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  Response to "Persistence of Neuropsychologic Deficits Despite Long-Term Highly Active Antiretroviral Therapy in Patients With HIV-Related Neurocognitive Impairment"

JAIDS Journal of Acquired Immune Deficiency Syndromes:

15 December 2007

Garvey, Lucy MB, ChB, MRCP; Thomson, Emma C MRCP; Main, Janice MBChB, FRCP; Winston, Alan MBChB, MRCP

*St. Mary's Hospital, London Imperial College, London

To the Editor:

We read with interest the manuscript by Tozzi et al1 reporting the outcome of 94 HIV-infected patients with evidence of neuropsychologic (NP) deficits using a battery of tests. When followed for a mean of 63 months, they reported that in 62.8% of cases of NP impairment, the deficits persisted. Persistent NP deficits were observed both in patients who had received highly active antiretroviral therapy (HAART) and those who were antiretroviral (ARV) naive, suggesting that current HAART regimens remain inadequate at treating and reversing HIV-related neurocognitive impairment (NCI).

We would like to consider the potential role of hepatitis C virus (HCV) in contributing to the NCI of this large Italian cohort. The demographic information describes a HCV seropositivity rate of 45.7% of the 94 studied patients (41.9% of the ARV-naive group and 53.1% of the ARV-experienced group) and injection drug use as the mode of HIV transmission in 40.4%. No information on serum HCV polymerase chain reaction (PCR), extent of hepatitis on liver biopsy (where known), liver function tests, or HCV therapy were included in the analysis. In their results, Tozzi et al1 found that 55.9% of patients with persistent NP deficits were HCV seropositive, compared to 28.6% of patients with reversible NP deficits. This difference was highly significant (P = 0.008); however, in the multivariate model, it did not remain independently associated with persistent deficits (odds ratio [OR] = 0.96; 95% confidence interval [CI]: 0.34 to 2.76). Although this finding seems to preclude HCV involvement in persistent HIV-related NCI, further variables may need consideration before such conclusions can be drawn from the study.

There is now increasing evidence to show that chronic HCV is associated with NCI, even in the absence of potential confounding factors such as recreational drug use and hepatic encephalopathy.2-4 HCV is a neurotropic virus that can enter and replicate within the central nervous system and has been shown to cause cerebral changes on magnetic resonance spectroscopy of the brain.3-5 The combined effect of both HIV and HCV coinfection on the central nervous system (and how they affect neurocognitive performance) remains unclear and difficult to predict. Some studies have found rates of neurocognitive dysfunction in HIV/HCV coinfection not to be significantly worse than rates in HCV-monoinfected individuals.6,7 Other studies observe a trend for patients with HIV/HCV coinfection to perform worse neurocognitively than patients infected solely with HIV. The role of relative immunosuppression and effect of taking HAART has been variable, both on the extent and prognosis of NCI, highlighting an area that merits further research.1,8-9

Whereas it is assumed patients with major depressive disorders were excluded from this study due to non-HIV-related major neurologic or psychiatric disorders, depression is strongly linked with HCV, and therefore there was likely to be a high rate of mild to moderate depression in the HIV/HCV-coinfected patients.6 Depression is also triggered or exacerbated on commencing HCV therapy (including pegylated interferon) and can impair NP performance.

It is possible that some patients with HIV and HCV were treated for HCV in accordance with European guidelines during the study period. Evidence exists that pegylated interferon can itself cause a deterioration in cognitive function, although this is an inconsistent finding.10,11 No information on whether patients underwent HCV therapy during the study period were reported, which could be a confounding factor. Another area for consideration is the effect of successful HCV therapy on established NCI. If patients were treated and cleared HCV during the study, this may have improved HCV-associated neurocognitive problems and contributed to the reversible NP deficits found.

In summary, Tozzi et al1 have provided further valuable data on persistence and reversibility of NP deficits in patients with NCI in the era of HAART. This is an area of HIV medicine that remains poorly understood, and studies are urgently required to aid our understanding on how best to identify and treat patients coinfected with HIV and HCV with NCI. We hope that larger, multicenter studies will take place in the future to address these issues and further explore the contribution of hepatitis C virus (both in the acute and chronic state), pegylated interferon therapy, and coexistent depression in these complex patients.


1. Tozzi V, Balestra P, Bellagamba R, et al. Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors. J Acquir Immune Defic Syndr. 2007;45:174-182.

2. Forton DM, Allsop JM, Main J, et al. Evidence for a cerebral effect of the hepatitis C virus. Lancet. 2001;358:38-39.

3. Forton DM, Thomas HC, Murphy CA, et al. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology. 2002;35:433-439.

4. Kramer L, Bauer E, Funk G, et al. Subclinical impairment of brain function in chronic hepatitis C infection. J Hepatol. 2002;37:349-354.

5. Laskus T, Radkowski M, Bednarska A, et al. Detection and analysis of hepatitis C virus sequences in cerebrospinal fluid. J Virol. 2002;76:10064-10068.

6. Thein HH, Maruff P, Krahn M, et al. Cognitive function, mood and health-related quality of life in hepatitis C virus (HCV)-monoinfected and HIV/HCV-coinfected individuals commencing HCV treatment. HIV Med. 2007;8:192-202.

7. Perry W, Carlson MD, Barakat F, et al. Neuropsychological test performance in patients co-infected with hepatitis C virus and HIV. AIDS. 2005;19(Suppl 3):S79-S84.

8. Ryan EL, Morgello S, Isaacs K, et al. Neuropsychiatric impact of hepatitis C on advanced HIV. Neurology. 2004;62:957-962.

9. Von Giesen HJ, Heintges T, Abbasi-Boroudjeni N, et al. Psychomotor slowing in hepatitis C and HIV infection. J Acquir Immune Defic Syndr. 2004;35:131-137.

10. Fontana RJ, Bieliauskas LA, Lindsay KL, et al. Cognitive function does not worsen during pegylated interferon and ribavirin retreatment of chronic hepatitis C. Hepatology. 2007;45:1154-1163.

11. Kraus MR, Schafer A, Wissmann S, et al. Neurocognitive changes in patients with hepatitis C receiving interferon alfa-2b and ribavirin. Clin Pharmacol Ther. 2005;77:90-100.

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