www.hivandhepatitis.com

CROI 2014: Neurocognitive Problems, Depression, and Early ART in People with HIV

In a particularly challenging area of HIV care where research is complicated by gaps in knowledge and invasive clinical procedures, there was significant attention to neurological manifestations -- or neuroAIDS -- at this year’s Conference on Antiretroviral Agents and Chemotherapy (CROI 2014) last month in Boston.

One plenary, another oral abstract session, a themed discussion session, and several posters brought needed consideration to this arena. Topics ranged from the onset of depression in people with HIV, cognitive impairment, inflammation in the brain related to HIV, and the impact of initiation and selection of antiretroviral therapy (ART) on brain biomarkers.

Depression

While depression in people with HIV is common, it has been unclear whether HIV itself is associated with its onset. Understanding how HIV levels in cerebral-spinal fluid (CSF) relate to depression may suggest that depression could be a surrogate marker for central nervous system (CNS) inflammation and damage.

In an analysis from the CHARTER (CNS HIV AntiRetroviral Therapy Effects Research) study, Edward Hammond from Johns Hopkins and colleagues looked at whether HIV positive people with persistent or worsening depression would benefit from CSF viral load testing, which could help in guiding antiretroviral and antidepressant treatment decisions.

CHARTER is a prospective 6-center U.S. cohort of nearly 700 people with HIV, predominantly men. The mean age was about 45 and the mean duration of antiretroviral treatment was around 18 months. The researchers found that detectable HIV RNA in CSF was associated with a 4.7-fold increase in new-onset depression. HIV RNA in plasma was not associated with a similar increase of depression scores. Depression symptoms appeared to get worse over time in those who had detectable CSF HIV RNA, but improved over time in those with undetectable viral levels.

Cognitive Impairment

Cognitive impairment was studied in another small trial, showing differences in outcomes depending on the methods used. Judith Schouten from Academic Medical center in Amsterdam and colleagues found that the multivariate normative comparison (MNC) method -- which balances sensitivity and specificity in cognitive function -- showed a more reliable difference in prevalence between HIV positive (mostly gay men) and uninfected participants in this study.

The model showed a 3-fold increase in the HIV positive group, who were long-term virally suppressed. In addition, after controlling for relevant confounding factors, evidence of increased innate immune activation -- rather than CD4 nadir, or lowest-ever level -- was associated with increased likelihood of cognitive impairment.

Early ART

Providing further support for early antiretroviral treatment, Julia Peterson from the University of California at San Francisco and colleagues studied CSF inflammatory biomarkers in a small longitudinal observational study of 27 recently infected individuals.

Levels of the CNS inflammation biomarker neopterin in CSF fell significantly when ART was started during primary infection, and became equivalent to levels seen in HIV negative controls. In addition, when ART was initiated, neopterin levels in the blood and CSF were lower than those recorded in a historical control group who began ART later during chronic infection. This analysis is useful in predicting yet another benefit of early ART initiation.

Another study by Michael Peluso from Brigham and Women’s Hospital in Boston also showed neurocognitive benefits of early antiretroviral treatment. This group looked at neurofilament light chain (NFL) levels in CSF, a marker of axonal injury. The study compared people in Thailand who started ART during either acute or chronic HIV infection.

Baseline CSF NFL levels were lower in the acute compared with the chronic infection group. Only 3% in the acute infection group had NFL above the upper limit of the normal range for their age, compared to 30% in the chronic infection group. In the acute group there was no change in NFL from baseline values to those at 24 and 96 weeks after starting ART. After at least 6 months on ART, the acute group still had lower median CSF NFL than the chronic group; again, only 4% in the acute group had CSF NFL above the upper limit of normal compared to 50% in the chronic group.

Neuronal injury as measured by CSF NFL was not detected during very acute HIV infection, the researchers concluded, and immediate ART may mitigate development of neuronal injury, which may be more difficult to reverse during later stages of infection.

Type of ART

Finally, Christoph Stephan from Goethe-University Hospital in Frankfurt and colleagues compared HIV replication in the central nervous system among people with HIV taking different antiretroviral regimens. They compared 24 people taking boosted double protease inhibitors versus a control group of 31 people taking standard triple therapy containing 2 NRTIs plus a protease inhibitor, NNRTI, or integrase inhibitor.

They found that HIV in CNS was higher among people on protease inhibitors only compared to those on NRTI-containing triple regimens, suggesting that CNS penetration is worse with protease inhibitors. Previously thought to be time-dependent, the observed increase was seen over 8 years, after protease inhibitor therapy was well established.

Despite the variable participant characteristics in terms of neurological symptoms, this trial confirms data from the CHARTER study. While it has been known that protease inhibitors have less activity beyond the blood-brain barrier, this is the first study that demonstrated that HIV activity in CSF increased over time in people taking dual protease inhibitors.

4/9/14

References

ER Hammond, RM Crum, GJ Treisman, et al. Persistent CSF, But Not Plasma HIV RNA Is Associated With Increased Risk of New-Onset Depression. 21st Conference on Retrovirus and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 33.

J Peterson, E Lee, D Fuchs, et al. Early Antiretroviral Therapy Appears To Normalize Intrathecal Markers of Immune Activation. 21st Conference on Retrovirus and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 30.

J Peluso, V Valcour, J Ananworanich, et al. Immediate Antiretroviral Therapy Mitigates the Development of Neuronal Injury in Acute HIV. 21st Conference on Retrovirus and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 31.

J Schouten, T Su, FW Wit, et al. Determinants of Cognitive Impairment in HIV-positive Men on cART and Uninfected Controls: HIV, immune activation.21st Conference on Retrovirus and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 481.

C Stephan, M Donath, T Wolf, et al. HIV-1 Replication in Central Nervous System Increases over Time on Protease Inhibitor Only Therapy. 21st Conference on Retrovirus and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 473.