Showing posts with label Daklinza(Daclatasvir). Show all posts
Showing posts with label Daklinza(Daclatasvir). Show all posts

Friday, April 28, 2017

China FDA Approves Daklinza® (daclatasvir) in Combination with Sunvepra® (asunaprevir) for Chronic Hepatitis C

Fox News
China Approves Bristol-Myers Squibb's Dual-Drug Hepatitis C Treatment

Press Release
China FDA Approves Country’s First All-Oral Regimen for Chronic Hepatitis C, Daklinza® (daclatasvir) in Combination with Sunvepra® (asunaprevir)

Daklinza and Sunvepra combination approved for genotype 1b, the most common chronic hepatitis C (HCV) genotype in China; combination has a 91-99% cure rate
Daklinza also approved in China for use in combination with other agents, including sofosbuvir, for HCV genotypes 1-6

PRINCETON, N.J.--()--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the China Food and Drug Administration (CFDA) has approved a direct-acting antiviral regimen comprised of Daklinza® (daclatasvir) and Sunvepra® (asunaprevir), for the treatment of treatment-naive or -experienced patients, with or without compensated cirrhosis, infected with genotype 1b chronic hepatitis C virus (HCV). This is China’s first all-oral, interferon- and ribavirin-free HCV treatment regimen. In addition, Daklinza has been approved in China for combination use with other agents, including sofosbuvir, for adult patients with HCV genotypes 1-6 infection. This is the only all-oral pan-genotypic regimen recommended by China’s HCV Prevention and Treatment Guideline. Daklinza must not be administered as monotherapy. Sofosbuvir is under review by the CFDA, and is not currently licensed in China.

In more than 60 countries, Daklinza is approved as part of a regimen with either Sunvepra or sofosbuvir. In China, Daklinza-based regimens provide a shorter treatment duration (12 or 24 weeks) compared to 48 weeks of treatment with previously approved regimens. The Daklinza and Sunvepra regimen is already approved by regulatory authorities in multiple countries across the Asia Pacific, Latin America, and Eastern Europe regions. Sunvepra is not approved in the United States.
“The burden of HCV in China is extremely high, and now for the first time, we have an all-oral treatment option in the combination of Daklinza and Sunvepra, which is a significant step forward for patients and doctors alike,” said Hui Zhuang, a professor at the Beijing University Medical School and a member of the Chinese Academy of Engineering. “This new option helps to address many of the unmet needs for our HCV genotype 1b patients, and is also included in the latest edition of China’s HCV Prevention and Treatment Guideline.”
The approval is based primarily upon results of the first completed Phase 3 036 trial of the Daklinza and Sunvepra regimen for HCV among Chinese patients, which was published in the November 2016 issue of the Journal of Gastroenterology and Hepatology. In the trial, 91% (145/159) of genotype 1b patients who had been previously interferon-ineligible or interferon-intolerant achieved sustained virologic response (“SVR”, or cure) at post-treatment week 24. The cure rate was higher, at 99%, in patients without baseline NS5A resistance-associated variants (RAVs; L31M or Y93H; n=137/139).
As detailed in the published Phase 3 trial, one death (0.6%), five on-treatment serious adverse events (3%), and three grade 4 laboratory abnormalities (2%) occurred on-treatment; none were considered related to study drugs. Two patients (1%) discontinued due to adverse events (AEs). The most common grade 1–4 on-treatment AEs (>5% of patients) were platelet count decrease (14, 9%), upper respiratory tract infection (13, 8%), ALT increase (a diagnostic indication of liver disease or damage) (11, 7%), neutrophil count decrease (11, 7%), monocyte (large white blood cell) count decrease (10, 6%), white blood cell count decrease (10, 6%), thrombocytopenia (decrease in the number of platelets in the blood) (10, 6%), and pruritus (itchiness) (9, 6%); most were mild or moderate in intensity. Treatment was generally well-tolerated regardless of cirrhosis status.
“We are proud to build on our legacy, infrastructure and experience in treating viral hepatitis throughout Asia by bringing Daklinza-based regimens to patients in China,” said Murdo Gordon, executive vice president and chief commercial officer, Bristol-Myers Squibb. “Beginning with our efforts to treat chronic hepatitis B, Bristol-Myers Squibb has been committed to combating viral hepatitis in China for over a decade.”

HCV represents a significant public health burden in China and is now the fourth most commonly reported infectious disease countrywide, with an estimated 10 million people currently living with the disease. Until now, standard of care in China has been interferon- and ribavirin-containing regimens which have left some patient groups with unmet needs. The cure rate for interferon- and ribavirin- containing regimens varies in a number of recent Chinese studies. In CCgenos, a real-world observation study, the cure rate for interferon- and ribavirin- containing regimens among GT-1b naïve patients is 62.4%.
Karl Lintel, MD, President of Bristol-Myers Squibb (China) Investment Co. Ltd and the Sino-American Shanghai Squibb Pharmaceutical Co., commented, “Today’s approval of Daklinza and Sunvepra is great news for patients in China, as we continue the global fight against chronic hepatitis C. This milestone is testament to our ongoing collaboration with multiple stakeholders, and aligning with government policies to provide continuing support to HCV patients at the community level.”
Bristol-Myers Squibb is committed to working with stakeholders to seek timely reimbursement for Daklinza and Sunvepra at the national and provincial levels, to ensure patients have access to these important products.
About the 036 Clinical Trial
In the multi-center Asian study, interferon-ineligible and -intolerant patients with genotype 1b infection received Daklinza 60 mg tablets once-daily plus Sunvepra 100 mg soft capsules twice-daily for 24 weeks. Of the 159 patients enrolled, 127 were from mainland China. The primary endpoint was SVR at post-treatment Week 24 (SVR24).
In the overall study population, the SVR24 was 91% (145/159) and was similarly high in cirrhotic patients (47/52, 90%). SVR24 rates were higher (137/139) [99%]) in patients without baseline NS5A RAVs (L31M or Y93H), and lower in patients with baseline NS5A RAVs (8/19 [42%]).
Prevalence of baseline NS5A RAVs was 12% (19/159) overall, and 8% in mainland China patients (10/127). HCV NS5A RAVs exist naturally (albeit in lower prevalence vs wildtype) and can emerge after virologic response failure. Screening for the presence of specific NS5A mutations can help physicians determine the most suitable patients for treatment by identifying those most likely to achieve cure with an NS5A-containing regimen.
Data from other studies conducted outside of China investigating Daklinza in combination with sofosbuvir were also considered as part of the approval.
About the 114 Clinical Trial  
In a multi-center study, treatment-naive patients with genotype 1b infection received Daklinza 60 mg tablets once-daily plus Sunvepra 100 mg soft capsule twice-daily for 24 weeks. Of the total 206 patients, 161 were from mainland China. Patients were randomized 3:1 into two treatment arms: an immediate Daklinza and Sunvepra treatment group (n=155) or a placebo-deferred Daklinza and Sunvepra treatment group (n=52). The primary endpoint was SVR at post-treatment Week 12 (SVR12) in the immediate treatment arm, for comparison with the historical SVR rate achieved with pegIFN/RBV (70%).
The SVR12 rate was 92% in treatment-naive patients with HCV genotype 1b infection in the immediate treatment arm. Baseline NS5A-L31 or Y93H polymorphisms were present in 11% (17/154) of these patients. The SVR12 rate was 96% (132/137) in patients without these baseline polymorphisms; 89% (17/19) with cirrhosis, 97% (115/118) without cirrhosis.
Discontinuations due to AEs were infrequent (1%). The most common AEs (any grade, ≥5%) in the overall population were ALT increase, upper respiratory tract infection, hypertension, AST elevation, INR elevation, blood bilirubin elevation, and fatigue.
Bristol-Myers Squibb’s Leadership in Viral Hepatitis
Bristol-Myers Squibb’s heritage in virology in China began with Baraclude® (entecavir), a market-leading oral treatment for patients suffering with chronic hepatitis B virus (CHBV). Baraclude is indicated in China for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum alanine aminotransferase (ALT) or histologically active disease. Since its approval in China in 2005, Bristol-Myers Squibb has worked to not only provide access to Baraclude, but also to coordinate with government, local hospitals and physicians, and NGOs to raise the standard of care and improve the quality of life and survival of patients with HBV. In China, more than 1 million patients have been treated with Baraclude, and Asia has accounted for more than two-thirds of all Baraclude prescriptions.
Since 2002, the Bristol-Myers Squibb Foundation also has been leading efforts at the community level in Asia in HBV and HCV awareness, destigmatization, prevention, and care through the Delivering Hope program. The multi-pronged program includes a variety of disease education and vaccination efforts, including prevention of the most common means of transmission, from mother to child. It also includes capacity building, and training in partnership with local NGOs, governments and healthcare workers. In China alone, more than 8 million people at high risk of hepatitis infection across 28 provinces have benefitted from these programs over the past decade. The Foundation has committed more than $9.6 million (U.S.) in grants to a diverse group of organizations for programs targeting specific populations.
About Daclatasvir
Daclatasvir, marketed as Daklinza, is a NS5A replication complex inhibitor which targets the NS5A protein by directly disrupting its normal function. The NS5A protein plays essential roles in the HCV viral life cycle, including viral RNA replication and virion (viral particle) assembly. Daklinza is approved by the U.S. Food and Drug Administration (FDA) for use with sofosbuvir, with or without ribavirin, for the treatment of patients with HCV genotype 1 or genotype 3 infection. Sustained virologic response (SVR12) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks. Daklinza is approved by the European Medicines Agency (EMA) for patients with HCV genotypes 1, 3, or 4.
Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with Daklinza. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate management for HBV infection as clinically indicated. Please see full Important Safety Information below for more details.  

About Asunaprevir  
Asunaprevir, marketed as Sunvepra, is an NS3 protease inhibitor, an agent that binds to the NS3 protein of the HCV virus to block its activity. The NS3/4A protease plays an essential role in the assembly of the viral replication complex. Sunvepra is approved in 17 countries around the world, including in the Asia Pacific, Latin America, and Eastern Europe regions; Sunvepra is not approved in the United States. Sunvepra is approved as part of a regimen with Daklinza for the treatment of HCV genotype 1b infection in adult patients. For patients receiving Sunvepra-containing regimens, frequent monitoring of liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and bilirubin is required until completion of therapy.

Bristol-Myers Squibb in HCV  
Bristol-Myers Squibb is focused on helping to eradicate hepatitis C around the world, with a primary emphasis on difficult-to-treat patients, including those millions in countries where population-based HCV solutions remain a high unmet need.
In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic hepatitis C. Since then, daclatasvir-based regimens have been approved in more than 60 countries across North, Central and South America, Europe, the Middle East and the Asia-Pacific region.
U.S. Indication and Important Safety Information - Daklinza™ (daclatasvir)
Daklinza™ (daclatasvir) is indicated for use with sofosbuvir, with or without ribavirin, for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1 or genotype 3 infection.
Limitations of Use:
  • Sustained virologic response (SVR12) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.
  • Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with Daklinza. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate management for HBV infection as clinically indicated.
  • When used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen; refer to the respective prescribing information.
  • Drugs contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to: phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).
  • Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV (additional information): HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation may be increased in these patients.
  • Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.
  • Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
    • Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.3 of the prescribing information.
    • Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.
    • Bradycardia generally resolved after discontinuation of HCV treatment.
  • Risks Associated with Ribavirin Combination Treatment: If ribavirin is used as part of the regimen, the warnings and precautions for ribavirin, particularly the pregnancy avoidance warning, apply. See the ribavirin full prescribing information for complete information.
  • In clinical trials (ALLY 2, 3) with the Daklinza and sofosbuvir regimen, the most common adverse reactions (≥5%) were, respectively: headache (8%, 14%), fatigue (15%, 14%), nausea (9%, 8%), diarrhea (7%, 5%).
  • In clinical trials (ALLY 1) with Daklinza, in combination with sofosbuvir and ribavirin, the most common adverse reactions (≥5%) were, in the cirrhosis cohort and the post-liver transplantation cohort, respectively: headache (12%, 30%), anemia (20%, 19%), fatigue (15%, 17%), nausea (15%, 6%), rash (8%, 2%), diarrhea (3%, 6%), insomnia (3%, 6%), dizziness (0, 6%), somnolence (5%, 0).
  • CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
  • P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.
See Sections 4, 7, and 12.3 of the Daklinza Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations. Refer to the prescribing information for other agents in the regimen for drug interaction information.
  • No adequate human data are available to determine whether or not Daklinza poses a risk to pregnancy outcomes. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity.
  • If Daklinza and sofosbuvir are administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to the ribavirin prescribing information.
  • It is not known whether Daklinza is present in human milk, affects human milk production, or has effects on the breastfed infant. Daklinza was present in the milk of lactating rats. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Daklinza and any potential adverse effects on the breastfed child from Daklinza or from the underlying condition.
  • When Daklinza is administered with ribavirin, the nursing mothers’ information for ribavirin also applies to this combination regimen. Refer to the nursing mothers’ information in the ribavirin prescribing information.
Please see Full Prescribing Information, including Boxed WARNING here.
U.S. Indication and Important Safety Information - BARACLUDE® (entecavir):
BARACLUDE (entecavir) is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults and pediatric patients 2 years of age or older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
The following points should be considered when initiating therapy with BARACLUDE:
  • In adult patients, this indication is based on clinical trial data in nucleoside-inhibitor treatment-naïve and lamivudine-resistant subjects with HBeAg-positive and HBeAgnegative HBV infection and compensated liver disease and a more limited number of subjects with decompensated liver disease.
  • In pediatric patients 2 years of age and older, this indication is based on clinical trial data in nucleoside-inhibitor-treatment-naïve and in a limited number of lamivudine experienced subjects with HBeAg-positive chronic HBV infection and compensated liver disease.
  • Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
  • Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic HBV infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, alone or in combination with antiretrovirals.
Warnings and Precautions
  • Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.
  • Lactic acidosis with BARACLUDE use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. BARACLUDE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
Adverse Reactions
  • In clinical trials in patients with compensated liver disease, the most common (≥3%) adverse reactions of any severity with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. In these trials, the most common adverse reactions of moderate to severe intensity (grades 2-4) were diarrhea, dyspepsia, nausea, vomiting, fatigue, headache, dizziness, somnolence, and insomnia.
  • In the decompensated liver disease trial, the most common adverse reactions of any severity among patients treated with BARACLUDE, regardless of causality, included: peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). In this trial, 18% (18/102) of BARACLUDE patients and 20% (18/89) of adefovir patients died during the first 48 weeks of therapy. The majority of those deaths were due to liver related causes.
Drug Interactions
  • BARACLUDE (entecavir) is primarily eliminated by the kidneys; therefore coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Patients should be monitored closely when receiving BARACLUDE with other renally-eliminated drugs.
Pregnancy and Nursing Mothers
  • There are no adequate and well-controlled studies of BARACLUDE in pregnant women. BARACLUDE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • There are no studies on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
  • It is not known whether BARACLUDE is excreted into human milk; however, many drugs are excreted into breast milk. Due to the potential for serious adverse reactions in nursing infants from BARACLUDE, risks and benefits should be considered when deciding whether to discontinue breast-feeding or discontinue BARACLUDE in nursing women.
Pediatric Use
  • The adverse reactions observed in pediatric patients who received treatment with BARACLUDE were consistent with those observed in clinical trials of BARACLUDE in adults. Adverse drug reactions reported in greater than 1% of pediatric patients included abdominal pain, rash events, poor palatability (“product taste abnormal”), nausea, diarrhea, and vomiting.
  • Due to limited data, in lamivudine-experienced pediatric patients, Baraclude should be used only if the potential benefit justifies the potential risk to the child. Consideration should be given to the impact of BARACLUDE on future treatment options.
Renal Impairment
  • Dosage adjustment of BARACLUDE is recommended for patients with a creatinine clearance <50 mL/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis. There is insufficient data to recommend specific dosage adjustments of BARACLUDE in pediatric patients with renal impairment, however dosage adjustments similar to those for adults should be considered.
Liver Transplant Recipients
Renal function must be carefully monitored both before and during treatment with BARACLUDE in a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus.
Duration of Therapy
  • The optimal duration of treatment with BARACLUDE for patients with chronic HBV infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellularcarcinoma are unknown.
Additional Information
BARACLUDE is not a cure for HBV. Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
Please click here for the BARACLUDE full prescribing information, including Boxed WARNINGS.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at or follow us on LinkedIn, Twitter, YouTube and Facebook.
Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2016, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Thursday, January 26, 2017

Hepatitis C Virus Genotype 4: Genotype 1's Little Brother

2017 Jan;24(1):4-12. doi: 10.1111/jvh.12620. Epub 2016 Dec 1.

Hepatitis C Virus Genotype 4: Genotype 1's Little Brother
J. Llaneras; M. Riveiro-Barciela; M. Buti; R. Esteban

Chronic hepatitis C virus (HCV) infection affects approximately 130-150 million individuals worldwide.[1] Twenty per cent of chronic HCV infections are caused by HCV genotype 4 (GT4).[2] Infection by this genotype is more common (and highly prevalent), in the Middle East and Africa, where GT4 is responsible for more than 80% of HCV infections. In some Mediterranean European countries, especially Italy, France, Greece and Spain, the prevalence of GT4 has increased, accounting for 10%-20% of HCV infections. This genotype is usually seen in intravenous drugs users, HCV/HIV co-infected patients and immigrants from Africa or the Middle East.[3, 4] The prevalence of this infection in the United States is estimated at around 1%.[5]

In the last 5 years, HCV treatment has undergone a major change due to emergence of the new direct-acting antiviral (DAA) agents. Various therapeutic strategies have been designed to treat several HCV genotypes with these drugs.

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recently approved several drugs for the treatment of chronic HCV GT4 infection. The classical therapies for GT4, such as pegylated alpha interferon 2a or 2b (PegIFN) and ribavirin (RBV), are giving way to the new DAA agents. The following combinations have been approved for GT4 therapy: sofosbuvir (SOF), an NS5B polymerase inhibitor[6] plus ribavirin; sofosbuvir plus simeprevir (SMV), an NS3/4A protease inhibitor[7]; sofosbuvir plus daclatasvir (DCV), an NS5A protease inhibitor[8]; ombitasvir (OBV), an NS5A protein inhibitor, plus paritaprevir, another NS3/4A protease inhibitor, boosted with ritonavir (PTV/r)[9]; the fixed-dose combination of sofosbuvir with ledipasvir (LDV), an NS5A protease inhibitor[10]; the fixed-dose combination of elbasvir (EBR), an NS5A inhibitor, and grazoprevir (GZR), an NS3/4A protease inhibitor[11]; and sofosbuvir with velpatasvir (VEL), an NS5A protein inhibitor.[12]

As compared with HCV genotype 1 (GT1), few trials have been performed in GT4 patients, and the samples studied are smaller. All the various DAA combinations have demonstrated effectiveness and safety in the treatment of patients with GT4 infection. However, the AASLD and EASL guidelines do not recommended them all, and rating of the evidence differs because of the type of studies performed, the safety profiles reported, drug–drug interactions, the availability across different countries and the cost of treatment.[13, 14] As in other HCV genotypes, the new DAA agents have led to improvements in the efficacy and safety of treatment in GT4 and have displaced PegIFN combined therapies to a secondary position (Tables 1 and 2).

Table 1. EASL recommended therapies for chronic HCV gentoype 4[13]
RecommendationRegimen and daily dosingDuration (weeks)
  1. DCV, daclatasvir; LDV, ledipasvir; OBV, ombitasvir; PTR/r, paritaprevir/ritonavir; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir.
  2. a Patients with compensated cirrhosis with contraindications to the use of ribavirin on treatment should receive the fixed-dose combination of sofosbuvir and ledipasvir for 24 weeks without ribavirin.
IFN-free regimens in treatment-naive patients with or without cirrhosis
A1LDV/SOF (90 mg/400 mg)12
A1SOF/VEL (400 mg/100 mg)12
A1OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV12
A1EBR/GZR (50 mg/100 mg)12
A1SOF + SMV (400 mg/150 mg)12
B2SOF + DCV (400 mg/60 mg)12
IFN-free regimens in treatment-experienced patients with or without cirrhosis
B1LDV/SOF (90 mg/400 mg) + weight-based RBV12a
A1SOF/VEL (400 mg/100 mg)12
A1OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV24
B1SOF + SMV (400 mg/150 mg) + weight-based RBV12a
B2SOF + DCV (400 mg/60 mg) + weight-based12a

Table 2. American Association for the Study of Liver Diseases (AASLD) recommended therapies for chronic hepatitis C virus (HCV) genotype 4

RecommendationRegimen and daily dosingDuration (weeks)
  1. a Patients with prior on-treatment virological failure should be treated with 16 weeks and adding weight-based ribavirin.
Treatment-naive or treatment-experienced with or without cirrhosis recommended regimens[14]
A1OBV/PTV/r (25/150/100 mg) + weight-based RBV12
A1SOF/VEL (400/100 mg)12
B2EBR/GZR (50/100 mg)12a
B2LDV/SOF (90/400 mg)12
This article reviews the currently available data and the new treatments under development for patients with chronic HCV GT4 infection.

2 Historical Situation
2.1 Interferon-based therapies
Four IFN-based therapies have been approved by the FDA and the European Medicines Agency (EMA). Currently, none of them are recommended by the American Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) guidelines because of the superiority of IFN-free therapies in terms of efficacy and safety.

2.1.1 Pegylated interferon plus ribavirin
The first treatment for GT4 patients was PegINF plus ribavirin (RBV), which provided a sustained virological response (SVR) rate of around 45% in treatment-naive patients receiving pegylated alpha interferon (2a or 2b) plus RBV for 24-48 weeks.[15-17] In a large real-world cohort study, PROPHESYS, 317 patients with chronic HCV GT4 infection received this regimen.[18] The overall SVR24 rate (sustained virological response at week 24) was 41%, with a lower value (27%) in patients with cirrhosis. The limitations of this therapy are the lengthy duration, adverse events associated with PegINF, and low applicability in patients with advanced liver disease.

2.1.2 Sofosbuvir plus pegylated interferon plus ribavirin
Sofosbuvir is a potent nucleotide analogue inhibitor of the HCV NS5B polymerase with activity against all HCV genotypes.[6] SOF plus PegINF and RBV for 12 weeks was evaluated in the NEUTRINO trial,[19] a phase-III study that included 28 patients infected by HCV GT4. SVR12 (sustained virological response at week 12) was achieved in 27 of the 28 patients (96%). The limitation of this regimen is that it is PegIFN-based, with all that this implies.

2.1.3 Simeprevir plus pegylated interferon plus ribavirin
Simeprevir, an NS3/4 inhibitor, is active against genotypes 1, 2 and 4.[7] The RESTORE study evaluated the efficacy and safety of SMV plus PegIFN plus RBV for 12 weeks followed by PegIFN and RBV for an additional period of 12 or 36 weeks in 107 patients HCV infected with GT4, including treatment-naïve and treatment-experienced patients.[20] Overall, 65.4% (70/107) of patients achieved SVR12, with a lower rate in treatment-experienced patients.

2.1.4 Daclatasvir plus pegylated interferon plus ribavirin
Daclatasvir is an NS5A inhibitor with activity against all HCV genotypes.[8] In the phase-III COMMAND-4 study, 124 GT4 patients were randomized to receive DCV plus PegIFN plus RBV for 24-48 weeks or PegIFN plus RBV for 48 weeks.[21] SVR12 rates were 82% (67/82) with DCV plus PegIFN plus RBV vs 43% (18/42) with PegIFN plus RBV.
Although SVR12 rates are higher in DAA plus PegIFN regimens than in PegIFN plus RBV, DAA plus PegIFN regimens do not achieve higher SVR12 rates than the currently available IFN-free combinations, which have the additional advantages of a shorter treatment duration and fewer adverse events.

3 Interferon-Free Therapies
Direct-acting antiviral agents have brought about a revolution in the efficacy and safety of HCV treatment and have enabled treatment of more complex cases: patients with advanced liver disease or decompensated disease, those with IFN contraindications or intolerance and those unwilling to receive IFN treatment.

Among IFN-free therapies, four combinations are recommended in the new, updated AASLD guidelines[14] for treating naïve and experienced patients (with or without cirrhosis): two NS5B inhibitor plus NS5A inhibitor combinations, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir; and two NS5A inhibitor plus NS3/4 inhibitor combinations, ombitasvir/paritaprevir/ritonavir (with RBV) and elbasvir/grazoprevir. In most cases, all these combinations are used in 12-week regimens (Table 3).

Table 3. Interferon-free combination regimens with new DAA agents with activity in GT4

  1. a Fixed-dose combination.
Paritaprevir/r Ombitasvira
Grazoprevir Elbasvira

3.1 NS5B inhibitor plus NS5A inhibitor
3.1.1 Sofosbuvir/ledipasvir
The NIAID SYNERGY study, a phase-IIA trial, evaluated the combination of SOF/LDV in a cohort of 21 HCV GT4-infected patients.[22] The regimen was SOF 400 mg combined with LDV 90 mg in one pill, once daily for 12 weeks. The cohort included 13 (62%) treatment-naïve patients and eight (38%) treatment-experienced patients; three patients had moderate–severe liver fibrosis (F3 in 2 and F4 in 1). Twenty (95%) patients achieved SVR12 (100% in the protocol analysis). One patient did not complete the 12-week treatment regimen because of nonadherence. There were no treatment discontinuations due to adverse events. The most common side effects were diarrhoea, fatigue, nausea and upper respiratory tract infection. This controlled study showed that this one-pill once-daily treatment was highly effective and safe in GT4-infected patients. Further studies are needed to expand the recommendations for difficult-to-treat patients with GT4 infection.

Abergel et al.[23] evaluated SOF/LDV for 12 weeks in 44 patients infected by HCV GT4, including 10 (23%) with cirrhosis and 22 (50%) who were treatment-experienced. The overall SVR12 rate was 93%. As to NS5A resistance-associated substitutions (RASs), 22 of 27 (89%) patients with NS5A RASs and all those without RASs achieved SVR12. L30R was the most prevalent NS5A resistant-associated substitution (RAS) in the cohort. NS5B RASs were not detected at baseline. Three patients relapsed within the first 4 weeks after completion of treatment. Two were treatment-experienced, and none had cirrhosis. The most common side effects were similar to those seen in other cohorts (asthenia, headache and fatigue).

3.1.2 Sofosbuvir/velpatasvir
Velpatasvir is a pangenotypic HCV NS5A inhibitor with antiviral activity against genotypes 1-6. The EMA and FDA have authorized use of the SOF 400 mg plus VEL 100 mg fixed combination in one pill daily.[12]

Sofosbuvir/velpatasvir was evaluated in ASTRAL-1, a phase-III study that enrolled 624 patients with HCV infection, including some cirrhotic and treatment-experienced patients.[24] Patients previously treated with DAA agents were excluded. Overall, 116 (19%) patients had genotype 4 infection, 121 (19%) had cirrhosis, and 423 (68%) were treatment-naïve. All patients received a 12-week regimen of SOF/VEL. SVR12 rates were 100% (116/116) in GT4-infected patients, regardless of their fibrosis status or whether they had previously received treatment. At baseline, 50 GT4-infected patients had NS5A RASs, but all achieved SVR12. No significant differences were observed in adverse event rates between the SOF/VEL regimen and placebo. The most frequent adverse effects were headache, fatigue and nasopharyngitis.

Although the GT4-infected sample size was small, this 12-week combination regimen was easy to comply with, highly effective, and safe, even in those with advanced liver fibrosis and treatment-experienced patients.

3.2 NS5A inhibitor plus NS3/4 inhibitor
3.2.1 Ombitasvir/paritaprevir/ritonavir
Ombitasvir is a NS5A inhibitor and paritaprevir a NS3/4A protease inhibitor that is coadministered with low-dose ritonavir to increase paritaprevir serum levels.[9] This combination was analysed in the multicentre phase-IIb, PEARL-I study[25] including 135 noncirrhotic GT4 patients, 86 (63.7%) of whom were treatment-naïve. Treatment-experienced patients had failed PegINF plus RBV. Treatment-naïve patients were randomly assigned to a 12-week regimen of OBV plus PTV/r with or without weight-based RBV. All treatment-experienced patients received a 12-week regimen of OBV plus PTV/r with weight-based RBV. In treatment-naïve patients, SVR12 rates were 100% (42/42) in the RBV-containing regimen and 91% (40/44) in the RBV-free regimen, with no significant differences. All treatment-experienced patients achieved SVR12 (49/49). Two patients in the treatment-naïve group with an RBV-free regimen prematurely discontinued treatment: one was lost to follow-up and the other experienced viral breakthrough at week 8 of treatment. Two other patients in the same group relapsed within 12 weeks post-treatment. All were subtype GT4d, and all had RASs at the time of failure that were not present at baseline. The predominant NS3 RAS was D168V, and the NS5A RASs were L28S or L28V. The regimen was found to be safe. The most common adverse effect was headache, but there were no adverse event-related discontinuations or dose interruptions.
The efficacy and safety of this regimen in cirrhotic patients was evaluated in the multicentre, phase-III AGATE-I study,[26] including HCV GT4-infected treatment-naïve or treatment-experienced patients with compensated cirrhosis. Patients were randomized into two arms; one received a 12-week regimen of OBV plus PTV/R with weight-based RBV once daily and the other a 16-week regimen with the same combination. Preliminary results showed SVR12 rates of 97% (57/59) in patients with the 12-week regimen vs 98% (60/61) with the 16-week regimen. One patient receiving the 12-week regimen who did not achieve SVR12 had discontinued treatment on day 1. The other was a man with HCV subtype GT4a and a previous null response to PegINF plus RBV. At baseline, he had the P58L NS5A RAS and no NS3 RASs. At failure, he showed newly emergent NS5A RASs: L28M and Y93H. Thirty-six patients in the AGATE-I cohort had RASs at baseline, and all but one achieved SVR12. In the 16-week regimen arm, SVR12 results could not be reported for one patient because of missing data. This combination was well tolerated, with no discontinuations due to adverse events. The most important events recorded were asthenia, fatigue, headache and anaemia, which were more common in the lengthier, 16-week arm.

AGATE-II is a phase-III trial carried out in Egypt, evaluating OBV plus PTV/r with RBV for GT4-infected patients, including those with compensated cirrhosis.[27] In total, 160 patients were enrolled, 100 noncirrhotic and 60 compensated cirrhotic patients. Half were treatment-experienced (61% prior null responders, 24% prior relapsers and 15% partial responders). Noncirrhotic patients received co-formulated OBV plus PTV/R once daily plus weight-based RBV for 12 weeks. Patients with compensated cirrhosis were randomized into two arms with the same regimen for 12 weeks and 24 weeks, respectively. SVR12 rates were high 94% (94/100) in the noncirrhotic arm: one patient failed while on treatment, one discontinued by withdrawing consent, data were missing in another, and three patients relapsed. SVR12 in the 12-week cirrhotic arm was 97% (30/31), with a single patient failing on treatment, and SVR12 in the 24-week arm was 96% (27/29), with missing data in one patient during follow-up and one on-treatment failure. The most common adverse events were fatigue (12%) and headache (15%). Extension of therapy to 24 weeks did not provide any additional benefits in cirrhotic patients, and there were more adverse events and a higher haemoglobin decrease in this arm.

3.2.2 Elbasvir plus grazoprevir
Elbasvir is an NS5A inhibitor, active against genotypes 1, 2a, 3, 4, 5 and 6. Grazoprevir is an NS3/4 protease inhibitor that is active against HCV genotypes 1, 2, 4, 5 and 6.[11]
The C-EDGE treatment-naïve study was an international, randomized, blinded, placebo-controlled trial investigating the combination of EBR 50 mg plus GZR 100 mg in one daily pill for 12 weeks in treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, genotype 4 and genotype 6 infection.[28] The overall SVR12 rate for all genotypes was 95%. SVR12 in GT4 treatment-naive patients was 100% (18/18). RASs were analysed in GT4 patients at baseline. NS3 RASs were present in seven of 18 (39%) patients, NS5A RASs in nine of 18 (50%) patients, and both RASs (NS5A and NS3) were found in two patients. In this study, the presence of RASs did not have an impact on SVR12 in GT4 patients. The most common adverse events in the cohort were headache (17%), fatigue (16%) and nausea (9%).

The C-EDGE treatment-experienced study evaluated the efficacy of a 12-week or 16-week regimen in HCV-infected patients who had failed PegIFN treatment. Patients received a one-pill regimen of EBR plus GZR with or without weight-based RBV.[29] SVR12 rates in GT4 patients receiving the 12-week regimen without or with RBV were 78% (7/9) and 93% (14/15), respectively. SVR12 rates in those receiving the 16-week regimen without or with RBV were 60% (3/5) and 100% (8/8), respectively. Baseline RASs and subgenotypes did not seem to have an impact on SVR12 rates.
Asselah et al.[30] reported data from phase-II and phase-III studies including a total of 103 GT4-infected patients treated with EBR/GZR. Sixty-six treatment-naïve patients were enrolled to receive EBR/GZR for 12 weeks and another 10 patients received the same regimen plus weight-based RBV for 12 weeks. Ninety-six (54/56) patients achieved SVR12 in the RBV-free regimen, one patient was lost to follow-up, and other relapsed. In the RBV regimen, SVR12 rates were 100% (10/10). Treatment-experienced patients were divided into four arms, 12 weeks or 16 weeks of treatment with or without weight-based RBV. SVR12 rates were higher in the 16-week regimens and RBV-associated regimens than in the 12-week regimens or RBV-free regimens. Two patients in the 12-week regimen relapsed, one in the RBV-associated regimen and the other in the RBV-free regimen. The other two patients failed on treatment in the 16-week regimen without RBV. All treatment-naive patients who had NS5A RASs at baseline achieved SVR12. In total, 81% (13/16) of treatment-experienced patients who achieved SVR12 had NS5A RASs at baseline, and 100% of treatment-experienced patients with NS3 RASs at baseline achieved SVR12.

The 12-week regimen without RBV is an attractive combination for treatment-naïve patients and PegIFN relapsers, including patients with compensated cirrhosis. In treatment-failed patients, 16-week therapy duration is associated with a higher SVR12 (Table 4).

Table 4. (a) SVR12 in GT4 hepatitis C virus (HCV)-infected patients without liver cirrhosis treated with IFN-free regimens. (b) SVR12 in GT4 HCV-infected patients with liver cirrhosis treated with IFN-free regimens. (c) SVR12 in GT4 HCV-infected patients with and without liver cirrhosis treated with IFN-free regimens
Treatment regimenDuration (weeks)NoPrior HCV treatmentSVR12 rate % (no SVR/total)Virological failures (no of cases)
  1. EBR, elbasvir; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PTR/R, paritaprevir/ritonavir; RBV, ribavirin; SOF, sofosbuvir; TE, treatment-experienced patients; TN, treatment-naive patients; VEL, velpatasvir.
  2. a Regimen without ribavirin.
  3. b Regimen with ribavirin.
(a) NS5B/NS5A
SOF/VEL (ASTRAL-1)[24]1289Treatment-experienced Treatment-naive100% (89/89)
SOF/LDV (NIAID SYNERGY)[22]1214Treatment-experienced Treatment-naive93% (13/14)
SOF/LDV Abergel et al.[23]1234Treatment-experienced Treatment-naive91% (31/34)Relapsers: 3
OBV/PTV/r (PEARL-1)[25]12135Treatment-experienced Treatment-naive91% (40/44) TNaVirological breakthrough: 1 Relapsers: 2
100% (42/42) TNb
100% (49/49) TEb
OBV/PTV/r + RBV (AGATE-II)[27]12100Treatment-experienced Treatment-naive94% (94/100)Breakthrough: 1 Relapsers: 3
(b) NS5B/NS5A
SOF/VEL (ASTRAL-1)[24]1227Treatment-experienced Treatment-naive100% (27/27)
SOF/LDV (NIAID SYNERGY)[22]127Treatment-experienced Treatment-naive100% (7/7)
SOF/LDV Abergel et al.[23]1210Treatment-experienced Treatment-naive100% (10/10)
OBV/PTV/r + RBV (AGATE-I)[26]12
97% (57/59) 12 weeks
98% (60/61) 16 weeks
Virological breakthrough: 1
OBV/PTV/r + RBV (AGATE-II)[27]12
97% (30/31) 12 weeks
96% (27/29) 24 weeks
Virological breakthrough: 2
(c) NS5A/NS3/4
GZR/EBR (C-EDGE TN)[28]1218Treatment-naive100% (18/18)
37Treatment-experienced78% (7/9) 12 weeksa
93% (14/15) 12 weeksb
60% (3/5) 16 weeksa
100% (8/8) 16 weeksb
GZR/EBR Asselah et al.[30]12
103Treatment-experienced Treatment-naiveTN
96% (54/56) 12 weeksa
100% (10/10) 12 weeksb
78% (7/9) 12 weeksa
93% (14/15) 12 weeksb
66% (3/5) 16 weeksa
100% (8/8) 16 weeksb
Relapsers: 3 Virological breakthrough: 2

3.3 Other interferon-free regimens accepted for treating HCV GT4 infection
3.3.1 Sofosbuvir plus ribavirin
Sofosbuvir plus RBV was the first IFN-free therapy used for GT4 infection, but it is no longer recommended. In a phase-II study, 60 patients of Egyptian ancestry with chronic HCV GT4 infection received a combination of SOF plus RBV.[31] Half of the patients had been previously treated. Patients were randomly allotted 1:1 to receive SOF 400 mg and weight-based RBV in both groups, but with treatment durations of either 12 or 24 weeks. SVR12 was achieved in 68% of patients in the 12-week group and 93% in the 24-week group. The most common adverse events were headache, insomnia and fatigue. A larger number of adverse events were reported in the 24-week group due to the longer treatment duration. This study had a limited sample, and it included only a few difficult-to-treat patients.

Another trial carried out in Egypt analysed the efficacy and safety of the same combination in 103 patients,[32] 52% treatment-experienced and 17% with cirrhosis at baseline. Patients were randomly assigned to one of two arms: SOF 400 mg and a weight-based daily dose of RBV for 12 or 24 days. SVR12 was 90% in the 24-week group and 77% in the 12-week group. Patients with cirrhosis had lower SVR12 rates than those without cirrhosis in both arms.
Despite the favourable SVR12 rates at 24 weeks, this combination is suboptimal compared with combinations including two DAAs, which allow shorter duration and show fewer associated side effects, particularly in patients with cirrhosis.

3.3.2 Sofosbuvir plus simeprevir
PLUTO is a multicentre Spanish study including 40 patients with HCV GT4 infection.[33] This single-arm study evaluated the efficacy and safety of a 12-week regimen of SOF 400 mg plus SMV 150 mg daily. All patients achieved SVR12 regardless of their baseline characteristics (18% cirrhosis and 68% treatment-experienced). Adverse events occurred in 50%; all were grade 1 and grade 2. The most common adverse event was headache (20%).

The preliminary efficacy results of the phase-IIa OSIRIS study are in line with those seen in the PLUTO study.[34] OSIRIS is being conducted in Egypt and includes 63 treatment-naïve or experienced patients with and without cirrhosis. All have HCV GT4 infection and are under treatment with SMV 150 mg plus SOF 400 mg daily. High SVR4 rates (95%-100%) have been seen with 12 weeks of treatment regardless of the prior PegIFN plus RBV response or cirrhosis stage. The initial safety data show no discontinuations due to adverse events, and no grade 3 or 4 treatment-related adverse events. The study remains open pending SVR12.

The SOF plus SMV regimen has also been evaluated in the real world. In the French HEPATHER cohort, 34 HCV GT4 patients (82% with compensated cirrhosis and 73% treatment-experienced) were treated with SOF 400 mg plus SMV for 12 or 24 weeks with or without RBV.[35] SVR12 was attained in all patients receiving RBV in their regimen. In a study conducted in the Netherlands, HCV GT4-infected patients were treated with SOF plus SMV (with or without RBV) for 12 weeks. Treatment-naive and treatment-experienced patients were included, and SVR12 was achieved in 49 of 53 patients (92%).[36]

Regarding these results, SOF plus SMV would be a combination option for HCV GT4 infected patients. RBV addition could be considered in treatment-experienced patients.

3.3.3 Sofosbuvir plus daclatasvir
The ATU study investigated a French cohort including 215 patients with HCV GT4 infection and characteristics associated with a low response to treatment, such as moderate liver fibrosis, extrahepatic manifestations, recurrence following liver transplantation and placement on the liver or kidney transplant lists.[37] Among the total, 110 (52%) patients were treated with a 24-week regimen including SOF 400 mg and DCV 30 mg daily, and 63 (30%) patients received the same regimen for 12 weeks. RBV was added in eight patients in the 12-week regimen group and in 31 patients receiving the 24-week regimen. The overall SRV12 rate in HCV GT4 patients was around 91%. SVR12 in patients with cirrhosis (including decompensated cirrhosis) was 90%. The 12-week regimen group showed the highest number of treatment failures. This is a safe regimen with few discontinuations (1%), and the most common adverse event was asthenia in 10% of patients.

4 Treatment of Decompensated Cirrhosis
There are few available studies using the new DAA agents in GT4-infected patients with decompensated cirrhosis. The phase-II SOLAR-I study enrolled GT1- and GT4-infected patients with cirrhosis and moderately or severely impaired liver function, and liver transplant recipients with or without cirrhosis and mild, moderate or severe liver impairment, or fibrosing cholestatic hepatitis.[38] Patients were randomized into two arms to receive 12 or 24 weeks of LDV/SOF plus RBV, respectively. In total, 337 patients were enrolled, and 1% (4/337) had HCV GT4. Overall SVR12 rates in patients with moderate hepatic impairment were 87% in the 12-week regimen and 88% in the 24-week regimen. In liver transplant recipients, SVR12 was lower in those in Child–Turcotte–Pugh class C, with 60% and 75% in the 12- and 24-week regimens, respectively, compared noncirrhotic transplant recipients, with SVR12 rates of 96% and 98%, respectively. Treatment had to be discontinued prematurely in 4% patients because of adverse events. Ten patients died, mainly from complications related to hepatic decompensation. LDV/SOF plus weight-based RBV was associated with high SVR12 rates and good tolerance in decompensated and severe liver impairment, but there were only four GT4 patients in the cohort.

SOLAR-II was a multicentre study that extended data on the LDV/SOF plus RBV regimen in GT4 decompensated cirrhotic patients.[39] In total, 333 patients with advanced liver impairment were enrolled, 37 of whom (11%) were HCV GT4. LDV/SOF plus weight-based RBV were administered in 12- or 24-week regimens. SVR12 rates in GT4 were 78% (14/18) in the group receiving a 12-week regimen and 94% (16/17) in those treated for 24 weeks. The discontinuation rates were similar to those of SOLAR-I. Seventeen patients died due to complications of hepatic decompensation.
The phase-III study, ASTRAL-4, enrolled treatment-naive and treatment-experienced patients with decompensated cirrhosis infected with HCV genotypes 1 (78%), 2 (4%), 3 (15%), 4 (3%) and 6 (<1%).[40] Patients were randomized at a 1:1:1 ratio to receive SOF/VEL once daily for 12 weeks, SOF plus RBV once daily for 12 weeks or SOF/VEL once daily for 24 weeks. Overall SVR12 rates were 83% in patients receiving 12 weeks SOF/VEL (100%, 4/4 in GT4 patients), 94% in those receiving SOF/VEL plus RBV (100%, 2/2 in GT4 patients) and 86% in those with 24 weeks of SOF/VEL (100%, 2/2 in GT4 patients). All GT4-infected patients achieved SVR12. There were no significant differences in SVR rates between the three groups. NS5A RASs were detected in 72 of 255 patients (28%). Of these 72 patients, 64 (89%) achieved SVR12 compared with 169 of 183 patients (92%) without RASs. Serious adverse events were observed in approximately 16%-18% of patients in each group.

Real-life data are scarce in GT4-infected patients with decompensated cirrhosis. Welzel et al.[41] reported on 49 decompensated HCV patients receiving SOF plus DCV with or without RBV. The overall SVR12 was 92% (45/49). Three patients had GT4 infection, and all achieved SVR12. According to the Child–Turcotte–Pugh scoring system for cirrhosis, 15 were classified as B and eight as C. SVR12 rates in these patients were 80% and 88%, respectively. Please note the low representation of genotype 4 in this cohort.
The benefits of this treatment are unclear, particularly in patients with an advanced Child–Turcotte–Pugh score, because viral clearance seems to have little impact on liver impairment or liver complications.

5 HCV/HIV Co-Infected Patients
The efficacy and safety of treatment for HCV GT4 infection in the HIV co-infected population has been evaluated in a few studies.

ION-4 is a multicentre study involving patients co-infected with HIV-1 and HCV genotypes 1 or 4.[42] All patients received an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine or raltegravir. In addition, all received LDV 90 mg plus SOF 400 mg in a single pill once daily for 12 weeks. In total, 335 patients were enrolled, 20% had cirrhosis, and 55% had received prior HCV treatment. SVR12 was achieved in 96% of the total cohort and in all patients (8/8) with GT4 infection. SVR12 rates were similar in the various subgroups regardless of treatment experience or cirrhosis stage. There were no cases of HIV-1 virological rebound, and none of the patients discontinued treatment because of adverse events.

The ALLY-2 study analysed 203 HCV/HIV co-infected patients (three patients had GT4) receiving 12 or 8 weeks of SOF 400 mg plus DCV 60 mg, daily.[43] SVR12 rates were 97% after 12 weeks of treatment and 76% after 8 weeks. All GT4-infected patients achieved SVR12.
A subanalysis by antiretroviral regimen class reported that SVR12 was 97% and was similar across the antiretroviral regimens included.[44] SOF plus DCV is an attractive combination for HCV/HIV co-infected patients, but further data in GT4-infected patients are needed.

The phase-III C-EDGE CO-INFECTION study is a multicentre trial including HIV patients co-infected with HCV genotypes 1, 4 and 6.[45] In total, 218 patients were enrolled and all received GZR/EBR for 12 weeks. The SVR12 rate in patients with GT4 infection was 96% (27/28), with only one relapse, occurring in a noncirrhotic patient. This RBV-free combination achieved a high SVR12 in HCV/HIV co-infected patients without RBV adverse events.

There is little information on GT4 HCV/HIV co-infected patients treated with ombitasvir and paritaprevir regimens. This would likely be an effective, safe combination, as indicated in genotype 1 by the TURQUOISE-I study,[46] but additional data are needed to recommend this combination in this specific population.

6 DAA Failures
6.1 Genotype 4. Resistance-associated substitutions
Only 2% to 5% of HCV GT4 patients fail DAA treatment. Pawlosky et al. reviewed the profiles of patients who experienced treatment failure in each of the major studies using any type of combination therapy. Most of the information came from HCV GT1-infected patients and very little from HCV GT4.

The emergence of HCV RASs is determined by the genetic barrier to the drug, the fitness of the resistant viral population and blood levels of the drug. The dynamics of RASs after discontinuation of DAAs differs depending on the antiviral agent. NS3/4 protease inhibitor RASs disappear within some time after completion of treatment. However, NS5A RASs persist for years and could impact on the selection of retreatment strategies.[47]

RASs to NS5A inhibitors at baseline did not demonstrate a significant impact on SVR12 in combination regimens of SOF/LDV, SOF/VEL or SOF plus DCV, except in treatment-experienced GT1a patients, with or without cirrhosis, in whom lower SVR12 rates were observed. Very limited data are available in GT4 infection. In patients with NS5A RASs failing DAA treatment, the current recommendation is to extend treatment to 24 weeks and add RBV. This is based on the findings from small studies showing a higher SVR12.[48] Although there are no available data in GT4 infection, NS5A inhibitor resistance did not have an impact on SVR12 in GT1 patients receiving an OBV/PTV/R regimen with RBV. Similar results were found for the EBR/GZR combination, with the exception of GT1a patients and treatment-experienced GT1b patients, in whom SVR12 rates were lower. Hence, associated RBV and 16-week or 18-week duration are required in these patients. Again, no resistance data are available in GT4 for this combination. NS3 RASs at baseline do not appear have impact on SVR12.

Presence of the Q80K NS3 resistance substitution does not affect SVR12 in GT4 infection, unlike what occurs in GT1a patients, especially treatment-experienced ones.[49]
Some re-treatment strategies after failing DAAs have been explored in a small number of patients. In a recent study, 15 GT1- and GT4-infected patients who failed a DCV-based regimen (DCV plus PegIFN plus RBV, with or without asunaprevir) received SOF plus SMV without RBV for 12 weeks. Thirteen (87%) achieved SVR12, including all those with GT4 infection.[50] Further data on re-treatment of GT4 patients are needed before a strong recommendation can be established. In the meantime, one re-treatment approach could be a combination of SOF with a DAA of a different class than that previously used plus RBV, and extending therapy to 24 weeks.

7 Summary
In summary, the treatment options for HCV GT4 are now continually growing. The lower SVR rates reported in the past have been eliminated since the development of the new DAA agents. The NS5B-inhibitor, sofosbuvir, has been and remains the cornerstone of the current IFN-free therapies, achieving high SVR12 rates with a good safety profile. Combinations of NS5B inhibitors with NS5A or NS3/4 may be optimal strategies for the treatment of GT4-infected patients with compensated cirrhosis and those previously treated with PegIFN/RBV regimens. Nonetheless, other combinations without NS5B inhibitors, such as NS5A plus NS3/4-inhibitors, have shown SVR rates and safety profiles similar to those of the sofosbuvir combination. Despite the paucity of studies in HCV GT4 infection, some cohorts have provided information of promising SVR12 rates and safety profiles in special populations, such as HCV/HIV co-infected patients and patients with decompensated cirrhosis. These limited data encourage more aggressive use of DAA agents in these populations.
Unfortunately, data on re-treatment strategies for GT4-infected patients who fail IFN-free therapy are nonexistent. We need a greater representation of GT4 patients in real-life studies to provide GT4 infection with a proper identity and remove it from the shadow of GT1.

Maria Buti and Rafael Esteban have received grant for Gilead, MSD, Abbvie and BMS. Mar Riveiro-Barciela has received grant for Gilead. Jordi Llaneras has no personal interests to declare.

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