Efficacy and Tolerability of Direct–Acting Antivirals for Hepatitis C in Older Adults

Chiara Mazzarelli, MD; Aisling Considine, MPharm; Kate Childs, MBBS, MPH; Ivana Carey, MD, PhD; Matteo Angelo Manini, MD; Abid Suddle, MBBS, MD; Geoffrey Dusheiko, MB, BCh; Kosh Agarwal, BMed Sci (Hons), MD; Mary D. Cannon, MB, BCh, PhD

Disclosures

J Am Geriatr Soc. 2018;66(7):1339-1345. 

In This Article

Discussion

DAA therapy is extremely well tolerated and highly efficacious for the treatment of HCV, as demonstrated in multiple clinical trials and real–life cohorts,[12,13,15,24] but the majority of registration trials enrolled limited numbers of individuals aged 65 and older, whereas in clinical practice, older adults make up one of the largest cohorts of individual attending viral hepatitis clinics. Moreover, older adults tend to have more advanced liver disease, a greater risk of liver cancer, and more comorbidities than younger adults.[4,6,7] Despite a recent contentious Cochrane review suggesting that the clinical effect of SVR in individuals with HCV is questionable,[25] there is a strong body of evidence to support the numerous health benefits derived from SVR, regardless of stage of liver disease.

SVR in individuals with HCV has been shown to reduce the risk of diabetes mellitus and HCC, as well as all–cause of mortality.[4,8,26,27] Quality–of–life and functionality studies have consistently demonstrated significant improvements after successful eradication of HCV infection, not only with interferon–based regimens, but also with DAA therapy.[9,28,29] In a subanalysis of clinical trials of sofosbuvir–based regimens, factors such as physical pain, social functioning, and work productivity improved from baseline after successful viral eradication.[30,31] A recent publication demonstrated that, although older adult pretreatment patient–reported outcomes are slightly lower than those of younger adults, they experienced a comparable improvement in patient–reported outcomes with clearance of HCV.[32]

Furthermore, data from the United States have shown that all–cause hospitalization rates are higher in individuals with HCV, with higher admission rates and longer durations of hospital stay.[33] Treatment of HCV and achievement of SVR has been shown to reduce this risk.[33,34] Finally, from the point of view of cost effectiveness, treatment benefit is greatest for individuals with advanced liver disease, which is strongly associated with older age and frailty status.[35]

Given the significant health benefits derived from the achievement of SVR, older adults should be prioritized for antiviral treatment, but the lack of data from clinical trials and real–life cohorts and the risk of DDIs related to polypharmacy can make treatment more challenging for physicians. We demonstrated excellent SVR rates, rivalling those reported in clinical trials. This is even more striking when the high rates of cirrhosis and large number of comorbidities of our participants are considered (Table 1). The rate of predicted DDIs was significantly greater in individuals aged 75 and older, probably as a consequence of a large number of chronic medications prescribed for this patient cohort (Table 2).

The data on AEs in older adults are contradictory. Older adults have a greater risk of treatment–related AEs secondary to age–related changes in pharmacodynamics and pharmacokinetics; a greater prevalence of comorbidities, inappropriate prescribing, and polypharmacy; and suboptimal monitoring of medications.[36] Although our study showed antiviral efficacy comparable with that of published clinical trials, individuals aged 75 and older also had a greater incidence of Grade 1 AEs, despite our cohorts being similar in terms of cirrhosis and comorbidities. A similar result was reported in the Hepa–C registry from our Spanish counterparts, in which AEs and mortality were associated with older age.[37]

Risk of ribavirin–related anemia, in the context of interferon–based treatment, increases with age,[4,10] often necessitating a reduction in dose during treatment.[38] It was recently reported that older adults treated with sofosbuvir and ribavirin have a greater risk of hemolytic anemia than younger individuals.[39] In our study, when comparing only individuals who received ribavirin, those aged 75 and older were more likely to have anemia (60% vs 20%) than the younger patients, despite appropriate dose adjustment for eGFR and the lower dose prescribed for the older adult cohort. Red blood cell distribution width is a hematological marker directly proportional to reticulocyte count and a marker of the bone marrow's response to anemia.[40] We observed that individuals aged 75 and older experienced less change in red blood cell distribution width between the start of treatment and Week 4 than the younger cohort, which was probably related to attenuated red cell production in older adults.[41]

Moreover, during a median follow–up of 38 weeks, we observed 4 deaths, unrelated to DAA therapy. Three individuals died of surgical or medical complications in the context of advanced and decompensated liver disease, consistent with the high reported perioperative mortality associated with Child–Pugh B cirrhosis.[42]

Eradication of HCV has been demonstrated in numerous studies to lead to improvements in liver function for the majority of individuals with cirrhosis. In individuals with decompensated liver disease, SVR can lead to resolution of ascites, a reduction in portal hypertension, and sustained improvement in synthetic liver function. Older adults are less likely to be candidates for liver transplantation, so the improvement in liver function associated with viral eradication can confer a significant mortality benefit for individuals with advanced liver disease.[43]

Our study has limitations related to its retrospective design and number of participants, especially those aged 75 and older. Despite this, we feel that our participant cohort was representative of older adults seen in daily clinical practice, with the majority of study participants having significant comorbidities and advanced liver disease.

To conclude, our data demonstrate an excellent SVR rate with DAA therapy in older adults who had high rates of cirrhosis and comorbidities. Although we found a greater likelihood of pretreatment DDIs, Grade 1 AEs, and ribavirin–related anemia in individuals aged 75 and older, this did not translate into clinically significant AEs or a lower likelihood of cure. As we move into an era of third–generation DAAs, highly efficacious short–duration, ribavirin–free regimens will make the treatment of HCV in older adults even simpler and safer. Our data demonstrate that age is not a consideration in the context of HCV treatment and that older adults should have the opportunity to benefit from the high cure rates and health benefits associated with viral eradication.

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