An Italian cross-sectional study has found that the use of antiretroviral drugs that are active in the brain is not linked to performance on a range of neurocognitive tests. The study was published in the March edition of The Journal of Acquired Immune Deficiency Syndromes.
Impairments of thought and movement are a common complication of HIV infection, particularly in the late stages of disease, with problems ranging from very mild disorders through to HIV-associated dementia. While antiretroviral therapy is known to reduce the incidence of dementia by reducing HIV levels in the brain, its impact on less severe forms of neurocognitive impairment is not well understood.
In addition, only some anti-HIV drugs can cross the blood-brain barrier and reach adequate levels to control HIV replication in the brain tissue. Previous studies have shown that these are AZT (zidovudine, Retrovir), d4T (stavudine, Zerit), 3TC (lamivudine, Epivir), abacavir (Ziagen), nevirapine (Viramune), efavirenz (Sustiva) and indinavir (Crixivan).
To assess the impact of the use of these drugs on brain function, investigators from Rome carried out a battery of 17 standard tests on 165 HIV-infected patients from their clinic. All of the patients had been on anti-HIV drug combinations for at least six months and were selected for testing if they had symptoms of brain impairment, or CD4 cell counts below 200 cells/mm3.
The researchers found that 83 (50%) of the patients had neurocognitive impairment, which they defined as having significantly lower scores than standard levels on one or more tests.
When they compared the patients with and without neurocognitive impairment, the investigators found no differences in the number of brain-penetrating drugs that the patients were taking as part of their anti-HIV combinations.
In contrast, using a multivariate analysis they found that older age (odds ratio [OR] = 4.8, p
“Our study indicates that the use of stable highly active antiretroviral therapy containing multiple neuroactive drugs was not associated with impaired or unimpaired neuropsychologic performance as assessed by qualitative and quantitative parameters,” the researchers conclude.
“Moreover, neither the exposure to a specific class of antiretrovirals nor the use of a specific single drug was associated with the patient’s neuropsychologic performance. HIV replication in plasma and older age were the only factors independently associated with neuropsychologic disorders,” they add.
While their results seem surprising, the investigators explain that the use of brain-penetrating anti-HIV drugs may not be necessary to prevent neurocognitive impairment in patients with only mild damage to the immune system.
“Patients included in the present study presented with a mild degree of immunodeficiency, as confirmed by the high mean CD4 count (476 cells/mm3),” they write. “It is conceivable that in the HIV-infected population with less advanced disease but mild neurocognitive impairment, multiple central nervous system-penetrating drugs are not strictly required to control central nervous system HIV-1 replication.
“In the early stages, when immune function is quite preserved and cognitive functions are moderately affected, the control of plasmatic HIV replication could be sufficient to control HIV replication in [the] central nervous system and the use of multiple central nervous system-penetrating drugs may not be absolutely required,” they add.
However, the investigators acknowledge that their study has several limitations, including their inability to measure HIV levels in the brain fluid and the use of various different drug combinations by the patients. The study's cross-sectional design also limits the study’s conclusions, since any changes in the patients’ brain function over time could not be followed. In addition, the patients included in the study were at risk of neurocognitive impairment rather than being selected at random from a cohort of HIV-positive patients.
Giancola ML et al. Neuroactive antiretroviral drugs do not influence neurocognitive performance in less advanced HIV-infected patients responding to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 41: 332-337, 2006.