Discussion
The Dat’AIDS cohort represents a collaboration between major French HIV treatment centers scattered throughout the country [
23] and today includes data on more than 34,000 patients. The present study indicates that HCV prevalence among HIV-infected patients decreased over the past decade, probably due to a decreased proportion of IVDU among newly infected HIV individuals. Since HCV coinfection is more frequent among IVDU than among MSM, the increased proportion of MSM and non-IVDU women among the HIV population over time results in a parallel decrease of HCV prevalence despite the occurrence of acute HCV infections in a sub-population of MSM in the last years. Similar trends have been described in other European and US cohorts [
4,
28,
29].
A significant improvement in HIV care was observed during the study, as measured by the proportion of patients with an undetectable HIV-RNA under cART. This improvement both reflects a better cART uptake in this population and a better virological control of HIV infection and results in a significant improvement of the immunological status of the population. Both trends were expected, since transversal analysis of several consecutive cohorts from 2004 to 2012 showed similar patterns [
4].
Fibrosis evaluation increased over time, notably after 2004, when non-invasive fibrosis evaluation techniques became widely available. Following the introduction of these techniques, they not only nearly replaced liver biopsy, but the number of patients evaluated every year more than doubled from 2000 to 2012. Variations in the proportion of patients with severe fibrosis or cirrhosis were observed over time. Whether these variations resulted from the inclusion in the cohort of patients with more recent infection when using non-invasive techniques, or to other factors could not be determined. Interestingly, fibrosis assessment was more frequent among patients with previous virological failure. Since fibrosis score is associated with the probability of complication of chronic hepatitis C and with the probability of response to Peg-Interferon/ribavirin, one can hypothesize that physicians were more willing to precisely quantify the risk/benefit ratio in these patients before considering another treatment course.
Until 2002, there was not in France any specific recommendation for HCV treatment in HIV-HCV patients [
30]. In 2002, treatment was recommended if the METAVIR score was ≥ F2 or ≥ A2/A3 with a CD4 cell count >200 cells/mm3 [
31]. In 2006, recommendations were extended to patients ≥ F2, ≥A2/A3, genotype 2 or 3 whatever the fibrosis score and to genotype 1 patients with HCV RNA <800,000 IU/mL [
32]. In 2008, treatment of acute HCV infection was also recommended [
33]. Fist-generation DAA, telaprevir and boceprevir became available in April and July 2011, respectively, for the treatment of patients with METAVIR F4 who had previously failed a PEG-IFN therapy. Our study allowed us to precisely describe the evolution of HCV treatment initiation rate (Fig.
1). A particularly high proportion of treated patients of 54.7 % was observed, resulting in a cure rate of 45.2 % of the treated patients. Previous studies have reported lower treatment uptake in HIV/HCV coinfected patients in various countries, including a recent study within the Swiss HIV cohort, a cohort with a similar number of patients [
15]. Differences in the study populations, differences between Health Care Systems and the time at which these studies were conducted may explain part of this difference. However, treatment uptake appears notably higher in cohorts of HIV/HCV coinfected patients than in HCV monoinfected patients. A recent systematic survey in European countries reported treatment uptake as low as 3.5 to 15 % in IVDU [
34] while treatment uptake of 10 to 23 % was reported from a review of studies among US veterans, mainly HCV monoinfected [
35]. Whether these differences were related to a better follow-up of coinfected patients under antiretroviral treatment, or to the effect of wider recommendations of treatment for HCV in coinfected patients [
21,
22] could not be asserted in this study.
Still, our data indicate that in 2012, 40.7 % of coinfected patients remained untreated for HCV, among whom 27.5 % had either cirrhosis or severe fibrosis and may require a priority access to treatment.
A decrease in all treatment initiations was observed between 2007 and 2011 possibly explained by physicians and patients choosing to wait for more potent and better tolerated oral anti-HCV regimens rather than initiating PEG-IFN/ribavirin therapy. A similar decrease was observed during the same period in the EuroSIDA cohort [
12]. This decrease was followed by an increase due to the arrival of the first-generation protease inhibitors (PI) telaprevir and boceprevir which accounted for 29.1 % of our treatment initiations in 2012. A similar increase was reported in US veterans, following the approval of these drugs in the US [
35].
Our results finally clearly show that treatment initiation is associated with a variety of host and viral factors and that the influence of these parameters could change over time. Among them, older age, male gender, controlled HIV infection, improved CD4 cell count , and non-C CDC stage are classically associated with more frequent treatment initiation [
12‐
15,
17,
18]. Interestingly, treatment initiation rate in patients with HCV duration below 1 year doubled from 2007 to 2010 reflecting the emergence of acute HCV infection at that time [
36,
37] and the perceived benefit of an early treatment [
38,
39]. In 2000, the proportion of F3-F4 patients initiating HCV therapy was almost twice that of F0-F2 patients but this difference regularly decreased until 2011, probably because of the evolution of recommendations of treating HIV/HCV coinfected patients regardless of the fibrosis stage [
40]. In 2012, the proportion of F3-F4 patients initiating therapy increased again probably because of availability of first-generation PI being initially recommended in pre-cirrhotic or cirrhotic patients. Since these molecules were effective on genotype 1 only, the proportion of genotype 1 patients initiating treatment drastically increased from 2011 onwards.
Our study presents several limitations. Data were obtained from a database mainly used in infectious diseases units. Since care for HCV infection can be shared between infectious diseases units and hepatology units, some data obtained in hepatology units could be missing, simply because the results were not entered in the database. This would be particularly accurate for HCV genotype and fibrosis evaluation. Thus, the data presented in this study may represent minimal estimates of the true numbers. The study was also not designed to precisely analyze the cause of death. Precise data regarding cirrhosis decompensation were not obtained, and the liver-related mortality reported in the study should also be considered as a minimal estimate rather than a definite rate. However, regular quality control in local and aggregated databases, including completeness analyzes for key data and automated processes within the database to obtain the virological response following HCV treatment all concurred to ensure good quality.
Some authors recently showed that low treatment uptake for HCV resulted from a combination of barriers at the system, practitioner, and patient levels [
11]. The authors suggested several strategies to enhance HCV treatment uptake in coinfected patients e.g. increasing the number of providers offering HCV treatment, lowering treatment costs, or providing enhanced HCV education and training programs for practitioners working in the field of HIV or addiction.
Acknowledgements
The authors gratefully thank Nicolas Voirin for performing the statistical analysis.
They also thank members of the Dat’AIDS study group : F. Raffi, C. Allavena, E. Billaud, C. Biron, B. Bonnet, S. Bouchez, D. Boutoille, C. Brunet, T. Jovelin, N. Hall, C. Bernaud, P. Morineau, V. Reliquet, O. Aubry, P. Point, M. Besnier, L. Larmet, H. Hüe, S. Pineau, E. André-Garnier, A. Rodallec (Nantes); S. Brégigeon, O. Faucher, V. Obry-Roguet, M. Orticoni, M.J. Soavi, I. Luquet-Besson, E. Ressiot, I. Pinot, M.J. Ducassou, H. Bertone, S. Gallie, S. Trijau, A.S. Ritleng, A. Ivanova, M. Guignard, C. Blanco-Betancourt, I. Poizot-Martin (Marseille) ; B. Marchou, P. Massip, E. Bonnet, M. Obadia, M. Alvarez, L. Porte, L. Cuzin, P. Delobel, M. Chauveau, D. Garipuy, I. Lepain, M. Marcel, E. Puntis, K. Sauné (Toulouse); P. Pugliese, C. Ceppi, E. Cua, J. Cottalorda, P. Dellamonica, E. Demonchy, J. Durant, C. Etienne, S. Ferrando, J.G. Fuzibet, R. Garraffo, K. Risso, V. Mondain, A. Naqvi, N. Oran, I. Perbost, S. Pillet, B. Prouvost-Keller, C. Pradier, S. Wehrlen-Pugliese, E. Rosenthal, S. Sausse, V. Rio, P.M. Roger (Nice); Ph. Choisy, S. Vandame, Th. Huleux, F. Ajana, I. Alcaraz, V. Baclet, T.H. Huleux, H. Melliez, N. Viget, M. Valette, E. Aissi, Ch. Allienne, A. Meybeck, B. Riff (Tourcoing) ; R. Agher, C. Katlama, M.A. Valantin, C. Duvivier , O. Lortholary, F. Lanternier, C. Charlier, C. Rouzaud, C. Aguilar, B. Henry, D. Lebeaux, G. Cessot, A. Gergely, P.H. Consigny, F. Touam (Paris) ; L. Cotte, D. Peyramond, C. Chidiac, T. Ferry, F. Ader, F. Biron, A. Boibieux, P. Miailhes, T. Perpoint, I. Schlienger, F. Dahoud, J. Lippmann, E. Braun, J. Koffi, C. Longuet, V. Guéripel, C. Augustin-Normand, S. Degroodt (Lyon); D. Rey, M.L. Batard, C. Bernard-Henry, C. Cheneau, E. de Mautort, P. Fischer, M. Partisani, M. Priester (Strasbourg).
Competing interests
Dr. Cotte reports grants from ViiV, MSD, non-financial support from Gilead, Janssen, BMS, ViiV, MSD, Abbott, outside the submitted work.
Dr. Pugliese has nothing to disclose.
Dr. Valantin reports personal fees from VIIV, personal fees from Janssen, other conflict of interest from Bristol Myers and Merck, outside the submitted work.
Dr. CUZIN reports personal fees from BMS, personal fees from ViiV healthcare, and other conflicts of interest from BMS, outside the submitted work.
Dr. Billaud has nothing to disclose.
Dr. Duvivier reports grants from Gilead Sciences, grants from BMS, grants from Janssen, grants from ViiV Healthcare, grants from MSD, outside the submitted work.
Dr. Naqvi has nothing to disclose.
Dr. Chéret has nothing to disclose.
Dr. REY reports personal fees from Gilead, non-financial support from Gilead, non-financial support from MSD, non-financial support from BMS, outside the submitted work.
Dr. Pradat has nothing to disclose.
Dr. Poizot-Martin reports personal fees from GILEAD, personal fees from BMS, personal fees from ABVIE, personal fees from ViiVhealthcare, outside the submitted work.