All-cause mortality according to hepatitis C virus treatment response
After a median of 4.0 (IQR 2.0–6.5) years of follow-up from T0, a total of 236 deaths had occurred. One hundred and thirty-eight (8.4%) of HCV treatment nonresponders had died vs. 39 (3.8%) deaths among responders and 59 (5.4%) with unknown HCV treatment response. The rates (per 1000 PYFU, 95% CI) of all-cause death were 17.59 (14.88–20.78), 10.43 (7.62–14.28) and 11.0 (8.54–14.23) for nonresponders, responders and unknown responders, respectively.
Figure 2 shows a Kaplan–Meier plot of the cumulative risk of all-cause mortality. For nonresponders, the 7-year risk (95% CI) of all-cause death was 11.6% (9.5–13.7), whereas the 7-year risk was significantly lower for responders 8.0% (5.1–10.8) and for patients with unknown treatment response 7.8% (5.6–10.1).
In the unadjusted Cox regression analysis, nonresponders had a relative hazard of 1.64 (95% CI 1.15–2.34) for all-cause death compared with responders. Results were similar after adjusting for demographics, HIV-related (prior AIDS, on cART at T0, current HIV-RNA and CD4+ cell count) and hepatitis-related factors (HBsAg and APRI) in separate models (Fig. 3). In the fully adjusted analysis, the relative hazard (nonresponders vs. responders) for all-cause death was 1.53 (95% CI 1.06–2.22). In all analyses, the relative hazard for all-cause death was NS when comparing responders with unknown responders.
Liver-related mortality according to hepatitis C virus treatment response
LRD accounted for a third of all deaths among nonresponders 48 of 139 (34.8%), but only 12.8% (5/39) among responders and 22.0% (13/59) among patients with unknown response. The rates (per 1000 PYFU, 95% CI) of LRD were 6.12 (4.61–8.12), 1.34 (0.56–3.21) and 2.40 (1.41–4.18) for nonresponders, responders and unknown responders, respectively.
Among the five responders who died from LRD, two had a baseline APRI score indicating cirrhosis, one had significant fibrosis and two had no information about fibrosis level. One patient had evidence of HCV reinfection, whereas the four other remained HCV-RNA-negative during follow-up. None were diagnosed with HCC.
The differences in risk of LRD between responders and nonresponders were more pronounced than for all-cause death, but the CIs were quite wide reflecting the relative low number of LRDs in each group. The 7-year cumulative risk of LRD was significantly higher for nonresponders (4.2%, 95% CI 2.9–5.5) compared with the risk for responders (1.6%, 95% CI 0.0–3.3) and for patients with unknown treatment response (1.4%, 95% CI 0.4–2.4) (Fig. 4).
In the unadjusted Cox regression analysis, nonresponders had a 4.43 (95% CI 1.76–11.14) increased risk of LRD compared with responders. Again, when adjusting for demographic, HIV-related and hepatitis-related factors, there was little change in the incidence rate ratios (Fig. 5). In the fully adjusted analysis, the relative hazard (nonresponders vs. responders) of LRD was 3.39 (95% CI 1.32–8.75).
Nonliver-related mortality according to hepatitis C virus treatment response
A total of 34 and 90 nonliver-related deaths occurred among responders and nonresponders, respectively. In both groups, non-HCC malignancy was the predominant cause of death (5/34 and 16/90, respectively) followed by ‘unknown cause’ (5/34 and 16/90, respectively). Four nonresponders died from AIDS, whereas there were no AIDS-related deaths in the responder group. To investigate whether a positive HCV treatment outcome also results in a lower risk of nonhepatic mortality, we repeated the analyses excluding all LRDs. In the unadjusted analysis, there was no difference (nonresponders vs. responders) in incidence of nonliver-related death (hazard ratio 1.23, 95% CI 0.83–1.83). Results were similar after adjustment for demographic factors (1.19, 95% CI 0.79–1.78), HIV-related factors (1.22, 95% CI 0.81–1.82) and APRI and HBsAg status (1.35, 95% CI 0.91–2.01). In the fully adjusted model, the relative hazard was (1.22, 95% CI 0.80–1.84). Similarly, there was no difference when comparing responders with patients with unknown response (results not shown).
In this large prospective study, we included 3755 HIV/HCV-coinfected patients, who had received PEG-IFN/RBV. After a median of 4.0 years follow-up from week 72 after treatment initiation, we found that patients who had a favourable treatment response had a significantly improved all-cause and liver-related mortality compared with patients who were nonresponders. Our findings confirm the survival benefit of an SVR, shown in previous studies of HCV-monoinfected [6,7] and HIV/HCV-coinfected patients [9,13]. However, compared with these studies, the improved survival in our study was relatively modest (hazard ratio 1.53 for comparing responders with nonresponders). In the Spanish study by Berenguer et al., which is the only other large observational study to include HIV/HCV-coinfected patients from routine clinical practice, the incidence of all-cause mortality among patients with SVR was lower compared with the incidence among responders in our study (0.46 vs. 1.04 per 100 PYFU), whereas the all-cause mortality was higher among nonresponders in their study (3.12 vs. 1.76 per 100 PYFU). The excess all-cause mortality among nonresponders in the Spanish study seems to be mainly explained by a high prevalence (39%) of patients with advanced fibrosis or cirrhosis, resulting in a high incidence of LRD among nonresponders compared with the incidence among nonresponders observed in our study (1.65 vs. 0.61 per 100 PYFU).
In our study, only five out of 37 deaths in the treatment response group were from liver-related causes, and none of them due to HCC. Two of the five patients had evidence of cirrhosis at the time of treatment initiation, whereas one had evidence of HCV reinfection. Other studies have documented, that although an SVR reduces the risk, liver-related complications can occur several years after SVR. This is particularly the case with HCC in patients with cirrhosis at the time of treatment [6,14]. Longer follow-up of our cohort is warranted to determine whether the incidence of HCC and other liver-related clinical events remains low for patients with treatment response.
As interferon is contraindicated in patients with advanced cirrhosis due to the risk of liver decompensation, it is likely that patients with more advanced liver disease, who would have gained more clinical benefits from HCV eradication, were excluded. It is therefore conceivable that with the new tolerable and effective interferon-free direct-acting antivirals (DAA), we will be able to prevent more liver-related and, possibly, nonliver-related complications, and this should be addressed in further observations. Although interferon-based therapy is no longer standard of care, the data presented in this article are still of relevance to inform the prognosis for the many patients who were treated and cured with interferon before the arrival of DAA. Furthermore, interferon-based therapy is still commonly used in some countries that cannot afford the market price of DAA. In addition, consequences of cure are likely to be similar regardless of which treatment was used to achieve success.
The link between chronic HCV infection and different autoimmune and lymphoproliferative conditions, for example mixed cryoglobulinaemia and some types of lymphoma, is well established . There is also emerging evidence of an association between HCV infection and risk of cardiovascular disease and other extrahepatic diseases [15–17]. If the association is causal, one would expect a decrease in risk of nonliver-related death after SVR. In our study, we did not find a lower risk of nonliver-related death among those with a favourable HCV treatment response. This is in contrast to a national Spanish study that found a three-fold lower risk of nonliver-related death in HIV/HCV-coinfected patients with SVR compared with patients who did not achieve an SVR . The reason for this difference is not clear, but with only five and 32 nonliver-related deaths among patients with and without SVR, respectively, the study had limited power to investigate the question. It is possible that some of the apparent extrahepatic health benefit of an SVR is related to behavioural differences after treatment and not the treatment outcome per se, as demonstrated by a Scottish observational study of HCV-monoinfected patients in which patients who achieved SVR after interferon-based therapy had lower risk of hospitalization for alcohol intoxication and violence-related injury after treatment compared with nonresponders to HCV treatment . These findings should be explored in other cohorts and in patients undergoing DAA therapy.
The major strengths of this analysis are the large number of coinfected patients recruited from a diverse geographical area throughout Europe, the long prospective follow-up after HCV treatment and our ability to adjust for relevant risk factors for all-cause and LRD. However, like in all observational studies, there remains the possibility of unmeasured confounding. Another limitation is the lack of follow-up HCV-RNA measurements on all patients at least 6 months after end of therapy. In addition, some of the patients categorized as responders could have had HCV-RNA relapse, and some patients categorized as nonresponders could have achieved an SVR. However, this limitation would only tend to underestimate the survival benefit of HCV therapy. Unexpectedly, the prevalence of cirrhosis, as determined by the APRI score, was higher among responders than among nonresponders. Data to calculate the APRI score were only available for 66 and 61% of responders and nonresponders, respectively. If the reason for not having an APRI score is associated with disease status, selection bias could have been introduced.
In conclusion, we have shown that among HIV/HCV-coinfected patients, a favourable virological response to HCV treatment is associated with reduced risk of both LRD and improved overall survival in the interferon era. Whether this holds true with the new direct-acting antivirals remains to be investigated.
Analysis and writing committee: Lars Peters, Robert Zangerle,Giota Touloumi, Frederic-Antoine Dauchy, Marc van der Valk, Gert Fätkenheuer, Antoni Noguera-Julian, Juan Gonzales, Francois Dabis, Antonella Castagna, Antonella d’Arminio Monforte, Carlo Torti, Christina Mussini, Jordi Ceescat, Helen Kovari, Stephane de Wit, Dorthe Raben, Geneviève Chene and Alessandro Cozzi-Lepri.
The study was designed by L.P. and A.C.L. A.C.L. performed the statistical analyses. L.P. drafted the article. All other members of the writing committee contributed to redrafting and refinement of the study.
Steering committee–contributing cohorts: Robert Zangerle (AHIVCOS), Giota Touloumi (AMACS), Josiane Warszawski (ANRS CO1 EPF/ANRS CO11 OBSERVATOIRE EPF), Laurence Meyer (ANRS CO2 SEROCO), François Dabis (ANRS CO3 AQUITAINE), Murielle Mary Krause (ANRS CO4 FHDH), Jade Ghosn (ANRS CO6 PRIMO), Catherine Leport (ANRS CO8 COPILOTE), Linda Wittkop (ANRS CO13 HEPAVIH), Peter Reiss (ATHENA), Ferdinand Wit (ATHENA), Maria Prins (CASCADE), Heiner Bucher (CASCADE), Diana Gibb (CHIPS), Gerd Fätkenheuer (Cologne-Bonn), Julia Del Amo (CoRIS), Niels Obel (Danish HIV Cohort), Claire Thorne (ECS), Amanda Mocroft (EuroSIDA), Ole Kirk (EuroSIDA), Christoph Stephan (Frankfurt), Santiago Pérez-Hoyos (GEMES-Haemo), Osamah Hamouda (German ClinSurv), Barbara Bartmeyer (German ClinSurv), Nikoloz Chkhartishvili (Georgian National HIV/AIDS), Antoni Noguera-Julian (CORISPE-cat), Andrea Antinori (ICC), Antonella d’Arminio Monforte (ICONA), Norbert Brockmeyer (KOMPNET), Luis Prieto (Madrid PMTCT Cohort), Pablo Rojo Conejo (CORISPES-Madrid), Antoni Soriano-Arandes (NENEXP), Manuel Battegay (SHCS), Roger Kouyos (SHCS), Cristina Mussini (Modena Cohort), Pat Tookey (NSHPC), Jordi Casabona (PISCIS), Jose Miró (PISCIS), Antonella Castagna (San Raffaele), Deborah Konopnick (St. Pierre Cohort), Tessa Goetghebuer (St Pierre Paediatric Cohort), Anders Sönnerborg (Swedish InfCare), Carlo Torti (The Italian Master Cohort), Caroline Sabin (UK CHIC), Ramon Teira (VACH) and Myriam Garrido (VACH). David Haerry (European AIDS Treatment Group).
Executive Committee: Stéphane De Wit (Chair, St. Pierre University Hospital), Jose Miró (PISCIS), Dominique Costagliola (FHDH), Antonella d’Arminio-Monforte (ICONA), Antonella Castagna (San Raffaele), Julia del Amo (CoRIS), Amanda Mocroft (EuroSIDA), Dorthe Raben (Head, Copenhagen Regional Coordinating Centre) and Geneviève Chêne (Head, Bordeaux Regional Coordinating Centre). Paediatric cohort representatives: Ali Judd and Pablo Rojo Conejo.
Regional coordinating centres: Bordeaux RCC: Diana Barger, Christine Schwimmer, Monique Termote, Linda Wittkop; Copenhagen RCC: Maria Campbell, Casper M. Frederiksen, Nina Friis-Møller, Dorthe Raben and Rikke Salbøl Brandt.
Project leads and statisticians: Juan Berenguer, Julia Bohlius, Vincent Bouteloup, Heiner Bucher, Alessandro Cozzi-Lepri, François Dabis, Antonella d’Arminio Monforte, Mary-Anne Davies, Julia del Amo, Maria Dorrucci, David Dunn, Matthias Egger, Hansjakob Furrer, Marguerite Guiguet, Sophie Grabar, Ali Judd, Ole Kirk, Olivier Lambotte, Valériane Leroy, Sara Lodi, Sophie Matheron, Laurence Meyer, Jose Miró, Amanda Mocroft, Susana Monge, Fumiyo Nakagawa, Roger Paredes, Andrew Phillips, Massimo Puoti, Michael Schomaker, Colette Smit, Jonathan Sterne, Rodolphe Thiebaut, Claire Thorne, Carlo Torti, Marc van der Valk, Linda Wittkop and Natasha Wyss.
Conflicts of interest
There are no conflicts of interest.
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* A list of the members of the writing committee of the Hepatitis C Working Group for the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord is shown in the Acknowledgements section.
Keywords:Copyright © 2017 Wolters Kluwer Health, Inc.
hepatitis C virus; hepatitis C; HIV; interferon; mortality; ribavirin