Globally, chronic hepatitis C virus (HCV) infection has been estimated to affect 2–3% (about 170 million) of the world’s population 1. A National Health and Nutrition Examination Survey 2003–2010 analysis estimated that ∼2.7 (1.0%) million USA residents have infection with chronic HCV 2. Chronic HCV is the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and its related complications, and thus elimination of HCV significantly reduces the risk of HCC, liver failure, and death 3.
An increased prevalence of chronic HCV infection is observed with advancing age. These patients are likely to have an advanced liver disease including cirrhosis of the liver and related complications 4,5. In countries such as Japan, Taiwan, and some European countries, the prevalence of chronic hepatitis C infection is the highest in the aged population 6. According to the USA Census Bureau, by 2030, more than 20% of USA residents are projected to be aged 65 years and older. The baby boomers (born between 1945 and 1965) began turning 65 in 2011 and currently account for three-fourth of all chronic HCV infections among adults in the USA 7.
Older individuals infected with chronic HCV are historically considered a difficult to treat category with less success and more treatment failures than the younger population. The pegylated interferon (peg IFN) and ribavirin (RBV) combination therapy was associated with a high discontinuation rate in the elderly because of the longer duration of treatment and associated adverse events 8. With the recent introduction of IFN-free direct-acting antivirals (DAAs), the treatment success for chronic HCV infection has improved markedly, with the overall cure rate reaching above 90%. Even though some of the newer drug trials included aged populations, the numbers of elderly patients enrolled were limited. Although we have achieved considerable advancements in treatment with newer agents, the coadministration of RBV in combination with newer agents still exists in certain patient groups to achieve an acceptable response rate. A shorter duration of treatment with these regimens and better tolerability are expected in both younger and older populations.
We, therefore, examined the effectiveness and tolerability of newer DAAs in older patients aged older than 65 years compared with younger patients. We also evaluated the factors associated with sustained virologic response (SVR) and the tolerability of DAAs in combination with Peg IFN, RBV, or both with a shorter duration of treatment in an aged population compared with younger patients aged younger than 65 years.
Patients and methods
This retrospective cohort study protocol was approved by the institutional review board of each hospital (New York Presbyterian Brooklyn Methodist Hospital New York and Interfaith Medical Center, New York).
A total of 279 consecutive patients with chronic HCV treated with either a combination of DAAs or at least one of the newer agents in combination with IFN and RBV between January 2013 and July 2015 at two institutions were retrospectively analyzed. Thirty-nine patients were excluded from the study for various reasons including insufficient documentation of viral load during the treatment and failure to attend follow-up after the end of treatment (Fig. 1).
All the 240 patients included in this retrospective cohort study received at least eight weeks of treatment with one of the recommended combination regimens in standard doses for chronic HCV infection. Patients were divided into two groups: patients aged younger than 65 years (N=156) and those aged 65 years and older (N=84). The choice of treatment regimens used was made on the basis of the American Association of Study of Liver Disease guidelines during that period. During early 2013, treatment recommendation was triple therapy with a protease inhibitor, Peg IFN, and RBV. In the years 2014 and 2015, the rest of the regimens were used as they were approved one after the other by the Food and Drug Administration. The combination treatment regimens used were Peg IFN α-2a+RBV+sofosbuvir (SOF), SOF+RBV, ledipasvir (LDV)+SOF (Harvoni; Gilead Sciences, Foster City, California, USA), LDV+SOF+RBV (Harvoni+RBV), ombitasvir+paritaprevir+ritonavir+dasabuvir (Viekira Pak; AbbVie Inc, Illinois, North Chicago, USA), ombitasvir+paritaprevir+ritonavir+dasabuvir+RBV (Viekira Pak+RBV), and simeprevir (SPV)+sofosbuvir. Only three patients were treated with Peg IFN+RBV+telaprevir and one patient each received the Peg IFN+RBV+boceprevir, Peg IFN+RBV+Harvoni, and SPV+SOF+RBV combination (Fig. 2). The duration of the treatment period ranged from a minimum of 8 weeks (N=3, all with Harvoni) to a standard 12 weeks (N=201) or 24 weeks (N=36) depending on their status of previous treatment and cirrhosis. All patients who received the IFN-based regimen received Peg IFN at a standard dose of 180 mg subcutaneously once a week. A weight-based RBV dose was used at 1200 mg daily in two divided doses for those weighing 75 kg and 1000 mg for those weighing less than 75 kg.
Pretreatment baseline characteristics (Table 1), laboratory studies, baseline HCV viral load, treatment efficacy with the end of treatment response (ETR), and sustained virologic response at 12 weeks after the completion of treatment (SVR12) were compared between the groups. We determined the factors associated with SVR on baseline characteristics by univariate analysis. A separate analysis was carried out in patients aged older than or equal to 65 years to determine the factors associated with SVR in the elderly group. The safety and tolerability of antiviral drug regimens were assessed by reviewing the documented common or serious adverse events, treatment completion rate, and reduction in the medication dosage or discontinuation of medications.
Assessment of liver fibrosis was performed with invasive liver biopsy in some cases and noninvasive testing with a fibrosure test or a fibroscore test and the aspartate aminotransferase (AST)-to-aspartate platelet ratio index (APRI) score. Patients who had clinical, laboratory, and radiologic evidence of cirrhosis were treated without any further assessment of fibrosis.
Treatment response was assessed with HCV RNA viral load (IU/ml) at four weeks after initiation of treatment, at the end of treatment, and 12 weeks after the completion of treatment. The test was performed using Cobas AmpliPrep/Cobas TaqMan HCV Quantitative Test, v2.0 (Roche Molecular Diagnostics, Pleasanton, California, USA) with a lower limit of quantification of HCV RNA 15 IU/ml. ETR was defined as undetectable viral load at the end of completion of treatment. SVR12 was defined as undetectable viral load at 12 weeks after the end of treatment.
The SPSS statistics software package (IBM SPSS Statistics, version 21; IBM Corp, Armonk, New York, USA) was used for statistical analysis. Values were expressed as mean±SD and the mean quantitative values were analyzed using Student’s t-test. The χ2-test was used to analyze differences in qualitative values. All P values were two tailed and a P value of less than 0.05 was considered significant. One-way analysis of variance was used to determine whether there were differences among the group means. Univariate analysis was used to identify the factors related to SVR.
Sixty-five percent (N=156) of the total of 240 patients were younger than 65 years and patients aged 65 years or older comprised 35% (N=84) of treated patients, with the range being 22–94 years (59.96±10.89). Ninety-nine patients were men and 57 patients were women in the group younger than 65 years of age and 46 were men and 38 were women in the group 65 years of age and older, respectively. Most of the patients were Black (51%, 123/240), followed by White (23%, 56/240), Hispanic (11%, 27/240), and Asians (1%, 2/240). The 32 (13%) patients categorized as others were genotype (GT) 4 and were of Middle-Eastern or Egyptian origin. Also, 32 patients were coinfected with HIV and were receiving their antiretroviral therapy for HIV infection during HCV treatment; no dose adjustment was required. The basic clinical characteristics of all treated patients are summarized in Table 1.
GTs 1a and 1b was present in 78.3% of the treated patients. The next most common genotype was GT 4, found in 11.7% of patients. GTs 2 and 3 were present in 6.7 and 3.3% of all treated patients, respectively. Seventy-five patients were treatment experienced, 50 of whom were <65 years old and 25 patients who were ≥65 years. These treatment experienced patients had either previously failed treatment with the IFN and RBV combination or IFN and RBV in combination with newer DAAs. Model for end-stage liver disease (MELD) score was high in patients aged 65 years and older and was statistically significant (P=0.048). A significant difference was observed between the groups with baseline medical comorbidities HTN (P=0.004), coronary artery disease (P=0.041), and chronic kidney disease (P=0.008) in patients aged 65 years and older, and tended to have more comorbidities than younger age groups. Except for baseline hemoglobin (P=0.004) and alanine aminotransferase (ALT) (P=0.018), no difference was noted between the initial laboratory studies within the groups. The mean viral load remained similar in both groups (P=0.624). No statistical significance was observed with sex (P=0.189), BMI (P=0.713), APRI score (P=0.619), or status of previous treatment (P=0.715).
Response to therapy
In seven out of the total 240 patients, no end of treatment response was recorded; however, viral load was recorded as undetectable at 4 or 8 weeks on treatment, except one patient, who had a quantifiable viral load at 2 weeks. SVR12 was not reported in 49 patients, either because of pending follow-up or because it was not determined and recorded. With all the treatment regimens combined, the overall ETR rate was 98.2% (N=233) and SVR12 was 94% (N=191) (Figs 3 and 4). No statistically significant difference was observed with ETR (98.8 vs. 98%, P=0.667) and SVR12 (93.1 vs. 94.1%, P=0.767) between patients aged 65 years and older and those younger than 65 years of age. SVR12 for DAA with IFN and RBV treatment was 98% (49/50), higher than 91.4% (118/129) achieved with IFN-free DAA regimens, but was not statistically significant. A similar response rate was observed in patients older than or equal to 65 years, with 100% of the patients on the IFN-based regimen achieving an SVR compared with only 91.07% SVR with the IFN-free treatment regimen. ETR and SVR12 for GTs 1a, 1b, 2, 3, and GT 4 were 97.7, 100, 93.8, 100, and 100% and 92, 100, 92.9, 83.3, and 91.7%, respectively (Fig. 6). Patients with GT 3 were the lowest responders, highlighting the fact that GT 3 is the most difficult to treat with DAA agents. The ETR rate and SVR12 rates for subgroups Peg IFN+RBV+SOF, SOF+RBV, Harvoni, Viekira Pak/Viekira Pak+RBV, and SPV+SOF were 100, 96.7, 97.4, 100, 98.1%, and 97.8, 88, 94.1, 100, and 90.6%, respectively. For patients who had previous treatment failure or were naïve to treatment, no significant difference in ETR (P=0.783) or SVR12 (P=0.947) was observed between the younger and the older age groups. The univariate analysis determined the factors associated with an SVR (Table 2). The SVR12 was significantly lower in patients with high APRI and a high MELD score, indicating that advanced fibrosis is a major factor in determining the response to treatment (P=0.001 and 0.008, respectively). Baseline ALT and AST were significantly higher in patients who failed to achieve an SVR than in patients who did achieve SVR12 (P=0.016 and 0.000, respectively). BMI was significantly higher in patients who achieved SVR12 (P=0.000) Table 2. Factors associated with SVR12 were analyzed separately for patients aged older than or equal to 65 years (Table 4). The ratio of GT 1 patients who achieved an SVR12 was significantly lower compare to other genotypes (P=0.001). Cirrhosis and MELD score of more than ten were associated with a low SVR (P=0.001 and 0.042, respectively). Baseline ALT and AST tended to be higher in those who did not achieve an SVR (P=0.020 and 0.000, respectively) and BMI tended to be lower in patients who failed to respond to treatment. Only seven patients had the IL28B GT tested and hence were not included in the evaluation of factors predicting the SVR.
There were 12 (6.28%) patients (5≥65 and 7<65 years) who failed to respond to treatment. Eight patients developed relapse after treatment, three responded partially, and one achieved a virologic breakthrough during the treatment period (Table 3). Nine out of 12 patients who did not respond to treatment were cirrhotic. The difference in the failure rate between the two groups was not significant statistically (P=0.767).
Safety and tolerability
None of the adverse reactions reported were severe, except severe anemia in two patients. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%) (Tables 5,6 and 7). Nearly half of the patients who received IFN and RBV developed anemia, leucopenia, or thrombocytopenia (Table 2). The RBV dose was reduced in eight (6<65 and 2≥ 65 years) patients (Fig. 5). Four (3<65 and 1≥ 65 years) patients discontinued the RBV treatment because of severe anemia (decrease in hematocrit >25% from baseline); however, they all achieved SVR12. RBV dose reduction or discontinuation did not reach statistical significance between the two groups (P=0.913) (Fig. 5).
Eradication of HCV reduces the risk of progression to cirrhosis, HCC, and liver-related mortality, and thus leads to an improvement in overall survival and quality of life 9. Historically, the standard longer duration of IFN and RBV treatment produced significant adverse events in elderly patients, necessitating dose reduction or discontinuation of medications 10,11. The overall SVR rate was less than 50% with standard dual therapy with Peg IFN and RBV regimens. With the introduction of first DAAs in 2011, the triple therapy (boceprevir or telaprevir with Peg IFN and RBV) increased the SVR12 to 65–70% in GT 1 patients. Subsequent, substantial progress with further trials including combination NS5A and NS5B inhibitors, SVR12 approached more than 90%.
Current guidelines do not specify the age limit for treating elderly patients. The American Association of Study of Liver Disease recommends one of the six- DAA combination regimens for GT 1, the most common type of chronic HCV infection in the United States 12. RBV is still an integral part of the treatment regimen and utilized in combination with DAAs in GT 4 and as an alternative treatment regimen in GTs 1 and 3 patients with compensated cirrhosis.
A recent meta-analysis by Yang et al.8 concluded that the overall SVR in patients aged older than or equal to 65 years treated with a prolonged course of IFN/RBV regimens was significantly lower and had a significantly higher risk of relapse than in patients younger than 65 years of age. IFN and RBV discontinuation rate were also significantly higher in older patients than in younger patients. We did not find any significant difference in RBV dose reduction or discontinuation rate (P=0.913) in patients aged 65 years and older compared with younger patients. These findings indicate that elderly patients are tolerating equally the shorter course of treatment involving IFN-based and RBV-based regimens as younger patients. ETR and SVR12 for elderly patients were similar to those of younger patients (93.06 vs. 94.12%), supporting previous observations, but with the improved virologic response rate in combination with DAAs 13. Fatigue is the most common adverse event observed in both IFN-based and IFN-free treatment regimens (Tables 6 and 7). Most of the incidences of anemia and leukopenia noted in IFN-free regimens were because of RBV in combination with newer agents. None of the patients discontinued the treatment because of adverse events, supporting the fact that a shorter duration of IFN/RBV-based treatment is better tolerated and can be administered to any age group safely with close monitoring during the treatment.
In most initial trials on protease inhibitors, a small number of patients older than 65 years of age were included. Although there was no upper age limit in NS5B nucleotide polymerase inhibitor SOF and NS3/4A second-generation protease inhibitor simeprevir trials, the number of elderly patients included was too small to draw any conclusion 14,15. In most of the trials involving SOF, most of the patients treated were in their 50s 16–21. In our study, 54 (27 in each group) patients treated with SPV and the SOF regimen showed similar SVR12 rates (P=0.607) and adverse events profile. Overall, SVR12 treated with an SOF-based regimen was 91–98%, in agreement with the results observed from the major trials involving SOF 18–22. In trials involving Viekira Pak, the study group involved were younger than 71 years, with a mean age in the 50s, and the SVR rate was well above 88% 22–26. Overall, the response rate with Viekira Pak in our study was 100% (12<65 and 6> 65 years), with good tolerance to medication in elderly patients.
Clinical trials involving IFN and RBV-free regimens also did not include enough patients aged 65 years and older to determine whether they respond differently from a younger population. Trials involving the NS5A inhibitor LDV and SOF in ION1, 2, and 3 trials included only 117 patients aged 65 years and older, and the patient population included in LONESTAR Study involving the LDV and the SOF combination was younger than 70 years 27–30. No overall difference in tolerability and effectiveness was observed with elderly patients, but the data available for the treatment of the aged population with newly approved therapies are still limited not only in registration trials but also in real-world treatments and community-based HCV regimens. Results of evaluation of 80 (52<65 and 28> 65 years) patients treated with Harvoni in our study yielded an ETR of 97% and an SVR12 of 94%, consistent with the results observed in clinical trials. No statistically significant difference was noted in our study with ETR (P=0.209) or SVR12 (P=0.120) between the two age groups, consistent with the recently published study by Saab et al.31. They analyzed the data from four open-label phase 3 clinical trials that evaluated the safety and efficacy of LDV+SOF and concluded that the combination of LDV and SOF is safe, effective, and well tolerated in patients older than 65 years of age who have GT 1 hepatitis C infection 31. Of the 2293 patients enrolled in four phase 3 trials, 264 (12%) were older than or equal to 65 years of age, of whom 24 were aged older than or equal to 75 years. 97% of patients aged younger than 65 years achieved SVR12 (1965/2029) and 98% (258/264) of patients aged older than or equal to 65 years achieved SVR12. The most common adverse events in both age groups that occurred in 10% or more patients were headache and fatigue. Most adverse events noted in our study were minor and did not require any intervention, comparable with the study reports from major trials involving similar treatment regimens (Table 5). Adverse events did not differ significantly between the groups, except abdominal pain (P=0.018). Ten (6.4%) patients, all younger than 65 years of age, complained of nonspecific abdominal pain on treatment. Considering that the population involved had significant pain issues at baseline, it appears that this symptom may not be entirely related to the medication agent used. There were two serious adverse reactions during treatment with the regimen involving RBV with severe anemia requiring a blood transfusion and two patients received darbepoietin infusion for correction of anemia. None of the patients discontinued the complete treatment regimen in our study because of adverse reactions, although four patients discontinued the RBV during the treatment; they all achieved SVR12. In 12% of the patients, the RBV dose was reduced during treatment. A recent study by Pernas 32 raised a concern about possible drug interactions and RBV dose reduction because of adverse reactions in a significant number of patients after following 125 patients 65 years and older who were treated for hepatitis C with newer DAA agents. Of the 61.2% of patients who received RBV, in almost half, the dose was reduced during treatment 32. Clinical trials involving a recently approved IFN-free regimen for GTs 1 and 4, elbasvir, and grazoprevir (Zepatier; Merck & Co Inc, Kenilworth, New Jersey, USA) with or without RBV included 187 patients aged 65 years or older 33. The higher rate of late ALT elevation was observed in elderly patients; however, no dosage adjustment was required and the ALT level of most patients normalized after the completion of treatment.
SVR differs with GTs. We found a statistically significant low SVR rate with GT 1 in an elderly age group. There are no data identifying which patients will achieve an SVR among older patients with a DDA-based treatment. Our analysis indicates that cirrhosis and increased MELD score are important factors for low SVR in general and in elderly patients. Univariate analysis showed that baseline BMI, ALT, AST, and hemoglobin are factors that are associated significantly with an SVR (P=0.020, 0.020, 0.000, and 0.013, respectively).
In our study, 12 (6.28%) patients failed to respond to treatment (7<65 and 5≥65 years). Age was not a factor for the poor virologic response and the failure rate between the groups was not significant (P=0.767). All patients reported adherence to the medication regimen, and there was no clinical evidence of any reinfection in relapsed patients. None of these patients had any pretreatment-resistant or post-treatment-resistant associated variants and are awaiting further treatment. Seventy-five (nine out of 12) percent of the patients who failed to respond to treatment were cirrhotic and 41% (five out of 12) were coinfected with HIV. Further studies are required to evaluate these significant numbers of relapses in HIV-coinfected patients. Nine patients who failed to treatment received one or the other SOF-based regimen.
Some of the limitations of this study are the retrospective nature of our study, the fact that documentation of the common adverse events may not be complete, and that elderly patients involved are still a small number compared with registration trials. However, to our knowledge, our study is the first study involving a real-world community-based treatment comparing HCV patients younger than 65 years of age and 65 years of age and older. Going forward, the IFN-free regimens seem to be the standard of care in both age groups. RBV in combination with other DAAs may still be useful in treating some of the difficult to treat patient groups and in less developed countries, where the cost of newer antiviral medicines is a major hurdle. Shortened treatment course may reduce the drug-related adverse events in general including elderly patients. There is a pressing need to include older patients in future trials involving IFN-free agents. They require more complex decision-making because of their age and comorbid conditions with multiple medications.
The age of the patient does not seem to have a major impact on the virologic response rate when treating chronic HCV infection. Older patients (age 65 years and older) do not appear to have a higher frequency of adverse events compared with younger patients. Increased fibrosis, cirrhosis, some of the baseline laboratory studies including AST, ALT, Hemoglobin, and platelet levels seem to affect the SVR in the elderly and require further studies. More studies should be carried out in an older population of patients to assess the safety, efficacy, and adverse reactions of newer DAAs regimens. Treatment should not be withheld purely on the grounds of advanced age.
Author contributions: Jagannath M. Sherigar, MD: substantial contribution to conception and design of the study, data acquisition, analysis, interpretation of the data and drafting of the manuscript. Smruti R. Mohanty, MD: principal investigator with study supervision, conception and design of the study and critical revision of the manuscript. Mohammad Mansour, MD: critical revision of the manuscript. Osama Mukhtar, MD and Vijay Gayam, MD: data acquisition and substantial contribution to statistical data analysis and interpretation of the data. Arifa Khan MD, Yavgeniy Arefiev MD, Mazin Khalid MD, Ayyappa M. Rangaraju, Nibash Budhathoki, Imran Siddiqui MD and Debra Guss: contributed in acquisition of patient data. Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C.
Conflicts of interest
Dr Mohanty is on the Speakers Bureau for Gilead Science, BMS, and Abbvie Pharmaceuticals. For the remaining authors, there are no conflicts of interest.
1. Ravi S, Nasiri-Toosi M, Karimzadeh I, Khalili H, Ahadi-Barzoki M, Dashti-Khavidaki S. Pattern and associated factors of anti-hepatitis C virus treatment-induced adverse reactions. Expert Opin Drug Saf 2014; 13:277–286.
2. Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al. Chronic hepatitis C
virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014; 160:293–300.
3. Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol 1998; 28:930–938.
4. Thabut D, Le Calvez S, Thibault V, Massard J, Munteanu M, Di Martino V, et al. Hepatitis C in 6,865 patients 65 yr or older: a severe and neglected curable disease? Am J Gastroenterol 2006; 101:1260–1267.
5. Huang CF, Yang JF, Dai CY, Huang JF, Hou NJ, Hsieh MY, et al. Efficacy and safety of pegylated interferon
combined with ribavirin
for the treatment of older patients with chronic hepatitis C
. J Infect Dis 2010; 201:751–759.
6. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945–65: recommendations from the centers for disease control and prevention. Ann Intern Med 2012; 157:817–822.
7. Yu JW, Sun LJ, Kang P, Yan BZ, Zhao YH, et al. Efficacy and factors influencing treatment with peginterferon alpha 2a and ribavirin
in elderly patients
with chronic hepatitis C
. Hepatobiliary Pancreat Dis Int 2012; 11:185–192.
8. Yang Z, Zhuang L, Yang L, Liu C, Lu Y, Xu Q, et al. Efficacy and safety of peginterferon plus ribavirin
for patients aged ≥65 years with chronic hepatitis C
: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2014; 38:440–450.
9. Imai Y, Kasahara A, Tanaka H, Okanoue T, Hiramatsu N, Tsubouchi H, et al. Interferon
therapy for aged patients with chronic hepatitis C
: improved survival in patients exhibiting a biochemical response. J Gastroenterol 2004; 39:1069–1077.
10. Manns MP, McHutchinson JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peg interferon
alfa-2b plus ribavirin
compared with interferon
alfa-2b plus ribavirin
for initial treatment of chronic hepatitis C
: a randomized trial. Lancet 2001; 358:958–965.
11. Fried MW, Schiffman ML, Reddy KR, Marinos G, Gonçales FL Jr, Häussinger D, et al. Peg interferon
alfa-2a plus ribavirin
for chronic hepatitis C
virus infection. N Engl J Med 2002; 347:975–982.
13. Frei PI, Leucht AK, Held U, Kofmehl R, Manser CN, Schmitt J, et al. Elderly age is not a negative predictive factor for virological response to therapy with pegylated interferon
-α and ribavirin
in chronic hepatitis C
virus patients. Liver Int 2014; 34:551–557.
14. Jacobson IM, Dore GJ, Foster GR, Fried MW, Radu M, Rafalsky V, et al. Simeprevir with pegylated interferon
alfa 2a plus ribavirin
in treatment-naive patients with chronic hepatitis C
virus genotype 1 infection (QUEST-1): a phase 3, randomized, double-blind, placebo-controlled trial. Lancet 2014; 384:403–413.
15. Manns M, Marcellin P, Poordad F, de Araujo ES, Buti M, Horsmans Y, et al. Simeprevir with pegylated interferon
alfa 2a or 2b plus ribavirin
in treatment-naive patients with chronic hepatitis C
virus genotype 1 infection (QUEST-2): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet 2014; 384:414–426.
16. Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin
for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomized, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13:401–408.
17. Lawitz EI, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C
infection. N Engl J Med 2013; 368:1878–1887.
18. Zeuzem SI, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al. Sofosbuvir and ribavirin
in HCV genotypes 2 and 3. N Engl J Med 2014; 370:1993–2001.
19. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin
for hepatitis C. N Engl J Med 2013; 368:34–44.
20. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Subramanian GM, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014; 146:736–743.
21. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Corregidor A, et al. Simeprevir plus sofosbuvir, with or without ribavirin
, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon
and treatment-naive patients: the COSMOS randomized study. Lancet 2014; 384:1756–1765.
22. Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin
for HCV. N Engl J Med 2014; 370:1983–1992.
23. Lawitz E, Poordad F, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. A phase 2a trial of 12-week interferon
-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin
in IL28B C/C patients with chronic hepatitis C
genotype 1. J Hepatol 2013; 59:18–23.
24. Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S, et al. Phase 2b trial of interferon
-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014; 370:222–232.
25. Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K. ABT-450/r-ombitasvir and dasabuvir with ribavirin
for hepatitis C with cirrhosis. N Engl J Med 2014; 370:1973–1982.
26. Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourlière M, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin
. N Engl J Med 2014; 370:1604–1614.
27. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370:1889–1898.
28. Afdhal NI, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370:1483–1493.
29. Kowdley KVI, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:1879–1888.
30. Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin
in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trial. Lancet 2014; 383:515–523.
31. Saab S, Park SH, Mizokami M, Omata M, Mangia A, Eggleton E, et al. Safety and efficacy of ledipasvir/sofosbuvir for the treatment of genotype 1 hepatitis C in subjects aged 65 years or older. Hepatology 2016; 63:1112–1119.
32. Pernas B. Paper presented at International Conference on Viral Hepatitis (ICVH) 2016. Presented 14-15 March 2016, San Francisco, California, USA.
Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
adverse drug reactions; chronic hepatitis C; direct-acting antiviral agents; elderly patients; interferon; ribavirin; sustained virologic response