Thursday, December 15, 2011

Hepatitis C-Impact of age > 65 years on svr and relapse

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Impact of age more then 65 years on svr and relapse in chronic hepatitis c (chc) patients (pts) treated with peginterferon alfa-2a (40kd) (pegifn?2a[40kd]) plus ribavirin (rbv): final analysis from the large multinational real-world prophesys cohorts
A. Aronsohn,1 I. Ancuta,2 F. Caruntu,3 C. Coppola,4 D. Delic,5 A. Digiacomo,6 G.M. Dusheiko,7 G. Lengyel,8 P. Marcellin,9 A. Orlandini,10 J. Pruthi,11 G.F. Silva,12 L. Tallarico,13 M. Schmitz,14 F. Hamzeh,15 H. Cheinquer16
1University of Chicago Medical Center, Chicago, IL, United States; 2Dr l. Cantacuzino Clinical Hospital, Bucharest, Romania; 3Matei Bals Infectious Diseases Institute, Bucharest, Romania; 4Unità Operativa Epatologia ed Ecografia Interventistica Ospedale Gragnano, Naples, Italy; 5Clinic for Infectious Disease, Clinical Center Serbia, Belgrade, Serbia;
6Divisione di Medicina Interna, Ospedale Regina Margherita, Comiso, Italy; 7Royal Free and University College School of Medicine, London, United Kingdom; 8Semmelweis University, 2nd Dept. of Medicine, Budapest, Hungary; 9Hôpital Beaujon, Clichy, France; 10Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
11High Desert Gastroenterology Suite B, Lancaster, CA, United States; 12Botucatu School of Medicine, Botucatu, Brazil; 13Divisione di Medicina , Ospedale Elena D’Aosta, Napoli, Italy; 14IST GmbH, Mannheim, Germany; 15Genentech, South San Francisco, CA, United States; 16Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil


Several mostly retrospective analyses have suggested that older patients with chronic hepatitis C are less likely than younger patients to achieve an SVR after treatment with peginterferon plus ribavirin.[1–4] This hypothesis is difficult to validate because randomized clinical trials generally enroll few patients aged more then 65 years.
Possible reasons for reduced SVR rates in the elderly include a higher incidence of advanced fibrosis, more frequent dose modifications, higher discontinuation rates, and poorer tolerability.[1–3, 5]

The large multinational, non-interventional PROPHESYS cohorts enrolled a diverse population of patients with chronic hepatitis C and thus provide an excellent opportunity to examine the effect of patient age on the outcome of treatment with peginterferon alfa plus ribavirin.

The objective of this analysis was to examine the association between patient age (less then 65 vs. more then 65 years), on-treatment virologic response (HCV RNA less then 50 IU/mL), and SVR in patients treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin in accordance with local labels.


PROPHESYS comprised three separate cohort studies of patients receiving treatment for chronic hepatitis C in accordance with the local label.

The prescribed treatment was at the sole discretion of the physician and eligibility for inclusion in PROPHESYS was determined only after the choice of treatment had been made.

According to country-specific requirements, PROPHESYS 1 included patients prescribed peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin, while patients included in PROPHESYS 2 and 3 received either peginterferon alfa-2a (40KD) or peginterferon alfa-2b (12KD) (PegIntron®) plus ribavirin.

This analysis was restricted to naive HCV mono-infected patients who were assigned to treatment with peginterferon alfa-2a (40KD) plus ribavirin.

Patients included in the analysis were stratified by age at enrollment
(less then 65 vs. more then 65 years).

Outcomes of interest included on-treatment virologic responses (undetectable HCV RNA, less then 50 IU/mL) by week 2, 4 (rapid virologic response; RVR), 12 and the end of treatment, and SVR, defined as undetectable HCV RNA after 24 weeks of untreated follow-up.

The percentage of patients with more then 80% exposure to both study drugs was calculated for the two age groups.

A multiple logistic regression analysis was conducted to examine associations between baseline factors and SVR. Age was entered as a dichotomous variable (less then 65 vs. more then 65 years).


A total of 6625 patients were enrolled in PROPHESYS and treated with peginterferon alfa-2a (40KD) plus ribavirin including 6276 individuals who were aged less then 65 years and 349 who were aged more then 65 years.

Of the 349 patients aged more then 65 years, 208, 109 and 15 individuals, respectively, were infected with HCV genotype 1, 2 and 3 (Table 1).

Across HCV genotypes 1, 2 and 3 a higher proportion of patients aged more then 65 years were of non-white race/ethnicity compared with patients aged less then 65 years (Table 1).

Compared with younger patients a higher proportion of patients aged more then 65 years had transition to cirrhosis or cirrhosis, numerically higher serum aspartate aminotransferase (AST) levels and lower mean platelet counts. The percentage of patients with platelet counts less then 140 x 109/L was also consistently higher in patients aged more then 65 years (Table 1).

Virologic response

In general, rates of on-treatment virologic response, defined as undetectable HCV RNA (less then 50 IU/mL), were lower in patients aged more then 65 years compared with those aged less then 65 years (Figure 1). In particular, RVR rates at week 4 were numerically lower in older patients across genotypes.

SVR rates were significantly lower and relapse rates were significantly higher in older genotype 1 patients compared with those individuals aged less then 65 years (both p=0.0002) (Figure 2).

In contrast to findings in genotype 1 patients, SVR and relapse rates were generally similar in genotype 2 and 3 patients aged more then 65 years and less then 65 years (Figure 2).

Of patients with an end of treatment response, 15% (714/4692) and 9% (23/243) of those aged less then 65 and more then 65 years, respectively, were imputed as treatment failures due to incomplete follow-up data.

The positive predictive value (PPV) of RVR for SVR was comparable between the two age groups in genotype 1 patients (less then 65 years: 68.6%; more then 65 years: 66.7%; Table 2). Among genotype 2 and 3 patients the
PPV of an RVR for SVR was higher in older patients compared with younger patients.

In general, HCV genotype 1 and 3 patients aged more then 65 years had shorter mean treatment duration compared with patients aged less then 65 years (Table 3).

Across all genotypes premature treatment discontinuations due to adverse events were about two times higher in patients aged more then 65 years (14.9%) compared with patients aged less then 65 years (7.4%), and ribavirin dose modifications due to anemia were reported in 31.5% of the patients aged more then 65 years compared with 13.4% in younger patients.

Fewer older patients had ribavirin exposure of more then 80% of the planned dosage compared with younger patients (Table 3). This was in spite of much higher rate of usage of erythropoietin in older individuals (102/349, 29.2% vs 706/6276, 11.2% among patients aged less then 65 years). The frequency of granulocyte colony stimulating factor usage was similar in older (19/349, 5.4%) and younger (273/6276, 4.3%) patients.

Although less pronounced than seen for ribavirin, generally fewer older patients had peginterferon alfa-2a (40KD) exposure more then 80% (Table 3).

Multiple logistic regression analysis in genotype 1 patients confirmed that older age was significantly associated with lower SVR rates in genotype 1 patients (Figure 3). Other factors that were significantly associated with higher SVR rates included well-established predictors of SVR such as ethnicity (Asian vs. White, White vs. Black and vs. Hispanic), lower HCV RNA level, higher ALT ratio, and no cirrhosis. Indicators of advanced fibrosis such as low platelets and high AST ratio, as well as injection drug use as the mode of infection, were negatively associated with SVR.

This analysis of data from the PROPHESYS cohorts suggests that patients aged more then 65 years tended to have inferior virologic responses compared with patients aged less then 65 years.

Older patients tended to have lower RVR rates regardless of HCV genotype.
Older patients with HCV genotype 1 infection (but not genotype 2 or 3 infection) had significantly lower SVR rates and significantly higher relapse rates. However, results for patients infected with HCV genotype 3 should be interpreted with caution since relatively few such patients were aged over 65 years.

RVR remains a reliable positive predictor of SVR in older patients.
In addition to well-established baseline predictors of SVR, age more then 65 years was significantly and negatively associated with SVR in patients with HCV genotype 1 infection.
Shorter treatment duration due to adverse events and lower exposure to ribavirin due to anemia may have contributed to the significantly lower SVR rates in older genotype 1 patients.

1. Antonucci G, Longo MA, Angeletti C, et al. The effect of age on response to therapy with peginterferon alpha plus ribavirin in a cohort of patients with chronic HCV hepatitis including subjects older than 65 yr. Am J Gastroenterol 2007; 102(7): 1383–1391.
2. Reddy KR, Messinger D, Popescu M, et al. Peginterferon alpha-2a (40 kDa) and ribavirin: comparable rates of sustained virological response in sub-sets of older and younger HCV genotype 1 patients. J Viral Hepat 2009; 16(10): 724–731.
3. Honda T, Katano Y, Shimizu J, et al. Efficacy of peginterferon-alpha-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C. Liver Int 2010; 30(4): 527–537.
4. Oze T, Hiramatsu N, Yakushijin T, et al. Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy. J Hepatol 2011; 54(4): 604–611.
5. Nudo CG, Wong P, Hilzenrat N, et al. Elderly patients are at greater risk of cytopenia duringPresented at The Liver Meeting® 2011 [62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)]
November 4–8, San Francisco, USA
This research was funded by Roche
Disclosure information: GD – Advisory Committees or Review Panels: Schering Plough, Vertex, Abbott, Beohringer Ingelheim, BMS, GSK, Pharmasett, Pfizer, Roche, Merck, Tibotec, Anchillion; Board Membership: Gilead Sciences ; PM – Consulting: Roche, Schering- Plough, Gilead, BMS, Vertex, MSD, Novartis, Tibotec, Boehringer, Abbott, Pfizer; Grant/ Research Support: Roche, Schering Plough, Gilead, Echosens; Speaking and Teaching: Roche, Schering- Plough, Gilead, BMS, Vertex, Novartis, Pharmasset, Tibotec, MSD, Abbott, Pfizer ; HC – Advisory Committees or Review Panels: Bristol-Myers Squibb, Roche; Grant/Research Support: Bristol-Myers Squibb, Roche; Speaking and Teaching: Bristol-Myers Squibb, Roche ; JP – Speaking and Teaching: Roche ; GFS – Grant/Research Support: Roche, Shering Plough; Speaking and Teaching: Roche, Shering Plough, Bristol-Myers Squibb, Bayer ; MS - Employed by IST GmbH and provides statistical consultancy and analysis for Roche; FH is an employee of Roche; AA, IA, FC, CC, DD, AD, GL, AO, LT have nothing to disclose.
Support for third-party writing assistance for this presentation was provided
by F.Hoffmann-La Roche Ltd

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