Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C
Sherigar, Jagannath M.a; Gayam, Vijayb; Khan, Arifab; Mukhtar, Osamab; Arefiev, Yavgeniya; Khalid, Mazinb; Siddiqui, Imranb; Rangaraju, Ayyappa M.b; Budhathoki, Nibashb; Mansour, Mohammedb; Guss, Debraa; Mohanty, Smruti R
Conclusion
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.
Abstract
Background: There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN).
Patients and methods: Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups.
Results: No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. 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%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups.
Conclusion: DAAs with or without IFN and RBV in the standard recommended 12 or 24-week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C.
Discussion Only
Full Text Article Available Online
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.
Conclusion
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.
Read full text,
here.
