Aa
Treatment for Hepatitis C Genotype 3
Excerpt from an excellent article in Medscape. I copied only the chapter on treatment. This excerpt discusses the current treatment guidelines, weight based Ribavine, and 48 weeks of treatment for those without an RVR, as well as the SVR rates for Genotype 3. To read the entire article, go to Medscape, register (free), and search for the article title:
Is 3 the New 1: Perspectives on Virology, Natural History and Treatment for Hepatitis C Genotype 3
E. B. Tapper, N. H. Afdhal
Treatment: Pegylated Interferon and Ribavirin (PEG-IFN/RBV)
Genotype has long been known to influence response to PEG-IFN and RBV therapy, with the potential for shorter durations of therapy and higher SVR rates for HCV-2 and HCV-3 compared with HCV-1 infection.[37,38] Historically, HCV-2 and HCV-3 have been lumped together as, relative to HCV-1, patients infected with these genotypes have responded best to interferon-based therapies. On closer inspection of treatment trials, however, HCV-3-infected patients clearly respond more poorly to interferon-based therapy than do patients with HCV-2. For much of the past decade, the focus on therapy has been the determination of therapy duration. There have been several landmark trials experimenting with duration of PEG-IFN and RBV for patients with chronic HCV-2 and HCV-3 infection examining 12, 14, 16 and 24 week treatment durations[39–48] (Table 1). These trials show consistent evidence of poorer therapeutic response in patients with HCV-3 compared with HCV-2, which might be explained by the concomitant steatohepatitis and more advanced fibrosis in HCV-3. .....
Two important early trials established shortened duration (24 weeks) therapy as a viable option. Mangia et al.[41] examined 12- and 24-week courses and found equal rates of SVR overall, 77% and 76%, respectively. There were, however, somewhat striking intergenotype differences. The rate of SVR was 80% for patients with HCV-2 and 66% for patients with HCV-3. Zeuzem et al.[46] treated 42 HCV-2-infected patients and 182 HCV-3-infected patients with PEG-RBV for 24 weeks. SVR was achieved in 93% of HCV-2 patients and 79% of HCV-3 patients.
In 2008, two trials were published comparing 24 weeks to 14 and 12 weeks of therapy. The North-C group found an overall SVR rate of 81.1% and 90.7% in 14- and 24-week courses following an RVR in the intention-to-treat analysis, respectively. Again, genotype-specific response was seen with SVR achieved in 97% of the 31 HCV-2 patients receiving 24 weeks of therapy compared with 92% of the 110 patients with HCV-3 experiencing RVR. Meanwhile, in the population who did not experience RVR, 75.0% (15 of 20) with HCV-2 and 56.3% (54 of 96) with HCV-3 experienced SVR.[39] The NORDynamic Study group saw a similar pattern of results after 24 weeks with HCV-3 patients achieving SVR 58% of the time after 12 weeks and 78% after 24 weeks.[45] More recently, in the PEG-RBV control arm of the FISSION trial, there was a significant difference in the attainment of SVR between genotype 2 and 3 patients, 77.6% vs 62.5%.[3]
ACCELERATE randomly assigned 1469 patients equally divided amongst HCV-2 or HCV-3 to receive 180 μg of peginterferon-alpha-2a weekly, plus 800 mg of ribavirin daily, for either 16 or 24 weeks.[43] 16 weeks of therapy was inferior to 24 with respect to SVR (62% vs 70%). SVR was achieved in 82% of HCV-2 patients receiving 24 weeks of therapy compared with 71% of HCV-3 patients in the per protocol analysis (67.0% in the intention-to-treat analysis). Amongst patients with a rapid virological response (RVR), SVR rates were 79% and 85% in the 16- and 24-week groups. Interestingly, there was no difference in the rate of SVR between genotypes for the patients that experienced RVR (85% vs 85%), confirming the findings of a prior, smaller trial.[42] ACCELERATE also showed that patients with advanced fibrosis fared poorly by comparison, achieving SVR 43% of the time after 16 weeks and 49% after 24 weeks. The major limitation of this trial is that it used fixed dose RBV 800 mg for all patients rather than weight based. The current consensus is that weight-based ribavirin is necessary for shortened treatment duration, particularly for HCV-3.[43]
For IFN-based treatment, RVR and IL-28b are important predictors of response. While patients with RVR experience SVR at a rate that ranges from 69% to 100%, those without RVR achieve SVR from 30% to 60% of the time.[48] In a follow-up analysis from ACCELERATE, it was shown using multiple logistic regression that patients with low baseline viral load who achieve RVR were the best candidates for abbreviated (16 week) therapy.[49] Confirmatory results were obtained by Mangia et al.[50] in their randomized trial of 24 weeks of PEG-RBV compared with 12 or 36 variable duration ('personalized') course depending on the viral response at week 4. Their results demonstrated that RVR resulted in comparable rates of SVR for patients with HCV-3 (86.4% vs 83.7%) in those treated for 24 weeks or the 12 weeks in the variable duration arm. This study also showed that for HCV-3 patients who did not achieve RVR, 36 weeks of therapy resulted in a higher rate of SVR than 24 weeks (72.5% vs 63.0%). Similarly, in their analysis of data from 3 large studies,[38, 43, 51] Fried et al. showed that RVR on PEG-RBV therapy (achieved by 60% of those with HCV-3) was the most important on-treatment predictor of SVR. The proportion of patients with RVR subsequently achieving SVR was similar across genotypes (88–100%).[52] Meanwhile, the odds of achieving RVR were significantly associated with genotype. Compared to HCV-1, the odds ratio for RVR was 36.017 and 11.943 for HCV-2 and HCV-3, respectively.[52] Accordingly, it is accepted that for HCV-3-infected patients, a 24-week duration is standard with only potential shortening of treatment for patients with RVR for a total duration of 12–16 weeks.[53] The N-CORE study compared treatment duration in 188 HCV-3 patients without RVR on PEG-RBV. Preliminary results from this study suggest that amongst patients completing the study, SVR is achieved in 73% after 48 weeks compared with 54% after 24 weeks.[54] The results of this literature are summarized in the EASL guidelines[55] (Fig. 1).
Guideline based therapy for patients with chronic Genotype 3 Hepatitis C infection. Treatment decisions are based on the patient's viral load response to therapy with measurements at the beginning of therapy as well as 4 and 12 weeks into treatment. Abbreviations: HCV (hepatitis C), RNA (ribonucleic acid), RVR (rapid virological response), and EVR (extended virological response).
The IL-28B gene codes for interferon (IFN)-k3 and has been shown to predict PEG-RBV treatment response in HCV-1.[56] Moghaddam et al. retrospectively reviewed 281 chronic HCV-3-infected patients who were treated with PEG-RBV to determine the role of IL-28b in post hoc prediction of response. They found that while IL-28b polymorphisms do not predict SVR, they do predict RVR; the odds ratio for RVR C/C versus T/T was 1.3 (95% CI: 1.0–1.6).[57] These findings were confirmed in a similar retrospective analysis..[58] On the other hand, in a retrospective evaluation of Mangia et al.'s 2005 trial, IL-28b polymorphisms were also predictive of SVR in the 55 patients with HCV-3 for whom RVR was not achieved.[59]
In summary, genotype 3 is an intermediate IFN responsive strain of HCV and should always be evaluated separately from genotype 2. Evaluating the data, overall genotype 3 has never been truly 'easy to treat' but has a larger subset compared with genotype 1 that attains RVR as a measure of viral response and can subsequently have shortened duration of therapy. Host factors such as Asian ethnicity, IL-28b status and presence of cirrhosis remain important factors in the response to IFN-based therapy.
Is 3 the New 1: Perspectives on Virology, Natural History and Treatment for Hepatitis C Genotype 3
E. B. Tapper, N. H. Afdhal
Treatment: Pegylated Interferon and Ribavirin (PEG-IFN/RBV)
Genotype has long been known to influence response to PEG-IFN and RBV therapy, with the potential for shorter durations of therapy and higher SVR rates for HCV-2 and HCV-3 compared with HCV-1 infection.[37,38] Historically, HCV-2 and HCV-3 have been lumped together as, relative to HCV-1, patients infected with these genotypes have responded best to interferon-based therapies. On closer inspection of treatment trials, however, HCV-3-infected patients clearly respond more poorly to interferon-based therapy than do patients with HCV-2. For much of the past decade, the focus on therapy has been the determination of therapy duration. There have been several landmark trials experimenting with duration of PEG-IFN and RBV for patients with chronic HCV-2 and HCV-3 infection examining 12, 14, 16 and 24 week treatment durations[39–48] (Table 1). These trials show consistent evidence of poorer therapeutic response in patients with HCV-3 compared with HCV-2, which might be explained by the concomitant steatohepatitis and more advanced fibrosis in HCV-3. .....
Two important early trials established shortened duration (24 weeks) therapy as a viable option. Mangia et al.[41] examined 12- and 24-week courses and found equal rates of SVR overall, 77% and 76%, respectively. There were, however, somewhat striking intergenotype differences. The rate of SVR was 80% for patients with HCV-2 and 66% for patients with HCV-3. Zeuzem et al.[46] treated 42 HCV-2-infected patients and 182 HCV-3-infected patients with PEG-RBV for 24 weeks. SVR was achieved in 93% of HCV-2 patients and 79% of HCV-3 patients.
In 2008, two trials were published comparing 24 weeks to 14 and 12 weeks of therapy. The North-C group found an overall SVR rate of 81.1% and 90.7% in 14- and 24-week courses following an RVR in the intention-to-treat analysis, respectively. Again, genotype-specific response was seen with SVR achieved in 97% of the 31 HCV-2 patients receiving 24 weeks of therapy compared with 92% of the 110 patients with HCV-3 experiencing RVR. Meanwhile, in the population who did not experience RVR, 75.0% (15 of 20) with HCV-2 and 56.3% (54 of 96) with HCV-3 experienced SVR.[39] The NORDynamic Study group saw a similar pattern of results after 24 weeks with HCV-3 patients achieving SVR 58% of the time after 12 weeks and 78% after 24 weeks.[45] More recently, in the PEG-RBV control arm of the FISSION trial, there was a significant difference in the attainment of SVR between genotype 2 and 3 patients, 77.6% vs 62.5%.[3]
ACCELERATE randomly assigned 1469 patients equally divided amongst HCV-2 or HCV-3 to receive 180 μg of peginterferon-alpha-2a weekly, plus 800 mg of ribavirin daily, for either 16 or 24 weeks.[43] 16 weeks of therapy was inferior to 24 with respect to SVR (62% vs 70%). SVR was achieved in 82% of HCV-2 patients receiving 24 weeks of therapy compared with 71% of HCV-3 patients in the per protocol analysis (67.0% in the intention-to-treat analysis). Amongst patients with a rapid virological response (RVR), SVR rates were 79% and 85% in the 16- and 24-week groups. Interestingly, there was no difference in the rate of SVR between genotypes for the patients that experienced RVR (85% vs 85%), confirming the findings of a prior, smaller trial.[42] ACCELERATE also showed that patients with advanced fibrosis fared poorly by comparison, achieving SVR 43% of the time after 16 weeks and 49% after 24 weeks. The major limitation of this trial is that it used fixed dose RBV 800 mg for all patients rather than weight based. The current consensus is that weight-based ribavirin is necessary for shortened treatment duration, particularly for HCV-3.[43]
For IFN-based treatment, RVR and IL-28b are important predictors of response. While patients with RVR experience SVR at a rate that ranges from 69% to 100%, those without RVR achieve SVR from 30% to 60% of the time.[48] In a follow-up analysis from ACCELERATE, it was shown using multiple logistic regression that patients with low baseline viral load who achieve RVR were the best candidates for abbreviated (16 week) therapy.[49] Confirmatory results were obtained by Mangia et al.[50] in their randomized trial of 24 weeks of PEG-RBV compared with 12 or 36 variable duration ('personalized') course depending on the viral response at week 4. Their results demonstrated that RVR resulted in comparable rates of SVR for patients with HCV-3 (86.4% vs 83.7%) in those treated for 24 weeks or the 12 weeks in the variable duration arm. This study also showed that for HCV-3 patients who did not achieve RVR, 36 weeks of therapy resulted in a higher rate of SVR than 24 weeks (72.5% vs 63.0%). Similarly, in their analysis of data from 3 large studies,[38, 43, 51] Fried et al. showed that RVR on PEG-RBV therapy (achieved by 60% of those with HCV-3) was the most important on-treatment predictor of SVR. The proportion of patients with RVR subsequently achieving SVR was similar across genotypes (88–100%).[52] Meanwhile, the odds of achieving RVR were significantly associated with genotype. Compared to HCV-1, the odds ratio for RVR was 36.017 and 11.943 for HCV-2 and HCV-3, respectively.[52] Accordingly, it is accepted that for HCV-3-infected patients, a 24-week duration is standard with only potential shortening of treatment for patients with RVR for a total duration of 12–16 weeks.[53] The N-CORE study compared treatment duration in 188 HCV-3 patients without RVR on PEG-RBV. Preliminary results from this study suggest that amongst patients completing the study, SVR is achieved in 73% after 48 weeks compared with 54% after 24 weeks.[54] The results of this literature are summarized in the EASL guidelines[55] (Fig. 1).
Guideline based therapy for patients with chronic Genotype 3 Hepatitis C infection. Treatment decisions are based on the patient's viral load response to therapy with measurements at the beginning of therapy as well as 4 and 12 weeks into treatment. Abbreviations: HCV (hepatitis C), RNA (ribonucleic acid), RVR (rapid virological response), and EVR (extended virological response).
The IL-28B gene codes for interferon (IFN)-k3 and has been shown to predict PEG-RBV treatment response in HCV-1.[56] Moghaddam et al. retrospectively reviewed 281 chronic HCV-3-infected patients who were treated with PEG-RBV to determine the role of IL-28b in post hoc prediction of response. They found that while IL-28b polymorphisms do not predict SVR, they do predict RVR; the odds ratio for RVR C/C versus T/T was 1.3 (95% CI: 1.0–1.6).[57] These findings were confirmed in a similar retrospective analysis..[58] On the other hand, in a retrospective evaluation of Mangia et al.'s 2005 trial, IL-28b polymorphisms were also predictive of SVR in the 55 patients with HCV-3 for whom RVR was not achieved.[59]
In summary, genotype 3 is an intermediate IFN responsive strain of HCV and should always be evaluated separately from genotype 2. Evaluating the data, overall genotype 3 has never been truly 'easy to treat' but has a larger subset compared with genotype 1 that attains RVR as a measure of viral response and can subsequently have shortened duration of therapy. Host factors such as Asian ethnicity, IL-28b status and presence of cirrhosis remain important factors in the response to IFN-based therapy.
"In summary, genotype 3 is an intermediate IFN responsive strain of HCV and should always be evaluated separately from genotype 2."
Indeed
Thanks Pooh!
Indeed
Thanks Pooh!
Thanks pooh,
Registered and its really a good article. About weight based Riba, this is what it says:
"The current consensus is that weight-based ribavirin is necessary for shortened treatment duration, particularly for HCV-3.[43]"
So if you are treating genotype 3 for 24 weeks, then standard 800mg Riba will work.
Regards
Registered and its really a good article. About weight based Riba, this is what it says:
"The current consensus is that weight-based ribavirin is necessary for shortened treatment duration, particularly for HCV-3.[43]"
So if you are treating genotype 3 for 24 weeks, then standard 800mg Riba will work.
Regards
24 weeks of treatment is standard but the article does state that those without an RVR should do longer than 24 weeks of treatment. They also discuss the weight based Ribavirin.
The article is longer. I picked out only the treatment part. It is an excellent article. So if you go to Medscape, you can read the entire article. Plus the article contains that chart with the algorithm, which is very helpful.
www.medscape.com
You have to register (it is free) and they will ask you which medical profession you are in. Just pick doctor or nurse. Then you can read all of their Hep C articles as well as tons of other article.
To get to this article after you register, just search for the title.
Is 3 the New 1: Perspectives on Virology, Natural History and Treatment for Hepatitis C Genotype 3
Or just search all of the Hep C articles. This was a newer article. I also have Medscape connected to my e-mail so that I get an e-mail every time they publish a new article about Hep C.
The article is longer. I picked out only the treatment part. It is an excellent article. So if you go to Medscape, you can read the entire article. Plus the article contains that chart with the algorithm, which is very helpful.
www.medscape.com
You have to register (it is free) and they will ask you which medical profession you are in. Just pick doctor or nurse. Then you can read all of their Hep C articles as well as tons of other article.
To get to this article after you register, just search for the title.
Is 3 the New 1: Perspectives on Virology, Natural History and Treatment for Hepatitis C Genotype 3
Or just search all of the Hep C articles. This was a newer article. I also have Medscape connected to my e-mail so that I get an e-mail every time they publish a new article about Hep C.
Very Helpful info Pooh,
I'm genotype 3, RVR (In sixth week of tx now). What I gather from this all is that one should complete the 24 week treatment irrespective of RVR, or no reduction in VL.
I'm genotype 3, RVR (In sixth week of tx now). What I gather from this all is that one should complete the 24 week treatment irrespective of RVR, or no reduction in VL.
The article contains a treatment algorithm, but it is a chart and I cannot copy and paste it. The treatment algorithm chart gives the details on exactly how long to treat in each given set of circumstances (ie if there is an RVR, if there is not an RVR, if there is insulin resistance or more advanced fibrosis, if the person has a less than 2 log drop at week 12, if the person has a greater than 2 log drop at week 12, if the person is DET at week 24, etc. The algorithm states who should treat for 24 weeks and who should treat for 48 weeks. Therefore it would be beneficial for those who are interested or who are Genotype 3 to actually log onto Medscape and read the entire article as well as look at the treatment algorithm chart.
I think this is great that they have finally realized this, we have seen it here for years. Lumping the two genotypes together has caused a lot of relapses. And I agree 100% that type 3 may be the new 1 as for hard to treat...
Great find Pooh.
---------------------------------------
Conclusion
Genotype 3 HCV is an important healthcare problem with its large global distribution, relatively unique pathophysiology and potentially more aggressive disease. It has also become the most difficult to treat based on SVR rates, not just because of any real host or viral issues but because of the neglect of the research hepatology community in developing novel agents against genotype 3. The polymerase inhibitors with only RBV are moderately effective, and this effect seems clearly duration dependent but the advent of newer DAAs moving rapidly into clinical trials have put a 'bullseye' on the head of genotype 3 HCV. We anticipate that with the renewed interest and targeting of genotype 3, the same success of 90% SVR will soon become attainable as we are seeing with the other HCV genotypes. Genotype 3 may be the new 1, but it will only stay there for a short time before innovative research, drug development and novel combinations make the concept of a hard-to-treat HCV genotype a historical footnote in our battle against chronic HCV.
Great find Pooh.
---------------------------------------
Conclusion
Genotype 3 HCV is an important healthcare problem with its large global distribution, relatively unique pathophysiology and potentially more aggressive disease. It has also become the most difficult to treat based on SVR rates, not just because of any real host or viral issues but because of the neglect of the research hepatology community in developing novel agents against genotype 3. The polymerase inhibitors with only RBV are moderately effective, and this effect seems clearly duration dependent but the advent of newer DAAs moving rapidly into clinical trials have put a 'bullseye' on the head of genotype 3 HCV. We anticipate that with the renewed interest and targeting of genotype 3, the same success of 90% SVR will soon become attainable as we are seeing with the other HCV genotypes. Genotype 3 may be the new 1, but it will only stay there for a short time before innovative research, drug development and novel combinations make the concept of a hard-to-treat HCV genotype a historical footnote in our battle against chronic HCV.
From same Medscape article:
New Direct-Acting Antivirals
Multiple targets are being developed for DAA therapy against HCV-1 but many of these particularly the protease inhibitors have limited activity against HCV-3.[60] There are some novel 2nd-generation NS5A inhibitors such as Achillion ACH-3102, IdenixIDX-719 and Gilead GS-5816 that have potent in vitro activity against HCV-3 and are moving into early-phase clinical trials in combination with other DAAs or IFN.[61–63] The class with the broadest pangenotypic activity to date is the NS5B nucleotide polymerase inhibitors, which includes merimepodib and sofosbuvir, which are in advanced clinical development and early-phase compounds such as Vertex VX-135. These compounds have the potential to be backbone agents for all oral DAA therapy for HCV-3 in combination with RBV or some of the newer NS5A or disease-modifying agents such as the cyclophilin inhibitors.
Mericitabine (also known as RG7128) is a nucleoside analogue with pangenotypic antiviral activity in vitro. Mericitabine was evaluated in HCV-2 and HCV-3 patients with prior PEG-RIBA treatment failure. After a 4-week triple combination, mericitabine at a twice-daily dose of 1500 mg was discontinued and PEG-RBV was resumed for 20–44 weeks. RVR was achieved in 95% of the mericitabine-treated patients versus 60% in the pegylated interferon ribavirin group. 68% of patients with RVR achieved SVR. SVR was higher in those treated for 48 weeks (90%) than in those treated for 24 weeks (67%). Overall, SVR rates did not differ between HCV-2 and HCV-3 patients (63% and 67%, respectively).[64] Unfortunately, this strategy still requires IFN use for up to 48 weeks and will likely be replaced by all oral therapies.
Sofosbuvir, formerly GS-7977, is a uridine nucleotide analogue that inhibits the NS5B HCV polymerase with in vitro pangenotypic activity. The ELECTRON trial randomly assigned previously untreated, noncirrhotic patients with HCV-2 or HCV-3 to 6 groups receiving sofosbuvir at a daily dose of 400 mg.[65] Five of these groups received 12 weeks of therapy, 4 of which also received weight-based ribavirin and 3 of which received pegylated interferon (alpha-2a). These groups included 6 to 7 HCV-3 and 3–4 HCV-2-infected patients. A final 6th group of 10 HCV-3-infected patients received 8 weeks of sofosbuvir-PEG-RBV. All (100%) of the 50 previously untreated patients with chronic HCV-2 or HCV-3 infection who received 8 or 12 weeks of treatment with sofosbuvir and ribavirin, with or without peginterferon-alpha 2a, had a SVR at 24 weeks after therapy. Of the 10 patients treated with sofosbuvir monotherapy, 6 achieved SVR, while 4 (including two of the seven patients with HCV-3) had relapsed after the end of treatment.
Jacobson et al.[66] reported the results of two much larger trials of sofosbuvir in HCV-2 and HCV-3 patients: POSITRON (interferon intolerant/ineligible patients) and FUSION (interferon treatment failures). POSITRON randomized 207 patients to 12 weeks of sofosbuvir at a daily dose of 400 mg and weight-based ribavirin to be compared to 71 patients on placebo. SVR was achieved in 78% of treated patients, in 92.7% in HCV-2 and 61.2% of 98 HCV-3 patients. The superior performance of this therapy in HCV-2 compared to HCV-3 was also seen in patients without cirrhosis with a 92% SVR rate in HCV-2 and 68% in HCV-3. In a multivariate regression, genotype was the strongest predictor of response. Beyond that, it appears that cirrhotic patients with chronic HCV-3 fare particularly poorly, with an SVR rate of only 21%. FUSION randomized patients to receive sofosbuvir 400 mg once daily and weight-based RBV for either 12 (100 patients) or 16 weeks (95 patients). SVR was achieved in 50% after 12 weeks and 73% after 16 weeks. Again, genotype played a significant role. For patients with HCV-2, SVR was achieved in 86.1% after 12 weeks and 93.8% after 16 weeks of therapy. By contrast, HCV-3-infected patients achieved SVR in 29.7% and 61.9% after 12 and 16 weeks, respectively. In a multivariate regression, genotype was again the most significant predictor of response to sofosbuvir therapy. The only other predictor was the presence of cirrhosis where patients with HCV-3 cirrhosis achieved SVR in only 19.2% of cases.
FISSION was a randomized, open label, active-control noninferiority study of 12 weeks of sofosbuvir plus ribavirin versus PEG-RIBA in an international cohort of untreated patients with HCV-2 and HCV-3. This trial included 183 HCV-3-infected patients in the sofusbuvir-RIBA arm and 176 HCV-3-infected patients in the PEG-RIBA arm. RVR was achieved in all but one patient in the sofusbuvir-RIBA arm compared with 67% in the PEG-RIBA arm. Both arms achieved SVR in 67% of cases. However, response rates in the sofosbuvir–ribavirin group were again lower amongst patients with HCV-3 infection than amongst those with HCV-2 infection (56% vs 97%).[3]
How can we best interpret these responses in HCV-3? Certainly with over 90%, SVR HCV-2 is now truly an easy-to-treat genotype with a simple all oral DAA regimen of sofosbuvir and RBV. However, this same combination was not superior to PEG-IFN and RBV for treatment-naïve HCV-3 patients and the SVR was somewhat disappointing at 67% in all HCV-3 groups studied but still very acceptable as a treatment for our patients in clinical practice. We need to also realize that in the presence of RBV as the 2nd agent, duration may be a critical factor. The studies were designed with 12-week treatment arms except for FUSION, which had a 16-week arm. Just increasing treatment by 4 weeks more than doubled SVR including patients with cirrhosis, where it went from 19% to 61% with just a 4-week increase in duration. Because all patients had RVR and all were negative at the end of treatment, the issue with sofosbuvir/RBV is clearly one of relapse, and as in prior studies with IFN, increasing duration prevented that relapse. The aetiology of the relapse is unclear, but its response so dramatically to duration does suggest that it is a reservoir effect. This level of relapse is not seen in therapies with sofosbuvir for genotype 1 and suggests that there may be something unique about the ability of genotype 3 to avoid complete eradication. To answer the relapse question, there is a large European trial that is looking both at 24 weeks of sofosbuvir and RBV and also combining these two agents with IFN for 12 weeks. An alternative is to add a 2nd more powerful genotype 3 active NS5A to sofosbuvir to see whether that can replace RBV and improve SVR rates.
An alternative approach has been taken with alisporivir, a host-targeting antiviral (HTA) with pangenotypic anti-HCV activity and high barrier to viral resistance. VITAL-1 randomized 340 treatment-naïve HCV-2 and HCV-3 patients (ratio 3:7) to five arms: alisporivir monotherapy (1 g daily), alisporivir (600 or 800 mg) and weight-based ribavirin, alisporivir (600 mg) and pegylated interferon, or PEG-RBV. Patients in alisporivir-containing arms that achieved RVR continued on their initial treatment for 24 weeks. Those without RVR continued with alisporivir and rescue PEG-RBV from week 6 to week 24. Of the interferon-free treatments, alisporivir and ribavirin achieved greater early HCV clearance at week 6 than alisporivir monotherapy: 49% (600 mg and ribavirin), 46% (800 mg and ribavirin) and 32% (1 g monotherapy). Of the 70 patients receiving any interferon-free alisporivir/ribavirin regimens, 88% achieved SVR. Of 177 patients receiving combined regimen – interferon-free alisporivir/ribavirin from baseline and alisporivir/ribavirin/interferon add-on, 90% had SVR versus 72% with standard pegylated interferon and ribavirin. There was no difference in HCV-2 and HCV-3 responses to alisporivir treatment.[67] Host-targeting agents with their high-resistance barrier and efficacy have more potential in combination with other DAAs for treatment of HCV-3.
New Direct-Acting Antivirals
Multiple targets are being developed for DAA therapy against HCV-1 but many of these particularly the protease inhibitors have limited activity against HCV-3.[60] There are some novel 2nd-generation NS5A inhibitors such as Achillion ACH-3102, IdenixIDX-719 and Gilead GS-5816 that have potent in vitro activity against HCV-3 and are moving into early-phase clinical trials in combination with other DAAs or IFN.[61–63] The class with the broadest pangenotypic activity to date is the NS5B nucleotide polymerase inhibitors, which includes merimepodib and sofosbuvir, which are in advanced clinical development and early-phase compounds such as Vertex VX-135. These compounds have the potential to be backbone agents for all oral DAA therapy for HCV-3 in combination with RBV or some of the newer NS5A or disease-modifying agents such as the cyclophilin inhibitors.
Mericitabine (also known as RG7128) is a nucleoside analogue with pangenotypic antiviral activity in vitro. Mericitabine was evaluated in HCV-2 and HCV-3 patients with prior PEG-RIBA treatment failure. After a 4-week triple combination, mericitabine at a twice-daily dose of 1500 mg was discontinued and PEG-RBV was resumed for 20–44 weeks. RVR was achieved in 95% of the mericitabine-treated patients versus 60% in the pegylated interferon ribavirin group. 68% of patients with RVR achieved SVR. SVR was higher in those treated for 48 weeks (90%) than in those treated for 24 weeks (67%). Overall, SVR rates did not differ between HCV-2 and HCV-3 patients (63% and 67%, respectively).[64] Unfortunately, this strategy still requires IFN use for up to 48 weeks and will likely be replaced by all oral therapies.
Sofosbuvir, formerly GS-7977, is a uridine nucleotide analogue that inhibits the NS5B HCV polymerase with in vitro pangenotypic activity. The ELECTRON trial randomly assigned previously untreated, noncirrhotic patients with HCV-2 or HCV-3 to 6 groups receiving sofosbuvir at a daily dose of 400 mg.[65] Five of these groups received 12 weeks of therapy, 4 of which also received weight-based ribavirin and 3 of which received pegylated interferon (alpha-2a). These groups included 6 to 7 HCV-3 and 3–4 HCV-2-infected patients. A final 6th group of 10 HCV-3-infected patients received 8 weeks of sofosbuvir-PEG-RBV. All (100%) of the 50 previously untreated patients with chronic HCV-2 or HCV-3 infection who received 8 or 12 weeks of treatment with sofosbuvir and ribavirin, with or without peginterferon-alpha 2a, had a SVR at 24 weeks after therapy. Of the 10 patients treated with sofosbuvir monotherapy, 6 achieved SVR, while 4 (including two of the seven patients with HCV-3) had relapsed after the end of treatment.
Jacobson et al.[66] reported the results of two much larger trials of sofosbuvir in HCV-2 and HCV-3 patients: POSITRON (interferon intolerant/ineligible patients) and FUSION (interferon treatment failures). POSITRON randomized 207 patients to 12 weeks of sofosbuvir at a daily dose of 400 mg and weight-based ribavirin to be compared to 71 patients on placebo. SVR was achieved in 78% of treated patients, in 92.7% in HCV-2 and 61.2% of 98 HCV-3 patients. The superior performance of this therapy in HCV-2 compared to HCV-3 was also seen in patients without cirrhosis with a 92% SVR rate in HCV-2 and 68% in HCV-3. In a multivariate regression, genotype was the strongest predictor of response. Beyond that, it appears that cirrhotic patients with chronic HCV-3 fare particularly poorly, with an SVR rate of only 21%. FUSION randomized patients to receive sofosbuvir 400 mg once daily and weight-based RBV for either 12 (100 patients) or 16 weeks (95 patients). SVR was achieved in 50% after 12 weeks and 73% after 16 weeks. Again, genotype played a significant role. For patients with HCV-2, SVR was achieved in 86.1% after 12 weeks and 93.8% after 16 weeks of therapy. By contrast, HCV-3-infected patients achieved SVR in 29.7% and 61.9% after 12 and 16 weeks, respectively. In a multivariate regression, genotype was again the most significant predictor of response to sofosbuvir therapy. The only other predictor was the presence of cirrhosis where patients with HCV-3 cirrhosis achieved SVR in only 19.2% of cases.
FISSION was a randomized, open label, active-control noninferiority study of 12 weeks of sofosbuvir plus ribavirin versus PEG-RIBA in an international cohort of untreated patients with HCV-2 and HCV-3. This trial included 183 HCV-3-infected patients in the sofusbuvir-RIBA arm and 176 HCV-3-infected patients in the PEG-RIBA arm. RVR was achieved in all but one patient in the sofusbuvir-RIBA arm compared with 67% in the PEG-RIBA arm. Both arms achieved SVR in 67% of cases. However, response rates in the sofosbuvir–ribavirin group were again lower amongst patients with HCV-3 infection than amongst those with HCV-2 infection (56% vs 97%).[3]
How can we best interpret these responses in HCV-3? Certainly with over 90%, SVR HCV-2 is now truly an easy-to-treat genotype with a simple all oral DAA regimen of sofosbuvir and RBV. However, this same combination was not superior to PEG-IFN and RBV for treatment-naïve HCV-3 patients and the SVR was somewhat disappointing at 67% in all HCV-3 groups studied but still very acceptable as a treatment for our patients in clinical practice. We need to also realize that in the presence of RBV as the 2nd agent, duration may be a critical factor. The studies were designed with 12-week treatment arms except for FUSION, which had a 16-week arm. Just increasing treatment by 4 weeks more than doubled SVR including patients with cirrhosis, where it went from 19% to 61% with just a 4-week increase in duration. Because all patients had RVR and all were negative at the end of treatment, the issue with sofosbuvir/RBV is clearly one of relapse, and as in prior studies with IFN, increasing duration prevented that relapse. The aetiology of the relapse is unclear, but its response so dramatically to duration does suggest that it is a reservoir effect. This level of relapse is not seen in therapies with sofosbuvir for genotype 1 and suggests that there may be something unique about the ability of genotype 3 to avoid complete eradication. To answer the relapse question, there is a large European trial that is looking both at 24 weeks of sofosbuvir and RBV and also combining these two agents with IFN for 12 weeks. An alternative is to add a 2nd more powerful genotype 3 active NS5A to sofosbuvir to see whether that can replace RBV and improve SVR rates.
An alternative approach has been taken with alisporivir, a host-targeting antiviral (HTA) with pangenotypic anti-HCV activity and high barrier to viral resistance. VITAL-1 randomized 340 treatment-naïve HCV-2 and HCV-3 patients (ratio 3:7) to five arms: alisporivir monotherapy (1 g daily), alisporivir (600 or 800 mg) and weight-based ribavirin, alisporivir (600 mg) and pegylated interferon, or PEG-RBV. Patients in alisporivir-containing arms that achieved RVR continued on their initial treatment for 24 weeks. Those without RVR continued with alisporivir and rescue PEG-RBV from week 6 to week 24. Of the interferon-free treatments, alisporivir and ribavirin achieved greater early HCV clearance at week 6 than alisporivir monotherapy: 49% (600 mg and ribavirin), 46% (800 mg and ribavirin) and 32% (1 g monotherapy). Of the 70 patients receiving any interferon-free alisporivir/ribavirin regimens, 88% achieved SVR. Of 177 patients receiving combined regimen – interferon-free alisporivir/ribavirin from baseline and alisporivir/ribavirin/interferon add-on, 90% had SVR versus 72% with standard pegylated interferon and ribavirin. There was no difference in HCV-2 and HCV-3 responses to alisporivir treatment.[67] Host-targeting agents with their high-resistance barrier and efficacy have more potential in combination with other DAAs for treatment of HCV-3.
They found that while IL-28b polymorphisms do not predict SVR, they do predict RVR; the odds ratio for RVR C/C versus T/T was 1.3 (95% CI: 1.0–1.6).[57] These findings were confirmed in a similar retrospective analysis..[58] On the other hand, in a retrospective evaluation of Mangia et al.'s 2005 trial, IL-28b polymorphisms were also predictive of SVR in the 55 patients with HCV-3 for whom RVR was not achieved.[59]
I don't think I have ever seen actual ratios for the IL28b. I knew that TT was much more difficult to treat but have never seen any numbers. Interesting thanks Pooh
I don't think I have ever seen actual ratios for the IL28b. I knew that TT was much more difficult to treat but have never seen any numbers. Interesting thanks Pooh
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