Associations of HIV and Depression with Incident Diabetes Mellitus: Veterans Aging Cohort Study.

BACKGROUND: Persons with HIV (PWH) are at increasingly higher risk for metabolic complications, including diabetes mellitus (DM). Additionally, depression is highly prevalent among PWH and has been associated with increased risk for DM in the general population. However, the association of HIV and depression with incident DM has not been well established. METHODS: Using the Veterans Aging Cohort Study (VACS), we selected adults with and without HIV who did not have DM at baseline. Prevalent depression was defined as having a Patient Health Questionnaire-9 (PHQ-9) score of ≥10. Incident DM was identified using validated Kelly's criteria. Basic clinical and demographic characteristics were collected, and cox proportional hazards regression models were run to test the association between depression and incident DM stratified by HIV serostatus. RESULTS: A total of 5,722 participants were analyzed, 2,886 (53%) had HIV and 1,124 (20%) had depression at baseline. 1,235 (22%) participants developed incident DM during follow-up, with 26% of HIV-negative participants developing DM compared to 17% of participants with HIV. Depression was significantly associated with increased risk of incident DM among HIV-negative participants (adjusted HR [aHR] = 1.31; p-value 0.003), but not among participants with HIV (aHR 1.09; p-value 0.44). However, among participants with HIV with baseline viral load < 500 copies/mL, we noted a stronger association between depression and incident DM. CONCLUSIONS: Incident DM in the VACS cohort is significantly higher for HIV-negative participants compared to veterans with HIV. A significant association between depression and incident DM was noted among HIV-negative participants but not among those with HIV.

Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor-Containing Regimens.

BACKGROUND: Unwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood. METHODS: We utilized 2 cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naive participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202 and did not receive INSTIs. RESULTS: In the observational cohort (n = 61), CYP2B6 slow metabolizers had greater weight gain after switch (P = .01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (n = 462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (P = .001), but not those receiving efavirenz with abacavir (P = .65). Findings were consistent when stratified by race/ethnicity and by sex. CONCLUSIONS: Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.

Risk of Incident Diabetes Mellitus, Weight Gain, and Their Relationships With Integrase Inhibitor-Based Initial Antiretroviral Therapy Among Persons With Human Immunodeficiency Virus in the United States and Canada.

BACKGROUND: Integrase strand transfer inhibitor (INSTI)-based combination antiretroviral therapy (cART) is associated with greater weight gain among persons with human immunodeficiency virus (HIV), though metabolic consequences, such as diabetes mellitus (DM), are unclear. We examined the impact of initial cART regimen and weight on incident DM in a large North American HIV cohort (NA-ACCORD). METHODS: cART-naive adults (≥18 years) initiating INSTI-, protease inhibitor (PI)-, or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from January 2007 through December 2017 who had weight measured 12 (±6) months after treatment initiation contributed time until clinical DM, virologic failure, cART regimen switch, administrative close, death, or loss to follow-up. Multivariable Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DM by cART class. Mediation analyses, with 12-month weight as mediator, similarly adjusted for all covariates. RESULTS: Among 22 884 eligible individuals, 47% started NNRTI-, 30% PI-, and 23% INSTI-based cART with median follow-up of 3.0, 2.3, and 1.6 years, respectively. Overall, 722 (3%) developed DM. Persons starting INSTIs vs NNRTIs had incident DM risk (HR, 1.17 [95% CI, .92-1.48]), similar to PI vs NNRTI initiators (HR, 1.27 [95% CI, 1.07-1.51]). This effect was most pronounced for raltegravir (HR, 1.42 [95% CI, 1.06-1.91]) vs NNRTI initiators. The INSTI-DM association was attenuated (HR, 1.03 [95% CI, .71-1.49] vs NNRTIs) when accounting for 12-month weight. CONCLUSIONS: Initiating first cART regimens with INSTIs or PIs vs NNRTIs may confer greater risk of DM, likely mediated through weight gain.

Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy.

BACKGROUND: Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)-based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens. METHODS: Adult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)-, and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals. RESULTS: Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/µL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P < .05), and 0.5 kg for elvitegravir (P < .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant. CONCLUSIONS: Treatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.

Inflammation and Metabolic Complications in HIV.

PURPOSE OF REVIEW: We aim to provide an in-depth review of recent literature highlighting the role of inflammation involving the adipose tissue, liver, skeletal muscles, and gastrointestinal tract in the development of metabolic complications among persons living with HIV (PLWH). RECENT FINDINGS: Recent studies in PLWH have demonstrated a significant association between circulating inflammatory markers and development of insulin resistance and metabolic complications. In adipose tissue, pro-inflammatory cytokine expression inhibits adipocyte insulin signaling, which alters lipid and glucose homeostasis. Increased lipolysis and lipogenesis elevate levels of circulating free fatty acids and promote ectopic fat deposition in liver and skeletal muscles. This leads to lipotoxicity characterized by a pro-inflammatory response with worsening insulin resistance. Finally, HIV is associated with gastrointestinal tract inflammation and changes in the gut microbiome resulting in reduced diversity, which is an additional risk factor for diabetes. Metabolic complications in PLWH are in part due to chronic, multisite tissue inflammation resulting in dysregulation of glucose and lipid trafficking, utilization, and storage.

Outcomes of Fecal Microbiota Transplantation for Clostridium difficile Infection in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Fecal microbiota transplantation (FMT) has recently been shown to be a promising therapy for recurrent and refractory Clostridium difficile infections (CDI) despite lack of protocol standardization. Patients with inflammatory bowel disease (IBD) present a particular challenge to CDI therapy as they are reported to have worse clinical outcomes, including higher colectomy rates and increased mortality. We aimed to assess the outcomes of FMT for recurrent CDI in patients with IBD at our healthcare system. METHODS: We constructed a retrospective cohort of all patients who underwent FMT at our healthcare system between December 2012 and May 2014. Patients with concurrent IBD were identified. We evaluated the differences in demographic and clinical characteristics, along with the outcomes to FMT between patients with IBD as compared to the general population. RESULTS: Over the study period, 201 patients underwent FMT of which 20 patients had concurrent IBD. Patients with IBD were younger but did not differ from the general population in terms of CDI risk factors or disease severity. The response to FMT and rate of CDI relapse in the IBD group were not statistically different compared to the rest of the cohort. The overall response rate in the IBD population was 75% at 12 weeks. Of the patients who failed FMT 4 of 5 patients had active or untreated IBD. CONCLUSION: Fecal microbiota transplantation provides a good alternative treatment option with high success rates for recurrent or refractory Clostridium difficile infection in patients with well-controlled IBD who fail standard antimicrobial therapy.

False-positive cerebrospinal fluid cryptococcus antigen in Libman-Sacks endocarditis.

BACKGROUND: Cryptococcus meningoencephalitis is a serious opportunistic infection associated with high morbidity and mortality in immunocompromised hosts, particularly patients with advanced AIDS disease. The diagnosis is established through cerebrospinal fluid (CSF) cryptococcus antigen detection and cultures. Cryptococcus antigen testing is usually the initial test of choice due its high sensitivity and specificity along with the quick availability of the results. CASE REPORT: We hereby report a case of a false-positive CSF cryptococcus antigen assay in a patient with systemic lupus erythematosus presenting with acute confusion. While initial CSF evaluation revealed a positive cryptococcus antigen assay, the patient's symptoms were inconsistent with cryptococcus meningoencephalitis. A repeat CSF evaluation, done 3 days later, revealed a negative CSF cryptococcus antigen assay. CONCLUSION: Given the patient's active lupus disease and the elevated antinuclear antibody titers, we believe that the initial positive result was a false positive caused by interference from autoantibodies.

Preswitch Regimens Influence the Rate of Weight Gain After Switch to Tenofovir Disoproxil Fumarate, Lamivudine, and Dolutegravir (TLD): Study From an East African Cohort.

Background: Switching from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to dolutegravir (DTG) has been associated with greater weight gain. Methods: We conducted our analysis using a longitudinal cohort of people with HIV (PWH) in Western Kenya. We evaluated changes in the rate of weight gain among treatment-experienced, virally suppressed PWH who switched from NNRTI to tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). We modeled the weights pre- and postswitch using a 2-phase model with linear trend preswitch and an inverted exponential function postswitch. We estimated an 18-month excess weight gain by comparing the projected weight with that expected using the preswitch rate. Results: A total of 18 662 individuals were included in our analysis, with 55% switching from efavirenz (EFV) and 45% from nevirapine (NVP). Of the studied individuals, 51% were female, and the median age and body mass index (BMI) were 51 years and 22 kg/m2, respectively. For the overall population, the rate of weight gain increased from 0.47 kg/year preswitch to 0.77 kg/year, with higher increases for females (0.57 kg/year to 0.96 kg/year) than males (0.34 kg/year to 0.62 kg/year). The rate of weight gain for individuals switching from EFV-based regimens significantly increased from 0.57 kg/year preswitch to 1.11 kg/year postswitch but remained stable at 0.35 kg/year preswitch vs 0.32 kg/year postswitch for individuals switching from NVP-based regimens. Conclusions: Switching from NNRTI-based regimens to TLD is associated with a modest increase in the rate of weight gain, with the preswitch NNRTI being the key determinant of the amount of weight gain experienced postswitch.

Weight Gain Among Treatment-Naïve Persons With HIV Receiving Dolutegravir in Kenya.

BACKGROUND: Several recent studies have linked integrase strand transfer inhibitors (INSTI) with increased weight gain. SETTING: The effects of sex on weight gain with dolutegravir (DTG)-based antiretroviral therapy (ART) among treatment-naïve participants in a lower-income, sub-Saharan population with high rates of pre-ART underweight and tuberculosis (TB) coinfection are unknown. METHODS: Our analysis included treatment-naïve participants in Kenya and starting their first treatment regimen between January 1, 2015, and September 30, 2018. Participants were grouped into 2 cohorts based on the initial treatment regimen [DTG vs. nonnucleoside reverse transcriptase inhibitors (NNRTI)]. We modelled weight changes over time using a multivariable nonlinear mixed-effect model, with participant as a random effect. Logistic regression models were constructed to evaluate the association between different variables with extreme increase in body mass index (≥10% increase). RESULTS: Seventeen thousand forty-four participants met our inclusion criteria. Sixty-two percent of participants were women, 6% were receiving active TB therapy, and 97% were on NNRTI-based regimens. Participants starting DTG-based regimens were more likely to gain weight when compared with participants starting NNRTI-based regimens. Female participants starting DTG-based regimens experienced the highest weight gain compared with other participants (mean gain of 6.1 kgs at 18 months). Female participants receiving DTG-based regimens, along with participants with lower CD4 cell counts, underweight at baseline, and those receiving active TB therapy were also at higher risk for extreme body mass index increase. CONCLUSIONS: Our study in a lower-income sub-Saharan African population confirms higher weight gain with DTG-based regimens compared with traditional ART for treatment-naïve patients.

Tennessee Healthcare Provider Practices, Attitudes, and Knowledge Around HIV Pre-Exposure Prophylaxis.

INTRODUCTION/OBJECTIVES: Pre-exposure prophylaxis (PrEP) use in the southern United States is low despite its effectiveness in preventing HIV acquisition and high regional HIV prevalence. Our objectives were to assess PrEP knowledge, attitudes, and prescribing practices among Tennessee primary care providers. METHODS: We developed an anonymous cross-sectional electronic survey from March to November 2019. Survey development was guided by the Capability, Opportunity, Motivation, and Behavior framework and refined through piloting and interviews. Participants included members of professional society and health center listservs licensed to practice in Tennessee. Respondents were excluded if they did not complete the question regarding PrEP prescription in the previous year or were not in a position to prescribe PrEP (e.g., hospital medicine). Metrics included PrEP prescription in the preceding year, PrEP knowledge scores (range 0-8), provider attitudes about PrEP, and provider and practice characteristics. Knowledge scores and categorical variables were compared across PrEP prescriber status with Wilcoxon rank-sum and Fisher's exact tests, respectively. RESULTS: Of 147 survey responses, 99 were included and 43 (43%) reported PrEP prescription in the preceding year. Compared with non-prescribers: prescribers had higher median PrEP knowledge scores (7.3 vs 5.6, P < .01), a higher proportion had self-reported patient PrEP inquiries (95% vs 21%, P < .01), and a higher proportion had self-reported good or excellent ability to take a sexual history (83% vs 58%, P = .01) and comfort taking a sexual history (92% vs 63%, P < .01) from men who have sex with men, a subgroup with high HIV risk. Most respondents felt obligated to provide PrEP (65%), and felt all primary care providers should provide PrEP (63%). CONCLUSION: PrEP provision is significantly associated with PrEP knowledge, patient PrEP inquiries, and provider sexual history taking ability and comfort. Future research should evaluate temporal relationships between these associations and PrEP prescription as potential routes to increase PrEP provision.

Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada.

INTRODUCTION: Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). METHODS: Adult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years. RESULTS: Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI). CONCLUSIONS: PWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.

Tuberculosis Meningitis.

PURPOSE OF REVIEW: As the most severe form of tuberculosis (TB), TB meningitis disproportionately affects developing countries and results in significant morbidity and mortality. In this report, we review recent updates in the epidemiology, diagnosis, and management of TB meningitis. RECENT FINDINGS: Young children and people living with HIV continue to be at highest risk for TB meningitis. Early diagnosis remains challenging, especially since conventional diagnostic tests have sub-optimal sensitivity and specificity. Recently, nucleic acid amplification testing emerged as the preferred diagnostic modality due to its rapid turnaround time and high specificity. Several recent studies have assessed the optimal treatment for TB meningitis. While the benefit of treatment intensification, by increasing rifampin dosing or adding a fluoroquinolone, is unclear, a growing body of evidence suggests that steroids confer a survival advantage, particularly in patients with mild disease. Additionally, TB meningitis management is further complicated by high rates of HIV co-infection. Recent data suggest that unlike other forms of TB, early initiation of antiretroviral therapy in patients with TB meningitis is associated with higher rates of adverse reactions, without improved survival. TB meningitis continues to be a significant problem worldwide. Despite recent advances, more studies are warranted to improve early disease detection and optimize therapy.

Clinical Impact of Nucleic Acid Amplification Testing in the Diagnosis of Mycobacterium Tuberculosis: A 10-Year Longitudinal Study.

BACKGROUND: Nucleic acid amplification (NAA) testing for Mycobacterium tuberculosis (MTB) offers improved diagnostic accuracy, compared with smear microscopy, in differentiating MTB from other mycobacteria. We aimed to evaluate the reliability and projected impact of NAA testing in patients with acid-fast bacilli (AFB) smear-positive respiratory samples. METHODS: We identified a retrospective cohort of all patients with AFB smear-positive respiratory specimens at Henry Ford Hospital from January 1, 2001 through December 31, 2011. We examined the association between patients' sociodemographic factors and clinical comorbidities with the likelihood of being diagnosed with MTB. We evaluated the projected change in duration of airborne isolation and unnecessary MTB treatment with introducing NAA testing into clinical decision making for AFB smear-positive patients. RESULTS: One hundred thirty patients had AFB smear-positive respiratory specimens, 80 of these patients had a positive NAA test result, and 82 patients grew MTB on culture. Nucleic acid amplification testing had a sensitivity and specificity of 97.6% and 100%, respectively. Integrating NAA testing into clinical decision making for patients with AFB-positive smears was associated with a significantly shorter time in airborne isolation (6.0 ± 7.6 vs 23.1 ± 38.0, P < .001) and 9.5 ± 11.32 fewer days of unnecessary MTB treatment in patients with negative NAA test. CONCLUSIONS: Nucleic acid amplification testing provided a rapid and accurate test in the diagnosis of MTB while significantly reducing the duration of isolation and unnecessary medications in patients with negative NAA test.

Health Disparities in Hepatitis C Screening and Linkage to Care at an Integrated Health System in Southeast Michigan.

With recommended screening for hepatitis C among the 1945-1965 birth cohort and advent of novel highly effective therapies, little is known about health disparities in the Hepatitis C care cascade. Our objective was to evaluate hepatitis C screening rates and linkage to care, among patients who test positive, at our large integrated health system. We used electronic medical records to retrospectively identify patients, in the birth cohort, who were seen in 21 Internal Medicine clinics from July 2014 to June 2015. Patients previously screened for hepatitis C and those with established disease were excluded. We studied patients' sociodemographic and medical conditions along with provider-specific factors associated with likelihood of screening. Patients who tested positive for HCV antibody were reviewed to assess appropriate linkage to care and treatment. Of 40,561 patients who met inclusion criteria, 21.3% (8657) were screened, 1.3% (109) tested positive, and 30% (30/100) completed treatment. Multivariate logistic regression showed that African American race, male gender, electronic health engagement, residency teaching clinic visit, and having more than one clinic visit were associated with higher odds of screening. Patients had a significant decrease in the likelihood of screening with sequential interval increase in their Charlson comorbidity index. When evaluating hepatitis C treatment in patients who screened positive, electronic health engagement was associated with higher odds of treatment whereas Medicaid insurance was associated with significantly lower odds. This study shows that hepatitis C screening rates and linkage to care continue to be suboptimal with a significant impact of multiple sociodemographic and insurance factors. Electronic health engagement emerges as a tool in linking patients to the hepatitis C care cascade.