Patel K, Ming X, Williams PL. Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS. 2009 Sep 10;23(14):1893-901.
IN CONTEXT: Human immunodeficiency virus (HIV) encephalopathy in children produces active and persistent brain infection resulting in the need for antiretroviral therapy that penetrates the blood-brain barrier.(1, 2) A system that ranks the ability of antiretroviral medications to penetrate into the central nervous system (CNS) has been developed but not validated in children.(3) The effect of HIV treatment on the incidence of encephalopathy in children has not been determined.
- To describe the incidence of HIV encephalopathy in perinatally infected children;
- to evaluate the effects of highly active antiretroviral therapy (HAART) and CNS-penetrating antiretroviral regimens on encephalopathy incidence; and
- to assess the effects of HAART and CNS-penetrating antiretroviral regimens on overall survival and on survival after developing encephalopathy.
Multiple study sites in the United States
Children with perinatally acquired HIV infection enrolled in the Pediatric AIDS Clinical Trials Group (PACTG) between 1993 and 2006
HIV encephalopathy incidence and survival
Children enrolled in PACTG (a study conducted at over 80 clinical sites) were those whose mothers were enrolled in PATCG perinatal trials or who were enrolled in the PACTG perinatal or clinical trials and aged less than 21 years between 1993 and 2000. In 2000, all HIV-infected children at the PACTG sites were eligible to enroll. The population for this analysis was restricted to the perinatally infected children who had at least one neurological examination between 1993 and 2006.
At each study visit, data on sociodemographic characteristics, clinical diagnoses, antiretroviral therapies, and CD4 cell measurements were collected. HIV-RNA measurements were routinely collected starting in 2000. Baseline CD4 cell percentage and viral load were defined as the closest CD4 cell and HIV-RNA measurement recorded before or a week after the first neurological examination. HIV encephalopathy that was considered to be progressive was included as cases. HAART exposure was defined as the concomitant use of at least three drugs from at least two classes of HIV drugs (nucleoside/nucleotide reverse-transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors). The date treatment started was the midpoint between the visit date at which use of treatment was recorded and the previous visit date. A modified version of the CNS penetration-effectiveness rank was used to classify medications into three categories for the degree of CNS penetration (low, medium, high).(3) A CNS-penetration score was calculated for each antiretroviral regimen by summing the individual ranks of each antiretroviral drug included in the regimen. In analyses, children could switch from no HAART to HAART use and from low CNS-penetrating regimens to higher CNS-penetrating regimens. In the analyses, once a child began HAART or initiated his/her highest CNS-penetrating regimen, he/she was considered to remain on HAART and the highest CNS penetrating regimen for the length of follow-up.
The baseline date for all children was defined as the date of their first neurological examination For the analyses of incident HIV encephalopathy, each child was followed from his/her baseline date to the date of HIV encephalopathy diagnosis, death, or his/her last visit before 31 May 2007, whichever came first. For overall survival analyses, each child was followed from his/her baseline date to date of death, or censored as of his/her last visit before study closure. For analyses of survival after HIV encephalopathy diagnosis, all children with an incident diagnosis of HIV encephalopathy were followed from their date of HIV encephalopathy diagnosis to their date of death or censored as of their last study visit. The loss to follow-up was 3%-4% per year.(4)
Of the 3553 HIV-infected children enrolled in the clinical trial, 2398 (75%) had at least one neurological examination. The prevalence of encephalopathy at baseline was 5.3% (95% confidence interval [CI]: 4.4-6.2). The incidence of encephalopathy was 5.1 cases per 1000 person-years (95% CI: 4.0-6.3) based upon 77 new cases and median follow-up of 6.4 years. A total of 1806 children (79%) had initiated HAART. Thirty-one of the 77 HIV encephalopathy cases (40%) were on HAART. HIV encephalopathy occurred among 34 (2%) of the 1741 children on a high CNS-penetrating antiretroviral regimen, among 24 (9%) of the 267 children on a medium CNS-penetrating, and among 19 (7%) of the 264 children on a low CNS-penetrating regimen.
Overall mortality was 13.5 per 1000 person-years (95% CI: 11.7-15.4). There were 111 deaths (6%) among the 1756 children who had initiated a high CNS-penetrating regimen, 26 deaths (10%) among 255 children on a medium CNS-penetrating regimen, and 70 deaths (27%) among 261 children on a low CNS-penetrating regimen. There were 43 deaths among the 77 incident cases of encephalopathy over 219 person-years of follow-up, resulting in a mortality rate of 196.3 per 1000 person-years (95% CI: 142.1-264.5). Children who initiated HAART had a 50% lower risk of developing HIV encephalopathy compared with those who were not on HAART (hazard ratio [HR] 0.50, 95% CI: 0.29-0.86). High CNS-penetrating regimens were associated with a 41% reduced incidence of HIV encephalopathy compared with low penetrating regimens, although this association was not statistically significant (HR 0.59, 95% CI: 0.31-1.10).
Among all children in the study, HAART and effective CNS-penetrating regimens were associated with increased survival compared with no HAART and low CNS-penetrating regimens. The risk of death was increased among the children with encephalopathy (HR 12.42, 95% CI: 8.46-18.24). HAART use among the incident cases of encephalopathy reduced the risk of death compared with non-HAART regimens (HR 0.51, 95% CI: 0.25-1.05), but use of high CNS-penetrating regimens conferred a larger survival benefit after HIV encephalopathy diagnosis compared with low CNS-penetrating regimens (HR 0.26, 95% CI: 0.11-0.61).
HAART reduces the incidence of HIV encephalopathy among children with perinatally acquired HIV, and regimens that penetrate the CNS improve survival after encephalopathy in this population.
Based upon the Newcastle-Ottawa criteria, this was a very good study. The participants were drawn from the same population, and exposed and unexposed subjects were comparable. In addition, the exposure was determined from medical records, prevalent cases were excluded, assessment of outcome was by clinical criteria, follow-up time was sufficient, and loss to follow-up was minimal.
This study supports the use of HAART regimens that can penetrate the CNS for treatment of children with HIV encephalopathy and treatment with any HAART regimen to reduce the risk of developing encephalopathy.
- Epstein LG, Sharer LR, Oleske JM, et al. Neurologic manifestations of human immunodeficiency virus infection in children. Pediatrics 1986;78:678-87.
- Epstein LG, Goudsmit J, Paul DA, et al. Expression of human immunodeficiency virus in cerebrospinal fluid of children with progressive encephalopathy. Ann Neurol 987;21:397-401.
- Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008;65:65-70.
- Williams PL, Van Dyke R, Eagle M, et al. Association of site-specific and participant-specific factors with retention of children in a long-term pediatric HIV cohort study. Am J Epidemiol 2008;167:1375-86.