Approximately 3% of the world’s population is chronically infected with hepatitis C virus (HCV). In some southeast Asian countries the prevalence of HCV (∼6%–7%) far exceeds that seen in the United States (1.8%). The lesser known HCV genotype 6 (HCV-6) is also common in patients from southeast Asia and the surrounding regions. Most data on direct-acting antivirals (DAAs) to date have been derived from clinical trials conducted in Western countries, where HCV-6 is rare. The standard of care for patients with HCV-6 is still pegylated interferon and ribavirin. However, data are emerging for several DAA combinations.
Key points
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Hepatitis C virus (HCV) genotype 6 is geographically limited to countries in southeast Asia and the surrounding regions, where there is limited access to newer anti-HCV medications.
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Preliminary small clinical studies with direct-acting agents (ledipasvir with sofosbuvir fixed-dosed combination; grazoprevir plus elbasvir combination) have reported high sustained virologic response (SVR) rates in patients with HCV genotype 6 (>90%).
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The mainstays of therapy for these patients are currently pegylated interferon and ribavirin, which also lead to high SVR rates (approximately 80%).
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Additional studies are needed on the clinical effectiveness and tolerability of new direct-acting agents in patients with HCV-6.
Introduction
Hepatitis C virus (HCV) chronically infects more than 175 million people globally and is also one of the leading causes of liver cirrhosis and hepatocellular carcinoma worldwide. HCV genotype 6 (HCV-6) is a subtype of HCV that is largely restricted to southeast Asia, its surrounding areas, and migrants coming from this region. In addition, the prevalence of HCV is also particularly high in several countries in southeast Asia and the surrounding regions (∼6%–7% in Vietnam and Thailand) compared with a prevalence of 1.8% in the United States.
It is widely recognized that HCV genotype is a major independent predictor of treatment response, measured by sustained virologic response (SVR; defined as undetectable HCV RNA, at 12 weeks [SVR12] or 24 weeks after end of treatment, which is considered to be a surrogate of virologic cure). As mentioned previously, HCV-6 is geographically restricted to southeast Asia and the surrounding regions (China, Taiwan, Macau, Vietnam, Thailand, and Myanmar) and can often be the most common genotype in patients infected with HCV from this region, with a prevalence of approximately 30% to 40%. However, the prevalence of HCV-6 in these countries also ranges widely: 18% in Thailand, 23.6% in Hong Kong, and 49% in Myanmar. Studies of southeast Asian Americans showed HCV-6 prevalence of 41% in a sample cohort of 308 consecutive clinic-based patients. Another important difference in the epidemiology of HCV infection in this region is that most patients contracted HCV via iatrogenic exposure with conventional medical care as well as with traditional remedies such as acupuncture, cupping, tattooing, and piercing, and this is the most likely route of HCV transmission for most patients with HCV-6 infection.
The current standard of care for the treatment of patients with HCV-6 in the past decade or so has been pegylated interferon and ribavirin (PEG-IFN and RBV). Data from older studies with mostly Asian patients suggest that patients with HCV-6 respond better to PEG-IFN and RBV therapy (SVR ∼80%) compared with patients with HCV-1 (SVR ∼50%). Previously, the question of the optimal treatment duration for patients with HCV-6 treated with PEG-IFN and RBV was unanswered, because results from older studies had been inconclusive because of small sample sizes. More recently, a meta-analysis on this topic found significantly lower SVR with 24 weeks compared with 48 weeks of PEG-IFN + plus RBV in patients with HCV-6 except for those with rapid virologic response (RVR; undetectable HCV RNA at 4 weeks after initiation of treatment) who may be treated with a shorter duration of 24 weeks.
Although there has been a rapid growth of new direct-acting antiviral agents (DAAs) in recent years, and with them high rates of SVR, most of the data have been derived from clinical trials conducted in Western countries, where HCV-6 is rare.
This article summarizes the currently available data for the treatment of patients with HCV-6 ( Box 1 ).
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Patients with the following risk factors should be tested and treated for HCV (per American Association for the Study of Liver Diseases guideline).
- ○
Persons who were born between 1945 and 1965 should receive a 1-time HCV test.
- ○
Men who have sex with men who undertake risky sexual behaviors.
- ○
Persons who are actively injecting drugs or using illicit drugs via intranasal route.
- ○
Persons who are incarcerated.
- ○
Persons who received tattoos in an unregulated setting.
- ○
Women who are wishing to become pregnant and are known to be infected with HCV.
- ○
Health care workers who are infected with HCV who perform procedures that may expose patients to the risk of acquiring HCV.
- ○
Persons who received blood transfusions, blood products, or any organ transplants before 1992. In addition, persons who received blood clotting factor concentrates that were produced before 1987 should also receive HCV testing.
- ○
Persons with human immunodeficiency virus infection.
- ○
- •
If patients are suspected to have HCV infection, then they should receive testing with an anti-HCV test. If the result is positive, then current HCV infection should be confirmed with an HCV RNA test.
- ○
HCV RNA should be quantitatively measured before starting treatment to establish the baseline level of viremia.
- ○
HCV genotype should also be determined to help guide selection of the most appropriate treatment regimen.
- ○
- •
The goal of anti-HCV treatment is to induce virologic cure (SVR). SVR has been shown to reduce all-cause mortality and deleterious liver-related health outcomes (end-stage liver disease and hepatocellular carcinoma).
Introduction
Hepatitis C virus (HCV) chronically infects more than 175 million people globally and is also one of the leading causes of liver cirrhosis and hepatocellular carcinoma worldwide. HCV genotype 6 (HCV-6) is a subtype of HCV that is largely restricted to southeast Asia, its surrounding areas, and migrants coming from this region. In addition, the prevalence of HCV is also particularly high in several countries in southeast Asia and the surrounding regions (∼6%–7% in Vietnam and Thailand) compared with a prevalence of 1.8% in the United States.
It is widely recognized that HCV genotype is a major independent predictor of treatment response, measured by sustained virologic response (SVR; defined as undetectable HCV RNA, at 12 weeks [SVR12] or 24 weeks after end of treatment, which is considered to be a surrogate of virologic cure). As mentioned previously, HCV-6 is geographically restricted to southeast Asia and the surrounding regions (China, Taiwan, Macau, Vietnam, Thailand, and Myanmar) and can often be the most common genotype in patients infected with HCV from this region, with a prevalence of approximately 30% to 40%. However, the prevalence of HCV-6 in these countries also ranges widely: 18% in Thailand, 23.6% in Hong Kong, and 49% in Myanmar. Studies of southeast Asian Americans showed HCV-6 prevalence of 41% in a sample cohort of 308 consecutive clinic-based patients. Another important difference in the epidemiology of HCV infection in this region is that most patients contracted HCV via iatrogenic exposure with conventional medical care as well as with traditional remedies such as acupuncture, cupping, tattooing, and piercing, and this is the most likely route of HCV transmission for most patients with HCV-6 infection.
The current standard of care for the treatment of patients with HCV-6 in the past decade or so has been pegylated interferon and ribavirin (PEG-IFN and RBV). Data from older studies with mostly Asian patients suggest that patients with HCV-6 respond better to PEG-IFN and RBV therapy (SVR ∼80%) compared with patients with HCV-1 (SVR ∼50%). Previously, the question of the optimal treatment duration for patients with HCV-6 treated with PEG-IFN and RBV was unanswered, because results from older studies had been inconclusive because of small sample sizes. More recently, a meta-analysis on this topic found significantly lower SVR with 24 weeks compared with 48 weeks of PEG-IFN + plus RBV in patients with HCV-6 except for those with rapid virologic response (RVR; undetectable HCV RNA at 4 weeks after initiation of treatment) who may be treated with a shorter duration of 24 weeks.
Although there has been a rapid growth of new direct-acting antiviral agents (DAAs) in recent years, and with them high rates of SVR, most of the data have been derived from clinical trials conducted in Western countries, where HCV-6 is rare.
This article summarizes the currently available data for the treatment of patients with HCV-6 ( Box 1 ).
- •
Patients with the following risk factors should be tested and treated for HCV (per American Association for the Study of Liver Diseases guideline).
- ○
Persons who were born between 1945 and 1965 should receive a 1-time HCV test.
- ○
Men who have sex with men who undertake risky sexual behaviors.
- ○
Persons who are actively injecting drugs or using illicit drugs via intranasal route.
- ○
Persons who are incarcerated.
- ○
Persons who received tattoos in an unregulated setting.
- ○
Women who are wishing to become pregnant and are known to be infected with HCV.
- ○
Health care workers who are infected with HCV who perform procedures that may expose patients to the risk of acquiring HCV.
- ○
Persons who received blood transfusions, blood products, or any organ transplants before 1992. In addition, persons who received blood clotting factor concentrates that were produced before 1987 should also receive HCV testing.
- ○
Persons with human immunodeficiency virus infection.
- ○
- •
If patients are suspected to have HCV infection, then they should receive testing with an anti-HCV test. If the result is positive, then current HCV infection should be confirmed with an HCV RNA test.
- ○
HCV RNA should be quantitatively measured before starting treatment to establish the baseline level of viremia.
- ○
HCV genotype should also be determined to help guide selection of the most appropriate treatment regimen.
- ○
- •
The goal of anti-HCV treatment is to induce virologic cure (SVR). SVR has been shown to reduce all-cause mortality and deleterious liver-related health outcomes (end-stage liver disease and hepatocellular carcinoma).
Pharmacologic treatment options
Pegylated Interferon and Ribavirin
Combination therapy with PEG-IFN and RBV has been the mainstay therapy for patients with HCV-6 for more than a decade. Previous studies examining the treatment response of PEG-IFN and RBV reported a wide range of SVR rates and were unable to definitely assess the optimal treatment duration with this regimen. Results from these studies were also limited by their small sample sizes and heterogeneous study methodologies.
A recent meta-analysis on PEG-IFN and RBV in HCV-6 was conducted to assess the effectiveness and optimal duration (48 vs 24 weeks) with this treatment regimen. The meta-analysis included 13 studies (10 observational studies and 3 randomized controlled trials) with a total of 640 patients with HCV-6. The investigators observed a pooled overall SVR estimate of 77% (95% confidence interval [CI], 70%–83%), which suggested that patients with HCV-6 generally have a more favorable treatment response compared with historical results with PEG-IFN and RBV combination for other genotypes, such as genotypes 1 and 4. This favorable treatment response could partly be explained by the single-polynucleotide polymorphisms near the gene IL-28B on chromosome 19 that influences interferon (IFN) sensitivity and thus SVR rates in patients treated with IFN-based therapies. The more treatment-favorable IL-28B polymorphism (CC genotype) has been shown to be selectively distributed by geographic region and is more common in areas with a high prevalence of HCV-6.
Subgroup analysis of 4 studies that had data available for direct comparison of SVR in patients with HCV-6 treated for 48 weeks versus 24 weeks in the meta-analysis mentioned earlier (149 patients treated for 48 weeks and 112 patients treated for 24 weeks) observed pooled SVR estimates of 74% and 59% in patients treated with PEG-IFN for 48 weeks and 24 weeks, respectively. This difference in SVR rates was statistically significant with an odds ratio (OR) of 1.86 (CI, 1.08–3.21; P = .026) favoring the 48-week treatment course. In a separate subgroup analysis inclusive of 2 studies with direct comparison of patients with RVR and SVR data treated for 48 versus 24 weeks, there was no statistically significant difference in treatment response rates (85.5% vs 77.6%, respectively; OR, 1.74; CI, 0.65–4.64; P = .27). Data from this meta-analysis suggest that patients with PEG-IFN and RBV should be treated for 48 weeks, whereas those who achieve RVR may be treated for a shorter duration. Preliminary results from a more recent randomized controlled trial in patients with HCV-6 with RVR treated for 24 versus 48 weeks with PEG-IFN and RBV further support the observation that there is no significant difference in treatment response rates if patients are treated for 24 versus 48 weeks if they have RVR.
Treatment with PEG-IFN and RBV combination has also been shown to be safe in patients with genotype 6 (GT6) and the side effect profile in GT6 seems to be similar to what has been reported in landmark trials for HCV genotypes 1 to 3.
Telaprevir-based or Boceprevir-based Regimens
The first-generation DAAs were the NS3/4A protease inhibitors boceprevir (Victrelis, Merck, Kenilworth, NJ) and telaprevir (Incivek, Vertex Pharmaceuticals, Boston, MA). Triple therapy with these protease inhibitors was highly potent with a low to intermediate barrier to resistance, and produced high rates of SVR compared with dual IFN-based therapies. In 2011, they were approved for the treatment of HCV in combination with PEG-IFN and RBV but subsequently fell out of favor in the United States because of poor tolerability and the introduction of newer DAAs/second-generation protease inhibitors with fewer side effects, easier dosing schedules, and greater efficacy.
Sofosbuvir
Sofosbuvir (SOF; GS-7977, Sovaldi, Gilead Sciences Inc, Foster City, CA) is a uridine nucleotide analogue that selectively inhibits HCV NS5B polymerase and has been shown to have intermediate to high potency, pangenotypic coverage, and a high resistance barrier. In the NEUTRINO study, which was an open-label, single-arm, phase III trial, 327 treatment-naive patients with genotypes 1 and 4 to 6 were treated with a 12-week regimen of SOF 400 mg orally daily plus PEG-IFN-2a 180 μg subcutaneously weekly and RBV 1000 to 1200 mg orally daily. Only 6 patients in this study had HV-6 but all 6 achieved SVR12 (undetectable HCV RNA by polymerase chain reaction [PCR] 12 weeks after end of therapy) and the adverse events in these patients were similar to those seen with PEG-IFN and RBV therapy.
In the ATOMIC trial, which was a separate open-label, randomized, multicenter phase II trial, there were 5 patients with HCV-6 who were assigned to 24 weeks of SOF (400 mg) plus PEG-IFN (180 μg weekly) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [≥75 kg]). All 5 patients achieved SVR (either at posttreatment week 12 or posttreatment week 24). Adverse event profiles for patients with HCV-6 were not available, but the investigators noted that, for the cohort, the most common adverse events were those typically seen with PEG-IFN and RBV: fatigue, headache, and nausea.
To date, there have been no clinical trials evaluating the treatment and tolerability of SOF plus RBV as a combination therapy in patients with HCV-6. The only available data are from a retrospective study by Vu and colleagues that reported treatment and safety data on patients with SMV-based and SOF-based treatments. A total of 5 patients with HCV-6 were treated with SOF plus weight-based RBV for either 12 or 24 weeks. SVR12 data were not yet available for these patients.
Although there are currently no data for SOF and weight-based RBV plus weekly PEG-IFN for 12 weeks in treatment-experienced patients, the American Association for the Study of Liver Diseases (AASLD) recommends that the same regimen can be used for treatment-experienced patients with HCV-6 infection in whom prior treatment has failed and who are IFN eligible.
In 2014, phase III trial of a new DAA combination with SOF plus GS-5816 for chronic hepatitis C genotypes 1 to 6 was launched, with results expected to be available in late 2015 to early 2016. GS-5816 is a pangenotypic NS5A inhibitor with picomolar potency against HCV genotypes 1 to 6. SOF plus GS-5816 was previously evaluated in an open-label, phase II trial in treatment-naive patients with HCV genotypes 1 to 6. Patients were assigned to 12 weeks of treatment with SOF (400 mg) plus GS-5816 (25 mg) or 12 weeks of treatment with SOF (400 mg) plus GS-5816 (100 mg). All patients were treatment naive and none had cirrhosis. No RBV was administered in this trial. There were a total of 154 patients enrolled in the study, with 9 patients with HCV-6: 4 were assigned to SOF plus GS-5816 25 mg and 5 were assigned to SOF plus GS-5816,100 mg. All 9 patients from both treatment groups achieved SVR12. Adverse event profiles for patients with HCV-6 were not analyzed separately but the treatment was well tolerated by the overall study patient population.
Simeprevir
Simeprevir (SMV; TMC435, Olysio, Janssen Therapeutics, Titusville, NJ) is a second-generation NS3/4A protease inhibitor that was shown in a phase IIa proof-of-concept trial to have potent activity in patients with genotypes 4, 5, and 6 and with higher barriers to resistance compared with the first-generation protease inhibitors. Although this phase II trial showed potent activity with SMV in patients with GT6, this medication was administered as a monotherapy, thus limiting the conclusion of these results. Since that small phase II study and the ensuing phase III clinical trials, SMV has been approved to be coadministered with SOF in the United States for the treatment of patients with HCV-1. However, there have been limited treatment and tolerability data with this regimen in patients with HCV-6, with the only study to investigate this combination therapy a retrospective study by Vu and colleagues. There were 3 patients who were treated with SMV plus SOF combination. RBV was not used in these patients, because they had severe renal insufficiency. Of these 3 patients, 2 had available SVR12 with both achieving SVR12. At present, the combination of SMV plus SOF has not received US Food and Drug Administration (FDA) approval in the United States for the treatment of HCV genotypes none-1, including HCV-6.
Daclatasvir
Daclatasvir (DCV; Daklinza, BMS-790052, Bristol-Myers Squibb, New York, NY) is a pangenotypic NS5A inhibitor that is given as a 60-mg once-daily dosing in combination with other DAAs and has been shown to be effective in patients with non-GT6. At present, clinical data on DCV-based regimens in patients with HCV-6 are limited.
Ledipasvir
Ledipasvir (LDV; GS-5885, Gilead Sciences Inc, Foster City, CA) is a once-daily, oral, 90-mg NS5A inhibitor. A small, 2-center, open-label study ( NCT01826981 ) investigated the safety and in vivo efficacy of LDV plus SOF in a fixed-dose combination pill (also known as Harvoni) for 12 weeks in treatment-naive and treatment-experienced patients with HCV-6 infection. The study include 25 patients, most of whom were treatment naive (92%) and Asian (88%) and included 7 different subtypes (32%, 6a; 24%, 6e; 12%, 6l; 8%, 6m; 12%, 6p; 8%, 6q; 4%, 6r). Only 2 patients (8%) had cirrhosis. The SVR12 rate was 96% (n = 24 out of 25), and the 1 patient who experienced relapse was discontinued from treatment at week 8 because of active illicit drug use. No patient discontinued treatment because of adverse events and the treatment was well tolerated ( Table 1 ).
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