Analyses restricted to individuals who initiated ART after entry into the cohort showed similar results. The adjusted change (95% CI) of absolute CD4+ T-cell counts was 26 (12,41; P = 0.0004) for those HCV RNA– and 3.5 (−0.64, 7.7; P = 0.097) for HCV RNA+, with the interaction between HCV RNA status and follow-up time highly significant at P < 0.0001.
Censoring ART exposed patients at the time of first treatment interruption also resulted in similar findings (interaction between HCV RNA status and follow-up time; P = 0.0036). Finally, when restricting to patients with an undetectable viral load throughout follow-up (n = 178), the impact of HCV RNA was attenuated. HCV PCR + patients still had slower CD4 cell recovery (square root CD4, 0.29 vs. 0.51/year) but the interaction term was no longer significant (P = 0.28).
There were only 31 first AIDS defining events in the post-ART period, nondifferentially distributed between HCV RNA– (n = 4, 20%) and HCV RNA+ (n = 27, 15%) individuals. There was no significant difference in the time to AIDS according to HCV PCR status before (hazard ratio 0.62, 95% CI, 0.22–1.80), or after adjustment for baseline CD4 cell and HIV RNA (hazard ratio 0.46, 95% CI, 0.16–1.39).
Understanding the impact of HCV infection on the progression of HIV has important implications for the management of patients with HIV–HCV coinfection. Although it is well established that chronic HCV infection causes premature liver disease in HIV-positive individuals [4,35], the impact of HCV on HIV progression has been thought to be negligible [17,18]. To the best of our knowledge, this is the first study to specifically examine the impact of spontaneous HCV RNA clearance on HIV-disease progression in the setting of HIV–HCV coinfection. We show that after accounting for many clinical and demographic factors that affect HIV progression, spontaneous clearance of HCV infection is independently associated with a better rate of CD4 cell recovery once ART is introduced. There was also a trend to greater CD4 cell decline prior to ART initiation among those chronically infected with HCV when compared with individuals who spontaneously cleared, although this did not reach statistical significance probably due to lack of power.
Our findings were robust with large differences in CD4 cell recovery seen in analyses using both absolute CD4 cell count and CD4%, and in sensitivity analyses restricting to naïve patients initiating ART. The effect of chronic HCV on CD4 cell recovery seen in those initiating ART persisted to a similar degree throughout stable ART, suggesting a continued impact of active HCV replication on immune restoration and potentially on immune function even after years of ART exposure. This effect was not explained by differences in CD4 cell set point, baseline HIV RNA or ART regimen between those chronically infected and spontaneous clearers. The negative association remained after accounting for IDU, updated ART exposure and HIV replication. We could not, however, detect a difference in clinical AIDS events, which were relatively few in number in this cohort of individuals largely well controlled virologically on HIV treatment.
Although data have been conflicting as to the impact of HCV coinfection on immune restoration in patients who commence ART compared with those with HIV infection alone, a metanalysis of eight studies involving 6216 patients concluded that coinfected patients had an increase in CD4 cell count that was on average 33.4 cells/μl (95% CI, 23.5–43.3 cells/μl) lower after at least 1 year of ART . This difference is similar to what we observed between HCV RNA negative and positive persons from the cohort. A recent paper however found no difference in CD4 cell responses after ART initiation among virologically suppressed HCV antibody positive patients according to the presence of HCV viremia  raising possibility that non-adherence or HCV-driven HIV replication may account for poorer CD4 cell outcomes among HCV RNA positive individuals. Although adjusting for HIV RNA in follow-up did not remove the independent effect of HCV RNA in our analyses, when we evaluated CD4 cell responses among those with complete HIV suppression in follow-up, the impact of HCV replication was attenuated. It is, however, difficult to draw conclusions from such post-hoc analyses given the smaller sample size and the biases inherent in selecting individuals based on future HIV response profiles.
The mechanism by which chronic HCV replication may have deleterious effects on CD4 cell count reconstitution cannot be determined from our study. Ongoing T-cell activation related to HCV infection may limit the immunologic responses of patients with sustained viral suppression on ART. For example, for every 5% increase in the proportion of activated CD8+ T-cells, 35 fewer CD4+ T-cells were gained . Significantly elevated CD38 expression in both CD8+ and CD4+ T-cells has been described in HIV–HCV coinfected compared with HCV monoinfected persons and healthy controls, indicating that coinfection is associated with high levels of chronic activation of both T-cell compartments despite effective control of HIV replication by HAART . Interestingly, a reduction in the frequency of activated CD8+ and CD4+ T-cells has been observed after HCV treatment . In fact, we observed higher CD8 cell counts were associated with better CD4 cell responses. However, adjusting for CD8 cell counts did not remove the independent effect of HCV RNA on CD4 cell slope.
Even though we did not observe an impact of poor CD4 cell recovery on AIDS-related outcomes, there may be other important potential consequences to HCV-associated blunted immune recovery. Persistently lower CD4 cell counts while virologically controlled have been associated with higher rates of ART toxicities (e.g. peripheral neuropathy, lipoatrophy, renal dysfunction) . There is also a growing recognition of the importance of immune activation in driving other conditions that are resulting in excess morbidity and mortality in the post-ART era (e.g. liver, cardiovascular and renal disease) [40,41]. Chronic HCV infection may thus handicap the immune system and eradicating HCV through successful HCV treatment may be necessary to allow more robust immune reconstitution and possibly mitigate the effects of chronic HCV on these comorbidities. It would also be of interest to determine in future if differential CD4 cell recovery rates observed might have implications for the risk of these other non-AIDS events in the coinfected population.
A strength of our study is that we compared patients derived from similar populations with similar risk behaviours and lifestyles with and without active HCV RNA replication. Further, we were able to account for IDU and other clinical confounders, as well as for, potential treatment interruptions.
Our primary limitation was insufficient numbers of naïve patients who spontaneously cleared their infection with too short a follow-up time to conclusively determine if chronic HCV infection also impacts CD4 cell count progression prior to ART. Observational studies such as ours are also subject to potential cohort effects. Although we accounted for known factors that might influence outcome measurements, we cannot exclude the possibility of residual confounding. Finally, we were not able to evaluate T-cell function beyond absolute lymphocyte quantification to determine to what degree chronic immune activation or other mechanisms are potentially explanatory.
We found that CD4 cell progression is negatively affected by the presence of ongoing HCV replication in coinfected individuals who are taking ART. Our data support the need to study individuals with chronic replicating HCV separately from those who have cleared their infection when conducting research into HIV–HCV coinfection. Elucidating the mechanisms by which this difference occurs and investigating the impact of HCV treatment on CD4 cell progression should be prioritized. When successful, HCV treatment might have an important role not only in improving HCV related outcomes, but for HIV-related prognosis as well for coinfected persons.
The Canadian co-infection cohort investigators (CTN222) are Drs Jeff Cohen, Windsor Regional Hospital Metroplitan Campus, Windsor, ON; Brian Conway, Downtown IDC, Vancouver, BC; Curtis Cooper, Ottawa General Hospital, Ottawa, ON; Pierre Côté, Clinique du Quartier Latin, Montreal, QC; Joseph Cox, Montreal General Hospital; Montreal, QC; John Gill, Southern Alberta HIV Clinic, Calgary, AB; Mark Tyndall; Native Health Cente, Vancouver, ON; Shariq Haider, McMaster University, Hamilton, ON; Marrianne Harris St Paul's Hospital, Vancouver, BC; David Hasse, Capital District Health Authority, Halifax, NS; Julio Montaner, St Paul's Hospital, Vancouver, BC; Erica Moodie, McGill University, Montreal, QC; Neora Pick Oak Tree Clinic, Vancouver, BC; Annita Rachlis Sunnybrook & Women's College Health Sciences Centre, Toronto, ON; Roger Sandre, HAVEN Program, Sudbury, ON; Danielle Rouleau, Centre Hospitalier de l'Université de Montréal, Montréal, QC; David Wong University Health Network, Toronto, ON; Mark Hull, BC Centre for Excellence in HIV/AIDS, Vancouver, BC; and Sharon Walmsley, Toronto General Hospital, Toronto, ON.
We thank Alex Schnubb, Manon Desmarais, Curtis Sikora, Christine O'Reilly, Brenda Beckthold, Heather Haldane, Laura Puri, Nancy McFarland, Claude Gagne, Elizabeth Knight, Lesley Gallagher, Warmond Chan, Sandra Gordan, Judy Latendre-Paquette, Natalie Jahnke, Viviane Josewski, Evelyn Mann, and Anja McNeil for their assistance with study coordination, participant recruitment and care. We thank Jim Young for statistical advice.
This work was presented in part at the 16th Conference on Retroviruses and Opportunistic Infections (Montreal, February 2009; abstract #836).
This study was funded by the Fonds de recherche en santé du Québec, Réseau SIDA/maladies infectieuses (FRSQ), the Canadian Institutes of Health Research (CIHR MOP-79529) and the CIHR Canadian HIV Trials Network (CTN222). Dr Martin Potter is supported by a CTN Postdoctoral Fellowship award. Dr Marina Klein is supported by a Chercheur-Boursier clinician senior career award from the FRSQ.
M.B.K. is the principal investigator for the study and with M.P. formulated the project, analysed the data and drafted the manuscript. A.O. and H.Y. performed statistical analyses. S.S. managed the study. All of the authors contributed to the acquisition and/or interpretation of the data and revising the manuscript. All of the authors approved the final version of the manuscript for publication.
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