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Background: Guidelines for initial antiretroviral treatment (ART) regimens have evolved, with integrase strand transfer inhibitors (INSTIs) increasingly prominent. Research on virologic failure (VF) with INSTI therapy is predominantly from clinical trials not care settings, especially for recently approved medications including dolutegravir. We compared outcomes among people living with HIV (PLWH) who initiated recommended regimens in clinical care across the United States. Setting: We examined 2 groups of PLWH at 8 clinics who initiated ART regimens (August 1, 2013-March 31, 2017): those ART treatment-naive at initiation, and those treatment-experienced. Methods: The outcome in this longitudinal cohort study was VF, defined as a viral load of ≥400 copies/mL ≥6 months after ART initiation. We examined the proportion of individuals who remained on, switched, or discontinued the regimen. Associations between regimens and outcomes were examined with adjusted Cox proportional hazards models. Results: Among 5177 PLWH, a lower proportion experienced VF on dolutegravir- versus other INSTI- or darunavir-based regimens for previously treatment-naive (7% vs. 12% vs. 28%) and treatment-experienced PLWH (6% vs. 10% vs. 21%). In adjusted analyses, hazard ratios were similar across regimens for the combined outcome of regimen discontinuation or treatment switch. The hazard ratios for VF comparing dolutegravir- to darunavir-based regimens was 0.30 (95% CI: 0.2 to 0.6) among previously treatment-naive PLWH and was 0.60 (95% CI: 0.4 to 0.8) among treatment-experienced PLWH. Conclusions: The proportion of previously treatment-naive PLWH remaining on recommended ART regimens did not differ by regimen. The likelihood of VF was lower with dolutegravir- than darunavir-based regimens for previously treatment-naive and treatment-experienced PLWH.

Background: HIV viral load (VL) and resistance testing are limited in sub-Saharan Africa, so individuals may have prolonged time on failing first-line antiretroviral therapy (ART). Our objective was to describe the evolution of drug resistance mutations among adults failing first-line ART in Zambia. Methods: We analysed data from a trial of VL monitoring in Lusaka, Zambia. From 2006 to 2011, 12 randomized sites provided either routine VL monitoring (intervention) or discretionary (control) after ART initiation. Samples were collected prospectively following the same schedule in each arm but analysed retrospectively in the control group. For those with virological failure (VF; >400 copies/ml), HIV genotyping was performed retrospectively on baseline (BL) and on all subsequent specimens until censored due to study completion, withdrawal or death. Results: Of 1,973 enrollees, 165 (8.4%) developed VF. 464 genotype results were available including 132 (80%) at BL, 116 (70%) at VF and 125 (76%) had at least one result between VF and censoring. Major nucleoside reverse transcriptase inhibitor (NRTI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations increased from 26% (BL) to 82% (VF) to 89% at last genotype (LG). M184 mutations increased from 2% to 59% to 71%; K65R from 2% to 11% to 13%; 2 or more thymidine analogue mutations from 1% to 3% to 12%. Among those on a failing tenofovir disoproxil fumarate (TDF)-based regimen, TDF resistance increased from 42% to 58%. Conclusions: We found substantial resistance to NRTIs and NNRTIs at VF with incremental increases after VF while still on a failing first-line ART; this resistance may compromise attainment of the UNAIDS 90-90-90 goals. ©2019 International Medical Press

IMPORTANCE Antiretroviral therapy (ART) is the cornerstone of prevention and management of HIV infection. OBJECTIVE To evaluate new data and treatments and incorporate this information into updated recommendations for initiating therapy, monitoring individuals starting therapy, changing regimens, and preventing HIV infection for individuals at risk. EVIDENCE REVIEW New evidence collected since the International Antiviral Society-USA 2016 recommendations via monthly PubMed and EMBASE literature searches up to April 2018; data presented at peer-reviewed scientific conferences. A volunteer panel of experts in HIV research and patient care considered these data and updated previous recommendations. FINDINGS ART is recommended for virtually all HIV-infected individuals, as soon as possible after HIV diagnosis. Immediate initiation (eg, rapid start), if clinically appropriate, requires adequate staffing, specialized services, and careful selection of medical therapy. An integrase strand transfer inhibitor (InSTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is generally recommended for initial therapy, with unique patient circumstances (eg, concomitant diseases and conditions, potential for pregnancy, cost) guiding the treatment choice. CD4 cell count, HIV RNA level, genotype, and other laboratory tests for general health and co-infections are recommended at specified points before and during ART. If a regimen switch is indicated, treatment history, tolerability, adherence, and drug resistance history should first be assessed; 2 or 3 active drugs are recommended for a new regimen. HIV testing is recommended at least once for anyone who has ever been sexually active and more often for individuals at ongoing risk for infection. Preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and appropriate monitoring is recommended for individuals at risk for HIV. CONCLUSIONS AND RELEVANCE Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.

Background: Because HIV viral suppression is essential for optimal outcomes and prevention efforts, understanding trends and predictors is imperative to inform public health policy. Objective: To evaluate viral suppression trends in people living with HIV (PLWH), including the relationship of associated factors, such as demographic characteristics and integrase strand transfer inhibitor (ISTI) use. Design: Longitudinal observational cohort study. Setting: 8 HIV clinics across the United States. Participants: PLWH receiving clinical care. Measurements: To understand trends in viral suppression (≤400 copies/mL), annual viral suppression rates from 1997 to 2015 were determined. Analyses were repeated with tests limited to 1 random test per person per year and using inverse probability of censoring weights to address loss to follow-up. Joint longitudinal and survival models and linear mixed models of PLWH receiving antiretroviral therapy (ART) were used to examine associations between viral suppression or continuous viral load (VL) levels and demographic factors, substance use, adherence, and ISTI use. Results: Viral suppression increased from 32% in 1997 to 86% in 2015 on the basis of all tests among 31 930 PLWH. In adjusted analyses, being older (odds ratio [OR], 0.76 per decade [95% CI, 0.74 to 0.78]) and using an ISTI-based regimen (OR, 0.54 [CI, 0.51 to 0.57]) were associated with lower odds of having a detectable VL, and black race was associated with higher odds (OR, 1.68 [CI, 1.57 to 1.80]) (P < 0.001 for each). Similar patterns were seen with continuous VL levels; when analyses were limited to 2010 to 2015; and with adjustment for adherence, substance use, or depression. Limitation: Results are limited to PLWH receiving clinical care. Conclusion: HIV viral suppression rates have improved dramatically across the United States, which is likely partially attributable to improved ART, including ISTI-based regimens. However, disparities among younger and black PLWH merit attention.

Purpose: Substance use is linked with poor outcomes among people living with HIV (PLWH) and is associated with mental health disorders. This analysis examines the impact of decreasing substance use, even without abstinence, on depressive symptoms among PLWH. Methods: Data are from PLWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Sites cohort. Participants completed longitudinal assessments of substance use (modified ASSIST) and depressive symptoms (PHQ-9). Changes in substance use frequency were categorized as abstinence, reduced use, and nondecreasing use. Adjusted linear mixed models with time-updated change in substance use frequency and depressive symptom scores were used to examine associations between changes in the use of individual substances and depressive symptoms. Analyses were repeated using joint longitudinal survival models to examine associations with a high (PHQ-9 ≥10) score. Results: Among 9905 PLWH, 728 used cocaine/crack, 1016 used amphetamine-type substances (ATS), 290 used illicit opiates, and 3277 used marijuana at baseline. Changes in ATS use were associated with the greatest improvements in depressive symptoms: stopping ATS led to a mean decrease of PHQ-9 by 2.2 points (95% CI: 1.8 to 2.7) and a 61% lower odds of PHQ-9 score ≥10 (95% CI: 0.30 to 0.52), and decreasing ATS use led to a mean decrease of 1.7 points (95% CI: 1.2 to 2.3) and a 62% lower odds of PHQ-9 score ≥10 (95% CI: 0.25 to 0.56). Stopping and reducing marijuana and stopping cocaine/crack use were also associated with improvement in depressive symptoms. Conclusions: We demonstrated that both substance use reduction and abstinence are associated with improvements in depressive symptoms over time.

Background. The long-term effectiveness of human immunodeficiency virus (HIV) treatments containing integrase inhibitors is unknown. Methods. We use observational data from the Centers for AIDS Research Network of Integrated Clinical Systems and the Centers for Disease Control and Prevention to estimate 4-year risk of AIDS and all-cause mortality among 415 patients starting a raltegravir regimen compared to 2646 starting an efavirenz regimen (both regimens include emtricitabine and tenofovir disoproxil fumarate). We account for confounding and selection bias as well as generalizability by standardization for measured variables, and present both observational intent-to-treat and per-protocol estimates. Results. At treatment initiation, 12% of patients were female, 36% black, 13% Hispanic; median age was 37 years, CD4 count 321 cells/µL, and viral load 4.5 log10 copies/mL. Two hundred thirty-five patients incurred an AIDS-defining illness or died, and 741 patients left follow-up. After accounting for measured differences, the 4-year risk was similar among those starting both regimens (ie, intent-to treat hazard ratio [HR], 0.96 [95% confidence interval {CI}, .63–1.45]; risk difference, −0.9 [95% CI, −4.5 to 2.7]), as well as among those remaining on regimens (ie, per-protocol HR, 0.95 [95% CI, .59–1.54]; risk difference, −0.5 [95% CI, −3.8 to 2.9]). Conclusions. Raltegravir and efavirenz-based initial antiretroviral therapy have similar 4-year clinical effects. Vigilance regarding longer-term comparative effectiveness of HIV regimens using observational data is needed because large-scale experimental data are not forthcoming.

We examined risk factors for advanced hepatic fibrosis [fibrosis-4 (FIB)-4 >3.25] including both current alcohol use and a diagnosis of alcohol use disorder among HIV-infected patients. Of the 12,849 patients in our study, 2133 (17%) reported current hazardous drinking by AUDIT-C, 2321 (18%) had a diagnosis of alcohol use disorder, 2376 (18%) were co-infected with chronic hepatitis C virus (HCV); 596 (5%) had high FIB-4 scores >3.25 as did 364 (15%) of HIV/HCV coinfected patients. In multivariable analysis, HCV (adjusted odds ratio (aOR) 6.3, 95% confidence interval (CI) 5.2–7.5), chronic hepatitis B (aOR 2.0, 95% CI 1.5–2.8), diabetes (aOR 2.3, 95% CI 1.8–2.9), current CD4 500 copies/mL (aOR 1.3, 95% CI 1.0–1.6) were significantly associated with advanced fibrosis. A diagnosis of an alcohol use disorder (aOR 1.9, 95% CI 1.6–2.3) rather than report of current hazardous alcohol use was associated with high FIB-4. However, among HIV/HCV coinfected patients, both current hazardous drinkers (aOR 1.6, 95% CI 1.1–2.4) and current non-drinkers (aOR 1.6, 95% CI 1.2–2.0) were more likely than non-hazardous drinkers to have high FIB-4, with the latter potentially reflecting the impact of sick abstainers. These findings highlight the importance of using a longitudinal measure of alcohol exposure when evaluating the impact of alcohol on liver disease and associated outcomes.

Optimal timing of initiating antiretroviral therapy has been a controversial topic in HIV research. Two highly publicized studies applied different analytical approaches, a dynamic marginal structural model and a multiple imputation method, to different observational databases and came up with different conclusions. Discrepancies between the two studies' results could be due to differences between patient populations, fundamental differences between statistical methods, or differences between implementation details. For example, the two studies adjusted for different covariates, compared different thresholds, and had different criteria for qualifying measurements. If both analytical approaches were applied to the same cohort holding technical details constant, would their results be similar? In this study, we applied both statistical approaches using observational data from 12,708 HIV‐infected persons throughout the USA. We held technical details constant between the two methods and then repeated analyses varying technical details to understand what impact they had on findings. We also present results applying both approaches to simulated data. Results were similar, although not identical, when technical details were held constant between the two statistical methods. Confidence intervals for the dynamic marginal structural model tended to be wider than those from the imputation approach, although this may have been due in part to additional external data used in the imputation analysis. We also consider differences in the estimands, required data, and assumptions of the two statistical methods. Our study provides insights into assessing optimal dynamic treatment regimes in the context of starting antiretroviral therapy and in more general settings.

Background: Persons with human immunodeficiency virus (HIV) have higher risks for myocardial infarction (MI) than the general population. This is driven in part by higher type 2 MI (T2MI, due to coronary supply-demand mismatch) rates among persons with HIV (PWH). In the general population, T2MI has higher mortality than type 1 MI (T1MI, spontaneous and generally due to plaque rupture and thrombosis). PWH have a greater burden of comorbidities and may therefore have an even greater excess risk for complication and death in the setting of T2MI. However, mortality patterns after T1MI and T2MI in HIV are unknown. Methods: We analyzed mortality after MI among PWH enrolled in the multicenter, US-based Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort (N = 28,186). Incident MIs occurring between January 1, 1996, and December 31, 2014, were centrally adjudicated and classified as T1MI or T2MI. We first compared mortality following T1MI vs. T2MI among PWH. Cox survival analyses and Bayesian model averaging were then used to evaluate pre-MI covariates associated with mortality following T1MI and T2MI. Results: Among the 596 out of 28,186 PWH who experienced MI (2.1%; 293 T1MI and 303 T2MI), mortality rates were significantly greater after T2MI (22.2/100 person-years; 1-, 3-, and 5-year mortality 39%, 52%, and 62%) than T1MI (8.2/100 person-years; 1-, 3-, and 5-year mortality 15%, 22%, and 30%). Significant mortality predictors after T1MI were higher HIV viral load, renal dysfunction, and older age. Significant predictors of mortality after T2MI were low body-mass index (BMI) and detectable HIV viral load. Conclusions: Mortality is high following MI for PWH and substantially greater after T2MI than T1MI. Predictors of death after MI differed by type of MI, reinforcing the different clinical scenarios associated with each MI type and the importance of considering MI types separately.

Background: Anemia is common among people living with HIV infection (PLWH) and is associated with adverse health outcomes. Information on risk factors for anemia incidence in the current antiretroviral therapy (ART) era is lacking. Methods: Within a prospective clinical cohort of adult PLWH receiving care at eight sites across the United States between 1/2010-3/2018, Cox proportional hazards regression analyses were conducted among a) PLWH free of anemia at baseline and b) PLWH free of severe anemia at baseline to determine associations between time-updated patient characteristics and development of anemia (hemoglobin < 10 g/dL), or severe anemia (hemoglobin < 7.5 g/dL). Linear mixed effects models were used to examine relationships between patient characteristics and hemoglobin levels during follow-up. Hemoglobin levels were ascertained using laboratory data from routine clinical care. Potential risk factors included: age, sex, race/ethnicity, body mass index, smoking status, hazardous alcohol use, illicit drug use, hepatitis C virus (HCV) coinfection, estimated glomerular filtration rate (eGFR), CD4 cell count, viral load, ART use and time in care at CNICS site. Results: This retrospective cohort study included 15,126 PLWH. During a median follow-up of 6.6 (interquartile range [IQR] 4.3-7.6) years, 1086 participants developed anemia and 465 participants developed severe anemia. Factors that were associated with incident anemia included: older age, female sex, black race, HCV coinfection, lower CD4 cell counts, VL ≥400 copies/ml and lower eGFR. Conclusion: Because anemia is a treatable condition associated with increased morbidity and mortality among PLWH, hemoglobin levels should be monitored routinely, especially among PLWH who have one or more risk factors for anemia.

OBJECTIVE: Anaemia is common among people living with HIV (PLWH) and has been associated with certain, often older, antiretroviral medications. Information on current antiretroviral therapy (ART) and anaemia is limited. The objective was to compare the associations between anaemia incidence or haemoglobin change with core ART classes in the current ART era. DESIGN: Retrospective cohort study. SETTING: USA-based prospective clinical cohort of PLWH aged 18 and above receiving care at eight sites between January 2010 and March 2018. PARTICIPANTS: 16 505 PLWH were included in this study. MAIN OUTCOME MEASURES: Anaemia risk and haemoglobin change were estimated among PLWH for person-time on a protease inhibitor (PI) or an integrase strand transfer inhibitor (INSTI)-based regimen, relative to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based reference. We also examined PLWH on regimens containing multiple core classes. Cox proportional hazards regression analyses were conducted to measure the associations between time-updated ART classes and incident anaemia or severe anaemia. Linear mixed effects models were used to examine the relationships between ART classes and haemoglobin change. RESULTS: During a median of 4.9 years of follow-up, 1040 developed anaemia and 488 developed severe anaemia. Compared with NNRTI use, INSTI-based regimens were associated with an increased risk of anaemia (adjusted HR (aHR) 1.26, 95% CI 1.00 to 1.58) and severe anaemia (aHR 1.51, 95% CI 1.07 to 2.11) and a decrease in haemoglobin level. Time on multiple core classes was also associated with increased anaemia risk (aHR 1.39, 95% CI 1.13 to 1.70), while no associations were found for PI use. CONCLUSION: These findings suggest INSTI use may increase the risk of anaemia. If confirmed, screening for anaemia development in users of INSTIs may be beneficial. Further research into the underlying mechanisms is warranted.