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The World Health Organization (WHO) estimates that 71 million people are living with chronic hepatitis C virus (HCV) infection worldwide. In 2015, an estimated 1.75 million new HCV infections occurred globally, but only 20% (14 million) of those were diagnosed. Only 1.1 million individuals started treatment in 2015, bringing the cumulative total to 5.5 million HCV-infected persons receiving treatment worldwide. WHO estimates that approximately 399,000 deaths occur each year from hepatitis C, most resulting from cirrhosis and hepatocellular carcinoma. Of the estimated 36.7 million persons worldwide living with human immunodeficiency virus (HIV) infection, about 2.3 million are co-infected with HCV, with liver disease being a major cause of morbidity and mortality among individuals co-infected with HIV/HCV (WHO, 2017a; WHO, 2017b). In the United States, an estimated 2.7–3.9 million persons have chronic hepatitis C infection. Recent reports estimate that ~25% of the 1.1 million persons living with HIV in the United States are co-infected with HCV. HIV/HCV co-infection more than triples the risk for liver disease, liver failure, and liver-related death compared with individuals who are not HIV-infected (CDC, 2016; CDC, 2017). Additionally, HIV/HCV co-infection increases the risk of mother-to-child transmission of HCV two- to threefold (CDC, 2016; WHO, 2017a).

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The substantial and growing burden of HCV infection has been met with critical studies on the virus and its pathogenic mechanisms, which have contributed to the successful development of safe and highly effective direct-acting antivirals (DAAs). Various ~12-week oral regimens of sofosbuvir, daclatasvir, and sofosbuvir-ledipasvir have achieved significant success rates (> 95%) in curing most genotypes of HCV for those individuals who can access and adhere to the treatment regimens (World Health Organization, 2017a, 2017b).

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The U.S. Food and Drug Administration (FDA) has approved multiple oral DAA regimens for the treatment of chronic HCV infection. Falade-Nwulia and colleagues (2017) recently conducted a systematic review of the published literature on phase 2 and 3 randomized clinical trials in adults that assessed the safety and efficacy of FDA-approved interferon-free HCV treatment regimens that included two or more DAAs administered for a minimum of 8 weeks. Their analysis included 42 English-language studies demonstrating sustained virologic response rates at a minimum of 12 weeks (SVR12) after treatment. The treatment regimens in this analysis included the following inhibitors of HCV: NS3 protease (grazoprevir, paritaprevir, and simeprevir); NS5A (daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir), and NS5B polymerase (sofosbuvir and dasabuvir). The authors also assessed the effects of ribavirin on adverse events and SVR rates. Studies included in this systematic review included patients with decompensated cirrhosis, HIV infection, renal failure, or liver transplantation.

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Overall, their analysis showed that all FDA-approved oral DAA regimens resulted in high rates of safety, efficacy, SVR, and tolerability for all HCV genotypes, with some variability due to specific patient populations and virus subtypes. The authors reported that the serious adverse events rate was <10%, the treatment discontinuation rate was <5%, and loss to follow-up rate was <10%, even in patients with cirrhosis or HIV. Of note, they reported that most of the six DAA regimens for HCV genotype 1 demonstrated SVR rates >95%.

HCV Genotype 1

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As HCV genotype 1 is the most common genotype globally, the high treatment rates are important when compared to the dismal SVR rates obtained with interferon-containing regimens that formerly were the standard of care before the advent of DAAs. One of the six regimens included in this systematic review was a once-daily single-tablet of ledipasvir and sofosbuvir for 12 weeks in HCV genotype 1 untreated patients with and without cirrhosis that resulted in a 99% SVR12 rate, with no additional benefit of extended treatment to 24 weeks or addition of ribavirin (Afdhal et al, 2014). Another study included in this systematic review, the OPTIMIST-1 clinical trial, evaluated an 8-week versus 12-week regimen of simeprevir-sofosbuvir that demonstrated that the longer treatment regimen was safe and more effective (SVR12 rate of 97%) compared with the 8-week regimen (SVR rate of 83%) in HCV genotype 1 treatment-naïve and treatment-experienced patients without cirrhosis (Kwo et al, 2016). The other four oral, once-daily, 12-week regimens for HCV genotype 1 for noncirrhotic patients assessed in the systematic review included grazoprevir-elbasvir (SVR12 rate of 92% for treatment naïve and 99–100% for treatment experienced); paritaprevir-ritonavir-ombitasvir-dasabuvir (SVR12 rates of 97–99% with ribavirin and 90–99% without ribavirin); daclatasvir-sofosbuvir (SVR12 rate of 96%); and velpatasvir-sofosbuvir (SVR12 rates of 97–99%) (Falade-Nwulia et al, 2017).

HCV Genotype 3

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HCV genotype 3 is the second most common genotype worldwide for which there are few approved DAA regimens. The systematic review of the FDA-approved regimens showed that a 12-week regimen of daclatasvir-sofosbuvir had SVR12 rates of 94–97% and velpatasvir-sofosbuvir had an SVR rate of 95% in noncirrhotic patients. The latter regimen resulted in higher SVR rates in patients with cirrhosis. Higher SVR rates were obtained in patients with compensated and decompensated cirrhosis, NS5A resistance-associated substitutions (RAS), or prior treatment experience, when treatment regimens included ribavirin or were of longer duration (Falade-Nwulia et al, 2017).

HCV Genotype 2, 4, 5, or 6

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While few patients with HCV genotype 2, 4, 5, or 6 were enrolled in the studies included in this systematic review, SVR rates >92% were seen with all regimens administered for a minimum of 12 weeks. The velpatasvir-sofosbuvir regimen for 12 weeks resulted in a 99% SVR rate for patients with genotypes 2, 4, 5, or 6 (Falade-Nwulia et al, 2017).

Ribavirin and HCV Treatment Regimens

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In the Falade-Nwulia systematic review, the addition of ribavirin to treatment regimens served to maximize SVR rates for patients with HCV genotype 1a, HCV genotype 3, cirrhosis, or prior treatment experience. In the studies assessed in this review, the number of serious adverse events and rates of treatment discontinuation are comparable for those patients on treatment regimens with or without ribavirin (Falade-Nwulia et al, 2017).

Regimens For Difficult-to-Treat Patients

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DAA regimens for patients with decompensated cirrhosis, severe chronic kidney disease, and liver transplants show similarly high SVR rates and minimal adverse events compared with regimens for patients who do not have these other conditions (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017a; Falade-Nwulia et al, 2017). For patients with cirrhosis, the treatment regimen of velpatasvir (100 mg) and sofosbuvir (400 mg) for 12 weeks demonstrated SVR rates of 97–99% in patients with any HCV genotype (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017b; Falade-Nwulia et al, 2017; Feld et al, 2015).

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Falade-Nwulia and colleagues conclude that all of the interferon-free, oral, FDA-approved DAA regimens in their systematic review are well tolerated, efficacious, and of short duration for HCV genotypes 1–6, as well as for patients previously categorized as difficult to treat (Falade-Nwulia et al, 2017).

New FDA-Approved DAA Regimens

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Several recent studies report additional safe and efficacious oral DAA regimens that result in high SVR rates for HCV-infected patients with specific HCV genotypes. Zeuzem and colleagues (2015) have demonstrated in the phase 3 C-EDGE clinical trial that a once-daily, oral, fixed-combination regimen of grazoprevir (100 mg) and elbasvir (50 mg) without interferon or ribavirin for 12 weeks was safe and efficacious. This regimen resulted in 92–99% SVR12 rates in both treatment-naïve, noncirrhotic patients, and compensated cirrhotic patients with HCV genotypes 1, 4, or 6. The overall virologic failure rate was 4%, and serious adverse events were reported in 2.8% of the study participants, although none was drug-related. This FDA-approved, 12-week, interferon-free and ribavirin-free treatment regimen is recommended for patients without baseline NS5A RAS for elbasvir by the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017c).

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A new DAA, Mavyret (glecaprevir-pibrentasvir), was recently approved by the FDA and represents the first 8-week treatment for treatment-naïve adults with HCV genotypes 1–6 without cirrhosis (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017c). This short treatment regimen is a daily fixed dose of glecaprevir (300 mg) and pibrentasvir (120 mg) for 8 weeks that was assessed in several key clinical trials:

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  • ENDURANCE-1, a phase 3 clinical trial in HCV genotype 1 treatment-naïve patients or those who failed an interferon-based regimen without cirrhosis, demonstrated a SVR12 rate of 99% (Zeuzem et al, 2016);

  • SURVEYOR-I and -II, two phase 2 clinical trials in HCV-infected patients with genotypes 1–6 without cirrhosis, resulted in SVR12 rates of 97–98% for patients with HCV genotypes 1–3 and no virologic failures, and SVR12 rates of 92–100% across all genotypes (Kwo et al, 2017);

  • ENDURANCE-3, a phase 3 clinical trial, demonstrated that this regimen resulted in a SVR12 rate of 95% in HCV genotype 3 treatment-naïve, noncirrhotic patients and was well tolerated with a safety profile similar to the standard treatment of sofosbuvir-daclatasvir (Foster et al, 2017); and

  • EXPEDITION-1, a phase 3 study, demonstrated that the regimen was safe and efficacious in untreated and previously treated HCV genotype 1, 2, 4, 5, or 6 patients with compensated cirrhosis. Serious adverse events were reported in 8% of patients, but none was deemed related to the study drugs. Fatigue and headaches were the common adverse events with this regimen. This regimen demonstrated a SVR12 rate of 99% in these patients and represented an alternative to the velpatasvir-sofosbuvir regimen (Forns et al, 2017).

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The 8-week, interferon-free and ribavirin-free treatment regimen of glecaprevir-pibrentasvir is recommended by the AASLD/IDSA (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017c) for patients without cirrhosis and 12 weeks for patients with compensated cirrhosis.

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A second new FDA-approved DAA regimen, Vosevi (sofosbuvir-velpatasvir-voxilaprevir), is the first treatment licensed for patients without cirrhosis previously treated with sofosbuvir or other HCV NS5A inhibitors (FDA, 2017). The regimen recommended by AASLD/IDSA is a daily fixed-dose combination of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) for patients of all HCV genotypes without cirrhosis for a 12-week duration who have failed NS5A inhibitor (sofosbuvir) treatment regimens (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017b). FDA approval of this regimen for patients with or without compensated cirrhosis was based on POLARIS-1 and POLARIS-4, two large phase 3 clinical trials. POLARIS-1 tested the 12-week three-DAA regimen compared with a placebo in HCV-infected patients with different genotypes who had previously received a treatment regimen including a NS5A inhibitor. The SVR12 rate for the treatment regimen was 96%. In POLARIS-4, the three-DAA regimen was compared with a regimen of sofosbuvir-velpatasvir for 12 weeks in non-NS5A inhibitor DAA-experienced patients with HCV genotype 1, 2, 3, or 4. Bourliere and colleagues (2017) reported that the SVR12 rate was 98% with the three-DAA regimen compared to 90% with the two-DAA regimen. The most common adverse reactions with this three-DAA regimen were headaches, fatigue, diarrhea, and nausea. The discontinuation rate due to adverse events was 1% or less in the active treatment groups in both studies.

Additional Notes

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WHO no longer recommends the first-generation DAAs telaprevir and boceprevir because of frequent adverse effects and less frequent cures compared with newer DAAs (World Health Organization, 2017b).

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The AASLD/IDSA site (www.hcvguidelines.org) should be consulted for the latest recommendations for treatment of HCV monoinfection.

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The FDA has issued a Drug Safety Communication concerning the risk of hepatitis B reactivation in some patients treated with DAAs for HCV infection. HBV reactivation is characterized by a rapid increase in HBV replication and results in a rapid increase in serum HBV DNA level or detectable hepatitis B surface antigen (HBsAg) in patients who previously were hepatitis B core antibody (anti-HBc) positive and HBsAg negative. Reactivation of HBV replication is often followed by hepatitis and, in severe cases, can result in an increase in bilirubin levels, hepatic failure, and death. While the cause of hepatitis B reactivation is unknown, health care providers are urged to screen all patients for evidence of current or prior HBV infection before beginning treatment with DAAs. Providers should also closely monitor patients for HBV flare-ups or reactivation using blood tests during treatment and posttreatment follow-up (FDA, 2016).

Treatment for HCV/HIV Co-Infection

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The current availability of numerous HCV DAAs provides an opportunity to successfully treat HCV infection in persons living with HIV and AIDS; however, it is critical to carefully select the appropriate DAA regimen to match with the antiretrovirals (ARVs) that the patient is also taking—and to closely monitor these co-infected patients for drug–drug interactions between oral DAAs and ARVs (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017a; Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents, 2017). Falade-Nwulia and colleagues (2017) report that patients co-infected with HCV/HIV show similar high SVR rates and minimal adverse events when on oral DAA regimens compared with patients who have HCV monoinfection.

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Wyles and colleagues (2015) reported the results of the phase 3 ALLY-2 trials that evaluated a combination of oral, daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 12 weeks in patients co-infected with HIV and HCV genotypes 1–4 who had not previously received treatment for HCV. The regimen was shown to be safe, efficacious, and well tolerated. An SVR rate of 97% was obtained across all four HCV genotypes after treatment duration of 12 weeks, compared with an SVR rate of 76% with an 8-week treatment duration. The ARVs used in this study included ritonavir-boosted darunavir, atazanavir, or lopinavir, efavirenz, nevirapine, rilpivirine, raltegravir, and dolutegravir (Wyles et al, 2015). Adjustments to dosages of ARVs are required per AASLD/IDSA recommendations (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017a).

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The results from the C-WORTHY phase 2 clinical trial demonstrated an SVR12 rate of 87% with an oral, once-daily, 12-week regimen of grazoprevir (100 mg) and elbasvir (50 mg) among previously untreated HCV genotype 1 patients with HIV. An SVR rate of 97% was reported when ribavirin was added to this DAA regimen. Mild to moderate adverse events were seen in 27% of patients, with fatigue, headache, nausea, and diarrhea being the most common adverse events reported (Sulkowski et al, 2015).

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Naggie and colleagues (2015) conducted the ION-4 clinical trial evaluating a once-daily, oral regimen of ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 weeks in patients co-infected with HIV and HCV genotype 1 or 4, including those who had previously failed DAA regimens and those with cirrhosis. The ARVs used in the study were tenofovir and emtricitabine along with efavirenz, rilpivirine, or raltegravir. The overall SVR12 rate was 96%. The most common adverse events were headache, fatigue, and diarrhea.

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Rockstroh and colleagues (2017) recently reported the safety and efficacy of glecaprevir (300 mg) and pibrentasvir (120 mg) in patients co-infected with HIV and HCV genotypes 1–6 with and without compensated cirrhosis. The EXPEDITION-2 phase 3 multicenter clinical trial evaluated this daily fixed-dose regimen for 8 weeks in patients with HCV/HIV co-infection without cirrhosis and for 12 weeks in patients with HCV/HIV co-infection with compensated cirrhosis. Study participants were either ARV treatment naïve with a CD4+ T cell count of >500/mm3 or on ART for at least 8 weeks with a CD4+ T cell count >200/mm3. The overall SVR12 rate was 98% for both the 8-week and 12-week regimens. The most common adverse events were fatigue and nausea. A total of 4 serious adverse events were reported; however, none was DAA-related. This study demonstrated that glecaprevir-pibrentasvir was well tolerated for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients co-infected with HCV/HIV. ARVs recommended with the glecaprevir-pibrentasvir regimen include raltegravir, dolutegravir, rilpivirine, tenofovir, abacavir, enfuvirtide, emtricitabine, and lamivudine (Rockstroh et al, 2017). A ritonavir-boosted protease inhibitor regimen is not recommended with this DAA regimen (American Association for The Study of Liver Diseases and Infectious Diseases Society of America, 2017a).

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As the FDA approves new DAAs, additional combinations may be possible with current ART regimens for the safe and successful treatment of patients co-infected with HCV/HIV. The AASDL/IDSA (www.hcvguidelines.org) and United States Health and Human Services Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents (aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-infection/345/hcv) sites should be consulted for the latest treatment recommendations for patients co-infected with HCV/HIV.

References

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Afdhal  N  et al: Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 370:1889, 2014.
[PubMed: 24725239]
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American Association for The Study of Liver Diseases and Infectious Diseases Society of America: Management of Unique Populations with HCV Infection. 2017a. Available at www.hcvguidelines.org/unique-populations.
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American Association for The Study of Liver Diseases and Infectious Diseases Society of America: Retreatment of Persons in Whom Prior Therapy Failed. 2017b. Available at www.hcvguidelines.org/treatment-experienced.
+
American Association for The Study of Liver Diseases and Infectious Diseases Society of America: Initial Treatment of HCV Infection. 2017c. Available at www.hcvguidelines.org/treatment-naive.
+
Bourliere  M  et al: Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 376:2134, 2017.
[PubMed: 28564569]
+
Centers for Disease Control and Prevention: Hepatitis C FAQs for Health Professionals. 2016. Available at www.cdc.gov/hepatitis/hcv/hcvfaq.htm.
[PubMed: 27308685]
+
Centers for Disease Control and Prevention: HIV and Viral Hepatitis. 2017. Available at www.cdc.gov/hiv/pdf/library/factsheets/hiv-viral-hepatitis.pdf.
+
Falade-Nwulia  O  et al: Oral direct-acting agent therapy for hepatitis C virus infection: A systematic review. Ann Intern Med 166:637, 2017.
[PubMed: 28319996]
+
Feld  JJ  et al: Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 373:2599, 2015.
[PubMed: 26571066]
+
U.S. Food and Drug Administration: FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. 2016. Available at www.fda.gov/drugs/drugsafety/ucm522932.htm.
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U.S. Food and Drug Administration: FDA Approves Vosevi for Hepatitis C. 2017. Available at www.fda.gov/newsevents/newsroom/pressannouncements/ucm567467.htm.
[PubMed: 22764848]
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Forns  X  et al: Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): A single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis 17:1062, 2017.
[PubMed: 28818546]
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Foster  GR  et al: ENDURANCE-3: Safety and efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naive HCV genotype 3-infected patients without cirrhosis. J Hepatol 66:S33, 2017.
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Kwo  P  et al: Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study. Hepatology 64:370, 2016.
[PubMed: 26799692]
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Kwo  PY  et al: Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol 67:263, 2017.
[PubMed: 28412293]
+
Naggie  S  et al: Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 373:705, 2015.
[PubMed: 26196665]
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Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents: Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. 2017. Available at aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-infection/345/hcv.
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Rockstroh  JLK  et al: Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: The EXPEDITION-2 Study. Presented at the International Liver Congress. EASL, Amsterdam, 2017. Available at www.hcvguidelines.org/references/rockstroh-2017.
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Sulkowski  M  et al: Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): A randomised, open-label phase 2 trial. Lancet 385:1087, 2015.
[PubMed: 25467560]
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World Health Organization: Global Hepatitis Report, 2017. Geneva, WHO, 2017a. Available at apps.who.int/iris/bitstream/10665/255016/1/9789241565455-eng.pdf?ua=1.
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World Health Organization: Hepatitis C Fact Sheet. Geneva, WHO, 2017b. Available at www.who.int/mediacentre/factsheets/fs164/en/.
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Wyles  DL  et al: Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 373:714, 2015.
[PubMed: 26196502]
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Zeuzem  S  et al: ENDURANCE-1: Efficacy and Safety of 8- versus 12-week Treatment with ABT-493/ABT-530 in Patients with Chronic HCV Genotype 1 Infection [Abstract 253]. Presented at the 67th Annual Meeting of the American Association for the Study of Liver diseases, Boston, 2016.
[PubMed: 29306043]
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Zeuzem  S  et al: Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: A randomized trial. Ann Intern Med 163:1, 2015.
[PubMed: 26595748]