Journal Article Annotations
2022, 4th Quarter

HIV Psychiatry

Annotations by John A R Grimaldi, MD, Mary Ann Cohen MD, FACLP, Kelly Cozza MD, DLFAPA, FACLP, Luis Pereira, MD
January, 2023

Integrase Inhibitors are Associated with Neuropsychiatric Symptoms in Women with HIVA.
Intervening for HIV prevention and mental health: a review of global literature.
When therapeutic drugs lead to diabetes.

PUBLICATION #1 — HIV Psychiatry

Integrase Inhibitors are Associated with Neuropsychiatric Symptoms in Women with HIV.

Leah H Rubin, Jane A O’Halloran, Dionna W Williams, Yuliang Li, Kathryn C Fitzgerald, Raha Dastgheyb, Alexandra L Damron, Pauline M Maki, Amanda B Spence, Anjali Sharma, Deborah R Gustafson, Joel Milam, Kathleen M Weber, Adaora A Adimora, Igho Ofotokun, Margaret A Fischl , Deborah Konkle-Parker, Yanxun Xu

Abstract: J Neuroimmune Pharmacol. 2022 Feb 17;10.1007/s11481-021-10042-3. doi: 10.1007/s11481-021-10042-3. Online ahead of print.

Women with HIV(WWH) are more likely to discontinue/change antiretroviral therapy (ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase strand transfer inhibitors (INSTIs) are particularly concerning. We focused on these ART agents and neuropsychiatric symptoms in previously developed subgroups of WWH that differed on key sociodemographic factors as well as longitudinal behavioral and clinical profiles. WWH from the Women’s Interagency HIV Study were included if they had ART data available, completed the Perceived Stress Scale-10 and PTSD Checklist-Civilian. Questionnaires were completed biannually beginning in 2008 through 2016. To examine ART-symptom associations, constrained continuation ratio model via penalized maximum likelihood were fit within 5 subgroups of WWH. Data from 1882 WWH contributed a total of 4598 observations. 353 women were previously defined as primarily having well-controlled HIV with vascular comorbidities, 463 with legacy effects (CD4 nadir < 250cells/mL), 274 aged ≤ 45 with hepatitis, 453 between 35-55 years, and 339 with poorly-controlled HIV/substance users. INSTIs, but not efavirenz, were associated with symptoms among key subgroups of WWH. Among those with HIV legacy effects, dolutegravir and elvitegravir were associated with greater stress/anxiety and avoidance symptoms (P’s < 0.01); dolutegravir was also associated with greater re-experiencing symptoms (P = 0.005). Elvitegravir related to greater re-experiencing and hyperarousal among women with well-controlled HIV with vascular comorbidities (P’s < 0.022). Raltegravir was associated with less hyperarousal, but only among women aged ≤ 45 years (P = 0.001). The adverse neuropsychiatric effects of INSTIs do not appear to be consistent across all WWH. Key characteristics (e.g., age, hepatitis positivity) may need consideration to fully weight the risk-benefit ratio of dolutegravir and elvitegravir in WWH.

Annotation

Findings:
Data from the Women’s Interagency HIV Study (WIHS) were used to examine associations between Efavirenz and Integrase Strand Transfer Inhibitors (INSTIs) and adverse neuropsychiatric effects. Participants were divided into 5 previously defined subgroups that differed by sociodemographic factors and longitudinal behavioral and clinical characteristics. The Perceived Stress Scale-10 and PTSD Checklist-Civilian were used to measure anxiety symptoms and symptoms of re-experiencing, avoidance, and hyperarousal. There was a significant association between dolutegravir and elvitegravir and stress/anxiety and avoidance symptoms in the subgroup of participants with the highest percentage of women with CD4 nadir < 250. There was also an association between elvitegravir and re-experiencing symptoms in this subgroup. In the subgroup of women with the greatest percentage of well-controlled HIV, elvitegravir was significantly associated with re-experiencing and hyperarousal symptoms. Raltegravir was associated with less hyperarousal among the subgroup of women younger than 45 years old and who were more likely to have comorbid hepatitis C. No significant associations were found between any of the INSTIs and stress symptoms in either the subgroup comprising 35-55 year-old women or the subgroup with the highest percentage of participants with poorer HIV clinical characteristics and substance use. None of nonnucleoside reverse transcriptase inhibitors (NNRTIs) were associated with symptomatology. Efavirenz was not associated with either greater or lower adverse neuropsychiatric effects in any of the subgroups. This finding was surprising in light of Efavirenz being the antiretroviral drug most commonly associated with adverse effects: vivid dreams, insomnia, dizziness, fatigue and suicidality. Although not of primary interest in this study, nucleoside reverse transcriptase inhibitors (NRTIs), tenofovir and abacavir, were associated with less neuropsychiatric effects in certain subgroups. The protease inhibitor atazanavir showed associations in both directions that varied by subgroup.

Strengths and limitations:
This large-scale study used data from the largest female cohort of people with HIV to date. It is the first study to examine the link between efavirenz and INSTIs and anxiety and PTSD symptoms in subgroups of women defined by sociodemographic factors, longitudinal behavioral, and clinical characteristics. Previous studies have demonstrated that depressive and cognitive symptoms secondary to antiretroviral medications, such as efavirenz, are variable depending on race/ethnicity. Findings from this study may similarly inform a more personalized medicine approach to INSTI-based regimens. This study employed advances in computational modeling and bioinformatics that facilitated identification of links among specific antiretroviral medications, neuropsychiatric symptoms, patient and HIV-related factors. Because not all participants were evaluated on all antiretroviral medications, interpretation of study results was limited. Additionally, findings applied only to women and were not generalizable to men.

Relevance:
Adverse effects of antiretroviral medications are a well-documented reason for treatment discontinuation. The majority of studies addressing this problem has involved only men and are not generalizable to women. Findings from this study may facilitate better tolerated medication choices. The study also demonstrated a method of statistical analysis that may promote personalized medicine with other populations.

PUBLICATION #2 — HIV Psychiatry

Intervening for HIV prevention and mental health: a review of global literature.

Collins PY, Velloza J, Concepcion T, Oseso L, Chwastiak L, Kemp CG, Simoni J, Wagenaar BH.

Abstract: J Int AIDS Soc. 2021 Jun;24 Suppl 2(Suppl 2):e25710. doi: 10.1002/jia2.25710.

Introduction:
Numerous effective HIV prevention options exist, including behaviour change interventions, condom promotion and biomedical interventions, like voluntary medical male circumcision and pre-exposure prophylaxis. However, populations at risk of HIV also face overlapping vulnerabilities to common mental disorders and severe mental illness. Mental health status can affect engagement in HIV risk behaviours and HIV prevention programmes. We conducted a narrative review of the literature on HIV prevention among key populations and other groups vulnerable to HIV infection to understand the relationship between mental health conditions and HIV prevention outcomes and summarize existing evidence on integrated approaches to HIV prevention and mental healthcare.

Methods:
We searched five databases for studies published from January 2015 to August 2020, focused on HIV prevention and mental health conditions among key populations and individuals with serious mental illness. Studies were included if they evaluated an HIV prevention intervention or assessed correlates of HIV risk reduction and included assessment of mental health conditions or a mental health intervention.

Results and discussion:
We identified 50 studies meeting our inclusion criteria, of which 26 were randomized controlled trials or other experimental designs of an HIV prevention intervention with or without a mental health component. Behaviour change interventions were the most common HIV prevention approach. A majority of studies recruited men who have sex with men and adolescents. Two studies provided distinct approaches to integrated HIV prevention and mental health service delivery. Overall, a majority of included studies showed that symptoms of mental disorder or distress are associated with HIV prevention outcomes (e.g. increased risky sexual behaviour, poor engagement in HIV prevention behaviours). In addition, several studies conducted among groups at high risk of poor mental health found that integrating a mental health component into a behaviour change intervention or linking mental health services to combination prevention activities significantly reduced risk behaviour and mental distress and improved access to mental healthcare.

Conclusions:
Evidence suggests that mental health conditions are associated with poorer HIV prevention outcomes, and tailored integrated approaches are urgently needed to address overlapping vulnerabilities among key populations and other individuals at risk.

Annotation

The finding:
This paper is structured review of HIV literature from 2015-2020 across many key populations (surprisingly 19 focused on teens and adolescents), associated health conditions that included SMI, and an emphasis on studies that evaluated HIV prevention and risk reduction while also including mental health parameters. Fifty papers met inclusion criteria for full review, of which 26 were randomized controlled trials (RCTs) and/or experimental designs (had pre-post-intervention evaluations). Many of the reviewed studies supported the need for more finely integrated approaches between primary and mental health care in order to improve HIV prevention and outcomes. Depression, anxiety, and serious mental illness (SMI) continues to greatly impact HIV prevention and treatment.

Strengths and weaknesses:
The presentation of these findings is burdened by a reliance on tables. The reader will benefit from focusing on Table 2, “Mental Health Outcomes” and “HIV Outcomes” in the “MH baseline prevalence and HIV/MH key findings” column. This paper includes many different types of studies and is commendable for its global approach.

Relevance:
An important collection of papers remind us about the bio-psycho-socio-cultural elements related to the care of persons with HIV: “60% of new HIV infections occur among key populations and their sexual partners, including gay men and other men who have sex with men (MSM), female sex workers (FSW), transgender women (TGW) (primarily), people who inject drugs (PWID), and prisoners and other incarcerated people” (Collins et al, 2021, p4). This is a very nice collection to have at one’s fingertips about the available literature related to mental health and interventions in HIV care. The authors have supported what we all know with a nice review of the literature: those with SMI/severe depression demonstrate fewer HIV prevention behaviors, and “In all but one study, depression impaired PrEP adherence. In the majority of HIV testing and counselling studies, having fewer symptoms of a mental disorder increased HIV testing. Depressive, anxiety and trauma symptoms usually reduced the likelihood of condom use or condom self-efficacy” (Collins et al, p31).

PUBLICATION #3 — HIV Psychiatry

When therapeutic drugs lead to diabetes.

Fève B, Scheen AJ.

Abstract: Diabetologia. 2022 May;65(5):751-762. doi: 10.1007/s00125-022-05666-w. Epub 2022 Mar 4.

Drug-induced diabetes mellitus is a growing problem in clinical practice. New, potent medications contribute to this problem in a population already at high risk of developing glucose disturbances because of poor lifestyle habits and high prevalence of being overweight/obese. The present review focuses on four important pharmacological classes: glucocorticoids; antipsychotics, especially second generation; antiretroviral therapies, which revolutionised the management of individuals with HIV; and immune checkpoint inhibitors, recently used for the immunotherapy of cancer. For each class, the prevalence of drug-induced diabetes will be evaluated, the most common clinical presentations will be described, the underlying mechanisms leading to hyperglycaemia will be briefly analysed, and some recommendations for appropriate monitoring and management will be proposed.

Keywords:
Antipsychotics; Antiretroviral therapy; Drug-induced diabetes; Glucocorticoids; Immune checkpoint inhibitors; Review; Secondary diabetes.

Annotation

The finding:
Psychotropics and antiretrovirals are potent risk factors for medication-induced hyperglycemia and glucose dyscontrol. This helpful review concisely summarizes how second-generation antipsychotics (SGAs), antiretrovirals (ARVs), and immune checkpoint inhibitors (ICIs) (chemotherapeutic agents) impact glucose control and elucidates their relevant mechanisms of action. Several key points follow: SGAs are noted exert their effects on glucose control by affecting “cellular insulin signalling, endogenous glucose production, glucose uptake and insulin secretion, thus implicating different key organs (liver, skeletal muscle and endocrine pancreas). The primary defect in insulin signalling appears to be a marked impairment of post-receptor IRS-1 phosphorylation. Downregulation of intracellular downstream biochemical pathways subsequently occurs…” Older ARVs, such as first-generation nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) and Protease Inhibitors (PIs) all greatly affect glucose metabolism, causing lipoatrophy and trunk fat hypertrophy, and efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) alters adipocyte development and function. The authors also remind the reader that INSTIs such as dolutegravir and raltegravir may also cause increased adiposity.

Strength and weaknesses:
The paper summarizes the impact of these medications on glucose control, and the authors discuss how behavioral change and medication can mitigate the effects of other medications. The authors pose a brief and simplified approach to a complicated topic that is easily accessible.

Relevance:
A very nice review of diabetogenic medications that includes HIV treatment medications and antipsychotics. This is a nice overview paper to share with primary care colleagues and trainees. This paper also has a simple (and downloadable) diagram depicting the mechanisms of drug-induced hyperglycemia for use in teaching.