My Treatment Approach to Chronic Hepatitis C Virus (Genotypes 1–6)

Article in Press

Mitchell L. Shiffman, MD, April G. Long, NP, Amy James, FNP, Phillip Alexander, NP

Published Online: May 24, 2014

DOI: http://dx.doi.org/10.1016/j.mayocp.2014.04.013

Publication stage: In Press Corrected Proof

Abstract

The treatment of chronic hepatitis C virus (HCV) is evolving rapidly. In 2014, the standard of care and new backbone of HCV treatment is the polymerase inhibitor sofosbuvir (SOF). Our treatment approach in patients with HCV genotype 1 is 12 weeks of SOF, peginterferon (PEGINF), and ribavirin (RBV). In patients with cirrhosis or extrahepatic manifestations of HCV who cannot tolerate PEGINF, we use 12 weeks of SOF and simeprevir. The latter is less costly and more effective than SOF and RBV for 24 weeks. Our treatment approach in all patients with genotype 2 is SOF and RBV for 12 weeks. Hepatitis C virus genotype 3 is now the most costly and difficult to cure. Our approach to treatment-naive patients with genotype 3 is SOF and RBV for 24 weeks. In patients who have previously undergone PEGINF and RBV treatment, we use PEGINF, SOF, and RBV for 12 weeks, which is equally if not more effective and less costly than SOF and RBV for 24 weeks. Patients with cirrhosis who cannot tolerate PEGINF should be treated for 24 weeks with SOF and RBV, although the sustained virologic response is suboptimal.

Chronic hepatitis C virus (HCV) affects an estimated 4 million persons in the United States and 300 million personsworldwide.¹ In the 1960s through the 1980s, most US patients were infected with HCV through the transfusion of blood products and injection drug use. These patients have been infected for 30 to 50 years, and this is the primary driver for the increasing rates of cirrhosis and hepatocellular carcinoma (HCC) in the United States today.² Many of these patients are asymptomatic, and the disease remains undiagnosed. The need to identify these patients is why the US Preventive Services Task Force and the Centers for Disease Control and Prevention have recommended that all persons born between 1945 and 1965 be screened for HCV.^{3, 4}

Long-term studies conducted over the past 2 decades have found that a sustained virologic response (SVR) is long-lasting and that HCV can be “cured.”^{5, 6} Patients who achieve an SVR have improvement in liver histologic features and regression of fibrosis.^{7, 8} Patients with cirrhosis who achieve an SVR rarely experience hepatic decompensation and have a 10-fold decrease in the risk of HCC and a significant reduction in mortality.^{9, 10, 11}

For the past 15 years, interferon and then peginterferon (PEGINF) have been the backbone of HCV treatment on which ribavirin (RBV) and more recently HCV protease inhibitors have been added.¹² In late 2013, the treatment of chronic HCV entered a new era when 2 new oral antiviral agents, simeprevir (SMV) and sofosbuvir (SOF), were approved by the US Food and Drug Administration (FDA). Simeprevir is a protease inhibitor, and its approval by the FDA was based on studies in which it was used with PEGINF and RBV in patients with HCV genotype 1.¹³ Although SMV inhibits the NS3/4A protease like telaprevir (TPV) and boceprevir (BOC), it is taken only once daily, has fewer adverse effects and drug-drug interactions, and appears to have a somewhat higher SVR rate.¹⁴

Sofosbuvir is a polymerase inhibitor that is highly effective in suppressing replication in all HCV genotypes.¹⁵ It is also taken once daily and has few drug-drug interactions and minimal adverse effects. Resistance is extremely rare, and SVR rates of over 90% are achieved in most patients with HCV. In 2014, SOF has become the new backbone of HCV treatment.

The treatment of HCV continues to evolve rapidly. Several pharmaceutical companies have developed and are currently testing combinations of oral antiviral agents for HCV (Table 1).^{16, 17, 18, 19, 20} Two of these treatments have already completed phase 3 clinical trials, and an all-oral antiviral treatment for HCV genotype 1 is expected to be available before the end of 2014. The current dilemma for physicians wanting to treat HCV and patients who want to be cured of this virus is not whether HCV should be treated but rather what agents should be used and when treatment should be initiated. This article summarizes the data that led to the FDA approval of SMV and SOF and describes our treatment approach to patients with chronic HCV in 2014. Given the rapid proliferation of new oral antiviral agent combinations for treatment of HCV, this approach will need to be modified in 2015.

Simeprevir

Simeprevir is a pangenotypic NS3/4A protease inhibitor that is effective in vitro against HCV genotypes 1 through 6.²¹ To date, clinical trials have been completed only in patients with genotype 1. A study in patients with HCV genotype 4 is currently under way. Preliminary data from this study suggest that PEGINF, SOF, and RBV could achieve SVR rates approaching 80%.²² Simeprevir is highly effective and has been approved by the FDA for treatment of patients with chronic HCV genotype 1. Simeprevir binds to the same site as TPV and BOC. It has not been studied in patients in whom TPV or BOC treatment failed or resistance to TPV or BOC developed. Given its mechanism of action, it is unlikely to be effective and should not be used in these patients.¹³

Simeprevir is used as triple therapy with PEGINF and RBV for 12 weeks, followed by an additional 12 weeks of PEGINF and RBV (total duration of therapy, 24 weeks) in all patients who are treatment naive or who have had a relapse while taking PEGINF and RBV, including those with cirrhosis. Approximately 80% of patients achieve a rapid virologic response (RVR), and HCV RNA is undetectable within 4 weeks of initiating treatment. The SVR in these patients is approximately90%.^{23, 24, 25} As opposed to TPV and BOC, for which the duration of therapy is adjusted on the basis of whether an RVR is achieved, response-guided therapy is not necessary with SMV. In patients who have no response to PEGINF and RBV, 12 weeks of SMV, PEGINF, and RBV is followed by 36 weeks of PEGINF and RBV (total duration of therapy, 48 weeks). The SVR rate in these patients is 53% to 65%.²⁶ All patients with HCV RNA levels greater than 25 IU/mL at weeks 4, 12, or 24 should stop treatment. Although controlled clinical trials comparing the SVR rates of the 3 protease inhibitors have not been conducted, each has been evaluated against a placebo control with PEGINF and RBV. Comparison of the improvement in SVR over control for the 3 protease inhibitors suggests that RVR and SVR rates are somewhat higher with SMV compared with TPV or BOC.¹³

Simeprevir offers considerable advantages over TPV and BOC, the most important of which is that SMV does not cause additional anemia compared with PEGINF and RBV.^{23, 24, 25, 26} In phase 2 and 3 clinical trials, patients treated with SMV, PEGINF, and RBV did not have any adverse events with greater frequency than those taking PEGINF and RBV. Simeprevir is taken as a single once-daily tablet, no special diet is required, and far fewer drug-drug interactions have been observed.

The success in patients treated with SMV, like other protease inhibitors, is dependent on an effective interferon response, which is modulated by IL28B genotype.²⁷ In treatment-naive patients, the SVR approaches 90% in patients with IL28BCC genotype and declines in patients with the CT and TT genotypes.^{23, 24} In patients with a previous nonresponse to PEGINF and RBV, the SVR rates during retreatment with SMV triple therapy follow a similar trend of interferon responsiveness: higher rates of SVR with a previous partial response and lower SVR rates in previous nonresponders.²⁶

The primary limitation of SMV is that a sequence variation at the Q80K loci of HCV significantly limits the antiviral efficacy of this protease inhibitor and reduces SVR to values that are similar to that achieved with PEGINF and RBV.^{23, 24, 25, 26}This sequence variation is present in about 40% of patients with HCV genotype 1a. It is not present in HCV genotype 1b. The FDA has suggested that all patients with genotype 1a undergo resistance testing for the presence of the Q80K sequence variation in HCV and that the physician strongly consider using a treatment other than SMV if this sequence variation is present.

The Q80K sequence variation has the greatest impact and considerably lowers SVR in patients who are genetically less sensitive to PEGINF. In contrast, patients with IL28B CC genotype, who are highly sensitive to interferon, have similar SVR rates regardless of the presence or absence of the Q80K sequence variation.^{23, 24, 25, 26} We therefore disagree with the FDA recommendations somewhat and strongly believe that patients with HCV genotype 1a and Q80K who haveIL28B CC genotype could be treated successfully with SMV, PEGINF, and RBV. We do not recommend and we do not treat our patients who have HCV genotype 1 with SMV, PEGINF, and RBV. However, if a physician or payer chooses this regimen, our recommendation would be to test those patients with genotype 1a for IL28B genotype. If the patient hasIL28B CC genotype, then no viral resistance testing is necessary. If the patient has IL28B CC or TT genotype, the patient would then need to be tested for Q80K, and if absent, they could also be treated with SMV, PEGINF, and RBV. In contrast, if the patient has IL28B CT or TT genotype and Q80K sequence variation, we would not recommend SMV.

Sofosbuvir

Sofosbuvir is the first polymerase inhibitor to be approved by the FDA for the treatment of chronic HCV.¹⁵ It is a nucleotide analogue that inhibits the NS5B polymerase and is effective in all HCV genotypes. Sofosbuvir is incorporated into the growing RNA sequence during replication and acts as a chain terminator. A specific sequence variation in the polymerase, S282T, is resistant to SOF by preventing incorporation of the nucleotide analogue into the growing polypeptide chain. However, this sequence variation also impacts the ability of HCV RNA to elongate with normal nucleotides and is therefore a nonviable sequence variation that cannot persist long-term. Resistance to SOF is therefore extremely uncommon and was not observed in any patient treated in the phase 3 clinical trials.^{28, 29, 30} Virtually all patients treated with SOF have undetectable HCV RNA within 2 to 4 weeks of initiating treatment, and all patients are treated for a fixed duration (12 or 24 weeks) on the basis of their genotype.

Sofosbuvir was studied as triple therapy with PEGINF and RBV for just 12 weeks in patients with genotypes 1, 4, 5, and6.²⁸ This was a single-arm study with no comparison with PEGINF and RBV. More than 90% of patients treated with SOF triple therapy had undetectable HCV RNA within 2 weeks, and virtually all patients achieved an RVR. The overall SVR rate was 90%; the SVR rate was 89% in patients with genotype 1 and 96% in patients with genotype 4. In patients with cirrhosis, the SVR rate was 80%. All 7 patients with HCV genotypes 5 and 6 achieved an SVR. Sofosbuvir triple therapy has not been evaluated in patients in whom either PEGINF and RBV or triple therapy with a protease inhibitor failed. However, because protease inhibitors and SOF have a completely different site of action, there is no virologic reason why SOF should not be equally effective in patients in whom treatment with a protease inhibitor failed. In treatment-naive patients with HCV genotype 1 who have the least favorable treatment response characteristics—Metavir fibrosis score of F3 or F4, high viral load, IL28B non-CC genotype—the SVR rate with SOF, PEGINF, and RBV was 71%. In contrast, the SVR rate for patients with these characteristics treated with PEGINF and RBV with or without a protease inhibitor is only 3% to 50%. On the basis of these data, the FDA recommended that all patients with chronic HCV genotypes 1 and 4, regardless of treatment history, could be treated with SOF, PEGINF, and RBV for 12 weeks.

The combination of SOF and RBV represents the first interferon-free regimen approved by the FDA to treat patients with chronic HCV. Sofosbuvir and RBV were studied in 4 clinical trials in patients with genotypes 2 and 3.^{28, 29, 30} In patients with HCV genotype 2, SOF and RBV for only 12 weeks yielded superior SVR rates compared with PEGINF and RBV for 24 weeks. In patients without cirrhosis, SOF and RBV achieved SVR rates of 90% to 97%. In patients with cirrhosis, the SVR ranged from 60% to 94%. The lowest SVR in patients with genotype 2 was observed in a single study that included only 10 patients in whom previous treatment with PEGINF and RBV had failed.²⁹ Extending the duration of SOF and RBV from 12 to 16 weeks in this study yielded an SVR of 78%. Excluding this one study, the SVR in patients with cirrhosis was 90%. The overall SVR rate for all patients with cirrhosis included in all 4 registration studies was 84%; in patients with cirrhosis and previous PEGINF and RBV treatment, the SVR was 82%. On the basis of these data, the FDA recommended that all patients with genotype 2 could be treated with SOF and RBV for 12 weeks.

In patients with genotype 3, treatment with SOF and RBV for 12 weeks yielded an SVR rate of only 61% to 68% in treatment-naive patients without cirrhosis and 21% to 34% in patients with cirrhosis.^{28, 29, 30} These SVR rates are somewhat lower, or at best similar, to that observed with 24 weeks of PEGINF and RBV. In patients in whom previous PEGINF and RBV therapy failed, 12 weeks of SOF and RBV yielded SVR rates of only 19% and 37% in patients with and without cirrhosis, respectively. Extending the duration of SOF and RBV to 16 weeks in patients with previous PEGINF and RBV failure did not significantly change the SVR in patients without cirrhosis but increased the SVR in patients with cirrhosis to 61%. The highest SVR rates in patients with genotype 3 were observed when the duration of SOF and RBV was extended to 24 weeks. In the treatment-naive population, the SVR rate was 92% to 93% in patients with or without cirrhosis. In patients in whom previous treatment with PEGINF and RBV failed, 24 weeks of SOF and RBV achieved an SVR rate of 85% in patient without cirrhosis but only 60% in patients with cirrhosis.³⁰ On the basis of these data, the FDA recommended that all patients with HCV genotype 3 could be treated with SOF and RBV for 24 weeks.

Sofosbuvir and RBV were also studied in patients with genotypes 1, 2, and 3 who had coinfection with human immunodeficiency virus (HIV).³¹ The duration of treatment was 24 weeks for patients with genotypes 1 and 3 and 12 weeks for patients with HCV genotype 2. Sustained virologic response rates of 76%, 88%, and 92% were observed for patients with genotypes 1, 2, and 3, respectively. This study led the FDA to approve SOF and RBV for the treatment of HCV in patients coinfected with HIV. This represents the first antiviral agent to be approved for treatment of HCV-HIV coinfection. The results of this study supported the FDA recommendation to use SOF and RBV for 24 weeks in patients with HCV genotype 1 who had intolerance or contraindications to the use of PEGINF.

Sofosbuvir and RBV have also been studied without PEGINF in patients with HCV and HCC awaiting liver transplant and in patients with post–liver transplant HCV recurrence. The pretransplant HCC study patients who met criteria for the MELD exception were treated with SOF and RBV up until the time they underwent liver transplant.³² Treatment was stopped at the time of the transplant. Overall, 64% of patients did not have HCV recurrence after the transplant. In patients with undetectable HCV RNA for at least 30 days before undergoing transplant, 95% did not experience HCV recurrence. These data led the FDA to approve SOF and RBV for use in patients with HCC awaiting liver transplant.

Two studies have been conducted in the post–liver transplant population.^{33, 34} One study included patients with stable normal graft function at least 6 months after transplant.³³ These patients were treated with SOF and RBV for 24 weeks. Of the 40 patients in this study, 83% had genotype 1. All patients had undetectable HCV RNA within 4 weeks of initiating SOF and RBV. Only data on HCV RNA undetectable 4 weeks after stopping treatment (SVR-4) are available to date, but this level was achieved in 77% of the patients. The other posttransplant study was a compassionate use program for patients with severe HCV recurrence after transplant.³⁴ Most of these patients had either fibrosing cholestatic hepatitis within the first year or had development of decompensated recurrent cirrhosis 2 or more years after their transplant. Of the 20 patients treated with SOF and RBV for 24 weeks, all had undetectable HCV RNA, 64% had clinical improvement, and 60% achieved an SVR; 30% of patients died of complications of their advanced liver disease despite achieving a virologic response.

Sofosbuvir is an extremely safe antiviral agent with minimal adverse effects.¹⁵ In a study in which SOF and RBV were compared with placebo in patients who could not take PEGINF and RBV, the only adverse effects occurring more frequently with SOF and RBV than with placebo were anemia and pruritus, both of which were attributed to RBV.²⁹ In the 5 phase 3 clinical trials, the drop-out rate due to adverse events was greatest in the placebo-treated group (4%); the drop-out rate was only 2% in patients treated with PEGINF, SOF, and RBV for 12 weeks and less than 1% in all SOF and RBV treatment groups.

Combining SOF and SMV in Patients With Genotype 1

The combination of SOF and SMV for either 12 or 24 weeks with or without RBV has been evaluated in 167 patients with HCV genotype 1.³⁵ No single arm of this 2-cohort, 4-arm study had more than 54 patients, and only SVR-4 data are currently available for half the patients. However, the results are extremely noteworthy. Sustained virologic response rates of 93% to 100% were observed in all but one of the groups regardless of whether patients were treated for 12 or 24 weeks and whether they received RBV or not. The lowest SVR (79%) was observed in the group treated with SOF, SMV, and RBV for 24 weeks in which 4 patients had nonvirologic failure. All 14 patients with cirrhosis achieved SVR-4 within just 12 weeks of initiating SOF and SMV. Of the 7 patients with cirrhosis and previous nonresponse, all achieved SVR. In patients with genotype 1a and the Q80K sequence variation, the SVR rate was 90%. In patients without this sequence variation, the SVR rate was 100%.

Adding PEGINF to SOF and RBV in Patients With Genotype 3

Of all patients with HCV, those with genotype 3 have the most difficulty achieving a cure. Many believe this is difficulty is related to the much higher hepatic content of micovesicular steatosis that is unique to patients with HCV genotype 3.³⁶Sustained virologic response in patients with genotype 3 is also negatively impacted by previous nonresponse to PEGINF and RBV. In patients without cirrhosis, a previous nonresponse to PEGINF and RBV is associated with a reduction in SVR from 93% to 85%, and in those with cirrhosis, the SVR is reduced from 92% to 60%.^{28, 29, 30} This negative impact of previous PEGINF and RBV treatment is also observed in patients with genotype 2 but to a far lesser extent. In patients with genotype 2 who have previously undergone PEGINF and RBV treatment, the SVR in response to SOF and RBV is reduced from 97% to 91% in those without cirrhosis and from 100% to 88% in those with cirrhosis.

The SVR in patients with HCV genotype 3, especially patients previously treated with PEGINF and RBV, appears to be enhanced by adding PEGINF to SOF and RBV.³⁷ In a small study of only 24 patients with genotype 3 and previous nonresponse to PEGINF and RBV (half of whom had cirrhosis), 12 weeks of treatment with PEGINF, SOF, and RBV yielded an SVR of 83% in patients with and without cirrhosis. In the same study, 14 patients with HCV genotype 2, cirrhosis, and previous nonresponse to PEGINF and RBV achieved an SVR of 93% when re-treated with PEGINF, SOF, and RBV.

Our Treatment Approach

In January 2014, a joint guideline for treating HCV was issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.³⁸ These recommendations and the FDA recommendations for use of SOF³⁹ are summarized in Table 2. Our treatment approach to chronic HCV at the Liver Institute of Virginia in 2014 is based on the available data and focuses on maximizing SVR while also respecting the cost of treatment (Table 2). In several situations, we believe the American Association for the Study of Liver Diseases/Infectious Diseases Society of America treatment guidelines are overly aggressive, are too costly, and have no clinical trial data to substantiate the recommendation.

Table 2 2014 Treatment Recommendations for Patients With HCV

Variable	AASLD/IDSA	FDA	LIV
Genotype 1: Treatment naive and prior PEGINF and RBV relapse
INF tolerant, no cirrhosis or compensated cirrhosis	PEGINF, SOF, and RBV for 12 wk
INF intolerant, no cirrhosis	SOF and SMV ± RBV for 12 wk	SOF and RBV for 24 wk	Defer treatment
INF intolerant, cirrhosis			SOF and SMV for 12 wk
Genotype 1: Prior PEGINF and RBV nonresponse
INF tolerant, no cirrhosis or compensated cirrhosis	SOF and SMV ± RBV for 12 wk	PEGINF, SOF, and RBV for 12 wk
INF intolerant, no cirrhosis	SOF and SMV ± RBV for 12 wk	SOF and RBV for 24 wk	Defer treatment
INF intolerant, cirrhosis			SOF and SMV for 12 wk
Genotype 1: Prior treatment with PEGINF, RBV, and TPV or BOC
INF tolerant, no cirrhosis or compensated cirrhosis	SOF for 12 wk, PEGINF and RBV for 12-24 wk	PEGINF, SOF, and RBV for 12 wk
INF intolerant, no cirrhosis	NR	SOF and RBV for 24 wk	Defer treatment
INF intolerant, cirrhosis			SOF and SMV for 12 wk
Genotype 2
Treatment naive or PEGINF-RBV relapse, no cirrhosis or compensated cirrhosis	SOF and RBV for 12 wk	SOF and RBV for 12 wk	SOF and RBV for 12 wk
Prior PEGINF-RBV nonresponse, no cirrhosis	SOF and RBV for 12 wk
Prior PEGINF-RBV nonresponse, cirrhosis	SOF and RBV for 12-16 wk
Genotype 3
Treatment naive	SOF and RBV for 24 wk	SOF and RBV for 24 wk	SOF and RBV for 24 wk
Prior PEGINF-RBV, INF tolerant, no cirrhosis or compensated cirrhosis			PEGINF, SOF, and RBV for 12 wk
Prior PEGINF-RBV, INF intolerant, no cirrhosis			Defer treatment
Prior PEGINF-RBV, INF intolerant, cirrhosis			SOF and RBV for 24 wk
Genotype 4
INF tolerant	PEGINF, SOF, and RBV for 12 wk
INF intolerant	SOF and RBV for 24 wk		SOF and SMV for 12 wk
Genotypes 5 and 6
INF tolerant	PEGINF, SOF, and RBV for 12 wk	NA	PEGINF, SOF, and RBV for 12 wk
INF intolerant	NR	NA	SOF and RBV for 24 wk

AASLD = American Association for the Study of Liver Diseases; BOC = boceprevir; FDA = Food and Drug Administration; IDSA = Infectious Diseases Society of America; INF = interferon; LIV = Liver Institute of Virginia; NA = not approved; NR = no recommendation; PEGINF = peginterferon; RBV = ribavirin; SMV = simeprevir; SOF = sofosbuvir; TPV = telaprevir.

Genotypes 1, 4, 5, and 6

Genotype 1 is the most common form of HCV worldwide. Genotype 4 is the dominant genotype in Egypt and the Middle East, genotype 5 is frequent in South Africa, and genotype 6 is common in Vietnam and Cambodia.⁴⁰ In the United States, genotypes 4 through 6 are uncommon and rarely seen except in immigrants from the aforementioned regions of the world.

In patients with genotypes 1, 4, 5, or 6 without cirrhosis, our treatment approach is PEGINF, SOF, and RBV for 12 weeks. The SVR rate is 92% or greater, and less than 2% of these patients will be unable to tolerate this regimen. For patients who have not achieved an SVR during previous treatment with PEGINF and RBV or PEGINF, RBV, and either TPV or BOC, our approach is the same. Patients without cirrhosis who prefer not to be treated with PEGINF or have intolerance or contraindications to PEGINF can defer treatment and wait for an FDA-approved all-oral antiviral combination. Two such regimens are expected to be available before 2015. We do not promote either SOF and RBV for 24 weeks or SOF and SMV for 12 weeks in patients without cirrhosis.

In patients with cirrhosis and genotypes 1, 4, 5, or 6, our approach is still PEGINF, SOF, and RBV for 12 weeks as long as the platelet count and serum albumin level are normal and there is no history of hepatic decompensation or evidence of esophageal varices or subclinical hepatic encephalopathy. In contrast, we would not treat patients with cirrhosis and any of these laboratory or clinical abnormalities with a PEGINF-containing regimen. In a previous study in which patients with these characteristics were treated with PEGINF, RBV, and either TPV or BOC, more than half experienced severe anemia, 25% discontinued treatment, and 1% to 2% died as a result of hepatic decompensation.⁴¹ In our opinion, the risk that this poor outcome could also occur with a 12-week PEGINF and RBV–containing regimen is considerable. In addition, the SVR that could be achieved with PEGINF, SOF, and RBV is reduced to 80% or less in such patients.

In patients with genotype 1 or 4 and cirrhosis who have intolerance or contraindications to PEGINF, our treatment approach is SOF and SMV for 12 weeks. In patients with HCV-induced extrahepatic manifestations such as symptomatic cryoglobulinemia, glomerulonephritis, or B-cell lymphoma, regardless of fibrosis stage, we also use SOF and SMV. We do not believe that testing for the Q80K sequence variation is necessary when treating patients who have genotype 1a with SOF and SMV. The SVR when this sequence variation is present is still 90%, and there is no suggestion from the data that adding RBV or extending the duration of therapy to 24 weeks enhances SVR. We do not recommend 24 weeks of SOF and RBV in these patients; the cost of this regimen is prohibitive, and the SVR rate is estimated to be only in the 70% to 75% range, approximately 20% lower than that observed with SOF and SMV. We also do not recommend deferring treatment in this population, and payers should recognize their need for treatment. These patients have cirrhosis, are at risk for development of severe and life-threatening complications of cirrhosis, and should not have to wait for an alternative all-oral regimen.

In patient with genotypes 5 or 6, cirrhosis, and intolerance or contraindications to PEGINF, we use SOF and RBV for 24 weeks. Although this regimen is costly, this group represents only a limited number of patients with HCV, and no alternative treatment is on the horizon. Simeprevir has activity against HCV genotypes 5 and 6 in vitro, but without any clinical data to support its use, it is difficult to recommend this treatment.

Our treatment approach to patients with HCV genotype 1 does not include TPV, BOC, or SMV in combination with PEGINF and RBV. All of these antiviral agents have a lower SVR rate and require a longer duration of PEGINF and RBV compared with an SOF-containing regimen.¹⁴

Genotype 2

Our treatment approach for all patients with genotype 2, regardless of fibrosis stage, is SOF and RBV for 12 weeks. This group includes patients with cirrhosis in whom PEGINF and RBV failed previously. The SVR rate in this nonresponse subpopulation with cirrhosis is 88% but exceeds 90% in all other subpopulations. A more effective, less costly regimen is unlikely to be developed for patients with HCV genotype 2 in the foreseeable future.

Genotype 3

Patients with genotype 3 are now the most difficult and costly to treat and the most controversial regarding recommendations for treatment. Treatment-naive patients, regardless of the degree of fibrosis, require twice the duration of SOF and RBV (24 weeks) and twice the cost to achieve an SVR of at least 90%. We believe that SOF, RBV, and PEGINF for 12 weeks would yield an SVR of at least 90% and be more cost-effective, but with no data in the treatment-naive population, this approach is difficult to adopt. Therefore, our approach to treatment-naive patients with genotype 3 with or without cirrhosis is SOF and RBV for 24 weeks.

In patients with genotype 3 who have previously undergone PEGINF and RBV treatment and do not have cirrhosis, 24 weeks of SOF and RBV is nearly twice as costly yet offers an SVR similar to 12 weeks of PEGINF, SOF, and RBV (85% vs 83%, respectively). Because only 12 weeks of PEGINF is generally tolerated, we use the cheaper regimen (PEGINF, SOF, and RBV for 12 weeks). Patients with genotype 3 who do not have cirrhosis and are intolerant of PEGINF can defer treatment until a more cost-effective therapy is available. In patients with cirrhosis who do not have contraindications to PEGINF, our approach is to also use PEGINF, SOF, and RBV. The SVR with this treatment is also 83% compared with only 60% for 24 weeks of SOF and RBV. In patients with cirrhosis that is too advanced for PEGINF (see criteria outlined in the “Genotypes 1, 4, 5, and 6” section) and patients with PEGINF intolerance for other reasons, we have no choice but to use the inferior and more costly treatment (SOF and RBV for 24 weeks).

Recommendations

For 2014, SOF has replaced PEGINF as the backbone of HCV therapy. Sofosbuvir is superior to all other currently available antiviral agents with respect to efficacy, adverse effects, drug-drug interactions, viral resistance, and duration of therapy. Peginterferon should still be used in many patients with genotype 1 and in selected patients with genotype 3 because it offers higher efficacy and is less costly than 24 weeks of SOF and RBV. In 2015, another era of HCV treatment will begin, and our need for PEGINF and possibly RBV will no longer exist. Patients with genotype 1 and no cirrhosis may choose to defer treatment until then.

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15. Koff, R.S. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2014; 39: 478–487

16. Kowdley, K.V., Lawitz, E., Poordad, F. et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1.N Engl J Med. 2014; 370: 222–232

17. Lawitz, E., Poordad, F.F., Pang, P.S. et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. ([published correction appears in Lancet. 2014;383(9920):870]) Lancet. 2014; 383: 515–523

18. Everson, G.T., Sims, K.D., Rodriguez-Torres, M. et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection.Gastroenterology. 2014; 146: 420–429

19. Lawitz, E, Hezode, C, Gane, E et al. Efficacy and safety of MK-5172 and MK-8742 ± ribavirin in hepatitis C genotype 1 infected patients with cirrhosis or previous null-response: the C-WORTHY Study. J Hepatol. 2014; 60: S25–26

20. Zeuzem, S., Soriano, V., Asselah, T. et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med.2013; 369: 630–639

21. Talwani, R., Heil, E.L., Gilliam, B.L., and Temesgen, Z. Simeprevir: a macrocyclic HCV protease inhibitor. Drugs Today (Barc). 2013; 49: 769–779

22. Moreno C, Hezode C, Marcellin P, et al. Simeprevir with peginterferon/ribavirin in treatment-naïve or -experienced patients with chronic HCV genotype 4 infection: a phase III study. Paper presented at: 14th European AIDs Conference; October 16-19, 2013; Brussels, Belgium.

23. Manns, M., Marcellin, P., Poordad, F.P.F. et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. ([abstract 1413]) J Hepatol. 2013; 58: S568

24. Jacobson, I., Dore, G.J., Foster, G.R. et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-1 a phase III trial. ([abstract 1425]) J Hepatol. 2013; 58: S574

25. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial [published online ahead of print March 3, 2014]. Gastroenterology. http://dx.doi.org/10.1053/j.gastro.2014.02.051.

26. Zeuzem, S., Berg, T., Gane, E. et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014; 146: 430–441

27. Thompson, A.J., Muir, A.J., Sulkowski, M.S. et al. IL28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139: 120–129.e18

28. Lawitz, E., Mangia, A., Wyles, D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368: 1878–1887

29. Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013; 368: 1867–1877

30. Zeuzem, S., Dusheiko, G.M., Salupere, R. et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. ([AASLD abstract 1085]) Hepatology. 2013; 58: 733A

31. Sulkowski, M.S., Rodriguez-Torres, M., Lalezari, J.P. et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). ([AASLD abstract 212]) Hepatology. 2013; 58: 313A

32. Curry, M.P., Forns, X., Chung, R.T. et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. ([AASLD abstract 213]) Hepatology. 2013; 58: 314A

33. Charlton MR, Gane EJ, Manns MP, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study [AASLD abstract LB2]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.

34. Forns, X., Fontana, R.J., Moonka, D. et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. ([AASLD abstract 1084]) Hepatology. 2013; 58:732A

35. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study [AASLD abstract LB3]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.

36. Restivo, L., Zampino, R., Guerrera, B., Ruggiero, L., and Adinolfi, L.E. Steatosis is the predictor of relapse in HCV genotype 3- but not 2-infected patients treated with 12 weeks of pegylated interferon-α-2a plus ribavirin and RVR.J Viral Hepat. 2012; 19: 346–352

37. Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study [AASLD abstract LB4]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC.

38.American Association for the Study of Liver Diseases, Infectious Diseases Society of America. Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org/full-report-view. Revised March 21, 2014. Accessed April 19, 2014.

39. Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc; December 2013. http://www.gilead.com/∼/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf.

40. Nguyen, M.H. and Keeffe, E.B. Chronic hepatitis C: genotypes 4 to 9. Clin Liver Dis. 2005; 9: 411–426

41. Hézode, C., Fontaine, H., Dorival, C...., and CUPIC Study Group. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol. 2013; 59: 434–441

Potential Competing Interests: Dr Shiffman has participated in advisor meetings with Achillion Pharmaceuticals, Inc, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead Sciences, Gen-Probe, Inc, Globeimmune Inc, GlaxoSmithKline, Janssen Pharmaceutical Companies, Merck & Co, Inc, Novartis Corp, Genentech, Inc, and Vertex Pharmaceuticals Inc; is on the speakers' bureau for Bayer AG, Gilead Sciences, Janssen Pharmaceutical Companies, Merck & Co, Inc, Genentech, Inc, and Vertex Pharmaceuticals Inc; and receives grant support from Abbott Laboratories, Achillion Pharmaceuticals, Inc, Beckman Coulter, Inc, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead Sciences, Globeimmune Inc, Idenix Pharmaceuticals, Inc, Intercept Pharmaceuticals, Inc, Merck & Co, Inc, Mochida Pharmaceutical Co, Inc, Novartis Corp, and Genentech, Inc. Ms Long has participated in advisor meetings with AbbVie Inc, Gilead Sciences, Janssen Pharmaceutical Companies, Kadmon Pharmaceuticals, Merck & Co, Inc, and Vertex Pharmaceuticals Inc and is on the speakers' bureau for Merck & Co, Inc, GlaxoSmithKline, Kadmon Pharmaceuticals, Salix Pharmaceuticals, Inc, and Vertex Pharmaceuticals Inc. Ms James has participated in advisor meetings with Gilead Sciences and Janssen Pharmaceutical Companies and is on the speakers' bureau for Janssen Pharmaceutical Companies. Mr Alexander has participated in advisor meetings with Gilead Sciences.

© 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Source

Clinical Trial: A Phase III Evaluation of Daclatasvir + Sofosbuvir in Genotype 1-6 Chronic HCV Subjects With Cirrhosis Who May Require Future Liver Transplant and Subjects Post-Liver Transplant

This study is not yet open for participant recruitment.

Verified January 2014 by Bristol-Myers Squibb

Sponsor: Bristol-Myers Squibb

Information provided by (Responsible Party): Bristol-Myers Squibb

ClinicalTrials.gov Identifier: NCT02032875
First received: January 9, 2014
Last updated: NA
Last verified: January 2014
History: No changes posted

Purpose

This trial is open to patients with cirrhosis due to chronic HCV, and to patients who have already received a liver transplant for chronic HCV. All subjects will be treated with Daclatasvir and Sofosbuvir for 12 weeks. Under certain conditions, the treatment duration may be extended for cirrhotic subjects. The study will test how well this combination of investigational drugs works to treat chronic HCV.

Condition	Intervention	Phase
Hepatitis C	Drug: Daclatasvir Drug: Sofosbuvir Drug: Ribavirin	Phase 3

Study Type:
Interventional

Study Design:
Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Official Title:
A Phase 3 Evaluation of Daclatasvir and Sofosbuvir in Genotype 1-6 Chronic Hepatitis C Infection Subjects With Cirrhosis Who May Require Future Liver Transplant and Subjects Post-Liver Transplant

Resource links provided by NLM:

Genetics Home Reference related topics: North American Indian childhood cirrhosis

MedlinePlus related topics: Cirrhosis Hepatitis Hepatitis A Hepatitis C Liver Transplantation

Drug Information available for: Ribavirin

U.S. FDA Resources

Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:

• Proportion of genotype (GT) -1 infected Cirrhotic subjects with sustained virologic response (SVR12) [ Time Frame: Post treatment Week 12 ] [ Designated as safety issue: No ]

  SVR12 defined as hepatitis C virus (HCV) ribonucleic acid (RNA) < lower limit of quantification (LLOQ) target detected (TD) or target not detected (TND) 12 weeks after end of treatment (EOT)

• Proportion of GT-1 infected Post-transplant subjects with SVR12 [ Time Frame: Post treatment Week 12 ] [ Designated as safety issue: No ]

  SVR12 defined as hepatitis C virus (HCV) ribonucleic acid (RNA) < lower limit of quantification (LLOQ) target detected (TD) or target not detected (TND) 12 weeks after end of treatment (EOT)

Secondary Outcome Measures:

• The proportion of subjects who achieve SVR12 rates in all Cirrhotic and Post-transplant subjects, respectively, regardless of infecting HCV genotype, and GT-2-6 independently [ Time Frame: Post treatment Week 12 ] [ Designated as safety issue: No ]
• Safety measured by frequency of deaths, serious adverse events (SAEs), discontinuations due to adverse events (AEs), Grade 3/4 AEs, and Grade 3/4 clinical laboratory abnormalities [ Time Frame: Up to end of treatment (Week 12 of the treatment phase) + 7 days ] [ Designated as safety issue: Yes ]
• The proportion of subjects who achieve HCV RNA < LLOQ-TD/TND [ Time Frame: At Weeks: 1, 2, 4, 6, 8, 12 and EOT; post-treatment Weeks 4, 8 and 24 ] [ Designated as safety issue: No ]
• The proportion of subjects who achieve HCV RNA < LLOQ TND [ Time Frame: At Weeks: 1, 2, 4, 6, 8, 12 and EOT ] [ Designated as safety issue: No ]
• The proportion of subjects with CC or non-CC genotype at the IL28B rs12979860 single nucleotide polymorphisms (SNPs) who achieve SVR12 in Cirrhotic and Post-transplant subjects respectively [ Time Frame: Post treatment Week 12 ] [ Designated as safety issue: No ]

Estimated Enrollment: 110
Study Start Date: March 2014
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm 1a: Daclatasvir and Sofosbuvir in Cirrhotic subjects Daclatasvir 60 mg tablet and Sofosbuvir 400 mg tablet orally once daily for 12 weeks	Drug: Daclatasvir Other Name: BMS-790052 Drug: Sofosbuvir
Experimental: Arm 1b: Daclatasvir+Sofosbuvir+Ribavirin(Relapse Re-treatment) Cirrhotic subjects who undergo transplant while on study treatment may enter an additional Treatment Extension or Relapse Re-treatment period Daclatasvir 60 mg tablet and Sofosbuvir 400 mg tablet orally once daily for 12 weeks. Ribavirin tablet daily dose of 1000 - 1200 mg orally in two divided doses for 12 weeks	Drug: Daclatasvir Other Name: BMS-790052 Drug: Sofosbuvir Drug: Ribavirin
Experimental: Arm 1c: Daclatasvir and Sofosbuvir (Treatment Extension) Cirrhotic subjects who undergo transplant while on study treatment may enter an additional Treatment Extension or Relapse Re-treatment period Daclatasvir 60 mg tablet and Sofosbuvir 400 mg tablet orally once daily for 12 weeks	Drug: Daclatasvir Other Name: BMS-790052 Drug: Sofosbuvir
Experimental: Arm 2: Daclatasvir and Sofosbuvir in Post-transplant subjects Daclatasvir 60 mg tablet and Sofosbuvir 400 mg tablet orally once daily for 12 weeks	Drug: Daclatasvir Other Name: BMS-790052 Drug: Sofosbuvir

Eligibility

Ages Eligible for Study:  18 Years and older
Genders Eligible for Study:  Both
Accepts Healthy Volunteers:  No

Criteria

Inclusion Criteria:

• Subjects must be able to understand and agree to comply with the prescribed dosing regimens and procedures, report for regularly scheduled study visits, and reliably communicate with study personnel about adverse events and concomitant medications
• Subjects chronically infected with HCV Genotype 1, 2, 3, 4, 5, or 6 with HCV RNA viral load of ≥ 10,000 IU/mL at screening
• Subjects may be treatment-naïve or treatment-experienced
• Cirrhotic subjects must have cirrhosis confirmed by biopsy, Fibroscan or fibrotest and Aspartate aminotransferase platelet ratio index (APRI) criteria as outlined in the protocol
• Post-transplant subjects must be at least 3 months post-transplant with no evidence of moderate or severe rejection

Exclusion Criteria:

• History of multi-organ transplant, with the exception of dual transplantation of the liver/kidney, is prohibited
• Current or known history of cancer (with the following exceptions: In situ carcinoma of the cervix, adequately treated basal or squamous cell carcinoma of the skin, or hepatocellular carcinoma within Milan criteria for transplantation) within 5 years prior to screening
• Evidence of an ongoing medical condition contributing to chronic liver disease other than HCV (such as, but not limited to: hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, or toxin exposures)
• History of HIV infection or chronic hepatitis B virus (HBV) as documented by HBV serologies (e.g., HBsAg-seropositive). Subjects with resolved HBV infection may participate (e.g., HBcAb-seropositive with concurrent HBsAg-seronegative)
• Active hospitalization for decompensated liver disease

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT02032875

Sponsors and Collaborators
Bristol-Myers Squibb

Investigators
Study Director: Bristol-Myers Squibb  Bristol-Myers Squibb

More Information

No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT02032875 History of Changes
Other Study ID Numbers: AI444-215
Study First Received: January 9, 2014
Last Updated: January 9, 2014
Health Authority: United States: Food and Drug Administration

-----------------------------------------

Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Review Article

You have free access to this content

J. M. Wantuck¹, A. Ahmed², M. H. Nguyen^2,*

Article first published online: 19 NOV 2013

DOI: 10.1111/apt.12551

© 2013 John Wiley & Sons Ltd

Summary

Background

The global burden of hepatitis C (HCV) infection is mostly found in Africa, the Middle East and Asia, where HCV genotypes 4, 5 and 6 are common. The literature on these genotypes is sparse and this synopsis will review characteristics of patients infected with these genotypes.

Aim

To review characteristics of patients infected with HCV genotypes 4, 5 and 6.

Methods

PubMed search for ‘hepatitis C’ AND ‘genotype 4’, ‘hepatitis C’ AND ‘genotype 5’, and ‘hepatitis C’ AND ‘genotype 6’ was conducted and relevant articles were reviewed.

Results

Intravenous drug use is generally responsible for HCV genotype 4 infection in developed countries, but unsafe medical practices cause most cases of HCV genotypes 4, 5 and 6 in endemic countries. The sustained virological response (SVR) rate for patients with HCV genotype 4 who receive pegylated interferon and ribavirin for 48 weeks ranges from 40% to 70% in various small studies. The SVR rate is in the 60–70% range for HCV genotype 5 and 70–80% range for HCV genotype 6 following 48 weeks with pegylated interferon and ribavirin. Preliminary data suggest that a shorter course of 24 weeks of pegylated interferon and ribavirin may be acceptable for HCV genotype 6, with an SVR rate of approximately 70%.

Conclusions

The current standard-of-care therapy for HCV genotypes 4, 5 and 6 is pegylated interferon and ribavirin for 48 weeks. A shorter course with 24 weeks of therapy may be considered for patients with genotype 6. Newer and much more effective therapies may be forthcoming in the next few years.

Introduction

The pivotal treatment trials and large epidemiological studies completed for chronic hepatitis C have generally been conducted in North America and Europe, where hepatitis C virus (HCV) genotypes 1, 2 or 3 are prevalent.[1-3] More developed countries in the East, such as Japan and Korea, also have a similar HCV genotype distribution. HCV genotypes 4, 5 and 6 are common in areas of Asia, Africa and the Middle East where HCV infection is endemic; however, data on the epidemiology and therapeutic response of these genotypes are much more limited. This synopsis will review the epidemiology of these lesser known genotypes as well as their response to anti-viral treatment, including the available data on newly approved protease inhibitors and other novel anti-HCV agents for HCV genotype 4, newer treatment studies for HCV genotype 5 and recent randomised controlled trials (RCT) comparing outcomes of 24 vs. 48 weeks of pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy for HCV genotype 6. Recent advances in the understanding of host IFN sensitivity and interleukin-28B (IL28B) genetic polymorphism, which has varying ethnic distribution, as does the distribution of infection of HCV genotypes 4, 5 and 6 infection, will also be reviewed.

Geographical distribution of hepatitis C virus and hepatitis C virus genotypes

Estimates of HCV prevalence vary according to geographical areas and are largely based on cross-sectional studies of various subpopulations, ranging from blood donors, ambulatory out-patients, to hospital-based and chronic dialysis patients. The World Health Organization in 1999 estimated that between 130 and 170 million people are infected with HCV worldwide.[4, 5] The minority of these people (13 million or 22%) are found in the Americas and Europe.

In the Middle East and Africa, prevalence is highest in Egypt (18%) due to public health campaigns against schistosomiasis in the second half of the last century.[6] Prevalence is approximately 1–2% in Syria and Saudi Arabia.[7] Sub-Saharan Africa is less well studied, but estimates of HCV prevalence are high. Countries in central Africa average 6% prevalence, with the highest prevalence in Cameroon (14%) and the lowest in Equatorial Guinea (2%). In West Africa, the average prevalence is 2.4%, with ranges from 1% to 6%. Similarly, south and east African countries have an average prevalence of 1.6%, with South Africa having the lowest prevalence at 0.1%, while Mozambique is closer to 2.8%.[7, 8]

In the Asia Pacific region, Australia as a developed country populated predominantly by ethnic Europeans has a relatively low prevalence of 1.3%,[9] and IVDU was implicated in 80% of infected subjects.[9] The most common risk factor in most other countries of this region is, however, iatrogenic exposure due to reuse of needles or transfusion of unscreened blood products, including more industrialised countries, such as Japan and Taiwan. HCV prevalence is as high as 6% in Thailand and Vietnam.[5]

In Europe, HCV prevalence is approximately 1–2% in most countries, but ranges from the lowest prevalence of ≤0.5% in northern countries to the highest (≥3%) in Romania and rural areas of Greece, Italy and Russia.[10]

Similarly, the distribution of HCV genotypes also varies according to geographical area and is noteworthy because it is one of the most important predictors of response to anti-viral therapy. HCV genotypes 1, 2 and 3 are widely distributed among the world's population, but the lesser known genotypes tend to have a more focused geography and are associated with certain methods of transmission according to regional medical practices and public health standards. HCV genotype 4 is common in Africa and the Middle East (Figure 1 and Table 1).[1, 8, 11-23] HCV genotype 5 is found almost exclusively in South Africa and expatriates from that area, while HCV genotype 6 is found mostly in Southeast Asia, Southern China and immigrants from those regions.

Table 1. Hepatitis C genotype 4 prevalence in a selection of countries in Europe, The Middle East, Africa and India

Country or region	HCV genotype 4 prevalence
Southwestern France[12]	7.4%
Germany[13]	3.6%
Southern Italy[14]	1.4%
Northern Italy[15]	3.1%
Southern Spain[16]	14%
Saudi Arabia[18]	60%
Lebanon[19]	30%
Syria[8]	30%
Cameroon[20]	76%
Nigeria[21]	60%
Egypt[17]	91%
Gabon[22]	71%
Southern India[23]	6.2%

 

Figure 1. Map of geographical areas in which hepatitis C virus (HCV) genotypes 4, 5 and 6 are prevalent.

Another important factor influencing treatment outcome in chronic hepatitis C is the recently discovered IL28B gene polymorphism that is also distributed according to ethnic and geographical areas. The CC allele polymorphism occurs in 33% of Americans of European ancestry, 14% of African Americans and 29% of Hispanic Americans.[24] The frequency of the CC genotype is much higher in studies of Asian populations, up to 84% in a recent study of 282 healthy Japanese volunteers.[25, 26] Individuals carrying IL28B polymorphism with CC alleles have the best prognosis, with two to three times the rate of sustained virological response (SVR) with IFN-based anti-HCV therapy, while those with TT alleles have the worst SVR rates.[27] Most of the initial studies of this polymorphism were completed on genotype 1 patients; however, a recent study has shown that, in patients with HCV genotype 4, patients with CC, CT and TT genotypes have 82%, 47% and 29% SVR rates respectively.[28]

The remainder of this synopsis will discuss the epidemiology and treatment outcomes of HCV genotypes 4, 5 and 6.

Hepatitis C virus genotype 4

Epidemiology of hepatitis C genotype 4

HCV genotype 4 (HCV-4) is encountered throughout Africa, eastern Mediterranean countries, and usually among immigrants from endemic areas or indigenous injection drug users or individuals infected with human immunodeficiency virus (HIV) in North America and Europe (Table 1).[8, 11-23] More recently, HCV-4 has been reported in the Caribbean region and in India.[23, 29, 30] In South Indian patients, HCV-4 prevalence is 6.2% among HCV-infected patients.[23, 30] With regard to the relatively high rates of HCV genotype 4 in southern European countries, the ancient historic link between regions in southern Italy and Spain and North Africa or the Middle East, injections with multiple-use needles and glass syringes, and the use of non-HCV-tested blood products may have contributed to the spread of HCV genotype 4 to this region. For instance, in a French study, phylogenetic analysis of HCV-4 patients showed two distinct patterns of subtypes: 4a or 4d among injection drug users of French origin and 4f, 4k or 4r among immigrants from Central Africa and the Middle East, thus showing that the subtypes have spread differently.[12] HCV genotype 4d was also a common subtype among homosexual men with acute hepatitis C and HIV co-infection in France.[31]

Regarding clinical characteristics, HCV-4 patients have been reported to have higher rates of liver-related complications leading to liver transplantation or liver-related death.[32, 33] Newer studies also reported poorer post-transplant outcomes from graft-related vascular complications and recurrent hepatitis C for patients with HCV-4.[34, 35] However, HCV-4 was not an independent predictor of clinical outcomes on multivariate analysis in such studies. Potential explanations for such inconsistencies may be lack of control for duration of infection and other ethnicity-related factors, as these studies were conducted outside the regions endemic for HCV-4 and usually included either IVDUs or immigrants with early acquisition of HCV infection related to medical procedures. A large study of HCV-4 patients in Europe comparing patients who were infected in France, Sub-Saharan Africa and Egypt showed that those infected in France were usually infected from IVDU (56.9%), while those from Egypt were infected primarily from other reasons (97.1%).[36] In addition, those infected in Egypt had higher rates of advanced fibrosis (44.6% vs. 24.2%) in concert with their longer duration of infection (22 vs. 28 years). These data could account for the lack of evidence identifying HCV-4 as an independent predictor of poorer outcomes in both the natural history of the disease and in post-transplant outcomes. There was also report of significant association of HCV subtypes 4a and 4o with hepatocellular carcinoma in Egypt, with subtype 4a accounting for 63% of those with genotype 4.[37] Similarly, studies to date have not confirmed that HCV-4 patients develop extrahepatic complications, such as cryoglobulinaemia, more often than patients with other genotypes.[38, 39] The literature, however, consistently demonstrates poor response of patients with HCV-4 to older regimens of anti-viral therapy.

Treatment of hepatitis C genotype 4

Combination therapy with interferon and ribavirin

Combination therapy with IFN and RBV produced SVRs ranging from 5% to 42%, whereas IFN-alone arms ranged from 6% to 8%, which was comparable to earlier studies of IFN monotherapy (10–11%).[40, 41] Thus, results for HCV-4 were similar to, or worse than, results for HCV-1.

Combination therapy with pegylated interferon and ribavirin

Pivotal trials of PEG-IFN and RBV included few patients with HCV-4, comprising only 2–4% of all subjects, which is far too small a sample from which to draw conclusions.[42, 43] The duration of treatment in most studies is 48 weeks, with few studies also comparing responses between 24- and 48-week treatment duration. Figure 2 summarises results of studies for HCV-4 with 48 weeks of therapy using standard-dose PEG-IFN and RBV (PEG-IFNα-2a 180 μg or PEG-IFNα-2b 1.5 mg/kg and RBV 1–1.2 g/day).[44-47] SVR generally ranged from 50% to 70%, except in one small study with SVR only 32%. Figure 3 summarises results of treatment responses with different duration of standard-dose PEG-IFN and RBV showing much more inferior SVR rates with 24 weeks of therapy and thus making the longer 48-week duration the standard of care.[48-50]

Figure 2. Sustained virological response to 48 weeks of combination therapy in patients with hepatitis C virus genotype 4. All studies were randomised control trials with intention-to-treat analysis: (P < 0.001);[44](P < 0.01);[45] (P = NS);[46] (P = 0.43).[47]

Figure 3. Hepatitis C genotype 4 treatment with PEG-IFN and RBV: 24 vs. 48 weeks. (P = not reported);[48](P = 0.001);[49] (P = 0.006).[50]

Nitazoxanide Therapy

Nitazoxanide is an agent capable of inhibition of HCV replication.[51] Several studies have evaluated its use in HCV treatment. In one study of HCV-4 patients, IFN monotherapy with nitazoxanide was compared with placebo, showing that 17% achieved an SVR vs. 0% in the placebo group (P = 0.05).[52] Another study comparing a regimen of standard PEG-IFN and RBV vs. pre-treatment for 12 weeks with nitazoxanide followed by 36 weeks of standard treatment in an ITT analysis found a 50% SVR in the first group (n = 40) and 79% SVR in the second (n = 28).[53] With newer agents becoming available, research into nitazoxanide therapy for HCV has been fading, although it remains a possibility for therapy in regions where novel and expensive therapies are not available.

Newly approved protease inhibitors (boceprevir and telaprevir) and investigational compounds

Current standard-of-care therapy for patients with chronic hepatitis C genotype 1 is a combination of PEG-IFN and RBV plus either boceprevir or telaprevir.[54-56] Both of these new agents are protease inhibitors with direct-acting activity against HCV and were recently approved by the Food and Drug Administration in the US for the treatment of patients with chronic hepatitis C genotype 1. With the new standard-of-care therapy, treatment-naive HCV-1 patients can expect an SVR of 75% overall with telaprevir and 68% with boceprevir (but lower rates of 53% for Black patients) compared to 40–44% with PEG-IFN and RBV only (23% for Black patients).

Very little has been published on the success of the novel targeted anti-virals specifically aimed at genotypes 4, 5 and 6. Patients with HCV genotypes 4, 5 and 6 were not included in the pivotal studies with boceprevir or telaprevir. In a phase IIa study of 24 HCV-4 patients randomised to three arms, including telaprevir alone, PEG-IFN and RBV only, and telaprevir plus PEG-IFN and RBV three-drug regimen induced a 4.32 log₁₀ decline in HCV RNA levels by day 15 of the study.[57] However, telaprevir monotherapy in HCV-4 patients was not nearly as effective as it was in HCV-1, inducing only a 0.77 log₁₀ decline in viral load vs. the 4.77 log₁₀ decline seen with HCV-1 patients.[58] SVR rates were approximately 50% in each group of this small study.

Currently, there are numerous anti-HCV investigational agents of various classes (‘second- generation’ protease inhibitors, nucleoside/nucleotide analogue polymerase inhibitors, nonnucleoside/nucleotide polymerase inhibitors, HCV NS5A inhibitors and cyclophilin inhibitors). Major effort is targeted at chronic hepatitis C genotype 1, but some of these newer agents have been shown to be pan-genotypic with activities against HCV genotypes 1 to 4 and 6.[59-64] Sofosbuvir (formerly PSI-7977 or GS-7977) in combination with PEG-IFN and RBV induced viral suppression in 11 HCV-4 subjects included in this preliminary study.[59] In a more recent phase III trial of 327 patients treated with a 12-week regimen of sofosbuvir plus peginterferon alpha-2a and ribavirin (NEUTRINO), 28 patients had HCV genotype 4 and SVR was achieved in 27 of these 28 patients (96%).[65] Other compounds with promising efficacy against HCV-4 are daclatasvir (BMS-790052, a NS5A inhibitor), PEG- IFN-γ and the cyclophilin inhibitor Debio 025.[60, 62, 63]

Hepatitis C virus genotype 5

Epidemiology of hepatitis C genotype 5

HCV genotype 5 (HCV-5) is found almost exclusively in South Africa.[66] Smuts et al. studied a population of 130 HCV-infected subjects from different areas of South Africa. HCV-5 was the most common genotype (39.2%), followed by HCV-1 (33%), HCV-2/3(21.5%) and HCV-4 (2.3%).[66] Most often found in South Africa, HCV-5 can also be found in European regions hosting a mixture of ethnicities, such as Belgium, the Netherlands and Luxembourg.[67] HCV-5 has also been reported at a surprisingly high prevalence of 14.2% among a population of settled, rural inhabitants of central France who had little contact with people from other countries.[68] However, studies on data collected between 1989 and 1997 from HCV-infected patients at 14 tertiary care centres in France and between 2000 and 2003 from HCV-infected patients in the Midi-Pyrenees showed a much lower prevalence of HCV-5 (1.2% and 1.4% respectively).[68, 69] In a follow-up study carried out to determine the mode of transmission, the authors enrolled 131 HCV-5 patients in France who were not of South African origin and determined that transmission was probably associated with exposure to the care of one local physician, and that those persons then donated blood and caused additional infections in transfused patients.[71] Another focus of infection was recently found in Syria, where 10% of HCV-infected patients had HCV-5.[72] Thirty-three per cent of these patients lived in the same town, which suggests an aetiology similar to that in central France. Similar localised outbreaks of HCV-5 have also occurred in southeast Spain and the Greek isles.[73, 74]

Treatment of hepatitis C genotype 5

Treatment response to HCV-5 is less studied, although HCV-5 appears to be an easier to treat genotype, with outcomes more similar to those seen with hepatitis C genotypes 2 and 3 (HCV-2/3). The largest study to date was a multicentre retrospective study from 12 centres in France by Bonny et al. and included 87 HCV-5 patients treated with either standard dose PEG-IFN plus RBV (n = 59) or IFN plus RBV (n = 28) for 48 weeks and demonstrated similar SVR rates in the two study groups (58% vs. 64%, P = 0.75).[75] The SVR rate for the total cohort of 87 HCV-5 patients was 60% overall and 75% for adherent patients. Of note, the limit of detection of HCV RNA PCR assay used in this study was 600–615 IU/mL, a much higher limit of detection than currently available. In this study, SVR rate was 37% for HCV-1 and 63% for HCV-2/3 overall. Figure 4 summarises results of treatment outcomes of HCV-5 patients.[75-78] SVR rates for HCV-5 in the study by D'Heygere was more similar to those of HCV-1 rather than HCV2/3, but this may be due to a much higher proportion of patients with cirrhosis in the HCV-5 group.

Figure 4. Sustained virological response to 48 weeks of pegylated interferon and ribavirin in hepatitis C genotype 5 patients, with comparison to other genotypes (Bonnyet al. and D'Heygere et al.).[75-78]

Another more recent, but also retrospective, study from Syria included 17 patients treated with IFN plus RBV and 9 patients with PEG-IFN and consisted of arms having both 24-week and 48-week treatment durations.[77] In this study, SVR rate was 75% in the 4 patients treated with PEG-IFN plus RBV for 48 weeks compared to 60% for the 24-week group. The corresponding SVR rates for the IFN plus RBV group were 48% and 44% respectively. However, the small sample size of this study limits its conclusion and the standard duration of 48 weeks with PEG-IFN plus RBV should be recommended.

To date, no studies have been performed to test activities by the two newly approved protease inhibitors boceprevir and telaprevir against HCV-5.

Hepatitis C virus genotype

Diagnosis of HCV genotype 6

The diagnosis of HCV-6 has not always been straightforward. Prior to approximately 2004, the primary assay used to genotype HCV-6 patients was a line probe assay (INNO-LiPA HCV I; Innogenetics, Zwijnaarde, Belgium) that characterised genotypes by the hybridisation of denatured 5'-UTR products. This assay was invalidated in a 2003 study of various genotyping methods and was found to mislabel HCV genotype 6a as 1b.[78, 79] A second version of the test was introduced (INNO-LiPA HCV II; Innogenetics) and has been shown, in multiple studies, to be highly accurate for distinguishing HCV-6 and HCV-1 and to correctly classify the genotype 99.4% of the time.[80, 81] The implications of this information are that earlier studies using the old INNO-LiPA HCV I assay could have significantly under-reported the prevalence of HCV-6 in the populations studied. Similarly, SVR rates in HCV-1 patients could also have been inflated if there were HCV-6 patients mislabelled as HCV-1 cases, as HCV-6 patients generally have better treatment response than HCV-1 patients as discussed below.

Epidemiology of hepatitis C genotype 6

Similar to HCV-4 and HCV-5, HCV genotype 6 (HCV-6) is more geographically restricted compared with HCV genotypes 1 to 3 and has been found in parts of East Asia (South China, Hong Kong, Taiwan, Macao) and Southeast Asia (Singapore, Malaysia, Vietnam, Thailand, Indonesia and Burma).[1, 84-91] Previously reported genotypes 7, 8, 9 and 11 (Southeast Asia) have recently been reclassified as variants of HCV-6, while genotype 10 (Indonesia) was reclassified as a variant of HCV-3.[92, 93] There are now six genotypes with various subtypes. For example, HCV-6 is divided into 21 subtypes, the most recently sequenced being 6r and 6s.[94]

The Philippines represents a unique genotypic distribution from its Southeast Asian neighbours.[95] A survey in Metro Manila reported an HCV prevalence of 7% (n = 41) with the following HCV genotype distribution: 68% for 1a, 11% for 1b and 10% for 2a/b. This genotypic distribution seems to be more similar to that found in the West, perhaps representing migration patterns or differences in the mode of transmission.

The prevalence of HCV genotype 6 in Hong Kong was 33% among 66 blood donors and 26% among 27 out-patients with HCV infection.[87, 88] In mainland China, HCV genotype 6a seems to be rare except in South China, where it is the second most common genotype after genotype 1b.[89] The unusual subtype 6v was also found in South China.[89] In a study conducted in the San Francisco Bay Area, HCV-1 and HCV-6 were the two most common genotypic groups among 308 HCV-infected Vietnamese out-patients seen at a community gastroenterology practice (42% and 41% respectively).[96]

Data on clinical characteristics of patients with chronic hepatitis C genotype 6 are very limited, but in one US study of Vietnamese and Chinese Vietnamese immigrant patients, no significant differences were found between patients with HCV-6 and those with HCV-1 and HCV-2/3 in regard to age, gender distribution, HCV RNA levels, cirrhosis, ALT levels and other hepatic synthetic markers.[96] Additional data on chronic hepatitis C in Asians have been discussed and summarised elsewhere.[97]

Treatment of hepatitis C virus genotype 6

In recent years, additional data on treatment outcomes of HCV-6 patients have been forthcoming, especially in regard to the effect of treatment duration, i.e. 24 vs. 48 weeks.[98, 99]

In general, several small studies have examined treatment outcomes in this patient population.[78, 81, 98, 100-106] Generally, SVR was 60–90% in patients treated for 48 weeks with standard doses of PEG-IFN and RBV (Figure 5).[101-105] The first multicentre RCT using PEG-IFN α-2a and weight-based RBV (1000/1200 mg) conducted in the US with ITT analysis showed no statistically significant differences in SVRs between the 24- and 48-week groups (n = 27, 33) (Figure 6).[98, 99] In this study, early virological response (EVR) did not correlate with SVR. Another RCT has also been conducted in Vietnam to compare SVRs of patients treated with 24 (n = 35) vs. 48 weeks (n = 70) of PEG-IFN α-2b and weight-based RBV (15 mg/kg/day).[99] As with the previous RCT on this topic, this study found no statistically significant differences in SVRs in the 24- and 48-week treatment groups. In addition, this latter study suggests that rapid virological response (RVR) may be predictive of SVR, as in the case of HCV-1; however, those without RVR did not seem to benefit from the longer treatment duration. Thus, while there were no statistically significant differences between SVRs with 24 vs. 48 weeks of therapy in these two RCTs, the small sample size in both of these studies did not allow for detection of smaller differences.

Figure 5. Sustained virological response to 48 weeks of pegylated interferon and ribavirin in hepatitis C genotype 6 patients.[101-105]

Figure 6. Hepatitis C virus genotype 6 treatment studies comparing 24–48 weeks of pegylated interferon and ribavirin. (P = 0.045);[98] (P = 0.24).[99]

As in the case of HCV-5 above, no studies including in vitro experiments have been performed to test activities by the two newly approved protease inhibitors boceprevir and telaprevir against HCV-6. In a preliminary study, the investigational compound GS-7977 (formerly PSI-7977) induced rapid viral suppression in five HCV-6 patients as well as in other patients with HCV-1 to HCV-4. In a recent phase III trial of sofosbuvir plus peginterferon alpha-2a and ribavirin in a 12-week regimen (NEUTRINO), six of the patients had genotype 6 and had a 100% SVR.[65] Additional data with larger study sample with sofosbuvir and other newer generations of anti-HCV therapies with pan-genotypic activities are probably forthcoming in the next few years.

Summary

Infection with HCV-4 through HCV-6 is relatively uncommon in most developed countries. However, these genotypes are widely distributed in many parts of Asia, Africa and the Middle East, where the disease burden of chronic hepatitis C is among the highest in the world. Injections with multiple-use needles and glass syringes and the use of non-HCV tested blood products in many parts of the developing world will continue to contribute to the spread of HCV infection in these areas. Further studies to examine epidemiological characteristics, natural history and clinical outcomes of patients infected with these lesser known HCV genotypes are needed. From the limited data available, it seems that HCV-4 and HCV-6 patients will respond well to some of the novel agents, but limited data do not allow for a general recommendation at this time. As novel therapies debut in the next several years, studies should be conducted to assess efficacy and safety in all of the HCV genotypes prior to widespread use. For the time being, HCV-4 and HCV-5 patients should be offered 48 weeks of standard PEG-IFN and RBV. For HCV- 6 patients, treatment with PEG-IFN and RBV should probably be offered for 48 weeks as well, although a 24-week course of treatment may be reasonable in those with RVR or poor tolerance to treatment.

Authorship

Guarantor of the article: Mindie Nguyen.

Author contribution: James Wantuck and Mindie Nguyen: concept development, data collection, drafting of the paper. Aijaz Ahmed: review of the paper. All authors approved the final version of the manuscript.

Acknowledgements

Declaration of personal interests: Aijaz Ahmed, MD: Grants/Research Support: Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche Genentech, Romark Laboratories; Consultant/Advisor: Bristol-Myers Squibb, Gilead Sciences, Kadman, Merck, Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Roche Genentech, Romark Laboratories, Vertex Pharmaceuticals. Mindie H. Nguyen: Research support: Roche Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Novartis Pharmaceuticals, Idenix Pharmaceuticals. Consulting: Bristol-Myers Squibb, Novartis Pharmaceuticals, Gilead Sciences.

Declaration of funding interests: None.

References

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