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To describe the prevalence of diagnosed depression, anxiety, bipolar disorder, and schizophrenia in people with HIV (PWH) and the differences in HIV care continuum outcomes in those with and without mental health disorders (MHDs).Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design.PWH (≥18 years) contributed data on prevalent schizophrenia, anxiety, depressive, and bipolar disorders from 2008 to 2018 based on International Classification of Diseases code mapping. Mental health (MH) multimorbidity was defined as having two or more MHD. Log binomial models with generalized estimating equations estimated adjusted prevalence ratios (aPR) and 95% confidence intervals for retention in care (≥1 visit/year) and viral suppression (HIV RNA ≤200 copies/ml) by presence vs. absence of each MHD between 2016 and 2018.Among 122 896 PWH, 67 643 (55.1%) were diagnosed with one or more MHD: 39% with depressive disorders, 28% with anxiety disorders, 10% with bipolar disorder, and 5% with schizophrenia. The prevalence of depressive and anxiety disorders increased between 2008 and 2018, whereas bipolar disorder and schizophrenia remained stable. MH multimorbidity affected 24% of PWH. From 2016 to 2018 (N = 64 684), retention in care was marginally lower among PWH with depression or anxiety, however those with MH multimorbidity were more likely to be retained in care. PWH with bipolar disorder had marginally lower prevalence of viral suppression (aPR = 0.98 [0.98-0.99]) as did PWH with MH multimorbidity (aPR = 0.99 [0.99-1.00]) compared with PWH without MHD.The prevalence of MHD among PWH was high, including MH multimorbidity. Although retention and viral suppression were similar to people without MHD, viral suppression was lower in those with bipolar disorder and MH multimorbidity.

Background The impact of adopting a race-free estimated glomerular filtration rate (eGFR) creatinine (eGFRcr) equation on racial differences in chronic kidney disease (CKD) progression among people with human immunodeficiency virus (PWH) is unknown. Methods We defined eGFR stages using the original race-adjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRcr equation and the new race-free CKD-EPI eGFRcr equation. We then estimated 5-year probabilities of transitioning from baseline kidney function to more advanced eGFR stages and examined the association of race (black vs white) with rates of CKD progression using Markov models. Results With the race-adjusted eGFRcr equation, black participants (n = 31 298) had a lower risk of progressing from eGFR stage 1 to 2 (hazard ratio [HR], 0.77; 95% confidence interval [CI], .73–.82), an equal risk of progressing from stage 2 to 3 (1.00; .92–.07) and a 3-fold risk of progressing from stage 3 to 4 or 5 (3.06; 2.60–3.62), compared with white participants (n = 27 542). When we used the race-free eGFRcr equation, 16% of black participants were reclassified into a more severe eGFR stage at baseline. The reclassified black individuals had a higher prevalence of CKD risk factors than black PWH who were not reclassified. With the race-free eGFRcr equation, black participants had a higher risk of disease progression across all eGFR stages than white participants. Conclusions The original eGFRcr equation systematically masked a subgroup of black PWH who are at high-risk of CKD progression. The new race-free eGFRcr equation unmasks these individuals and may allow for earlier detection and management of CKD.

SummaryBackgroundThe widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) in first- and second-line antiretroviral therapy (ART) may facilitate emerging resistance. We combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for DTG resistance.MethodsEight cohorts from Canada, Europe, and South Africa contributed data on individuals with genotypic resistance testing on DTG-based ART. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models.ResultsWe included 750 people with genotypic resistance testing on DTG-based ART between 2013 and 2022. Most had HIV subtype B (N=444, 59·2%) and were treatment-experienced; 134 (17.9%) were on DTG dual and 19 (2.5%) on DTG monotherapy. INSTI DRMs were detected in 100 (13·3%) individuals; 21 (2·8%) had more than one mutation. Most (N=713, 95·1%) were susceptible to DTG, 8 (1·1%) had potential-low, 5 (0·7%) low, 18 (2·4%) intermediate and 6 (0·8%) high-level DTG resistance. The risk of DTG resistance was higher on DTG monotherapy (adjusted odds ratio (aOR) 37·25, 95% CI 11·17 to 124·2) and DTG lamivudine dual therapy (aOR 6·59, 95% CI 1·70 to 25·55) compared to combination ART, and higher in the presence of potential-low/low (aOR 4.62, 95% CI 1.24 to 17.2) or intermediate/high-level (aOR 7·01, 95% CI 2·52 to 19·48) nucleoside reverse transcriptase inhibitors (NRTI) resistance. Viral load on DTG showed a trend towards increased DTG resistance (aOR 1·42, 95% CI 0·92 to 2·19 per standard deviation of log10area under the viral load curve).InterpretationAmong people experiencing virological failure on DTG-based ART, INSTI DRMs were uncommon, and DTG resistance was rare. DTG monotherapy and NRTI resistance substantially increased the risk for DTG resistance, which is of concern, notably in resource-limited settings.FundingUS National Institutes of Health, Swiss National Science Foundation.Research in contextEvidence before this studyWe searched SCOPUS on 20 March 2023 for all publications from inception using the terms “dolutegravir” or “DTG”, “resistant” or “resistance”, and “HIV”. The available evidence on resistance evolution in people living with HIV (PLHIV) with virological failure on DTG-based ART is limited. Most studies assessed the efficacy of DTG-based regimens in clinical studies and reported drug resistance in individuals experiencing virological failure as a secondary objective or reported single or multiple cases of patients developing resistance on DTG-based ART. Clinical trials such as the NADIA trial showed a high degree of viral suppression even in people with NRTI resistance. Consequently, previous analyses included only a small number of people experiencing failure on DTG; the SINGLE trial with 39 people with virologic failure on DTG was the largest. The highest number of individuals with DTG resistance was nine study participants in the NADIA trial. There is evidence that DTG resistance in PLHIV on a DTG monotherapy may be more likely. Other studies suggest that HIV subtype and mutations acquired during a first-generation INSTI-based regimen might affect the risk of DTG resistance.Added value of this studyTo our knowledge, this is the first study systematically investigating resistance in PLHIV experiencing virologic failure on DTG-based ART using a multi-cohort collaboration design reflecting real-world routine care. We collected genotypic resistance tests and clinical data from eight observational HIV cohorts. This resulted in a large dataset of PLHIV experiencing virologic failure on a DTG regimen (over 700 individuals). It allowed a robust assessment of drug resistance mutations and risk factors for DTG resistance. Cross-resistance of first-generation INSTIs does not appear to explain the mutation patterns in HIV-infected individuals who experience virological failure on DTG-based ART regimens. PLHIV who received DTG monotherapy or DTG lamivudine dual therapy and those infected with non-B subtypes were more likely to develop resistance. Resistance to NRTIs was a major risk factor for DTG resistance, indicating that PLHIV receiving functional monotherapy are more likely to develop DTG resistance.Implications of all the available evidenceHIV drug resistance is a significant threat to the sustainability of current and future antiretroviral therapy for combating the ongoing HIV pandemic. Our collaborative analysis shows that cases of DTG resistance are so far rare but not negligible. Given the global DTG roll-out, this might lead to increased frequencies and transmission of DTG resistance, particularly in PLHIV with resistance to NRTIs. While the evidence regarding subtype differences is tentative, it indicates that non-B subtypes, which are most relevant for the global roll-out of DTG, might be associated with an increased risk of resistance.

Background: Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018. Methods: This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data. Findings: 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs. Interpretation: This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality. We would like to thank our funders (US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council) and all patients and the clinical teams associated with the participating cohort studies. The antiretroviral therapy cohort collaboration is funded by the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026209). UK Collaborative HIV Cohort is funded by the UK Medical Research Council (grant numbers G0000199, G0600337, G0900274, and M004236/1). JACS is funded by National Institute for Health Research Senior Investigator award (NF-SI-0611-10168). AT is funded by the Wellcome Trust under a Sir Henry Wellcome Postdoctoral Fellowship (222770/Z/21/Z). Funding for the individual antiretroviral therapy cohort collaboration cohorts included in this analysis was from Alberta Health, Gilead, National Agency for AIDS Research (France REcherche Nord&Sud Sida-hiv Hépatites), the French Ministry of Health, the Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment, the TP-HIV by the German Centre for Infection Research (NCT02149004), Instituto de Salud Carlos III (through the Red Temática de Investigación Cooperativa en Sida [RD06/006, RD12/0017/0018, and RD16/0002/0006]) as part of the Plan Nacional I + D + i. Other funders of the individual cohorts participating data for this analysis are ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional, ViiV Healthcare, Preben og Anna Simonsens Fond, ANRS-Maladies infectieuses émergentes, Institut National de la Santé et de la Recherche Médicale (INSERM), Bristol Myers Squibb, Janssen, Merck, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026230), the Spanish Ministry of Health, the Swiss National Science Foundation (grant 33CS30_134277), Centers for AIDS Research Network of Integrated Clinical Systems (1R24 AI067039-1, P30-AI-027757), the US Department of Veterans Affairs, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026224, U01-AA026209, U24-AA020794), the Veterans Health Administration Office of Research and Development, and the US National Institute of Allergy and Infectious Diseases (Tennessee Center for AIDS Research P30 AI110527). Sí

The emergence of dual therapy for antiretroviral (ARV)-experienced persons living with HIV (PWH) offers the opportunity to reduce lifetime exposure to unnecessary ARV drugs while maintaining viral suppression and reducing the cost of care. Our objective, using retrospective analysis of a quality care initiative, was to examine in routine clinical practice the clinical impact of switching PWH stable on a three-drug to a two-drug single-tablet formulation (STF) ARV regimen. We also examined the cost implications of this STF adjustment. Between January 1, 2020 and January 1, 2021 eligible patients (i.e., virally suppressed, no active hepatitis B infection, no documented nucleoside reverse transcriptase inhibitors/integrase strand transfer inhibitor resistance) were offered, on a convenience basis and as part of routine care, the opportunity to adjust their current three-drug STF to a two-drug STF (dolutegarvair/lamivudine). The acceptance, clinical efficacy, safety, tolerability, and cost of treatment were measured for patients who switched in 2020. Of 989 eligible PWH, 408 were approached and 391 (39.5%) switched to two-drug regimen; 99% remained on the two-drug STF at year's end (median 240 days follow-up). Only 2/391 patients who switched lost viral control. The total ARV drug cost for all 989 patients decreased by 10.3% generating an actual savings of $1,596,666 among patients approached and switched in 2020. Patient interest and uptake in switching to two-drug STF was substantial and resulted in few discontinuations for any reason. It provided significant and immediate cost savings within the first year. Our results bring clarity to discussions on whether using two-drug regimens would be practical and acceptable in nonclinical trial settings.

Background The age-distribution of men who have sex with men (MSM) continues to change in the ‘Treat-All’ era as effective test-and-treat programs target key-populations. However, the nature of these changes and potential racial heterogeneities remain uncertain. Methods The PEARL model is an agent-based simulation of MSM in HIV care in the US, calibrated to data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Results PEARL projects a gradual decrease in median age of MSM at ART initiation from 36 to 31 years during 2010–2030, accompanied by changes in mortality among Black, White, and Hispanic MSM on ART by -8.4%, 42.4% and -19.6%. The median age of all MSM on ART is projected to increase from 45 to 47 years from 2010–2030, with the proportion of ART-users age ≥60y increasing from 6.7% to 28.0%. Almost half (49.7%) of White MSM ART-users are projected to age ≥60y by 2030, compared to 19.5% of Black and 17.2% of Hispanic MSM. Conclusions The overall age of US MSM in HIV care is expected to increase over the next decade, and differentially by race/ethnicity. As this population age, HIV programs should expand care for age-related causes of morbidity and mortality.

BACKGROUND: People with HIV (PWH) have a higher hospitalization rate than the general population. The Veterans Aging Cohort Study (VACS) Index at study entry well predicts hospitalization in PWH, but it is unknown if the time-updated parameter improves hospitalization prediction. We assessed the association of parameterizations of the VACS Index 2.0 with the 5-year risk of hospitalization. SETTING: PWH ≥ 30 years old with at least 12 months of antiretroviral therapy (ART) use, and contributing hospitalization data from 2000 to 2016 in North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Three parameterizations of the VACS Index 2.0 were assessed and categorized by quartile: 1) “baseline” measurement at study entry, 2) time-updated measurements, and 3) cumulative scores calculated using the trapezoidal rule. METHODS: Discrete-time proportional hazard models estimated the crude and adjusted associations (and 95% confidence intervals [CI]) of the VACS Index parameterizations and all-cause hospitalizations. The Akaike information criterion (AIC) assessed the model fit with each of the VACS Index parameters. RESULTS: Among 7,289 patients, 1,537 were hospitalized. Time-updated VACS Index fitted hospitalization best with a more distinct dose-response relationship (score

In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz-based regimen than an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly 16,000 patients from the North American AIDS Cohort Collaboration on Research and Design from 2009–2016, statistical methods for precision medicine were employed to estimate an optimal treatment rule that minimizes the 5-year risk of the composite outcome of acquired immune deficiency syndrome (AIDS)-defining illnesses, serious non-AIDS events, and all-cause mortality. The treatment rules considered were functions that recommend either an efavirenz- or InSTI-based regimen conditional on baseline patient characteristics such as demographic information, laboratory results, and health history. The estimated 5-year risk under the estimated optimal treatment rule was 10.0% (95% confidence interval (CI): 8.6, 11.3), corresponding to an absolute risk reduction of 2.3% (95% CI: 0.9, 3.8) when compared with recommending an efavirenz-based regimen for all patients and 2.6% (95% CI: 1.0, 4.2) when compared with recommending an InSTI-based regimen for all. Tailoring ART to individual patient characteristics may reduce 5-year risk of the composite outcome compared with assigning all patients the same drug regimen.

Background Cryptococcal meningitis (CM) is a major cause of morbidity and mortality in persons with human immunodeficiency virus (HIV; PWH). Little is known about CM outcomes and availability of diagnostic and treatment modalities globally. Methods In this retrospective cohort study, we investigated CM incidence and all-cause mortality in PWH in the International Epidemiology Databases to Evaluate AIDS cohort from 1996 to 2017. We estimated incidence using quasi-Poisson models adjusted for sex, age, calendar year, CD4 cell count (CD4), and antiretroviral therapy (ART) status. Mortality after CM diagnosis was examined using multivariable Cox models. A site survey from 2017 assessed availability of CM diagnostic and treatment modalities. Results Among 518 852 PWH, there were 3857 cases of CM with an estimated incidence of 1.54 per 1000 person-years. Mortality over a median of 2.6 years of post-CM diagnosis follow-up was 31.6%, with 29% lost to follow-up. In total, 2478 (64%) were diagnosed with CM after ART start with a median of 253 days from ART start to CM diagnosis. Older age (hazard [HR], 1.31 for 50 vs 35 years), lower CD4 (HR, 1.15 for 200 vs 350 cells/mm3), and earlier year of CM diagnosis (HR, 0.51 for 2015 vs 2000) were associated with higher mortality. Of 89 sites, 34% reported access to amphotericin B; 12% had access to flucytosine. Conclusions Mortality after CM diagnosis was high. A substantial portion of CM cases occurred after ART start, though incidence and mortality may be higher than reported due to ascertainment bias. Many sites lacked access to recommended CM treatment.

ImportanceIntegrase strand transfer inhibitor (INSTI)–containing antiretroviral therapy (ART) is currently the guideline-recommended first-line treatment for HIV. Delayed prescription of INSTI-containing ART may amplify differences and inequities in health outcomes.ObjectivesTo estimate racial and ethnic differences in the prescription of INSTI-containing ART among adults newly entering HIV care in the US and to examine variation in these differences over time in relation to changes in treatment guidelines.Design, Setting, and ParticipantsRetrospective observational study of 42 841 adults entering HIV care from October 12, 2007, when the first INSTI was approved by the US Food and Drug Administration, to April 30, 2019, at more than 200 clinical sites contributing to the North American AIDS Cohort Collaboration on Research and Design.ExposuresCombined race and ethnicity as reported in patient medical records.Main Outcomes and MeasuresProbability of initial prescription of ART within 1 month of care entry and probability of being prescribed INSTI-containing ART. Differences among non-Hispanic Black and Hispanic patients compared with non-Hispanic White patients were estimated by calendar year and time period in relation to changes in national guidelines on the timing of treatment initiation and recommended initial treatment regimens.ResultsOf 41 263 patients with information on race and ethnicity, 19 378 (47%) as non-Hispanic Black, 6798 (16%) identified as Hispanic, and 13 539 (33%) as non-Hispanic White; 36 394 patients (85%) were male, and the median age was 42 years (IQR, 30 to 51). From 2007-2015, when guidelines recommended treatment initiation based on CD4+ cell count, the probability of ART initiation within 1 month of care entry was 45% among White patients, 45% among Black patients (difference, 0% [95% CI, −1% to 1%]), and 51% among Hispanic patients (difference, 5% [95% CI, 4% to 7%]). From 2016-2019, when guidelines strongly recommended treating all patients regardless of CD4+ cell count, this probability increased to 66% among White patients, 68% among Black patients (difference, 2% [95% CI, −1% to 5%]), and 71% among Hispanic patients (difference, 5% [95% CI, 1% to 9%]). INSTIs were prescribed to 22% of White patients and only 17% of Black patients (difference, −5% [95% CI, −7% to −4%]) and 17% of Hispanic patients (difference, −5% [95% CI, −7% to −3%]) from 2009-2014, when INSTIs were approved as initial therapy but were not yet guideline recommended. Significant differences persisted for Black patients (difference, −6% [95% CI, −8% to −4%]) but not for Hispanic patients (difference, −1% [95% CI, −4% to 2%]) compared with White patients from 2014-2017, when INSTI-containing ART was a guideline-recommended option for initial therapy; differences by race and ethnicity were not statistically significant from 2017-2019, when INSTI-containing ART was the single recommended initial therapy for most people with HIV.Conclusions and RelevanceAmong adults entering HIV care within a large US research consortium from 2007-2019, the 1-month probability of ART prescription was not significantly different across most races and ethnicities, although Black and Hispanic patients were significantly less likely than White patients to receive INSTI-containing ART in earlier time periods but not after INSTIs became guideline-recommended initial therapy for most people with HIV. Additional research is needed to understand the underlying racial and ethnic differences and whether the differences in prescribing were associated with clinical outcomes.

PURPOSE Despite effective antiretroviral therapy, rates of end-stage liver disease (ESLD) remain high. It is not clear whether contemporary antiretrovirals contribute to the risk of ESLD. METHODS We included patients from cohorts with validated ESLD data in the North American AIDS Cohort Collaboration on Research and Design. Patients had to initiate antiretroviral therapy after 1 January 2004 with a nucleos(t)ide backbone of either abacavir/lamivudine or tenofovir/emtricitabine and a contemporary third (anchor) drug. Patients were followed until a first ESLD event, death, end of a cohort's ESLD validation period, loss to follow-up or 31 December 2015. We estimated associations between cumulative exposure to each drug and ESLD using a hierarchical Bayesian survival model with weakly informative prior distributions. RESULTS Among 10 564 patients included from 12 cohorts, 62 had an ESLD event. Of the nine anchor drugs, boosted protease inhibitors atazanavir and darunavir had the strongest signals for ESLD, with increasing hazard ratios (HR) and narrowing credible intervals (CrI), from a prior HR of 1.5 (95% CrI 0.32-7.1) per 5 year's exposure to posterior HRs respectively of 1.8 (95% CrI 0.82-3.9) and 2.0 (95% CrI 0.86-4.7). Both backbones and efavirenz showed no signal. Hepatitis C coinfection was the most important covariate risk factor (HR 4.4, 95% CrI 2.6-7.0). CONCLUSIONS While contemporary antiretrovirals pose less risk for ESLD than hepatitis coinfection, atazanavir and darunavir had a toxicity signal. We show how hierarchical Bayesian modelling can be used to detect toxicity signals in cohort event monitoring data even with complex treatments and few events.

Unsuppressed HIV viremia damages immunity and increases the risk for secondary HIV transmission. Successful engagement of persons with HIV (PWH) into care resulting in viral suppression is vital. PWH already engaged in care, who, after achieving viral suppression, experience viral breakthrough episodes (VBEs) with a sequence of suppressed/unsuppressed/suppressed viral loads remain problematic. We examined the frequency and outcomes of PWH experiencing VBE. HIV care is provided at no cost to all patients under Alberta's universal health program. All PWH followed at Southern Alberta Clinic, Canada, with two or more viral load tests between January 1, 2010, and January 1, 2020, were evaluated. Sociodemographic, clinical, and lifestyle variables were determined along with health outcomes (CD4 levels, HIV-related hospitalizations, and HIV/AIDS-related mortality). Descriptive and multi-variable analyses were performed comparing PWH with and without VBEs. Of 2096 PWH, 386 (18%) experienced one or more VBEs. A higher risk of VBEs was seen in adjusted analyses in those diagnosed age ≤40 years. Increased risk of VBE was seen with injection drug use (46%) and in heterosexuals (56%) compared with MSM. Experience of intimate partner violence, unstable housing, homelessness, and past incarceration also increased risks by 36%, 44% 79%, and 51%, respectively. PWH with VBEs experienced lower CD4 counts (median -417/mm

To characterize the prevalence of anemia and risk factors between 2007 and 2017 for moderate/severe anemia among people with HIV (PWH) in North America who have initiated antiretroviral therapy (ART).Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).We estimated the annual prevalence between 1 January 2007 and 31 December 2017 of mild (11.0-12.9 g/dl men, 11.0-11.9 g/dl women), moderate (8.0-10.9 g/dl regardless of sex) and severe (8.0 g/dl regardless of sex) anemia. Poisson regression models with robust variance and general estimating equations estimated crude and adjusted prevalence ratios (aPR) with 95% confidence intervals ([-]) comparing risk factors for moderate/severe vs. no/mild anemia between 2007 and 2017.Among 73 898 PWH we observed 366 755 hemoglobin measurements following ART initiation, 37 301 (50%) had one or more measures of anemia during follow-up (mild = 17 743 [24%]; moderate = 13 383[18%]; severe = 6175 [8%]). Moderate/severe anemia was more prevalent among women, non-Hispanic Black and Hispanic PWH (vs. non-Hispanic white), those with underweight body mass index (18.5 kg/m2) and with comorbidities and coinfections. Older age had increased prevalence of moderate/severe anemia among males and decreased prevalence among females. Prevalence of moderate/severe anemia was greater among those with lower CD4+ cell count (≤200 cells/μl) [aPR = 2.11 (2.06-2.17)] unsuppressed HIV viral load (200 copies/ml) [aPR = 1.26 (1.23-1.29)] and within the first 6 months of ART initiation (vs.1 year of ART) [aPR = 1.66 (1.61-1.72)].The prevalence of anemia among PWH is reduced after ART initiation but remains high. Risk factors differ by sex and include comorbidities and HIV disease severity. The persistent, substantial prevalence of anemia among PWH merits further investigation, targeted screening, and clinical interventions.

ImportanceEstimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs.ObjectiveTo project the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the US through 2030.DesignAgent-based simulation modelSettingHIV clinics in the United States in the recent past (2020) and near future (2030)ParticipantsIn 2020, 674,531 PWH were using ART; 9% were men and 4% women with history of injection drug use; 60% were men who have sex with men (MSM); 8% were heterosexual men and 19% heterosexual women; 44% were non-Hispanic Black/African American (Black); 32% were non-Hispanic White (White); and 23% were Hispanic.Exposure(s)Demographic and HIV acquisition risk subgroupsMain Outcomes and MeasuresProjected prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV).ResultsWe projected 914,738 PWH using ART in the US in 2030. Multimorbidity increased from 58% in 2020 to 63% in 2030. The prevalence of depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension and dyslipidemia decreased, diabetes and CKD increased, MI increased steeply, but there was little change in cancer and ESLD. Among Black women with history of injection drug use (oldest demographic subgroup in 2030), CKD, anxiety, hypertension, and depression were most prevalent and 93% were multimorbid. Among Black MSM (youngest demographic subgroup in 2030), depression was highly prevalent, followed by hypertension and 48% were multimorbid. Comparatively, 67% of White MSM were multimorbid in 2030 (median age in 2030=59 years) and anxiety, depression, dyslipidemia, CKD, and hypertension were highly prevalent.Conclusion and relevanceThe distribution of multimorbidity will continue to differ by race/ethnicity, gender, and HIV acquisition risk subgroups, and be influenced by age and risk factor distributions that reflect the impact of social disparities of the health on women, people of color, and people who use drugs. HIV clinical care models and funding are urgently required to meet the healthcare needs of people with HIV in the next decade.KEY POINTSQuestionHow will the prevalence of multimorbidity change among people with HIV (PWH) using antiretroviral therapy in the US from 2020 to 2030?FindingsIn this agent-based simulation study using data from the NA-ACCORD and the CDC, multimorbidity (≥2 mental/physical comorbidities other than HIV) will increase from 58% in 2020 to 63% in 2030. The composition of comorbidities among multimorbid PWH vary by race/ethnicity, gender, and HIV acquisition risk group.MeaningHIV clinical programs and policy makers must act now to identify resources and care models to meet the increasingly complex medical needs of PWH over time, particularly mental healthcare needs.

Integrase strand transfer inhibitor (InSTI)-based regimens have been recommended as first-line antiretroviral therapy (ART) for adults with HIV. But data on long-term effects of InSTI-based regimens on virologic outcomes remain limited. Here we examined whether InSTI improved long-term virologic outcomes compared with efavirenz (EFV).We included adults from the North American AIDS Cohort Collaboration on Research and Design who initiated their first ART regimen containing either InSTI or EFV between 2009 and 2016. We estimated differences in the proportion virologically suppressed up to 7 years of follow-up in observational intention-to-treat and per-protocol analyses.Of 15 318 participants, 5519 (36%) initiated an InSTI-based regimen and 9799 (64%) initiated the EFV-based regimen. In observational intention-to-treat analysis, 81.3% of patients in the InSTI group and 67.3% in the EFV group experienced virologic suppression at 3 months after ART initiation, corresponding to a difference of 14.0% (95% CI 12.4-15.6). At 1 year after ART initiation, the proportion virologically suppressed was 89.5% in the InSTI group and 90.2% in the EFV group, corresponding to a difference of -0.7% (95% CI -2.1 to 0.8). At 7 years, the proportion virologically suppressed was 94.5% in the InSTI group and 92.5% in the EFV group, corresponding to a difference of 2.0% (95% CI -7.3 to 11.3). The observational per-protocol results were similar to intention-to-treat analyses.Although InSTI-based initial ART regimens had more rapid virologic response than EFV-based regimens, the long-term virologic effect was similar. Our findings may inform guidelines regarding preferred initial regimens for HIV treatment.

Background Understanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general population. Objective To assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality among matched persons in the general U.S. population and trends in this difference over time. Design Observational cohort study. Setting Thirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design. Participants 82 766 adults entering HIV clinical care between 1999 and 2017 and a subset of the U.S. population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data compiled by the National Center for Health Statistics. Measurements Five-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function. Results Overall 5-year mortality among persons entering HIV care was 10.6%, and mortality among the matched U.S. population was 2.9%, for a difference of 7.7 (95% CI, 7.4 to 7.9) percentage points. This difference decreased over time, from 11.1 percentage points among those entering care between 1999 and 2004 to 2.7 percentage points among those entering care between 2011 and 2017. Limitation Matching on available covariates may have failed to account for differences in mortality that were due to sociodemographic factors rather than consequences of HIV infection and other modifiable factors. Conclusion Mortality among persons entering HIV care decreased dramatically between 1999 and 2017, although those entering care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population. Primary funding source National Institutes of Health.

Many challenges remain in successfully engaging people with HIV (PWH) into lifelong HIV care. Living in non-urban or rural areas has been associated with worse outcomes. Uncertainties remain regarding how to provide optimal HIV care in non-urban areas.Using a retrospective descriptive analysis framework, we compared multiple measurable HIV care metrics over time on the basis of urban versus non-urban residency, under a centralized HIV care model. We examined rates of HIV diagnosis, access to and retention in HIV care, and longitudinal outcomes for all newly diagnosed PWH between January 1, 2008, and January 1, 2020, categorized by their home location at the time of HIV diagnosis in southern Alberta.Of 719 newly diagnosed PWH, 619 (86%) lived in urban areas and 100 (14%) lived in non-urban areas. At HIV diagnosis, the groups had no significant differences in initial CD4 count or clinical characteristics (Sustained retention in care was more challenging for non-urban PWH; however, adherence to ART and viral suppression rates were more than 90%. Although encouraging, challenges remain in identifying and reducing unique barriers for optimal care of PWH living in non-urban areas.Il reste de nombreux défis à relever pour mobiliser les personnes atteintes du VIH (PAV) à adhérer aux soins du VIH jusqu’à la fin de leurs jours. La résidence en région non urbaine ou rurale est associée à des résultats cliniques plus négatifs. Il reste des incertitudes quant aux moyens d’offrir des soins optimaux du VIH hors des régions urbaines.Au moyen d’une analyse descriptive rétrospective, les chercheurs ont comparé de multiples mesures des soins du VIH au fil du temps d’après le lieu de résidence en milieu urbain ou non urbain, en fonction d’un modèle de soins du VIH centralisé. Ils ont examiné les taux de diagnostic du VIH, l’accès aux soins du VIH et la rétention de ces soins, ainsi que les résultats cliniques longitudinaux de toutes les PAV nouvellement diagnostiquées entre le 1Sur les 719 PAV nouvellement diagnostiquées, 619 (86 %) vivaient en région urbaine et 100 (14 %), en région non urbaine. Au diagnostic du VIH, les groupes ne présentaient pas de différence significative pour ce qui est de la numération initiale des CDIl était plus difficile de maintenir une rétention soutenue des soins pour les PAV hors des milieux urbains, mais l’adhésion au TAR et les taux de suppression virale étaient supérieurs à 90 %. C’était encourageant, mais il reste des défis pour déterminer et réduire les obstacles à des soins optimaux chez les PAV qui habitent hors des milieux urbains.

Objective Peripheral neuropathies in HIV-infected patients are highly debilitating because of neuropathic pain and physical disabilities. We defined prevalence and associated predictive variables for peripheral neuropathy subtypes in a cohort of persons living with HIV (PWH). Design Adult PWH in clinical care were recruited to a longitudinal study examining neurological complications. Methods Each subject was assessed for symptoms and signs of peripheral neuropathy and demographic, laboratory and clinical variables. Univariate, multiple logistic regression and machine learning analyses were performed by comparing patients with and without peripheral neuropathy. Results Three patient groups were identified: those with peripheral neuropathies (PNP, n = 111) that included HIV-associated distal sensory polyneuropathy (DSP, n = 90) or mononeuropathy (MNP, n = 21), and those without neuropathy (NNP, n = 408). Univariate analyses showed multiple variables differed significantly between the NNP and PNP groups including age, estimated HIV-1 duration, education, employment, neuropathic pain, peak viral load, polypharmacy, diabetes, cardiovascular disorders, AIDS, and prior neurotoxic nucleoside antiretroviral drug exposure. Classification algorithms distinguished those with PNP, all with area under the receiver operating characteristic curve (AUROC) values of >0.80. Random forest models showed greater accuracy and AUROC values compared with the multiple logistic regression analysis. Relative importance plots showed that the foremost predictive variables of PNP were HIV-1 duration, peak plasma viral load, age, and low CD4 T-cell levels. Conclusions PNP in HIV-1 infection remains common affecting 21.4% of patients in care. Machine learning models uncovered variables related to PNP that were undetected by conventional analyses, emphasizing the importance of statistical algorithmic approaches to understanding complex neurological syndromes.

We aimed to identify “high-cost” patients with HIV (PWH) and determine drivers behind higher costs. All PWH at the Southern Alberta HIV Clinic, Canada, and active in 2017 were included. Sociodemographic, clinical, and healthcare utilization data were collected. The direct care costs from the payers’ perspective including antiretroviral drugs (ARV), outpatient visits, and hospital admissions were determined for 2017. Patients’ annual total costs were grouped into top 5% (i.e., high-cost), top 20%, middle 60%, and bottom 20%. High-cost patients were older, Caucasian or indigenous Canadian, and more likely acquired HIV from intravenous drug use (all p < 0.05). High-cost patients had lower nadir CD4, more comorbidities, missed more clinic appointments, had more ARV interruptions, and developed more ARV resistance ( p < 0.01). The overall median cost of HIV care was US$14,064 [IQR US$13,121–US$17,883] (2017 Cdn$). High-cost patients had a median cost of US$29,902 [IQR US$27,229–US$37,891] and accounted for 14% of total costs and 84% of all inpatient costs. Hospitalizations constituted 58% of costs for high-cost patients. Although heterogeneous, high-cost patients have distinct sociodemographic and clinical characteristics driving their healthcare utilization. Addressing these social determinants of health and using novel ARV administration approaches may preserve health and save costs.

Background Studies suggest lower risk of breast cancer in women with HIV versus without HIV. These estimates may be biased by lower life expectancy and younger age distribution of women with HIV. Our analysis evaluated this bias and characterized secular trends in breast cancer among women with HIV initiating antiretroviral therapy. We hypothesized breast cancer risk would increase over time as mortality decreased. Setting Women with HIV prescribed antiretroviral therapy in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from 1997 through 2016. Methods We estimated breast cancer hazard (cause-specific hazard ratios) and cumulative incidence accounting for competing risks (subdistribution hazard ratios) to assess changes in breast cancer risk over time. This was assessed overall (1997-2016) and within/across calendar periods. Analyses were adjusted for race/ethnicity and inverse probability weighted for cohort. Cumulative incidence was graphically assessed by calendar period and race/ethnicity. Results We observed 11,587 women during 1997-2016, contributing 63 incident breast cancer diagnoses and 1,353 deaths [73,445 person-years (median follow-up = 4.5 years)]. Breast cancer cumulative incidence was 3.2% for 1997-2016. We observed no secular trends in breast cancer hazard or cumulative incidence. There were annual declines in the hazard and cumulative incidence of death (cause-specific hazard ratios and subdistribution hazard ratios: 0.89, 95% confidence interval: 0.87 to 0.91) which remained within and across calendar periods. Conclusions These findings contradict the hypothesis of increasing breast cancer risk with declining mortality over time among women with HIV, suggesting limited impact of changing mortality on breast cancer risk. Additional inquiry is merited as survival improves among women with HIV.

OBJECTIVE To examine recent trends and differences in all-cause and cause-specific hospitalization rates by race, ethnicity, and gender among persons with HIV (PWH) in the United States and Canada. DESIGN HIV clinical cohort consortium. METHODS We followed PWH at least 18 years old in care 2005-2015 in six clinical cohorts. We used modified Clinical Classifications Software to categorize hospital discharge diagnoses. Incidence rate ratios (IRR) were estimated using Poisson regression with robust variances to compare racial and ethnic groups, stratified by gender, adjusted for cohort, calendar year, injection drug use history, and annually updated age, CD4+, and HIV viral load. RESULTS Among 27 085 patients (122 566 person-years), 80% were cisgender men, 1% transgender, 43% White, 33% Black, 17% Hispanic of any race, and 1% Indigenous. Unadjusted all-cause hospitalization rates were higher for Black [IRR 1.46, 95% confidence interval (CI) 1.32-1.61] and Indigenous (1.99, 1.44-2.74) versus White cisgender men, and for Indigenous versus White cisgender women (2.55, 1.68-3.89). Unadjusted AIDS-related hospitalization rates were also higher for Black, Hispanic, and Indigenous versus White cisgender men (all P

Background Varicella-zoster virus (VZV) infection disproportionately affects people with HIV (PWH), primarily presenting as herpes zoster. However, VZV seroprevalence, its association with zoster, and clinical outcomes remain understudied in era of modern antiretroviral therapy (ART). We assessed VZV seroprevalence, rates of VZV illness, and associated health care costs in a large cohort of PWH over 20 years. Methods We performed retrospective chart reviews of patients followed at a regional HIV clinic from January 1, 2000, to December 31, 2020. Serological, immunization, clinical, and costing data were extracted from in-house databases. VZV-related inpatient admissions, emergency department (ED), and urgent care (UC) visits were identified using relevant International Classification of Disease (ICD-10) codes and validated where possible by 2 physicians. Health care utilization costs were adjusted to 2020 Canadian dollars. Results Of 3006 PWH, VZV serology was available for 2628; of these, 2503 (95.2%) were seropositive. Only 39% of known seronegative patients were subsequently immunized for varicella. During 29 768 years of patient follow-up, 38 hospitalizations and 138 ED/UC visits due to VZV infection were identified. Most occurred in VZV-seropositive PWH Conclusions Despite ART and vaccines for chickenpox and shingles, VZV still caused significant costs and morbidity for PWH, occurring at younger ages and often as encephalitis/meningitis. Supporting ART adherence may reduce VZV illness and hospitalization costs in PWH, and the cost-effectiveness of expanding shingles vaccine use warrants further study.

We characterized trends in statin eligibility and subsequent statin initiation among people with HIV (PWH) from 2001 to 2017 and identified predictors of statin initiation between 2014 and 2017.PWH participating in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) enrolled in 12 US cohorts collecting data on statin eligibility criteria/prescriptions from 2001 to 2017.We determined the annual proportion eligible for statins, initiating statins, and median waiting time (from statin eligibility to initiation). Eligibility was defined using ATP III guidelines (2001-2013) and ACC/AHA guidelines (2014-2017). We assessed initiation predictors in 2014-2017 among statin-eligible PWH using Poisson regression, estimating adjusted prevalence ratios (aPRs) with 95% confidence intervals (95% CIs).Among 16,409 PWH, 7386 (45%) met statin eligibility criteria per guidelines (2001-2017). From 2001 to 2013, statin eligibility ranged from 22% to 25%. Initiation increased from 13% to 45%. In 2014, 51% were statin-eligible, among whom 25% initiated statins, which increased to 32% by 2017. Median waiting time to initiation among those we observed declined over time. Per 10-year increase in age, initiation increased 46% (aPR 1.46, 95% CI: 1.29 to 1.67). Per 1-year increase in calendar year from 2014 to 2017, there was a 41% increase in the likelihood of statin initiation (aPR 1.41, 95% CI: 1.25 to 1.58).There is a substantial statin treatment gap, amplified by the 2013 ACC/AHA guidelines. Measures are warranted to clarify reasons we observe this gap, and if necessary, increase statin use consistent with guidelines including efforts to help providers identify appropriate candidates.

Despite the availability of modern antiretroviral therapy (ART), neurocognitive impairment persists among some persons with HIV (PWH). We investigated the role of exposure to four major classes of ARTs in neurocognitive impairment in PWH. A single-site cohort of 343 PWH was recruited. Lifetime ART medication history was obtained from medical health records. We evaluated the role of ART exposure as a predictor of neurocognitive impairment using univariate analyses and machine learning, while accounting for potential effects of demographic, clinical, and comorbidity-related risk factors. Out of a total of 26 tested variables, two random forest analyses identified the most important characteristics of a neurocognitively impaired group (N = 59): Compared with a neurocognitively high-performing group (N = 132; F1-score = 0.79), we uncovered 13 important risk factors; compared with an intermediate-performing group (N = 152; F1-score = 0.75), 16 risk factors emerged. Longer lifetime ART exposure, especially to integrase inhibitors, was one of the most important predictors of neurocognitive impairment in both analyses (rank 2 of 13 and rank 4 of 16, respectively), superseding effects of age (rank 11/13, rank 15/16) and HIV duration (rank 13/13, rank 16/16). Concerning specific integrase inhibitors, the impaired group had significantly longer dolutegravir exposure (p = 0.011) compared with the high-performing group (p = 0.012; trend compared with the intermediate group p = 0.063). A longer duration to integrase inhibitor intake was negatively related to cognition in this cohort. Our findings suggest that possible cognitive complications of long-term exposure to integrase inhibitors, in particular dolutegravir, should be closely monitored in PWH.

Bloodstream infections (BSIs) among people with human immunodeficiency virus (PWH) remain a poorly studied source of morbidity and mortality. We characterize the epidemiology, microbiology, and clinical outcomes including reinfection, hospitalization, and mortality rates of both community-acquired and hospital-acquired BSI in PWH.We identified all BSI, between January 1, 2000 and December 31, 2017 in PWH in care at Southern Alberta Clinic, by linking data from laboratory and clinical databases. Crude incidence rates per 1000 person-years for BSI and death were calculated. Cox proportional hazards models estimated crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) to conduct a risk factor analysis of BSI in PWH. Logistic regression models with generalized estimating equations estimated crude and adjusted odds ratios (aORs) to identify characteristics associated with 1-year mortality after BSI.Among 2895 PWH, 396 BSI episodes occurred in 228 (8%) PWH. There were 278 (72%) Gram-positive and 109 (28%) Gram-negative BSI. People with human immunodeficiency virus with lower CD4 nadirs, higher Charlson comorbidity indices, and hepatitis C virus were at highest risk for BSI. Long-term all-cause mortality was greater in those experiencing BSI (HR, 5.25; 95% CI, 4.21-6.55). CD4 count200 cells/mmBloodstream infections continue to occur at an elevated rate among PWH with high reoccurrence rates and associated morbidity and mortality. To risk stratify and develop targeted interventions, we identified PWH at greatest risk for BSI. People with human immunodeficiency virus with low immunity at the time of BSI are at highest risk of poor outcomes.

BackgroundMortality among adults with human immunodeficiency virus (HIV) remains elevated over those in the US general population, even in the years after entry into HIV care. We explore whether the elevation in 5-year mortality would have persisted if all adults with HIV had initiated antiretroviral therapy within 3 months of entering care.MethodsAmong 82 766 adults entering HIV care at North American AIDS Cohort Collaboration clinical sites in the United States, we computed mortality over 5 years since entry into HIV care under observed treatment patterns. We then used inverse probability weights to estimate mortality under universal early treatment. To compare mortality with those for similar individuals in the general population, we used National Center for Health Statistics data to construct a cohort representing the subset of the US population matched to study participants on key characteristics.ResultsFor the entire study period (1999–2017), the 5-year mortality among adults with HIV was 7.9% (95% confidence interval [CI]: 7.6%–8.2%) higher than expected based on the US general population. Under universal early treatment, the elevation in mortality for people with HIV would have been 7.2% (95% CI: 5.8%–8.6%). In the most recent calendar period examined (2011–2017), the elevation in mortality for people with HIV was 2.6% (95% CI: 2.0%–3.3%) under observed treatment patterns and 2.1% (.0%–4.2%) under universal early treatment.ConclusionsExpanding early treatment may modestly reduce, but not eliminate, the elevation in mortality for people with HIV.