Assessing the Efficacy of Highly Active Antiretroviral Therapy in the Brain

Abstract

The devastating effects of HIV infection have been documented for the last 2 decades. Since the 1980s over 60 million people have been infected and at present 40 million people globally are living with HIV (72). HIV infects the central nervous system (CNS) early in the disease process. Indeed, numerous studies document the presence of HIV within the cerebrospinal fluid (CSF) (14,15). Direct infection of the brain by HIV ultimately results in HIV associated dementia (HAD), which (prior to the advent of antiretroviral therapy) affected 20% of patients (48, 55). An increasing number of drugs have been developed to treat this infection and delay the development of AIDS. Current treatment is aimed at inhibiting viral replication, and thus, lowering the viral load. However a subsequent increase in viral load can occur as patients become resistant to drug therapy. In the era of HAART, the incidence of HAD has been reduced, whereas the prevalence rate is increasing as people with HIV survive longer. However, in a study of initial AIDS defining illnesses, the proportion with HIV related dementia did not decline following introduction of HAART (19). In a separate study, no decrease was found in the incidence of dementia per se, although there was a decrease in the incidence of all AIDS‐defining illnesses during this time period (50). It is evident from most studies that since the introduction of HAART, its effect on HAD is not entirely clear, although the majority of findings indicate that it is beneficial. Here we will outline the issues relevant to preventing HAD by HAART.

Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2′,3′-dideoxycytidine (ddC): Relevance to HIV-dementia

“…Despite the use of HAART, neurological complications still remain an important cause of disability and death associated with AIDS (Kandanearatchi et al 2003;McArthur et al 2003). The efficacy of these drugs in the brain is still controversial and research into the effect of HAART on the signs and symptoms of HIVD has resulted into a number of conflicting findings.…”

“…Just like endogenous nucleic acids, NRTIs have to undergo phosphorylation by a number of kinases to give the active triphosphorylated form (Kakuda 2000). It is known that the concentrations of NRTIs decrease progressively as they move from the plasma to the CSF (Sawchuk and Yang 1999;Kandanearatchi et al 2003). The penetration of NRTIs into the CNS has been an issue to date (Enting et al 1998;Sawchuk and Yang 1999).…”

“…Despite the decline of HIVD incidence, neurological complications still remain an important cause of disability and death associated with AIDS (Kandanearatchi et al 2003;McArthur et al 2003). The rise in the prevalence of HIVD despite the use of HAART is consistent with the poor penetration of some of these antiretrovirals into the CNS, hence increasing the longevity of the virus in the CNS (Deutsch et al 2001).…”

“…It has recently been reported that these drugs can effectively cross into the CNS, therefore, raising the question of their efficacy in the CNS and their possible role in HIVD (Enting et al 1998;Sawchuk and Yang 1999;Gibbs et al 2003a;Gibbs et al 2003b). For example, one treatment study showed variable results on the efficacy of NRTIs in the brain: one group of patients on HAART and having HIVD remained stable from cognitive impairment, while the other group showed signs of progressive neurological impairment even with treatment (Kandanearatchi et al 2003). This disparity could possibly be due to the increased survival of the virus in the brain or could possibly be due to the NRTIs on their own being neurotoxic as has recently been shown with the increase in damage to brain mitochondria in HIV positive patients using NRTI's (Schweinsburg et al 2005).…”

The blood-brain barrier: Bottleneck in brain drug development

“…Consequently, the brain remains a sanctuary for HIV in AIDS even with HAART. 4,5 Brain cancer, stroke, and brain or spinal cord trauma are all examples of serious CNS disorders for which there is no effective drug therapy. The childhood disorders including autism, lysosomal storage disorders, fragile X syndrome, the ataxis, and blindness, are serious disorders where there is little effective treatment.…”