Emulating a trial of joint dynamic strategies: An application to monitoring and treatment of HIV-positive individuals.

Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen? We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the "no direct effect" assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/µl compared with 500 cells/µl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The "no direct effect" assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size.

Evaluating the Population Impact on Racial/Ethnic Disparities in HIV in Adulthood of Intervening on Specific Targets: A Conceptual and Methodological Framework.

Reducing racial/ethnic disparities in human immunodeficiency virus (HIV) disease is a high priority. Reductions in HIV racial/ethnic disparities can potentially be achieved by intervening on important intermediate factors. The potential population impact of intervening on intermediates can be evaluated using observational data when certain conditions are met. However, using standard stratification-based approaches commonly employed in the observational HIV literature to estimate the potential population impact in this setting may yield results that do not accurately estimate quantities of interest. Here we describe a useful conceptual and methodological framework for using observational data to appropriately evaluate the impact on HIV racial/ethnic disparities of interventions. This framework reframes relevant scientific questions in terms of a controlled direct effect and estimates a corresponding proportion eliminated. We review methods and conditions sufficient for accurate estimation within the proposed framework. We use the framework to analyze data on 2,329 participants in the CFAR [Centers for AIDS Research] Network of Integrated Clinical Systems (2008-2014) to evaluate the potential impact of universal prescription of and ≥95% adherence to antiretroviral therapy on racial disparities in HIV virological suppression. We encourage the use of the described framework to appropriately evaluate the potential impact of targeted interventions in addressing HIV racial/ethnic disparities using observational data.

Multiple Imputation to Account for Measurement Error in Marginal Structural Models.

BACKGROUND: Marginal structural models are an important tool for observational studies. These models typically assume that variables are measured without error. We describe a method to account for differential and nondifferential measurement error in a marginal structural model. METHODS: We illustrate the method estimating the joint effects of antiretroviral therapy initiation and current smoking on all-cause mortality in a United States cohort of 12,290 patients with HIV followed for up to 5 years between 1998 and 2011. Smoking status was likely measured with error, but a subset of 3,686 patients who reported smoking status on separate questionnaires composed an internal validation subgroup. We compared a standard joint marginal structural model fit using inverse probability weights to a model that also accounted for misclassification of smoking status using multiple imputation. RESULTS: In the standard analysis, current smoking was not associated with increased risk of mortality. After accounting for misclassification, current smoking without therapy was associated with increased mortality (hazard ratio [HR]: 1.2 [95% confidence interval [CI] = 0.6, 2.3]). The HR for current smoking and therapy [0.4 (95% CI = 0.2, 0.7)] was similar to the HR for no smoking and therapy (0.4; 95% CI = 0.2, 0.6). CONCLUSIONS: Multiple imputation can be used to account for measurement error in concert with methods for causal inference to strengthen results from observational studies.

The Ryan White HIV/AIDS Program in the Age of Health Care Reform.

Thanks to the Affordable Care Act, thousands of people living with HIV who have received Ryan White HIV/AIDS Program-funded care are now eligible for Medicaid or subsidized insurance. The protection against insurance discrimination on the basis of preexisting conditions is increasing health care access for many, but this does not mean that the Ryan White Program is no longer needed. Services essential to improving outcomes on the continuum of HIV care are not supported by any other source. Because of the growing number of people living with HIV, we must increase funding for the Ryan White Program and increase the number of HIV care providers.

Comprehensive transgender healthcare: the gender affirming clinical and public health model of Fenway Health.

This report describes the evolution of a Boston community health center's multidisciplinary model of transgender healthcare, research, education, and dissemination of best practices. This process began with the development of a community-based approach to care that has been refined over almost 20 years where transgender patients have received tailored services through the Transgender Health Program. The program began as a response to unmet clinical needs and has grown through recognition that our local culturally responsive approach that links clinical care with biobehavioral and health services research, education, training, and advocacy promotes social justice and health equity for transgender people. Fenway Health's holistic public health efforts recognize the key role of gender affirmation in the care and well-being of transgender people worldwide.

Characterizing HIV transmission networks across the United States.

BACKGROUND: Clinically, human immunodeficiency virus type 1 (HIV-1) pol sequences are used to evaluate for drug resistance. These data can also be used to evaluate transmission networks and help describe factors associated with transmission risk. METHODS: HIV-1 pol sequences from participants at 5 sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort from 2000-2009 were analyzed for genetic relatedness. Only the first available sequence per participant was included. Inferred transmission networks ("clusters") were defined as ≥2 sequences with ≤1.5% genetic distance. Clusters including ≥3 patients ("networks") were evaluated for clinical and demographic associations. RESULTS: Of 3697 sequences, 24% fell into inferred clusters: 155 clusters of 2 individuals ("dyads"), 54 clusters that included 3-14 individuals ("networks"), and 1 large cluster that included 336 individuals across all study sites. In multivariable analyses, factors associated with being in a cluster included not using antiretroviral (ARV) drugs at time of sampling (P < .001), sequence collected after 2004 (P < .001), CD4 cell count >350 cells/mL (P < .01), and viral load 10,000-100,000 copies/mL (P < .001) or >100,000 copies/mL (P < .001). In networks, women were more likely to cluster with other women (P < .001), and African Americans with other African Americans (P < .001). CONCLUSIONS: Molecular epidemiology can be applied to study HIV transmission networks in geographically and demographically diverse cohorts. Clustering was associated with lack of ARV use and higher viral load, implying transmission may be interrupted by earlier diagnosis and treatment. Observed female and African American networks reinforce the importance of diagnosis and prevention efforts targeted by sex and race.

Emerging models of clinical services for men who have sex with men: focused versus comprehensive approaches.

By the early 1970s, it was increasingly recognised that men who have sex with men (MSM) were at risk for specific sexually transmissible infections (STI), and clinician awareness regarding MSM STI grew significantly after the AIDS epidemic was first recognised in 1981. In many urban centres in the USA and other resource-rich countries, the development of clinical infrastructure to address the AIDS epidemic led to the creation of clinics that provided services for large numbers of MSM. During the same time period, other health centres were created that were community-focused, providing comprehensive behavioural health and medical services for all sexual and gender minority patients. Over the next few years, multiple models for MSM sexual health will evolve, ranging from centres that embed STI care in primary care, to more focused centres that can use new technology to provide an efficient assessment for at-risk MSM desiring quick screening services.

Sociodemographic and Clinical Factors Associated With Increasing Bacterial Sexually Transmitted Infection Diagnoses in Men Who Have Sex With Men Accessing Care at a Boston Community Health Center (2005-2015).

BACKGROUND: The reasons why bacterial sexually transmitted infections (BSTIs) are increasing in US men who have sex with men (MSM) have not been fully characterized. METHODS: An open cohort of MSM accessing medical care at a Boston community health center was used to assess secular trends in BSTI diagnoses. Frequency of infection and the estimated population size were used to calculate diagnosis rates. Poisson models were fit for multivariable analyses. RESULTS: Between 2005 and 2015, 19 232 men had at least 1 clinic visit. Most (72.4%) were white; 6.0% were black, and 6.1% were Latino. Almost half had documented self-report of identifying as gay (42.6%) or bisexual (3.2%). Most had private health insurance (61.7%); 5.4% had Medicare, 4.6% had Medicaid, and 8.4% reported no insurance. Between 2005 and 2015, BSTI diagnoses increased more than 8-fold. In 2015, of 1319 men who were diagnosed with at least 1 BSTI; 291 were diagnosed with syphilis, 554 with gonorrhea (51.4% rectal, 31.0% urogenital), and 679 with chlamydia (69.1% rectal, 34.3% urogenital). In 2015, 22.7% of BSTIs were diagnosed among HIV-infected patients (15.4% of the clinic population), and 32.8% of BSTIs were diagnosed among HIV-uninfected patients using pre-exposure prophylaxis (PrEP; 10.1% of all men in care). In multivariable analyses, age 18 to 24 years, being HIV-infected, using PrEP, being nonwhite, or reporting Medicaid or not reporting having private insurance or Medicare were independently associated with being diagnosed with a new BSTI. CONCLUSIONS: Over the past decade, BSTI diagnosis rates increased in HIV-infected and uninfected MSM, with disproportionate increases in PrEP users, racial and ethnic minority MSM, those aged 25 to 34 years, and those without stable health insurance, warranting focused education, screening, and accessible services for these key subpopulations.

Comparative effectiveness of single versus multiple tablet antiretroviral therapy regimens in clinical HIV practice.

We determined risk of virologic failure (VF) in individuals initiating tenofovir/emtricitabine/efavirenz as single versus multiple tablet regimens (MTR). We found no significant difference in the risk of VF, though did observe a trend toward more VF and M184 V mutations among persons initiating MTR. Temporal trends in care may have confounded results.

Comparison of dynamic monitoring strategies based on CD4 cell counts in virally suppressed, HIV-positive individuals on combination antiretroviral therapy in high-income countries: a prospective, observational study.

BACKGROUND: Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals. METHODS: In this observational study, we used data from prospective studies of HIV-positive individuals in Europe (France, Greece, the Netherlands, Spain, Switzerland, and the UK) and North and South America (Brazil, Canada, and the USA) in The HIV-CAUSAL Collaboration and The Centers for AIDS Research Network of Integrated Clinical Systems. We compared three monitoring strategies that differ in the threshold used to measure CD4 cell count and HIV RNA viral load every 3-6 months (when below the threshold) or every 9-12 months (when above the threshold). The strategies were defined by the threshold CD4 counts of 200 cells per µL, 350 cells per µL, and 500 cells per µL. Using inverse probability weighting to adjust for baseline and time-varying confounders, we estimated hazard ratios (HRs) of death and of AIDS-defining illness or death, risk ratios of virological failure, and mean differences in CD4 cell count. FINDINGS: 47 635 individuals initiated an antiretroviral therapy regimen between Jan 1, 2000, and Jan 9, 2015, and met the eligibility criteria for inclusion in our study. During follow-up, CD4 cell count was measured on average every 4·0 months and viral load every 3·8 months. 464 individuals died (107 in threshold 200 strategy, 157 in threshold 350, and 200 in threshold 500) and 1091 had AIDS-defining illnesses or died (267 in threshold 200 strategy, 365 in threshold 350, and 459 in threshold 500). Compared with threshold 500, the mortality HR was 1·05 (95% CI 0·86-1·29) for threshold 200 and 1·02 (0·91·1·14) for threshold 350. Corresponding estimates for death or AIDS-defining illness were 1·08 (0·95-1·22) for threshold 200 and 1·03 (0·96-1·12) for threshold 350. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2·01 (1·17-3·43) for threshold 200 and 1·24 (0·89-1·73) for threshold 350, and 24 month mean CD4 cell count differences were 0·4 (-25·5 to 26·3) cells per µL for threshold 200 and -3·5 (-16·0 to 8·9) cells per µL for threshold 350. INTERPRETATION: Decreasing monitoring to annually when CD4 count is higher than 200 cells per µL compared with higher than 500 cells per µL does not worsen the short-term clinical and immunological outcomes of virally suppressed HIV-positive individuals. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further follow-up studies are needed to establish the long-term safety of these strategies. FUNDING: National Institutes of Health.

Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection.

CONTEXT: Plasma human immunodeficiency virus (HIV) RNA level predicts HIV disease progression, but the extent to which it explains the variability in rate of CD4 cell depletion is poorly characterized. OBJECTIVE: To estimate the proportion of variability in rate of CD4 cell loss predicted by presenting plasma HIV RNA levels in untreated HIV-infected persons. DESIGN: Repeated-measures analyses of 2 multicenter cohorts, comprising observations beginning on May 12, 1984, and ending on August 26, 2004. Analyses were conducted between August 2004 and March 2006. SETTING: Two cohorts of HIV-infected persons: patients followed up at 4 US teaching medical institutions or participating in either the Research in Access to Care for the Homeless Cohort (REACH) or the San Francisco Men's Health Study (SFMHS) cohorts and participants in the Multicenter AIDS Cohort Study (MACS) cohort. PARTICIPANTS: Antiretroviral treatment-naive, chronically HIV-infected persons (n = 1289 and n = 1512 for each of the 2 cohorts) untreated during the observation period (> or =6 months) and with at least 1 HIV RNA level and 2 CD4 cell counts available. Approximately 35% were nonwhite, and 35% had risk factors other than male-to-male sexual contact. MAIN OUTCOME MEASURES: The extent to which presenting plasma HIV RNA level could explain the rate of model-derived yearly CD4 cell loss, as estimated by the coefficient of determination (R2). RESULTS: In both cohorts, higher presenting HIV RNA levels were associated with greater subsequent CD4 cell decline. In the study cohort, median model-estimated CD4 cell decrease among participants with HIV RNA levels of 500 or less, 501 to 2000, 2001 to 10,000, 10,001 to 40,000, and more than 40,000 copies/mL were 20, 39, 48, 56, and 78 cells/microL, respectively. Despite this trend across broad categories of HIV RNA levels, only a small proportion of CD4 cell loss variability (4%-6%) could be explained by presenting plasma HIV RNA level. Analyses using multiple HIV RNA measurements or restricting to participants with high HIV RNA levels improved this correlation minimally (R2, 0.09), and measurement error was estimated to attenuate these associations only marginally (deattenuated R2 in the 2 cohorts, 0.05 and 0.08, respectively). CONCLUSIONS: Presenting HIV RNA level predicts the rate of CD4 cell decline only minimally in untreated persons. Other factors, as yet undefined, likely drive CD4 cell losses in HIV infection. These findings have implications for treatment decisions in HIV infection and for understanding the pathogenesis of progressive immune deficiency.

Poorly Controlled HIV Infection: An Independent Risk Factor for Liver Fibrosis.

BACKGROUND: Liver disease is a major cause of mortality among HIV-infected persons. There is limited information about the extent to which HIV disease severity impacts liver disease progression. METHODS: We determined the incidence and predictors of advanced hepatic fibrosis measured by the Fibrosis-4 index (≥3.25) in a large diverse population of HIV-infected patients without significant liver disease at baseline (Fibrosis-4 score <1.45) in care between January 2000 and March 2014. We used Cox proportional hazards analysis to examine factors associated with progression to Fibrosis-4 score ≥3.25. RESULTS: Among 14,198 HIV-infected patients, hepatitis C virus (HCV) coinfection [adjusted hazard ratio (aHR) 1.9, 95% confidence interval (CI): 1.6 to 2.1], hepatitis B virus coinfection (aHR 1.5, 95% CI: 1.2 to 1.8), alcohol-use disorder (aHR 1.4, 95% CI: 1.2 to 1.6), and diabetes (aHR 1.9, 95% CI: 1.6 to 2.3) were associated with progression to advanced fibrosis in multivariable analysis. In addition, patients at each lower level of time-varying CD4 cell count had a significantly greater risk of progression, with ∼7-fold higher risk in those with CD4 <100 cells per cubic millimeter (aHR 6.9, 95% CI: 5.8 to 8.3) compared with CD4 ≥500 cells per cubic millimeter. An increasing gradient of risk was also observed among patients with higher time-varying HIV viral load (VL), with the greatest risk noted with VL ≥100,000 copies per milliliter (aHR 2.6, 95% CI: 2.2 to 3.1) compared with VL <500 copies per milliliter. CONCLUSIONS: Lower CD4 cell count and higher HIV VL were significantly associated with progression to advanced hepatic fibrosis in a dose-dependent manner, independent of the risk associated with traditional factors: hepatitis C virus or hepatitis B virus coinfection, alcohol, and diabetes. Our findings suggest that early treatment of HIV infection could mitigate liver disease.

When to Monitor CD4 Cell Count and HIV RNA to Reduce Mortality and AIDS-Defining Illness in Virologically Suppressed HIV-Positive Persons on Antiretroviral Therapy in High-Income Countries: A Prospective Observational Study.

OBJECTIVE: To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART). DESIGN: Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems. METHODS: Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9-12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes. RESULTS: In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9-12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were -5.3 (-18.6 to 7.9) and -31.7 (-52.0 to -11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies. CONCLUSIONS: Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question.

Using observational data to emulate a randomized trial of dynamic treatment-switching strategies: an application to antiretroviral therapy.

Background: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). Methods: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Results: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Conclusions: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

High levels of antiretroviral use and viral suppression among persons in HIV care in the United States, 2010.

BACKGROUND: Contemporary data on patterns of antiretroviral therapy (ART) use in the United States are needed to inform efforts to improve the HIV care cascade. METHODS: We conducted a cross-sectional study of patients in the Centers for AIDS Research Network of Integrated Clinical Systems cohort who were in HIV care in 2010 to assess ART use and outcomes, stratified by nadir CD4 count (≤350, 351-500, or >500 cells/mm), demographics, psychiatric diagnoses, substance use, and engagement in continuous care (≥2 visits ≥3 months apart in 2010). RESULTS: Of 8633 patients at 7 sites who had ≥1 medical visit and ≥1 viral load in 2010, 94% had ever initiated ART, 89% were on ART, and 70% had an undetectable viral load at the end of 2010. Fifty percent of ART-naive patients had nadir CD4 counts >500 cells per cubic millimeter, but this group comprised just 3% of the total population. Among patients who were ART naive at the time of cohort entry (N = 4637), both ART initiation and viral suppression were strongly associated with nadir CD4 count. Comparing 2009 and 2010, the percentages of patients with viral suppression among those with nadir CD4 counts 351-500 and >500 cells per cubic millimeter were 44% vs. 57% and 25% vs. 33%, respectively. Engagement in care was the only factor consistently associated with ART use and viral suppression across nadir CD4 count strata. CONCLUSIONS: Our findings suggest that ART use and viral suppression among persons in HIV care may be more common than estimated in some previous studies and increased from 2009 to 2010.

Transmitted drug resistance in the CFAR network of integrated clinical systems cohort: prevalence and effects on pre-therapy CD4 and viral load.

Human immunodeficiency virus type 1 (HIV-1) genomes often carry one or more mutations associated with drug resistance upon transmission into a therapy-naïve individual. We assessed the prevalence and clinical significance of transmitted drug resistance (TDR) in chronically-infected therapy-naïve patients enrolled in a multi-center cohort in North America. Pre-therapy clinical significance was quantified by plasma viral load (pVL) and CD4+ cell count (CD4) at baseline. Naïve bulk sequences of HIV-1 protease and reverse transcriptase (RT) were screened for resistance mutations as defined by the World Health Organization surveillance list. The overall prevalence of TDR was 14.2%. We used a Bayesian network to identify co-transmission of TDR mutations in clusters associated with specific drugs or drug classes. Aggregate effects of mutations by drug class were estimated by fitting linear models of pVL and CD4 on weighted sums over TDR mutations according to the Stanford HIV Database algorithm. Transmitted resistance to both classes of reverse transcriptase inhibitors was significantly associated with lower CD4, but had opposing effects on pVL. In contrast, position-specific analyses of TDR mutations revealed substantial effects on CD4 and pVL at several residue positions that were being masked in the aggregate analyses, and significant interaction effects as well. Residue positions in RT with predominant effects on CD4 or pVL (D67 and M184) were re-evaluated in causal models using an inverse probability-weighting scheme to address the problem of confounding by other mutations and demographic or risk factors. We found that causal effect estimates of mutations M184V/I (-1.7 log10pVL) and D67N/G (-2.1[³âˆšCD4] and 0.4 log10pVL) were compensated by K103N/S and K219Q/E/N/R. As TDR becomes an increasing dilemma in this modern era of highly-active antiretroviral therapy, these results have immediate significance for the clinical management of HIV-1 infections and our understanding of the ongoing adaptation of HIV-1 to human populations.