patients. 194/260 had HCV GT1, 44/260 HCV GT3.
RESULTS
Two hundred and forty/256 (93.7%) patients achieved SVR12 (mITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/nL, 88% post-liver transplantation, 95% for GT1a, 93% for GT1b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10 (P < 0.0001), liver cirrhosis (P = 0.005) at baseline. In Interferon-free treatment GT3 had significantly lower SVR rates than GT1 (P = 0.016). Side effects were mild.
Two hundred and forty/256 (93.7%) patients achieved SVR12 (mITT); 4/260 were lost to follow-up. SVR12 rates for subgroups were: 92% for SOF/DCV, 93% for each SOF/SMV, SOF/PR, 94% for SOF/LDV, 100% for 3D, 94% for pretreated, 87% for liver cirrhosis, 82% for patients with platelets < 100/nL, 88% post-liver transplantation, 95% for GT1a, 93% for GT1b, 90% for GT3, 100% for GT2, 4, and 6. 12 patients suffered from relapse, 6 prematurely discontinued treatment, of which 4 died. Negative predictors of SVR12 were a platelet count < 100/nL, MELD score ≥ 10 (P < 0.0001), liver cirrhosis (P = 0.005) at baseline. In Interferon-free treatment GT3 had significantly lower SVR rates than GT1 (P = 0.016). Side effects were mild.
CONCLUSION
Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into “real-world”. Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/nL and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.
Excellent SVR12 rates and the favorable side-effect profile of DAA-combination therapy can be well translated into “real-world”. Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/nL and patients with GT3 are in special need for further research efforts to overcome comparatively higher rates of virological failure.
Key Words: Sofosbuvir, Simeprevir, Ledipasvir, Hepatitis C, Liver transplant, Sustained virological response, Liver cirrhosis, Side effects, Resistance, Daclatasvir
Core tip: From 2014 on the second wave of direct acting antiviral agents was available for treatment of chronic hepatitis C infection. Due to the more heterogeneous character of patients in the “real world”, the therapeutic performance of these new drugs outside randomized clinical trials is of interest. Therefore, in this monocentric retrospective cohort study, we analyzed the efficacy, safety, and predictors of sustained virological response 12 for treatment with combinations of second generation direct acting antivirals in a “real-world” setting.
DISCUSSION ONLY
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This “real-world” monocentric retrospective cohort study analyzing safety, efficacy, and predictors of SVR12 of second generation DAA treatment shows impressive overall SVR rates (93.7%).
Due to the relatively small number of patients and the retrospective character of this study a comparison between subgroups according to DAA combination partners is only of limited significance.
Furthermore, due to the lesser tolerability and presumed lower activity of SOF/PR in patients with advanced liver disease, this treatment a priori was reserved in our hands to patients showing up with a well-compensated liver function only.
The results in our heterogeneous cohort, containing meaningful fractions of hard-to-treat patients (liver cirrhosis, portal hypertension, post-liver transplantation) are similar to SVR rates of so far published study trials: our cohort of PR or R co-treated patients achieved a SVR rate of 93%, while in the NEUTRINO trial the cohort treated with SOF/PR achieved a SVR rate in previously untreated patients of 90%[19], and the VA-real world cohort achieved SVR12 in 66.8%-79%[20].
In other “real-world” analyses with SMV ± R as combination partners of SOF, SVR rates of 74.1%-84.2% were achieved[20-22]. In the OPTIMIST study, a phase III trial, a SVR12 rate of 97% in non-cirrhotic patients[23], while in the OPTIMIST-2 study treating cirrhotic patients with SOF, SMV ± R, SVR 12 in 83% of patients was achieved[24]. However, in our cohort, with more than half of patients being patients with liver cirrhosis, we achieved a SVR rate of 93% with this combination of drugs.
For patients with SOF, DCV ± R as combination partners, SVR rates of 86%-93% have been reported[25]. In our cohort, we were in line with those results and could achieve a SVR rate of 92%, including two patients with recurrent cholestatic Hepatitis C post-liver transplantation, one of those being a non-responder to a prior Telaprevir triple therapy being undertaken post-liver transplantation, and both decompensated at the beginning of treatment.
In previously treated and untreated patients with HCV, a combination of LDV ± R, and SOF led to SVR rates of 94%-99%[26-28], which is in line with results of our cohort, in which we could register a SVR12 rate of 94%, while in another real-world analysis, SVR rates of 91.3%-92% were achieved[29].
For our small group of 3D regimen-receiving patients, we could achieve SVR in 100%, while in the Phase III trials SVR rates of 91.8%-99.5% were observed[30,31].
Thus, altogether, favorable SVR rates achieved in the randomized controlled clinical trials could be translated into the “real-world”, and importantly, in our cohort; even extra hard-to-treat groups of patients exhibited favorable treatment outcomes (SVR12 post-liver transplantation: 88%, SVR12 in cirrhotic patients with platelets < 100/nL: 82%), which exceed results with former treatment options by far[15,32].
Nevertheless, patients with liver cirrhosis show significantly lower response rates (87% with liver cirrhosis, 97% without; P = 0.005), and especially those with advanced portal hypertension (platelets < 100/nL), or high MELD score (≥ 10) show significantly lower SVR12 rates than patients without (P < 0.0001, uni- and multivariate analysis). These findings were also observed in other real world studies with low platelets, low albumin and liver cirrhosis as negative predictors of SVR in larger cohorts[21,33,34]. Thus, this subgroup of patients still resembles a group of patients in the “catch 22”-situation of being in the greatest need of treatment while showing the lowest response rates. Moreover, the whole drug class of HCV protease inhibitors (represented by SMV, and Paritaprevir/r) is not recommendeded for those patients (CTP B “plus”) due to hepatotoxicity. Therefore, new strategies are needed to tackle this problem, e.g., by implementation of screening programs to identify patients infected with HCV at an early stage of their liver disease, and more importantly by development of more potent agents in the near future. However, 4 patients were lost in our cohort. Even if not associated with anti-HCV medication, this emphasizes, that treatment of patients with advanced liver disease should remain in the hands of experienced tertiary centers even in times of “easy” treatment with second generation DAA.
In our cohort, results of early viral kinetics had no impact on prediction of SVR12, thus costly “in-between” measurements of HCV viral load possibly are expendable.
Previous treatment with PR may not play a role any more in treatment decisions, as in our cohort previous treatment was not identified as a negative predictor of SVR, as it was in the HCV-TARGET cohort[21].
Most probably due to the favorable tolerability and low-toxicity profile of second generation DAA, and the omission of pegylated Interferon, now also senior patients benefit from SOF-based DAA treatment on the same scale as younger patients do[21].
Another subgroup of patients in need of further research efforts seems to be the one with GT3: Even though we could achieve a favorable overall SVR rate of 90%, at least in IFN-free treatment regimens, the SVR rates in a “per-protocol” analysis are significantly lower in GT3 patients than in GT1 (80% in GT3, 98% in GT1, respectively, P = 0.016; univariate analysis), again with a special negative focus on patients with GT3 and concomitant advanced liver disease. Moreover, means are limited with respect to treatment of GT3 due to the insufficient antiviral activity of protease- and NS5A-inhibitors (except DCV) in this GT. However, new pangenotypic NS5A inhibitors like Velpatasvir or upcoming new pangenotypic protease inhibitors hopefully close that gap in the near future.
However, since DAA treatment forms RAVs in the viriom of patients, pretreatment with DAA of any generation has to be considered more and more in future treatment attempts after any prior exposure to DAA. All patients in our cohort, who suffered from virological relapse showed RAVs at time-point of relapse. Especially NS5A-RAVs are frequent due to the low resistance barrier of NS5A-inhibitors, as exemplified also in our “real-word” cohort. Since NS5A-RAVs lead to just minimal impairment of viral “fitness”, unfortunately they are detectable for a long time in exposed patients[35]. While for some RAVs (like NS5A L31M, Y93H) clear associations between existence of RAV and virological failure exist, for others (like NS5A A30S) this association is not well established[35].
This may lead to confusion in case of a future re-treatment, if minor RAVs have been detected, and even more in case of a baseline test in treatment naïve patients. However, as the population of patients with relapse after DAA treatment grows, the need for controlled trials with new DAA-combinations (e.g., pangenotypic protease inhibitor) for those patients to address this problem is obvious. Therefore, after virological relapse we recommend resistance testing for individualized adjustment of future DAA therapies.
This may lead to confusion in case of a future re-treatment, if minor RAVs have been detected, and even more in case of a baseline test in treatment naïve patients. However, as the population of patients with relapse after DAA treatment grows, the need for controlled trials with new DAA-combinations (e.g., pangenotypic protease inhibitor) for those patients to address this problem is obvious. Therefore, after virological relapse we recommend resistance testing for individualized adjustment of future DAA therapies.
In our retrospective analysis excellent SVR12 rates of second generation DAA could be translated from the large study trials into “real-world” scenarios. Patients with advanced liver disease, signs of portal hypertension, especially with platelets < 100/nL, or MELD ≥ 10, and patients with GT3 are at relatively higher risk to suffer from virological failure and development of resistance associated variants after exposure to DAA. To overcome this unsolved problem, further research efforts are needed.
COMMENTS
Background
From 2014 on, successively the second wave of direct acting antiviral agents (Sofosbuvir, Daclatasvir, Simeprevir, Ledipasvir, Dasabuvir, Ombitasvir, Paritaprevir/r) was available for treatment of chronic hepatitis C infection. In randomized clinical trials, superb rates of sustained virological response (SVR) 12 could be achieved.
Research frontiers
Due to the more heterogeneous character of patients in the “real world”, the therapeutic performance of these new drugs outside randomized clinical trials is of interest. Therefore, in this monocentric retrospective cohort study, we analyzed the efficacy, safety, and predictors of SVR 12 for treatment with combinations of second generation direct acting antivirals in a “real-world” setting.
Innovations and breakthroughs
In this retrospective study, similar SVR rates could be achieved compared to randomized clinical trials. However, certain subgroups of patients have significantly lower viral response rates: Significant negative predictors of SVR12 were a platelet count < 100/nL, a MELD score ≥ 10 (both P < 0.0001), liver cirrhosis at baseline (P = 0.005). Moreover, in Interferon-free treatment patients with HCV genotype 3 had significantly lower SVR rates than patients with HCV genotype 1 (P = 0.016). In the future, these subgroups of patients should be more in the focus of research efforts to overcome lower rates of SVR.
Applications
Current retrospective analysis shows that excellent SVR12 rates and the favorable side-effect profile of direct acting antiviral-combination therapy can be well translated into “real-world”.
Peer-review
Good level-study to be ameliorated in the presentation of characteristics of cirrhotic patients that are an important part of the studied population.
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