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Twelve-year neurocognitive decline in HIV is
associated with comorbidities, not age: a CHARTER study
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Download the PDF here
Download the PDF here
See commentary by Brew & Cysique
But should we be concerned about the additional impact of chronological age when there is such a high rate of neurocognitive impairment (40-45%) in American people with HIV despite treatment and viral suppression? Should we worry about chronological age when there is evidence of serious neurocognitive worsening in so many, old and young (up to 81% in those worst affected)? Should we care about the effects of ageing when neurocognitive improvement is already the exception?
From a pathophysiological and hence treatment perspective, the answer is yes. If HIV-related premature, accentuated or accelerated ageing4 is being masked in these older Americans with treated HIV disease by their high levels of multimorbidity, then this means that the risk of dementia is becoming very real and will be greater than what would be expected in the general population; HIV disease may reach a tipping point. Evidence for this potential tipping point can be seen in findings from HIV basic science, including HIV-associated mechanisms driving multimorbidity via immune senescence, immune activation and inflammation,8 as well as signs of continued HIV transcriptional activity despite years of viral suppression.9 The clear trajectory of decline in this CHARTER sample is worrying and should sound an alarm bell to clinicians and the community. In this context, calls to action like the recent 'Glasgow Manifesto' by the International Coalition of Older People with HIV (iCOPe HIV)10 ought to be heeded.
The reasons for the lack of evidence of accelerated ageing here are likely to becomplex......The authors are to be commended for acknowledging the limitations of their analyis, including the absence of data on survivor bias, on the timing of comorbidities, and on treatment efficacy; the lack of dedicated biomarkers of biological ageing5; the lack of a control group without HIV; and the fact that there were no data on social determinants of cognition, which may limit the generalizability of the findings beyond the USA. Focusing on biological ageing, we note that the younger CHARTER participants appeared to show abnormally high levels of biological ageing, as assessed by their comorbidity burden (i.e. the deficit model of biological ageing6), which increased further at follow-up. Notably, the under and over 60's did not differ at either baseline or 12-year follow-up in age-related comorbidities including diabetes, chronic pulmonary disease, metabolic syndrome and frailty. There was also evidence that many people with HIV in the study were not treated for their comorbidities.... the impact of comorbidities on cognitive decline is masking the effect of the nadir CD4-T cell count. Put simply, with respect to biological ageing, was the younger group really that young? Hence, was it the right comparator for the older group?
Abstract
Modern antiretroviral therapy (ART) has increased longevity of people with HIV and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical ageing due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of ART and biological ageing. Here we present results of comprehensive assessments over 12 years of 402 people with HIV in the CNS HIV ART Effects Research (CHARTER) programme, who at follow-up were composed of younger (<60 years) and older (≥60 years) subgroups.
Over the 12 years, ART use and viral suppression increased in both subgroups as did systemic and psychiatric comorbidities; participants in both subgroups also evidenced neurocognitive decline beyond what is expected in typical ageing. Contrary to expectations, all these adverse effects were comparable in the younger and older CHARTER subgroups, and unrelated to chronological age. Neurocognitive decline was unrelated to HIV disease or treatment characteristics but was significantly predicted by the presence of comorbid conditions, specifically diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression and lifetime history of cannabis use disorder. These results are not consistent with premature or accelerated neurocognitive ageing due to HIV itself but suggest important indirect effects of multiple, potentially treatable comorbidities that are more common among people with HIV than in the general population.
Good medical management of HIV disease did not prevent these adverse outcomes, and increased attention to a range of comorbid conditions in people with HIV may be warranted in their care.
Neurocognitive change
The primary neurocognitive outcome was the GCS, a continuous variable reflecting direction and degree of 12-year neurocognitive change....on average, neurocognitive performance declined modestly over 12 years, regardless of age or age group.
The GCS......Based upon this metric, 23.7% declined, 70.0% remained stable, and 6.2% improved. Figure 1A shows the mean of demographically corrected T-scores on the total test battery for decliners and non-decliners at baseline and then after 12 years.....with decliners doing much worse over time. Figure 1B shows the neurocognitive impairment rates for these two groups at the two time points. As in Fig. 1A for mean T-scores, these impairment rates were quite similar at baseline (P = 0.83) but very different after 12 years (P = 2.9 x 10-18); in fact, the impairment rate dropped by about 15% for the non-decliners (45% to 31%), and almost doubled for the decliners (44% to 81%).
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