These analyses suggest that neither neurocognitive disability nor neuropathy in HCV/HIV coinfection is significantly driven by active replication of HCV in the plasma. This study is important as it includes a relatively large sample size and utilizes HCV VLs to define active HCV disease. This result suggests that clinically important neurologic deficits are unlikely to be the result of HCV viral replication.
It is interesting that when HCV antibody status is considered, a marginally significant difference in performance favoring the HCV antibody–negative group emerges, much as we saw in our previous antibody-based retrospective analysis of participants in a single ACTG treatment trial.14
This might suggest that a history of infection by HCV reflected in the antibody status is more important than the contribution of HCV replication when the performance is measured. While this could be the result of prior neurologic damage, it might also be biased more heavily by group differences that might impact performance, most notably for IDU, education, or race.
This analysis has several limitations. It is a retrospective study and we were unable to completely match on the confounders believed to be important. Instead we attempted to statistically adjust our analyses to minimize the bias these confounders might introduce. There may be additional unrecognized/unmeasured confounders for which we could not control. Potential confounders not analyzed included alcohol use, diet, liver function status, and CSF (HCV and HIV) VL status. Had we found a significant decrement in performance in the active HCV population, these uncontrolled confounders might be of greater concern. However, it seems unlikely that they would be protective and result in a false negative finding in our study.
The measures that we used were also brief and administered by staff that was not specialty trained in neurology. More rigorous or more difficult tests might detect functional changes in other domains, or smaller degrees of dysfunction. However, these are not practical in exploratory studies of large cohorts such as the ALLRT study, and brief and robust measures such as our battery have served well to probe neurocognitive function. The performance characteristics of this brief neurocognitive and peripheral neuropathy battery have been characterized and validated with this group.18
One important way in which this study differs from others that have attempted to describe the specific impact of HCV in the setting of HIV infection is that we have chosen to control the impact of the HIV infection by studying HCV in the setting of virologically controlled HIV infection. It might be true that an entirely different dynamic could occur if both infections were untreated (i.e., with higher HIV-1 RNA VLs) or unsuccessfully treated. However, we believe that in a practical sense, the major issue about coinfection will revolve around the additional impact of HCV for the majority of HIV-positive patients who currently benefit from successful control of their HIV, but are concerned about the additional risk to the nervous system of a second potentially neuroinvasive virus. We believe the observations that we report are relevant to this population and suggest that neurologic consequences will not be the driving feature requiring HCV treatment.
Our findings are largely consistent with those from the coinfection experience reported from the Manhattan HIV Brain Bank study.19
did not find that HCV/HIV coinfection resulted in greater neuropsychological impairment than HCV alone. A rather large study in the Hemophilia Growth and Development Study reported that after controlling for multiple factors, HCV monoinfection was not associated with deficits in adaptive behavior, intelligence, or attention/concentration.21
Still, several investigators have carefully studied substantial numbers of patients and concluded that HCV is associated with negative neurocognitive consequences. Letendre et al.22
concluded that HCV contributed to neuropsychological deficits observed in a study of HIV-infected and stimulant-dependent participants. More detailed neuropsychometric analysis was performed as part of this study, but the numbers of HCV antibody–positive subjects (83) were smaller than our study, and the demographic characteristics between populations diverged significantly in this study.
Our observations are consistent with observations in a study of HAART, HIV, and HCV coinfection in which untreated coinfected patients showed worse performance on testing than HIV monoinfected patients, but after 6 months of HIV therapy, the groups no longer differed.23
While the observations in this study were interpreted to suggest interaction of active coinfection, they also replicate our observation that in treated HIV-positive patients, coinfected participants perform similarly to the monoinfected population, suggesting that HAART may eliminate negative impact of coinfection.
Our analysis is one of the largest to link HCV VL data with specific quantitative neurologic testing. In undertaking the project we could not get reliable data on the degree of incongruity to be expected between HCV antibody testing and demonstration of HCV VL. The evaluation of the HCV antibody–negative subjects yielded 5 in whom HCV VLs ranged from 741,000 to 4,800,960 IU/mL. Because the testing of antibody and RNA was not performed precisely at the same time, it could be that the incongruent results were due to recent conversions, rather than false negative results. However, others have described as many as 19% false negative HCV antibody testing in the setting of HIV infection.24
Our study makes an important statement about pragmatic issues in the setting of HIV and HCV coinfection. While both viruses likely enter and can replicate in the brains of patients, and may well impact neurocognitive function as a result of this, when the HIV infection is pharmacologically controlled, the addition of HCV appears not to have clinically important additive impact. The long-term consequences of HCV coinfection remain important, and will be necessarily a focus for ongoing treatment development due to the significant morbidity and mortality of liver disease in this population. The liver disease will independently impair brain function. However, it appears that primary neurocognitive disease is unlikely to represent a critical reason for initiation of HCV therapy in the setting of coinfection, and it is unlikely to be a major cause of neurocognitive impairment that is still seen in the treated HIV populations.