We found that increased peak VL correlated with reduced total grey matter, bilateral rostral middle and superior frontal volumes. Youth with recent unsuppressed VL had smaller volumes for these regions, although associations attenuated after adjustment for sex, age at neuroimaging, and age at peak VL. Moreover, PHIV youth who reported alcohol and marijuana use showed further reduction in grey matter volumes compared with PHIV youth who reported no use. Finally, smaller volumes of primary ROIs and total grey matter correlated with lower performance on standardized measures of working memory, processing speed, and cognitive proficiency. Patterns of smaller volumes appeared to be symmetric bilaterally for these tested associations: 1) PHIV youth vs. typically-developing, HIV-unexposed and uninfected youth 2) higher peak VL and 3) recent unsuppressed VL for regions that were significantly different or trended towards significance. In addition to these selective losses associated with PHIV, higher VL, substance use,vertical harvest farms and poorer cognitive performance were also associated with smaller total grey matter volumes. Total decreased grey matter volume may be due to abnormal development in primary ROIs as well as subtler abnormalities in the rest of the brain that did not reach statistical significance after multiple comparisons with our sample size. Prior neuroimaging studies in adults with HIV have reported that HIV severity was related to reduced global and regional brain volumes in both untreated patients and those treated with cART . Findings on cortical changes varied but overlapped between studies.Some studies have identified frontal and parietal lobe grey matter volume loss ; others have shown volume loss in temporal and limbic regions . Cortical thinning has been reported in postcentral and precentral gyri with degree of atrophy correlating with cognitive impairment in HIV+ adults .

Our study of PHIV youth identifies reduced volume in the prefrontal cortex, a brain region not specifically reported in studies of adults with horizontally-transmitted HIV. Importantly, prefrontal regions undergo tremendous development during adolescence . Differences in findings between our study and prior studies could be due in part to differing patient populations and different environmental exposures . Although brain volumes in adults with horizontally-transmitted HIV have been studied, the long-term effects of HIV infection treated with cART on developing brains of adolescents have not been extensively examined . Importantly, PHIV youth are exposed to HIV and cART during critical developmental periods of the brain. Other studies of our PHIV cohort have found overall and regional white matter micro-structure and functional connectivity as well as subcortical deformation differences in those with worse HIV disease severity and/or compared to controls . In a recent study on another cohort of PHIV youth, Sarma et al. found that compared to age-matched controls, adolescents with PHIV had reduced white matter volume, but increased grey matter volumes in superior frontal and temporal gyri. Differences in findings between our studies may be due to the smaller sample size, more severe HIV disease and later onset of cART in the PHIV youth in the Sarma et al study . The authors suggest that larger grey matter volume may be due to inflammation. Another recent study on a slightly younger cohort of PHIV youth by Cohen et al. found that youth had lower overall grey matter volumes, but did not study regional differences compared to controls. We also found lower total grey matter volume in our cohort of PHIV, a geographically-different and older clinical population than in the Cohen et al. study. Importantly, our study also considered additional effects of substance use on brain structure as well as an examination of relationships between regional brain differences and cognition. Substance use in adolescence may lead to aberrant development during a vulnerable period of significant brain maturation and/or or pre-existing structural brain differences may lead to increased substance use .

Previous studies have demonstrated that adolescents who are more likely to drink alcohol have thinner frontal cortices and distributed regions in the frontal, parietal, temporal, and occipital lobes . A larger study of PHIV youth in the PHACS AMP study found that substance use among PHIV youth may lead to greater risky behavior . In our neuroimaging cohort, we found that substance use among PHIV youth may exacerbate total and regional grey matter reductions. Notably, PHIV youth who reported substance use had reductions in bilateral frontal gyri, regions involved in executive functioning, logical thinking, goal setting, planning, and self-control, which may be associated with decision-making and risky behaviors . While these findings are consistent with some studies on brain volume reductions among HIV-uninfected adolescents who use alcohol or marijuana, they also differ from others identifying increased volumes with marijuana use . Differing patterns found in our study may be due to dose-related effects; we examined ever-use, not frequency or duration of use. Moreover, concurrent marijuana and alcohol could have complex and perhaps interacting effects on brain structure . An additional consideration for interpreting our findings is that socioeconomic status may affect brain development. Previous studies have demonstrated that altered grey matter measures such as volume, cortical thickness, and surface area in distributed cortical and subcortical regions are associated with socioeconomic status . Despite differences in socioeconomic status between our HIV-unexposed and uninfected youth and PHIV youth cohorts, regional and total grey matter volume differences persisted after controlling for socioeconomic status. Unlike some previous studies, socioeconomic status alone was not associated with regional brain volume differences. There are some potential limitations to consider when interpreting our results. One limitation is the difficulty of teasing apart individual effects of PHIV, cART, and substance use on brain volumes. Although we attempted to address this limitation by including a measure of persistence of unsuppressed VL, we observed no associations with this measure; other cumulative measures of HIV severity may add additional insight on HIV effects on the brain.

Another limitation is the availability of only a single neuroimaging study during adolescence, making it more difficult to isolate effects of HIV, treatment, and preexisting pathology. A further limitation is that we only report cognitive and substance use findings in the PHIV youth and did not have comparable measures for the typically-developing control cohort. However, it should be noted that the relationship between brain volume changes in the general population is relatively well-researched and our volume findings in many regions in PHIV youth overlap with previous findings on cognition and substance use-brain volume findings in typically-developing youth . Finally, while our study only evaluated brain volumes with respect to HIV infection status and past HIV disease severity measures such as peak HIV RNA load and nadir CD4%, examining measures of inflammation and interleukins with respect to brain volumes may deepen our understanding of structural brain changes in youth with PHIV. Other studies have found that cognitive performance is related to a variety of cytokines and that certain cytokine markers, especially IL-6 and IL-16, significantly relate to brain volumes in adult HIV patients. Proton magnetic resonance spectroscopy studies have found that in adult HIV patients, elevated neurofilament light chain in the cerebrospinal fluid correlated with MRS abnormalities in the anterior cingulate, frontal white matter,vertical farming systems and parietal grey matter . In youth with PHIV, the relationship of brain volumes to inflammatory markers has not yet been studied, though studies in youth with PHIV have found that neopterin and sCD14 levels are elevated and that aggregate measures of fibrinogen, CRP, and IL-6 are associated with decreased processing speed in youth with PHIV and in uninfected youth with perinatal HIV exposure . Future studies should aim to assess effects of PHIV, cART, and substance use with longitudinal neuroimaging and include diverse measures of HIV disease severity and inflammation, which may provide more information on when the brain is most vulnerable to HIV and substance use, as well as when treatment is most effective. With increased longevity due to cART, preservation of neurological function becomes important for quality of life and adequate functional outcomes. Our study provides preliminary insight into the effects of HIV and substance use on the brain in PHIV youth as well as potential clinical biomarkers for evaluating HIV-related brain atrophy and cART efficacy in the brain. PHIV youth may demonstrate distinct and particular vulnerability toHIV compared to adults due to exposure to HIV and antiretroviral treatment during critical developmental periods. Older persons living with HIV , often defined as age 50 years, represent a rapidly growing population. More than 50% of PLWH in the U.S. are 50 years, . Furthermore, older PWLH have high rates of multi-morbidity . Chronic pain and substance use occur commonly in this population and are associated with poor health outcomes and increased use of healthcare services . PLWH are also at risk for declining physical functioning and reduced physical performance . Given the high prevalence of co-morbid pain, substance use, and reduced physical functioning in older PLWH, multi-component interventions targeting all three are needed. Cognitive behavioral therapy is an evidence-based approach for managing both pain and substance use .

According to the Infectious Diseases Society of America guidelines, CBT is a recommended first line non-pharmacologic treatment for chronic pain management among PLWH . In addition, exercise therapies reduce pain, reverse muscle atrophy, and decrease fall risk among older adults with chronic pain . Tai chi is a mind-body exercise that combines gentle movement, meditation and deep breathing. Tai chi can be feasibly administered to diverse groups of older adults and is associated with reduced pain, risk of falling and depressive symptomatology . Given high rates of physical deconditioning in PLWH , tai chi constitutes a particularly appealing movement-based therapy due to its use of low impact, graded, weight bearing exercises. Finally, text messaging has recently demonstrated efficacy in reinforcing elements of behavioral interventions, including those directed at changing addictive behaviors and managing chronic pain . Text messaging may also be an acceptable continuing care strategy following intensive treatment for a substance use disorder and in reducing problem drinking . We conducted a pilot randomized controlled trial to assess the feasibility, acceptability and preliminary efficacy of a multi-component behavioral intervention—a combined CBT and tai chi protocol reinforced with text messaging—to reduce levels of pain and substance use, and improve physical performance among older PLWH. We hypothesized that participants randomized to the intervention arm would demonstrate reductions in substance use, pain-related disability and pain intensity along with improvements in physical performance. Prior to the RCT, we conducted focus groups with prospective end users of the intervention to ascertain their preferences regarding behavioral treatments for pain ; developed the integrated intervention and trained APAIT staff to deliver it; and conducted a small pilot study, using the results to refine study materials and procedures prior to the current trial. We also obtained supplemental funding to conduct daily diary assessments of overall health, pain, behavioral responses to pain, mood, sleep, exercise, drinking and drug use, and social contact among all study participants via their cell phones. These data are reported in a separate paper . The Institutional Review Boards of all participating institutions approved the study. All participants provided written informed consent and participants assigned to the CBT/TC/TXT arm granted permission for the CBT sessions to be audiotaped.Study investigators developed an eight session, manualized treatment protocol to be delivered once weekly over 60 minutes in a group format by behavioral health counselors. The eight week, open-group program was adapted from three manualized interventions: 1) Manage Your Pain ; 2) Integrated CBT ; and 3) Mindfulness Based Relapse Prevention . All CBT sessions began with homework review, followed by delivery of didactic materials, coping skills, rehearsal exercises, and a new homework assignment. Therapy content focused on a different theme each week including 1) coping with chronic pain, 2) using mindfulness to cope with pain, 3) understanding and changing problematic patterns of substance use, 4) building motivation for change, 5) stress management and problem solving, 6) coping with negative thoughts and emotions, 7) improving sleep, and 8) building social support. Participants were given a copy of the client manual to facilitate between-session homework practice of coping skills presented in the weekly sessions. Three behavioral health counselors, including two members of APAIT’s staff, participated in a day-long training led by a Master’s level clinician experienced in administering manualized CBT interventions. To maintain fidelity during the trial, a clinical psychologist provided monthly supervision with review of audiotaped CBT sessions and feedback to counselors. Ongoing fidelity monitoring was conducted on all CBT sessions using a previously developed fidelity rating scale that assessed the extent of study therapists’ use of CBT-specific skills .