The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression. The association of sustained impairment with worse current immune status (low CD4 cell count) suggests that restoring immunocompetence increases the likelihood of neurocognitive recovery. Finally, the lack of association between incident neurocognitive impairment and virological and immunological indicators implies that neural injury continues in some patients regardless of the success of antiretroviral therapy on these laboratory measures.

Objectives To estimate neuropathic sign/symptom rates with initiation of combination antiretroviral therapy (cART) in HIV-infected ART-naive patients, and to investigate risk factors for: peripheral neuropathy and symptomatic peripheral neuropathy (SPN), recovery from peripheral neuropathy/SPN after neurotoxic ART (nART) discontinuation, and the absence of peripheral neuropathy/SPN while on nART. Design AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial participants who initiated cART in randomized trials for ART-naive patients were annually screened for symptoms/signs of peripheral neuropathy. ART use and disease characteristics were collected longitudinally. Methods Peripheral neuropathy was defined as at least mild loss of vibration sensation in both great toes or absent/hypoactive ankle reflexes bilaterally. SPN was defined as peripheral neuropathy and bilateral symptoms. Generalized estimating equation logistic regression was used to estimate associations. Results Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/µl. Associations with higher odds of peripheral neuropathy included older patient age and current nART use. Associations with higher odds of SPN included older patient age, nART use, and history of diabetes mellitus. Associations with lower odds of recovery after nART discontinuation included older patient age. Associations with higher odds of peripheral neuropathy while on nART included older patient age and current protease inhibitor use. Associations with higher odds of SPN while on nART included older patient age, history of diabetes, taller height, and protease inhibitor use. Conclusion Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN.

Background Treatment initiation with integrase strand transfer inhibitors (INSTIs) has been associated with excess weight gain. Whether similar gains are seen after switch to INSTIs among virologically suppressed persons is less clear. We assessed pre/post-INSTI weight changes from AIDS Clinical Trials Group participants (A5001 and A5322). Methods Participants who were in follow-up from 1997–2017 and switched to INSTI-based antiretroviral regimens were included. Piecewise linear mixed-effects models adjusting for age, sex, race/ethnicity, baseline BMI, nadir and current CD4+ T-cell count, smoking, diabetes and follow-up time with suppressed HIV-1 RNA examined weight and waist circumference change before and after first switch to INSTIs. Linear spline models with a single knot at time of switch accounted for nonlinear trends. Results The 972 participants who switched to INSTIs were 81% male and 50% nonwhite with a median age at switch of 50 years, CD4+ T-cell count 512 cells/μL, and BMI 26.4 kg/m2. Restricting to persons with suppressed HIV-1 RNA at switch (n = 691), women, blacks, and persons ≥60 years experienced greater weight gain in the 2 years after versus before switch. In adjusted models, white or black race, age ≥60, and BMI ≥30 kg/m2 at switch were associated with greater weight gain following switch among women; age ≥60 was the greatest risk factor among men. Trends for waist circumference were similar. Conclusions Yearly weight gain increased following switch to INSTIs, particularly for women, blacks, and persons aged ≥60. Concomitant increases in waist circumference suggest that this weight gain is associated with an increase in fat mass.

Objective-Differences in antiretroviral (ARV) distribution into the central nervous system (CNS) may impact neurocognitive status. We assessed the relationship between estimates of ARV therapy penetration into the CNS, using a published ranking system, and neurocognitive status in HIV-positive subjects with plasma HIV-1 RNA (vRNA) suppression.Design-Subjects with ≥6 weeks ongoing ARV use and vRNA<50 copies/mL (N=2,636; 83% male, median baseline CD4 T-cells: 244 cells/uL) had ≥1 neuroscreen assessment (Trailmaking A,B, WAIS-R Digit Symbol) at 10,413 neurovisits. Neuroscreen test scores were demographically adjusted and converted to Z-scores (NPZ3: lower scores imply more impairment). CNS penetration-effectiveness (CPE) ranks of 0.0(low), 0.5(medium) or 1.0(high) were assigned to ARVs and summed per regimen, per neurovisit. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Role of author:Marlene Smurzynski: study and conceptual design, assisted with data analysis, interpretation of findings, wrote and edited manuscript, finalized manuscript for publication Kunling Wu: data analysis, created figures and tables, interpretation of findings, reviewed manuscript Scott Letendre: study and conceptual design, interpretation of findings, contributed to manuscript development, edited manuscript Kevin Robertson: study and conceptual design, interpretation of findings, edited manuscript Ronald J. Bosch: assisted with data analysis, interpretation of findings, edited manuscript David B. Clifford: interpretation of findings, edited manuscript Scott Evans: assisted with data analysis, interpretation of findings, reviewed manuscript Ann C. Collier: interpretation of findings, edited manuscript Michael Taylor: completed the normalized neurocognitive test scores (NPZ3 scores), reviewed manuscript Ronald Ellis: study and conceptual design, interpretation of findings, contributed to manuscript development, edited manuscript NIH Public Access Methods-Multivariate linear regression models using generalized estimating equations assessed NPZ3 scores with respect to ARV regimen. Covariates were retained if p≤0.1.Results-A final model demonstrated that better NPZ3 scores were associated with higher CPE among subjects taking >3 ARVs (+0.07 per one unit increase in CPE score; p=0.004) but not among subjects with ≤3 ARVs in the regimen (+0.01; p=0.5). Results were adjusted for demographics, injection drug use, HCV serostatus, CD4 count (current and nadir), baseline vRNA, ARV experience and years since first ARV use.Conclusions-Use of ARVs with better estimated CNS penetration may be associated wi...

Objective Both frailty and falls occur at earlier than expected ages among HIV-infected individuals, but the contribution of frailty to fall risk in this population is not well understood. We examined this association among participants enrolled in AIDS Clinical Trials Group (ACTG) A5322. Design A prospective, multi-center cohort study of HIV-infected men and women ≥40 years. Methods Frailty assessment included a 4-meter walk, grip strength, and self-reported weight loss, exhaustion, and low physical activity. Multinomial logistic regression assessed the association between baseline frailty, grip, and 4-meter walk and single and recurrent (2+) falls over the next 12 months; logistic regression assessed effect modification by several factors on association between frailty and any (1+) falls. Results Of 967 individuals, 6% were frail, 39% pre-frail, and 55% non-frail. Eighteen percent had ≥1 fall, and 7% had recurrent falls. In multivariable models, recurrent falls were more likely among frail (OR=17.3; 95% CI=7.03-42.6) and pre-frail (OR=3.80; 95% CI=1.87-7.72) than non-frail individuals. Significant associations were also seen with recurrent falls and slow walk and weak grip. The association between frailty and any falls was substantially stronger among individuals with peripheral neuropathy. Conclusions Aging HIV-infected pre-frail and frail individuals are at significantly increased risk of falls. Incorporation of frailty assessments or simple evaluations of walk speed or grip strength in clinical care may help identify individuals at greatest risk for falls. Peripheral neuropathy further increases fall risk among frail persons, defining a potential target population for closer fall surveillance, prevention, and treatment.