HIV has been shown to have a significant neuropsychiatric impact. There have been a myriad of pre-HAART era studies documenting neurocognitive and psychiatric effects of HIV.7,25–27
In general these studies reveal that advanced symptomatic patients exhibit greater rates of impairment.28
The correlation of cognitive impairment with advanced HIV disease persists in the HAART era. While the severity of dementia has lessened, its existence remains. Recently, a large autopsy series showed increased incidence of mild to moderate encephalopathy from the pre-AZT to the HAART era29
revealing a direct effect of HIV on the brain despite HAART. Thus, the longevity afforded to patients by HAART may make them susceptible to progressive CNS disease. For example, the median CD4 count at ADC diagnosis appears to be increasing30
although the disorder is still most apparent in populations with CD4 ≤ 200. In the HAART era, ADC appears to be evolving from a disorder of rapid deterioration to a more insidious and chronic condition. Our cohort, the MHBB, with advanced AIDS and a mean CD4 count of 168 (SD = 17), is thus a population at risk for cognitive dysfunction.
HCV as well as liver disease has also been associated with significant neuropsychiatric dysfunction. Neurocognitively, HCV-infected patients exhibit decrements in sustained attention, psychomotor speed, and set-shifting.8,31,32
Although one study8
was unable to differentiate an effect of HCV from other chronic liver diseases, another31
demonstrated that HCV viremia in the absence of cirrhosis or significant fibrosis was associated with cognitive impairment. Furthermore, these deficits (i.e., working memory and concentration deficits) were independent of IV drug use history, depression, or fatigue. Another study33
also found neurometabolic elevations of choline/creatine in basal ganglia and white matter in patients with histologically mild HCV. Thus, there is evidence of a cerebral effect of HCV even in the absence of liver failure and resulting hepatic encephalopathy.
Whether cognitive effects seen in HCV individuals are due to CNS viral penetration of HCV is unclear. The data regarding extrahepatic replication of HCV are controversial with some studies not finding evidence of replication.34,35
Recently, there has been preliminary evidence that HCV can replicate at extrahepatic sites particularly under conditions of immunodeficiency. Among HIV patients, HCV has been detected in lymph and peripheral blood mononuclear cells (PBMC), suggesting that HCV is lymphotropic in vivo under conditions of impaired immunity.36
Most recently, replicative forms of HCV were detected in the CNS that were more closely related to viral strains in PBMC than in serum.37–39
Thus, it appears that HCV-infected leukocytes can carry the virus into the CNS where viral replication may be sustained in an independent compartment. Replication could be facilitated by immunosuppression as replicative forms of HCV are commonly found in HIV-coinfected patients or liver transplant recipient patients40,41
and rarely found in PBMC from normal subjects.34,42
In addition to the possible extrahepatic manifestations of HCV, decompensated liver functioning may result in cognitive dysfunction (hepatic encephalopathy or minimal hepatic encephalopathy) either through reduced extraction and metabolism of encephalopathic substances or portosystemic shunting.43
Either phenomenon or the combined effect of both could potentiate neuropsychiatric impairment in coinfected individuals and may affect different anatomic (basal ganglia versus cortical) and cellular (astrocytic versus macrophage) compartments.
Regardless of mechanism, the MHBB cohort, with 61% having HCV antibodies, is at high risk for HCV-related CNS dysfunction. HCV replication in monocytes/macrophages and also in T and B lymphocytes has been documented in HIV-infected patients, and there is indication that HCV may replicate in the same cells as HIV thereby potentially causing direct interactions between the two viruses.37
The neuropsychological impairment reported among HCV patients is similar to that of HIV-infected patients with both affecting cognitive domains subserved by frontal-subcortical circuits.
Preliminary studies indicate a neuropsychiatric impact of HCV/HIV coinfection. In a small sample, coinfected individuals (n = 14) were more likely to show overall cognitive impairment than patients with exclusively HIV (n = 58) or HCV (n = 19).44
In our study, we see evidence of neurocognitive effects of coinfection in an advanced HIV cohort without significant hepatic decompensation. There was a trend for the coinfected group to perform worse neurocognitively. In addition to greater rates of impairment, we also found significantly more perseveration among the coinfected patients. Our ability to detect greater impairment is surprising given that HIV and HCV appear to have similar patterns of neurocognitive disruption and advanced HIV is associated with significant cognitive decline. Further investigation of executive functioning among coinfected individuals with an earlier stage of HIV infection may elucidate whether executive functioning is differentially affected by coinfection. The significant burden of HIV in our cohort may mask the HCV contribution to cognitive dysfunction. Finally, HCV+ patients in our sample were more likely to meet criteria for ADC and thus appear to have a more severe neurocognitive disorder despite similar HIV (CD4 and RNA plasma level) and liver disease (MELD) indices.
Although there appears to be a neuropsychiatric impact of HCV, future studies with indicators of HCV disease severity (HCV RNA load and fibrosis stage) as well as a broader spectrum of HIV disease may help clarify the pattern and extent of CNS dysfunction.