Taking antiretroviral drugs which penetrate into the central nervous system was associated with a reduced risk of death and substantial protection against HIV encephalopathy in a large cohort study of US children with HIV, investigators report in the September 10th edition of AIDS.
Prior to the introduction of three- or four-drug combination antiretroviral therapy in children, HIV encephalopathy was a common event in children with HIV. HIV encephalopathy is a progressive infection of the brain by HIV, resulting in worsening cognitive and motor problems, leading eventually in some to AIDS dementia.
Since the introduction of HAART there is some evidence that the incidence of HIV encephalopathy in children has declined, or that its onset has been delayed. However, to date no one has studied the question in a large prospective study.
The Pediatric AIDS Clinical Trials Group began recruiting children to a long-term prospective study, ACTG Protocol 219, in 1993. This study is following children with HIV at 80 sites in the US.
This study covered 2398 perinatally-infected children recruited to the ACTG 219 natural history study who had undergone at least one neurological examination. The group were evenly divided by gender and the vast majority (85%) were aged ten or below. 56% had a CD4 percentage above 25, implying a relatively intact immune system, but only 19.4% remained antiretroviral-naïve.
Of those who took antiretroviral drugs the majority (65%) received a non-HAART regimen.
In order to analyse the effect of antiretroviral drugs on the incidence of HIV encephalopathy, the researchers examined the incidence of the condition across time periods and according to the drugs received.
The incidence of HIV encephalopathy declined tenfold after 1996, when HAART was introduced, reaching a stable incidence after 2002.
Over a median follow-up of 6.4 years 77 cases of HIV encephalopathy occurred, an incidence rate of 5.1 cases per 1000 person-years. However, incidence declined from over 20 cases per 1000 person-years in 1995 to less than two cases per 1000 person-years in 2000.
The proportion of children receiving antiretroviral regimens with high ability to penetrate the central nervous system – and act on HIV in the brain – increased after 1996, and children who received these regimens had a significantly lower risk of death than children who received regimens with low CNS penetration (hazard ratio 0.31, 95% confidence interval 0.22 – 0.45, p
However receipt of a regimen with high CNS penetration had no significant effect on the risk of developing HIV encephalopathy, due to the small sample size. HAART of whatever type was associated with a 50% reduction in the risk of HIV encephalopathy however (95% confidence interval 0.29 – 0.86).
Other risk factors for HIV encephalopathy were a baseline CD4 percentage below 15% (hazard ratio 8.41, 95% CI 4.79-14.76) and age below one year at first neurological examination (hazard ratio 3.38, 95% confidence interval 1.36-8.44).
“These results suggest that HAART inhibits or delays HIV dissemination in the CNS and may also decrease viral replication if an active and persistent infection is already established in the brain,” the authors conclude.
However the authors are not able to draw firm conclusions about the mechanism by which HAART may inhibit or delay HIV dissemination in the brain due to lack of direct measurement of HIV in the CNS, leaving the question open as to whether drugs with higher CNS penetration necessarily have a greater preventive effect in children not already diagnosed with HIV encephalopathy. A newly-published animal study suggests that even drugs which do not penetrate the brain exert an indirect effect on HIV activity in the brain by means of changes in the immunological environment in the central nervous system.
Patel K et al. Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS 23: 1893-1901, 2009.