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PI Regimens Tied to Cerebral Small Vessel Disease--and CSVD Tied to HAND
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CROI 2014, March 3-6, 2014, Boston
from Jules: its important to listen to the webcast, link below, apparently many of these patients were taking the early protease inhibitors including indinavir which all were associated with lipid elevations & indinavir was associated with insulin resistance; the authors did not look at whether the patients had insulin resistance so they don't know if that could have affected these outcomes because apparently based on comments during the Q&A after the presentation it was mentioned that insulin resistance could contribute to developing CVSD. We know that more recent protease inhibitors do not appear to have the degree of lipid abnormalities associated with early protease inhibitors. During the post-talk Q&A I think the author Ron Ellis said the patients died or discontinued PIs in 2011, so based upon the slides & the post-talk Q&S its uncertain exactly how many of these study participants were on early PIs, ritonavir full dose, saquinavir, indinavir, nelfinavir or saquinavir+ritonavir, or the new PIs darunavir, reyataz, therefore for me its impossible to know if the association they found with protease inhibitors was completely due to the early protease inhibitors. Lastly, the presenter Dr Ellis said that despite successful ART HAND persists so perhaps this study finding suggests PI use could contribute to HAND since apparently CVSD can contribute to HAND, as well as diabetes can too, or perhaps insulin resistance as well. But its difficult to sort through the questions I raised above. However the association found by the author is interesting & deserves further evaluation but with a clearer understanding of exactly which protease inhibitors patients were taking, old or new, and if insulin resistance was present, if we are to understand these findings.
Mark Mascolini
A 144-autopsy study found associations between protease inhibitor (PI) regimens and cerebral small-vessel disease (CSVD) [1]. And mild CSVD more than quadrupled chances of HIV-associated neurocognitive disorder (HAND). Presenting author Ronald Ellis cautioned, though, that some autopsies date back to the early combination antiretroviral therapy (cART) era, when people were taking more toxic PIs.
Mild and moderate forms of HAND remain prevalent in people otherwise responding well to cART [2,3]. Although prevalence of severe HAND declined with widespread cART use [4], University of California, San Diego (UCSD) researchers hypothesized that toxic effects of long-term cART on blood vessel walls could contribute to CSVD [1]. Even early CSVD, the UCSD team noted, "could lead to disturbance of cerebrovascular autoregulation and deficiency in functional hyperemia." To test their hypothesis, they conducted this autopsy study.
The analysis involved 144 consecutive HIV-positive autopsy cases with detailed antiretroviral histories. Autopsies were done from 1999 through 2011. The UCSD team defined cART as a regimen including at least three antiretrovirals from at least two classes. They defined CSVD by standard histopathology and divided cases in three groups: moderate/severe, mild, or absent. Logistic regression analysis to probe for links between (1) antiretroviral exposure and CSVD and (2) between CSVD and HAND adjusted for HIV-related neuropathologic changes, older age at death, gender, and hepatitis C virus infection.
Of the 144 participants, 120 (83%) were men and median HIV duration measured 11.9 years at death. Median age at death was 45 years (interquartile range 26 to 70), but only 47 people (33%) were 50 or older when they died. Sixty-nine people had stopped cART for more than a year before dying or were antiretroviral-naive, 11 people were taking a non-cART regimen (not including a PI), and 64 (44%) were on cART. Of those 64 people, 51 (80%) were taking a PI-based regimen.
One quarter of autopsies revealed mild CSVD and 47% showed moderate/severe CSVD. In logistic regression analysis, PI-based regimens were associated with almost tripled odds of CSVD (odds ratio [OR] 2.84). Non-PI regimens were not linked to CSVD, but Ellis stressed that only 13 people (20% of those taking cART) were taking a non-PI combination. He also noted that numbers were too small to distinguish between the impact of older and newer PIs on odds of CSVD.
Mild CSVD boosted odds of HAND almost 5 times (OR 4.82). Moderate/severe CSVD was associated older age (OR 2.56) and diabetes (OR 6.55). These analyses adjusted for smoking and hypertension, neither of which was associated with CSVD or HAND.
The UCSD team proposed that PI-based cART "may contribute to CSVD through direct toxicity to cerebral small vessels or indirectly by inducing metabolic abnormalities." They believe the finding that mild CSVD predicted HAND substantiates the clinical importance of mild CSVD in people with HIV.
The investigators surmised that neurologists may be able to detect CSVD before arteriosclerosis develops, perhaps through brain imaging or CSF measurements of amyloid and vascular markers. Neuroprotective interventions that affect the final step of lamin A processing, they suggested, might prevent CSVD.
References
1. Soontornniyomkij V, Umlauf A, Soontornniyomkij B, et al. Cerebral small vessel disease and HAND in ARV-treated subjects. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 35. For webcast http://www.croiwebcasts.org/console/player/22059?mediaType=audio&
2. Clifford DB, Ances BM. HIV-associated neurocognitive disorder. Lancet Infect Dis. 2013;13:976-986.
3. Letendre S. Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med. 2011;19:137-142.
4. Ances BM, Clifford DB. HIV-associated neurocognitive disorders and the impact of combination antiretroviral therapies. Curr Neurol Neurosci Rep. 2008;8:455-461.
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