Effect of HCV in HIV-Infected Patients Initiating HAART
Effect of HCV in HIV-Infected Patients Initiating HAART
This meta-analysis of 21 studies demonstrated that HCV co-infection adversely affects early immune responses in HIV+ patients who start HAART or c-ART, especially those with baseline CD4 T-cell counts below 350 cells/mm. This impact was less pronounced 2 years after ART initiation. The virological suppression in persons receiving potent antiretroviral therapy seems to remain unaffected by the simultaneous existence of HCV.
HIV/HCV co-infection hastens HCV-associated hepatic disease in the HAART era. The reciprocal effect of HCV on the natural history of HIV disease is not clarified. Our meta-analysis showed the negative impact of HCV on early CD4 T-cell counts recovery in HIV+ subjects. This phenomenon has biological basis. CD4 T-cells can be infected by HCV and interactions of HIV and HCV at the cellular level could affect the immune efficacy of HAART. Moreover, chronic HCV infection, in the presence of HIV, increases T-cell immune activation, which is known to limit CD4 T-cell gains. Finally, HCV has also been found to enhance CD4 T-cell apoptosis. As a matter of fact, if apoptosis is partly implicated in the poorer CD4 T-cell recovery of co-infected patients, the restoration of their CD4 T-cells over time that was found in this meta-analysis dovetails with the observation that HIV replication control by HAART gradually attenuates the CD4 T-cell apoptosis rates in HIV+ patients with concomitant HCV infection.
This meta-analysis showed that there was a comparable virological response to HAART in HIV+ persons regardless of HCV status. By contrast, a recent analysis of randomized clinical trials (RCTs) reported that HCV carriage was associated with altered HIV-RNA suppression in co-infected individuals. This report, however, considered studies that were not designed to assess the impact of co-infection as the primary outcome of their analysis, recruited HAART-experienced patients and lacked clear description of meta-analytic techniques. Because most of the results of these trials were presented as abstracts, a new analysis of forthcoming full-text publications or of individual data would help clarify potential discrepancies between RCTs and observational research.
The meta-analysis of CD4 T-cell count change was characterized by substantial between-studies heterogeneity that predicated the conduct of subgroup analyses to explore its sources and potential impact. Previous receipt of antiretrovirals could result in heterogeneous effect estimates. Although it would be ideal to consider not only HAART- (as we did) but also ART-naïve individuals in this meta-analysis, some of the eligible studies had recruited patients with ART experience. Previous ART therapy could compromise HAART adherence, HIV load control and immunological response. However, as shown in Table 2, in spite of unexpected differences in magnitude, the effect estimates were statistically significant in both cases indicating a diminished CD4 T-cell response in HIV/HCV individuals irrespective of prior ART exposure.
It is important to diagnose HCV infection based on HCV-RNA detection to avoid misclassification of HCV antibody positive patients who are HCV aviremic. To explore the effect of potential misclassification, the meta-analysis of CD4 T-cell increase was performed separately by method of HCV diagnosis. The subanalyses showed that the results ceased being statistically significant in studies that adopted both serological and molecular testing. Although this could be a chance finding, it certainly calls for more accurate and consistent across studies definition of HCV infection.
The negative effect of co-infection on immunological response to HAART was observed only in patients with baseline CD4 T-cell counts below 350 cells/mm. This finding supports the current European Guidelines for Antiretroviral Treatment, which recommend immediate ART administration in HIV/HCV co-infected patients when CD4 T-cell counts drop below 500 cells/mm. It should be noted, however, that this meta-analysis included a limited number of studies that had involved patients with initial CD4 counts above 350 cells/mm. Future research needs to address this stratifying always immunological response by baseline CD4 T-cell counts.
The differences in CD4 T-cell recovery could be attributed to unmeasured confounding effects. For instance, the rates of HCV infection are extremely high among IDUs and previous research has shown that CD4 T-cell recovery is compromised in drug injectors compared with other groups, although this finding was not corroborated in other studies. It seems, however, that the immunological response of IDUs to ART could be influenced by many factors that result in poor adherence to the prescribed regimen including their potential incarceration, their participation in substitution programmes, their current injection status, the presence of psychiatric conditions or the provision of psychological support. The optimal way to elucidate the confounding effect of HIV risk groups in CD4 T-cell increase is to compare HIV mono-infected and HIV/HCV co-infected individuals by HIV risk group. Unfortunately, many of the eligible studies in this meta-analysis lacked the necessary information to perform this type of subgroup investigations.
The current work updates a previous synthesis using thirteen more reports, performing many subgroup analyses, and implementing some new meta-analytic methods. It indicates a delayed immunological response in HIV/HCV co-infected patients receiving potent combinations of antiretrovirals, especially among those with CD4 T-cell counts below 350 cells/mm. The delayed recovery of CD4 T-cells during the first year of HAART could increase the risk of toxicities or non-AIDS events. However, the clinical significance of the blunted CD4 T-cell response in the first months of HAART therapy is not fully elucidated yet and future prospective studies should explore its short-term and long-term consequences.
Discussion
This meta-analysis of 21 studies demonstrated that HCV co-infection adversely affects early immune responses in HIV+ patients who start HAART or c-ART, especially those with baseline CD4 T-cell counts below 350 cells/mm. This impact was less pronounced 2 years after ART initiation. The virological suppression in persons receiving potent antiretroviral therapy seems to remain unaffected by the simultaneous existence of HCV.
HIV/HCV co-infection hastens HCV-associated hepatic disease in the HAART era. The reciprocal effect of HCV on the natural history of HIV disease is not clarified. Our meta-analysis showed the negative impact of HCV on early CD4 T-cell counts recovery in HIV+ subjects. This phenomenon has biological basis. CD4 T-cells can be infected by HCV and interactions of HIV and HCV at the cellular level could affect the immune efficacy of HAART. Moreover, chronic HCV infection, in the presence of HIV, increases T-cell immune activation, which is known to limit CD4 T-cell gains. Finally, HCV has also been found to enhance CD4 T-cell apoptosis. As a matter of fact, if apoptosis is partly implicated in the poorer CD4 T-cell recovery of co-infected patients, the restoration of their CD4 T-cells over time that was found in this meta-analysis dovetails with the observation that HIV replication control by HAART gradually attenuates the CD4 T-cell apoptosis rates in HIV+ patients with concomitant HCV infection.
This meta-analysis showed that there was a comparable virological response to HAART in HIV+ persons regardless of HCV status. By contrast, a recent analysis of randomized clinical trials (RCTs) reported that HCV carriage was associated with altered HIV-RNA suppression in co-infected individuals. This report, however, considered studies that were not designed to assess the impact of co-infection as the primary outcome of their analysis, recruited HAART-experienced patients and lacked clear description of meta-analytic techniques. Because most of the results of these trials were presented as abstracts, a new analysis of forthcoming full-text publications or of individual data would help clarify potential discrepancies between RCTs and observational research.
The meta-analysis of CD4 T-cell count change was characterized by substantial between-studies heterogeneity that predicated the conduct of subgroup analyses to explore its sources and potential impact. Previous receipt of antiretrovirals could result in heterogeneous effect estimates. Although it would be ideal to consider not only HAART- (as we did) but also ART-naïve individuals in this meta-analysis, some of the eligible studies had recruited patients with ART experience. Previous ART therapy could compromise HAART adherence, HIV load control and immunological response. However, as shown in Table 2, in spite of unexpected differences in magnitude, the effect estimates were statistically significant in both cases indicating a diminished CD4 T-cell response in HIV/HCV individuals irrespective of prior ART exposure.
It is important to diagnose HCV infection based on HCV-RNA detection to avoid misclassification of HCV antibody positive patients who are HCV aviremic. To explore the effect of potential misclassification, the meta-analysis of CD4 T-cell increase was performed separately by method of HCV diagnosis. The subanalyses showed that the results ceased being statistically significant in studies that adopted both serological and molecular testing. Although this could be a chance finding, it certainly calls for more accurate and consistent across studies definition of HCV infection.
The negative effect of co-infection on immunological response to HAART was observed only in patients with baseline CD4 T-cell counts below 350 cells/mm. This finding supports the current European Guidelines for Antiretroviral Treatment, which recommend immediate ART administration in HIV/HCV co-infected patients when CD4 T-cell counts drop below 500 cells/mm. It should be noted, however, that this meta-analysis included a limited number of studies that had involved patients with initial CD4 counts above 350 cells/mm. Future research needs to address this stratifying always immunological response by baseline CD4 T-cell counts.
The differences in CD4 T-cell recovery could be attributed to unmeasured confounding effects. For instance, the rates of HCV infection are extremely high among IDUs and previous research has shown that CD4 T-cell recovery is compromised in drug injectors compared with other groups, although this finding was not corroborated in other studies. It seems, however, that the immunological response of IDUs to ART could be influenced by many factors that result in poor adherence to the prescribed regimen including their potential incarceration, their participation in substitution programmes, their current injection status, the presence of psychiatric conditions or the provision of psychological support. The optimal way to elucidate the confounding effect of HIV risk groups in CD4 T-cell increase is to compare HIV mono-infected and HIV/HCV co-infected individuals by HIV risk group. Unfortunately, many of the eligible studies in this meta-analysis lacked the necessary information to perform this type of subgroup investigations.
The current work updates a previous synthesis using thirteen more reports, performing many subgroup analyses, and implementing some new meta-analytic methods. It indicates a delayed immunological response in HIV/HCV co-infected patients receiving potent combinations of antiretrovirals, especially among those with CD4 T-cell counts below 350 cells/mm. The delayed recovery of CD4 T-cells during the first year of HAART could increase the risk of toxicities or non-AIDS events. However, the clinical significance of the blunted CD4 T-cell response in the first months of HAART therapy is not fully elucidated yet and future prospective studies should explore its short-term and long-term consequences.
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