Daniel M. Keller, PhD

October 18, 2011

October 18, 2011 (Belgrade, Serbia) — Researchers in Romania have found a high rate of HIV-associated neurocognitive disorders in a cohort of young adults who acquired HIV infections parenterally during childhood.

Luminita Ene, MD, from the AIDS Department at the Dr. Victor Babes Hospital for Infectious and Tropical Diseases in Bucharest, told delegates here at the 13th European AIDS Conference of the European AIDS Clinical Society that, unlike in adults, the adolescents in her pilot study showed deficits mainly in the motor function and speed of information processing domains, suggesting a subcortical pattern of neurocognitive impairment.

She explained that HIV-associated neurocognitive disorders need to be addressed in adolescents and young adults living with HIV since childhood, but that better tools are needed for assessing neurocognitive function. In addition, longitudinal studies are needed to evaluate neurocognitive impairment and the effect of combination antiretroviral therapy (ART), because little information exists on the effects on the developing brain of chronic HIV infection and exposure to combination ART.

Dr. Ene noted that the young adults in the Romanian cohort were all infected parenterally with a single HIV clade (clade F) from 1987 to 1990, have a similar genetic background, and have been exposed to combination ART for about 8 to 10 years. Most other data have been derived from individuals with vertically acquired infections.

The study prospectively evaluated neurocognitive impairment in the 49 infected adolescents and 20 age- and sex-matched HIV-negative control subjects using HIV-associated neurocognitive disorder diagnostic criteria. All were about 18 years of age and had 10 to 11 years of education. Most of the subjects had good immune status and undetectable viral loads at the time of evaluation.

Forty-eight of the HIV-infected subjects had a history of treatment with antiretroviral drugs. The mean time of exposure was 5.8 ± 3.2 years (range, 0.46 to 15.4 years), and the median number of regimens was 2 (range, 1 to 6).

The investigators evaluated everyday functioning and assessed 7 cognitive domains: verbal fluency, speed of information processing, attention and working memory, abstraction/executive functioning, learning, delayed recall, and motor function. Few confounders, such as previous drug abuse, brain injury, and other central nervous system conditions, were present.

When English norms for neurocognitive testing were used, the measured rates of impairment were quite high for both the HIV-positive and HIV-negative groups; when Spanish norms were used, the rates were lower (47% vs 15%).

Dr. Ene reported that there were no significant differences between neurocognitively impaired and unimpaired HIV-infected subjects in terms of their exposure time to antiretroviral drugs, their nadir CD4 cell counts, and the time with CD4 counts below 200 cells/mm3. None of the subjects was institutionalized.

Overall, 25% of the HIV-infected cohort had asymptomatic neurocognitive impairment, 20% had mild neurocognitive impairment, 2% had HIV-associated dementia, and 53% had normal functioning.

"More than half of the patients had impairment in the speed of the information processing [55%] and motor domain [53%]," she said. In contrast, 35% and 20% of the control subjects showed impairment on each of these domains, respectively. Learning and abstraction domains were not greatly affected in the HIV-infected individuals (6% and 12% were impaired, respectively).

"When we look globally, the overall pattern of impairment in our young adult population was similar to those" in the period before combination ART, Dr. Ene said. "That is the interesting finding of our study." In pilot neuroimaging studies, subtle white-matter abnormalities were apparent in adolescents with asymptomatic neurocognitive impairment but decreased speed of information processing.

No subjects had major depression (a score of at least 29 on the Beck Depression Inventory), but the total median Beck Depression Inventory score tended to be higher in the HIV-infected than in the uninfected group (7.0 vs 4.5; P = .07). The difference in moderate depression between the HIV-infected and uninfected groups was not statistically significant (8.1% vs 5.0%).

Some limitations of the study were its small size and the lack of Romanian norms for neurocognitive testing. Also, the researchers are unsure whether the findings reflect the risk for HIV-associated neurocognitive disorders in vertically infected children.

Dr. Ene speculated about possible mechanisms for the impairments her group found. First, HIV infection might have induced irreversible brain injury before combination ART was initiated. Second, there could have been a persistent low level of viral replication in the brain because of poor drug penetration or the presence of drug-resistant viral strains. Third, inflammation and immune activation might have persisted in the brain. And finally, the drugs themselves might have had a neurotoxic effect.

Whether the measurable neurocognitive impairment has an effect on development, learning, daily activities, and life skills, and to what extent, is an open question. Session cochair Karina Butler, MB, consultant in pediatric infectious diseases and head of the multidisciplinary infectious disease/immunology service at Our Lady's Hospital for Sick Children in Dublin, Ireland, told Medscape Medical News that "up until now, this has really been an area that has been relatively poorly studied. In the early days of HIV in children, there was a lot of attention paid to the neurocognitive status as a manifestation, if you like, of HIV treatment and of treatment effect, but then when children got better generally, I think we sort of lost sight of that as important. Now that our children are living longer, we need to look at that again."

She said that the study by Dr. Ene's team looks at the reasons some HIV-infected children might not be attaining higher education levels. It will also be important to look at what interventions are needed to support certain areas of neurocognitive development, and to see if there are differential treatment effects.

Dr. Butler recommended studies on HIV-exposed but uninfected children of mothers who received treatment during pregnancy to investigate those children's development. In light of the myriad interacting effects of the infection and drugs, and social factors influencing development, "it's a very difficult area of study," she said.

The study received no commercial funding. Dr. Ene and Dr. Butler have disclosed no relevant financial relationships.

13th European AIDS Conference of the European AIDS Clinical Society (EACS): Abstract PS4/2. Presented October 13, 2011.

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