Comparing results from multiple imputation and dynamic marginal structural models for estimating when to start antiretroviral therapy

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

Anal cancer incidence in men with HIV who have sex with men: are black men at higher risk?

Objective:To assess differences in anal cancer incidence between racial/ethnic groups among a clinical cohort of men with HIV who have sex with men.Design:Clinical cohort studyMethods:We studied men who have sex with men (MSM) in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) who initiated antiretroviral therapy (ART) under HIV care in CNICS. We compared anal cancer incidence between Black and non-Black men and calculated hazard ratios controlling for demographic characteristics (age, CNICS site, year of ART initiation), HIV disease indicators (nadir CD4+, peak HIV RNA), and co-infection/behavioral factors including hepatitis B virus (HBV), hepatitis C virus (HCV), tobacco smoking and alcohol abuse.Results:We studied 7473 MSM with HIV who contributed 41 810 person-years of follow-up after initiating ART between 1996 and 2014 in CNICS. Forty-one individuals had an incident diagnosis of anal cancer under observation. Crude rates of anal cancer were 204 versus 61 per 100 000 person-years among Black versus non-Black MSM. The weighted hazard ratio for anal cancer in Black MSM (adjusting for demographics, HIV disease factors, and co-infection/behavioral factors) was 2.37 (95% confidence interval: 1.17, 4.82) compared to non-Black MSM.Conclusions:In this large multicenter cohort, Black MSM were at significantly increased risk for anal cancer compared to non-Black MSM. Further detailed studies evaluating factors impacting anal cancer incidence and outcomes in Black men with HIV are necessary. Inclusion of more diverse study cohorts may elucidate modifiable factors associated with increased anal cancer risk experienced by Black MSM

Assessing effects of behavioral intervention on treatment outcomes among patients initiating HIV care: Rationale and design of iENGAGE intervention trial

During the initial year of HIV diagnosis, while patients are often overwhelmed adjusting to this life changing diagnosis, they must develop self-care behaviors for attending regular medical care visits and antiretroviral therapy (ART) adherence to achieve and sustain viral suppression (VS). Maintaining “HIV adherence” and integrating it into one's daily life is required to sustain VS over time. The HIV care continuum or “treatment cascade,” an epidemiological snapshot of the national epidemic in the United States (US), indicates that a minority of persons living with HIV (PLWH) have achieved VS. Little evidence exists regarding the effects of interventions focusing on PLWH newly initiating outpatient HIV care. An intervention that focuses on both retention in care and ART adherence skills delivered during the pivotal first year of HIV care is lacking. To address this, we developed a theory-based intervention evaluated in the Integrating Engagement and Adherence Goals upon Entry (iENGAGE) study, a National Institute of Allergy and Infectious Diseases (NIAID) funded randomized behavioral intervention trial. Here we present the study objectives, design and rationale, as well as the intervention components, targeting rapid and sustained VS through retention in HIV care and ART adherence during participants' first year of HIV care. The primary outcome of the study is 48-week VS (<200 c/mL). The secondary outcomes are retention in care, including HIV visit adherence and visit constancy, as well as ART adherence

Risk factors for atrial fibrillation in a multicenter United States clinical cohort of people with HIV infection

To assess atrial fibrillation risk factors in people with HIV, we identified incident atrial fibrillation in a large clinical cohort of people receiving care. Compared with 970 controls without atrial fibrillation, the 97 with adjudicated incident atrial fibrillation were older, less likely Hispanic, and had more coronary disease, heart failure, and chronic obstructive pulmonary disease. In multivariable analysis, nonuse of antiretroviral therapy and prescription of antiretroviral regimens with multiple core agents were associated with increased atrial fibrillation risk

Antiretroviral drug class and anaemia risk in the current treatment era among people living with HIV in the USA: a clinical cohort study

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

Incident AIDS or death after initiation of human immunodeficiency virus treatment regimens including raltegravir or efavirenz among adults in the United States

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

Anemia risk factors among people living with HIV across the United States in the current treatment era: A clinical cohort study

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

Marijuana Use Is Not Associated with Changes in Opioid Prescriptions or Pain Severity among People Living with HIV and Chronic Pain

Background:People living with HIV (PLWH) commonly report marijuana use for chronic pain, although there is limited empirical evidence to support its use. There is hope that marijuana may reduce prescription opioid use. Our objective was to investigate whether marijuana use among PLWH who have chronic pain is associated with changes in pain severity and prescribed opioid use (prescribed opioid initiation and discontinuation).Methods:Participants completed self-report measures of chronic pain and marijuana use at an index visit and were followed up for 1 year in the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). Self-reported marijuana use was the exposure variable. Outcome variables were changes in pain and initiation or discontinuation of opioids during the study period. The relationship between exposure and outcomes was assessed using generalized linear models for pain and multivariable binary logistic regression models for opioid initiation/discontinuation.Results:Of 433 PLWH and chronic pain, 28% reported marijuana use in the past 3 months. Median pain severity at the index visit was 6.3/10 (interquartile range 4.7-8.0). Neither increases nor decreases in marijuana use were associated with changes in pain severity, and marijuana use was not associated with either lower odds of opioid initiation or higher odds of opioid discontinuation.Conclusions:We did not find evidence that marijuana use in PLWH is associated with improved pain outcomes or reduced opioid prescribing. This suggests that caution is warranted when counseling PLWH about potential benefits of recreational or medical marijuana

Brief report: The association of chronic pain and long-term opioid therapy with HIV treatment outcomes

Background: Chronic pain occurs in up to 85% of persons living with HIV and is commonly treated with long-term opioid therapy (LTOT). We investigated the impact of chronic pain and LTOT on HIV outcomes. Methods: This was prospective cohort study conducted between July 2015 and July 2016 in 5 HIV primary care clinics. Chronic pain was defined as ≥moderate pain for ≥3 months on the Brief Chronic Pain Questionnaire. Chronic pain and LTOT were assessed at an index visit. Suboptimal retention, defined as at least one "no-show" to primary care, and virologic failure were measured over the subsequent year. Multivariable logistic regression models were built for each outcome adjusting for site. Results: Among 2334 participants, 25% had chronic pain, 27% had suboptimal retention, 12% had virologic failure, and 19% were prescribed LTOT. Among individuals not on LTOT, chronic pain was associated with increased odds of suboptimal retention [adjusted odds ratio (aOR) 1.46, 95% confidence interval (CI): 1.10 to 1.93, P = 0.009] and virologic failure (aOR 1.97, 95% CI: 1.39 to 2.80, P < 0.001). Among individuals with chronic pain, there was no association between LTOT and retention, but LTOT was associated with lower rates of virologic failure (aOR 0.56, 95% CI: 0.33 to 0.96, P = 0.03). Conclusions: Chronic pain in participants not on LTOT was associated with virologic failure. This reinforces the need to identify effective chronic pain treatments for persons living with HIV and investigate their impact on HIV outcomes. The apparent protective association between LTOT and virologic failure in those with pain merits further exploration

Virologic Failure Among People Living With HIV Initiating Dolutegravir-Based Versus Other Recommended Regimens in Real-World Clinical Care Settings

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