In this study, the possible impact of HCV co-infection on viro-immunological effectiveness of different HAART regimens was explored both in the early and in the late follow-up and using both a stratified and a multivariable analysis.
In the overall population we found that 88% patients reached HIV RNA suppression within months 4–8 months from initiation of HAART at ITT analysis. However, percentages differed by HCV co-infection and by anchor class received. In fact, HCV Ab-positive patients obtained HIV RNA suppression less likely than HIV mono-infected patients, though this difference was greater in those treated with PI/r (88% versus 92.2%) and NNRTI (84.7% versus 88.5%) than in those treated with PI (76.7% versus 75%). It is possible that this finding reflects a treatment adherence phenomenon. In fact, on one hand, if one assumes that HCV Ab-positivity is a proxy for a negative behavior related to IVDU, with a negative influence on treatment adherence [5, 21], the difference in virological suppression would be magnified in patients who received more complex regimens (such as the PI/r most frequently used at the time of the study) . On the other hand, in patients prescribed less potent regimens (such as PI), differences between the two groups could have been diluted. Indeed, the rate of treatment success in these patients was the lowest.
However, when predictors of HIV RNA response were investigated, HCV co-infection appeared to be a negative predictor independently from IVDU, suggesting that the effects of these two variables were not entirely overlapping. This may be due either to HCV co-infection “per se” (probably affecting the immune control of HIV replication) or to adherence as unmeasured variable because HCV co-infected patients may have been less adherent to treatment even though they were not IVDU. Further bio-psycho-social investigations are needed to understand the complex relationship between HCV co-infection, the role of adherence behaviors and IVDU as risk factor.
Regarding the other predictors of virological success, the positive impact of aging (possibly reflecting better adherence in older patients) is not new [23, 24], as well as the positive impact of more recent calendar years, possibly reflecting a significant improvement in the drug regimens and in the overall standard of care [25, 26].
We found a positive impact of higher CD4+ T-cell count as a protective variable for achieving HIV RNA suppression. It is possible that the immune system (either at baseline or reconstituted by HAART) has a role in better controlling HIV replication. If this is the case, our results point to earlier HAART initiation as a means to preserve immune system so that virological suppression is more frequent. But also the lack of virological suppression (or virological suppression in presence of suboptimal adherence), may be a cause rather than a consequence of lower CD4+ count, supporting the importance of a continuing assessment of treatment adherence, especially in HIV/HCV co-infected patients who appear to be disadvantaged.
Regarding the immunological outcomes, reactivity for HCV Ab was associated with a lower probability of obtaining ≥100 CD4+ T-cell count increase within 8 months from HAART initiation and with a smaller CD4+ T-cell count recovery up to 12 months in a multivariable analysis. It has been hypothesized that CD4+ T-cell depletion might result from ongoing cell activation and apoptosis driven by HCV  and therefore HCV could lower the CD4+ T-cell recovery through a direct pathogenic effect on lymphocytes even after HAART . Our results, together with this interpretation, suggest that it is important to treat HCV infection aimed at obtaining its eradication, not only with the main goal of treating liver disease but also as a means to improve the viro-immunological outcomes of HAART, especially early upon its inception.
Greub et al. studied a group of 1596 patients (33% of them were HCV Ab-positive) with sustained HIV RNA <400 copies/ml and found that HCV Ab-positive subjects had an impaired CD4+ T-cell recovery in the long term . By contrast, data from Kaufmann’s studies did not show any significant difference in CD4+ T-cell recovery when comparing HCV Ab-positive and HCV Ab-negative patients . Our results suggest that, even though HCV infection may have an impact in the short term (either because immune activation has not yet been down-regulated or because HIV RNA is less effectively controlled early upon HAART), a more prolonged undetectability of HIV RNA may eventually counteract the apparent disadvantage occurring in HCV co-infected patients.
The present study suffers from limitations: first, HCV RNA was not considered, therefore patients with HCV Ab-positive but negative HCV RNA may have been included in the analysis, even if patients treated with anti-HCV drugs were excluded with the aim to reduce this possible bias. Second, HCV genotypes were not considered. A small study found that, among 171 HIV/HCV co-infected patients, those infected by HCV genotype 3 had inferior CD4+ T-cell increase after 12 months of follow-up . However data from Antonucci et al.  did not find any correlation between HCV genotypes and immune-reconstitution in a cohort of 284 antiretroviral naïve patients. Therefore, further studies are needed to investigate the possible role of HCV genotypes on immune reconstitution in larger cohorts of patients over a longer follow-up. Third, other possible confounders such as severity of liver disease were not measured. Fourth, a <500 copies/ml cut-off for undetectability was considered. It is possible that persistent HIV replication below this cut-off may have had an impact on immune-reconstitution but this effect was not captured in our analysis.
In conclusion, the analysis of virological response suggests that HCV Ab-positive patients need focused interventions to maximize the effectiveness of HAART, especially early upon HAART initiation. Moreover, an higher CD4+ T-cell count predicted better virological control suggesting that preservation of immune functions is important not only to prevent clinical complications but also as a means to better control HIV replication. Thus, earlier HAART initiation is supported, especially in HIV/HCV co-infected subjects whose viro-immunological response may be compromised relative to HIV mono-infected patients. Lastly, it is possible that HCV eradication through specific treatments is beneficial not only for the main goal of treating liver disease but also for the viro-immunological effectiveness of HAART.