Hypertension and one-year risk of all-cause mortality among women with treated HIV in the United States.

OBJECTIVE: Hypertension is a critical cause of cardiovascular disease, and women with HIV have a higher prevalence of hypertension than women without HIV. The relationship between hypertension and mortality has not been well characterized in women with treated HIV. Here, we estimate the effect of hypertension on 1-year risk of all-cause mortality among women with HIV on antiretroviral therapy (ART) in the United States. DESIGN: An analysis of multicenter, observational cohort data from the Women's Interagency HIV Study (WIHS) collected between 1995 and 2019. METHODS: We included women with HIV who reported ever using ART. We used parametric g-computation to estimate the effect of hypertension (SBP ≥140  mmHg, DBP ≥90 mmHg, or use of hypertensive medication) on all-cause mortality within 1 year of a WIHS visit. RESULTS: Among 2929 unique women, we included 57 034 visits with a median age of 45 (interquartile range: 39, 52) years. Women had hypertension at 34.5% of visits, and 641 deaths occurred within 1 year of a study visit. Comparing women at visits with hypertension to women at visits without hypertension, the standardized 1-year risk ratio for mortality was 1.16 [95% confidence interval (95% CI): 1.01-1.33]. The risk ratios were higher in Hispanic (risk ratio: 1.23, 95% CI: 0.86-1.77) and non-Hispanic black women (risk ratio: 1.19, 95% CI: 1.04-1.37) and lower in non-Hispanic white women (risk ratio: 0.93, 95% CI: 0.58-1.48). CONCLUSION: Among women with treated HIV, those with hypertension, compared with those without, had an increased 1-year risk of all-cause mortality.

Five-Year Mortality for Adults Entering Human Immunodeficiency Virus Care Under Universal Early Treatment Compared With the General US Population.

BACKGROUND: Mortality 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. METHODS: Among 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. RESULTS: For 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. CONCLUSIONS: Expanding early treatment may modestly reduce, but not eliminate, the elevation in mortality for people with HIV.

A new smoking cessation 'cascade' among women with or at risk for HIV infection.

OBJECTIVES: The aim of this study was to define a smoking cessation 'cascade' among USA women with and without HIV and examine differences by sociodemographic characteristics. DESIGN: An observational cohort study using data from smokers participating in the Women's Interagency HIV Study between 2014 and 2019. METHODS: We followed 1165 women smokers with and without HIV from their first study visit in 2014 or 2015 until an attempt to quit smoking within approximately 3 years of follow-up, initial cessation (i.e. no restarting smoking within approximately 6 months of a quit attempt), and sustained cessation (i.e. no restarting smoking within approximately 12 months of a quit attempt). Using the Aalen-Johansen estimator, we estimated the cumulative probability of achieving each step, accounting for the competing risk of death. RESULTS: Forty-five percent of smokers attempted to quit, 27% achieved initial cessation, and 14% achieved sustained cessation with no differences by HIV status. Women with some post-high school education were more likely to achieve each step than those with less education. Outcomes did not differ by race. Thirty-six percent [95% confidence interval (95% CI): 31-42] of uninsured women attempted to quit compared with 47% (95% CI: 44-50) with Medicaid and 49% (95% CI: 41-59) with private insurance. CONCLUSION: To decrease smoking among USA women with and without HIV, targeted, multistage interventions, and increased insurance coverage are needed to address shortfalls along this cascade.

Reflection on modern methods: combining weights for confounding and missing data.

Inverse probability weights are increasingly used in epidemiological analysis, and estimation and application of weights to address a single bias are well discussed in the literature. Weights to address multiple biases simultaneously (i.e. a combination of weights) have almost exclusively been discussed related to marginal structural models in longitudinal settings where treatment weights (estimated first) are combined with censoring weights (estimated second). In this work, we examine two examples of combined weights for confounding and missingness in a time-fixed setting in which outcome or confounder data are missing, and the estimand is the marginal expectation of the outcome under a time-fixed treatment. We discuss the identification conditions, construction of combined weights and how assumptions of the missing data mechanisms affect this construction. We use a simulation to illustrate the estimation and application of the weights in the two examples. Notably, when only outcome data are missing, construction of combined weights is straightforward; however, when confounder data are missing, we show that in general we must follow a specific estimation procedure which entails first estimating missingness weights and then estimating treatment probabilities from data with missingness weights applied. However, if treatment and missingness are conditionally independent, then treatment probabilities can be estimated among the complete cases.

Mortality Among Persons Entering HIV Care Compared With the General U.S. Population : An Observational Study.

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.

Two-stage g-computation: Evaluating Treatment and Intervention Impacts in Observational Cohorts When Exposure Information Is Partly Missing.

Illustrations of the g-computation algorithm to evaluate population average treatment and intervention effects have been predominantly implemented in settings with complete exposure information. Thus, worked examples of approaches to handle missing data in this causal framework are needed to facilitate wider use of these estimators. We illustrate two-stage g-computation estimators that leverage partially observed information on the full study sample and complete exposure information on a subset to estimate causal effects. In a hypothetical cohort of 1,623 human immunodeficiency virus (HIV)-positive women with 30% complete opioid prescription information, we illustrate a two-stage extrapolation g-computation estimator for the average treatment effect of shorter or longer duration opioid prescriptions; we further illustrate two-stage inverse probability weighting and imputation g-computation estimators for the average intervention effect of shortening the duration of prescriptions relative to the status quo. Two-stage g-computation estimators approximated the true risk differences for the population average treatment and intervention effects while g-computation fit to the subset of complete cases was biased. In 10,000 Monte Carlo simulations, two-stage approaches considerably reduced bias and mean squared error and improved the coverage of 95% confidence limits. Although missing data threaten validity and precision, two-stage g-computation designs offer principled approaches to handling missing information.

Estimating a Set of Mortality Risk Functions with Multiple Contributing Causes of Death.

BACKGROUND: There are few methodologic examples of how multiple causes of death may be summarized in cause-specific mortality analyses to address limitations of attributing death to a single underlying cause. We propose a cause-of-death weighting approach to estimate the set of risk functions of specific causes of mortality using both underlying and contributing cause-of-death information. METHODS: We constructed weights according to a user-specified function. Using data from four southern US human immunodeficiency virus (HIV) clinics, we constructed a cause of death-weighted Aalen-Johansen estimator of the cumulative incidence function to estimate risks of five specific causes of mortality in the full sample and by injection drug use history. RESULTS: Among 7740 HIV-positive patients initiating antiretroviral therapy between 1999 and 2014, the 8-year risk of all-cause mortality was 17.5% [95% confidence interval (CI) = 16.5, 18.4]. The cause of death-weighted risk of HIV-related mortality was 6.7% (95% CI = 6.0, 7.3) and accounted for 39% (95% CI = 35, 42) of total mortality risk. This compared with 10.2% (95% CI = 9.2, 11.2) using only the underlying cause, in which case HIV-related deaths accounted for nearly 60% of total mortality risk. The proportion attributable to cardiovascular disease among those whose HIV risk factor was injection drug use was twice as high using cause-of-death weights compared with only the underlying cause (8%; 95% CI = 5, 11 vs 4%; 95% CI = 1, 6). CONCLUSION: Using cause of death-weighted estimators to incorporate multiple causes of death may yield different conclusions regarding the importance of certain causes of mortality. See video abstract: http://links.lww.com/EDE/B706.

Generalizing the per-protocol treatment effect: The case of ACTG A5095.

BACKGROUND: Intention-to-treat comparisons of randomized trials provide asymptotically consistent estimators of the effect of treatment assignment, without regard to compliance. However, decision makers often wish to know the effect of a per-protocol comparison. Moreover, decision makers may also wish to know the effect of treatment assignment or treatment protocol in a user-specified target population other than the sample in which the trial was fielded. Here, we aimed to generalize results from the ACTG A5095 trial to the US recently HIV-diagnosed target population. METHODS: We first replicated the published conventional intention-to-treat estimate (2-year risk difference and hazard ratio) comparing a four-drug antiretroviral regimen to a three-drug regimen in the A5095 trial. We then estimated the intention-to-treat effect that accounted for informative dropout and the per-protocol effect that additionally accounted for protocol deviations by constructing inverse probability weights. Furthermore, we employed inverse odds of sampling weights to generalize both intention-to-treat and per-protocol effects to a target population comprising US individuals with HIV diagnosed during 2008-2014. RESULTS: Of 761 subjects in the analysis, 82 dropouts (36 in the three-drug arm and 46 in the four-drug arm) and 59 protocol deviations (25 in the three-drug arm and 34 in the four-drug arm) occurred during the first 2 years of follow-up. A total of 169 subjects incurred virologic failure or death. The 2-year risks were similar both in the trial and in the US HIV-diagnosed target population for estimates from the conventional intention-to-treat, dropout-weighted intention-to-treat, and per-protocol analyses. In the US target population, the 2-year conventional intention-to-treat risk difference (unit: %) for virologic failure or death comparing the four-drug arm to the three-drug arm was -0.4 (95% confidence interval: -6.2, 5.1), while the hazard ratio was 0.97 (95% confidence interval: 0.70, 1.34); the 2-year risk difference was -0.9 (95% confidence interval: -6.9, 5.3) for the dropout-weighted intention-to-treat comparison (hazard ratio = 0.95, 95% confidence interval: 0.68, 1.32) and -0.7 (95% confidence interval: -6.7, 5.5) for the per-protocol comparison (hazard ratio = 0.96, 95% confidence interval: 0.69, 1.34). CONCLUSION: No benefit of four-drug antiretroviral regimen over three-drug regimen was found from the conventional intention-to-treat, dropout-weighted intention-to-treat or per-protocol estimates in the trial sample or target population.

Cumulative Burden of Depression and All-Cause Mortality in Women Living With Human Immunodeficiency Virus.

Background: Research linking depression to mortality among people living with human immunodeficiency virus (PLWH) has largely focused on binary "always vs never" characterizations of depression. However, depression is chronic and is likely to have cumulative effects on mortality over time. Quantifying depression as a cumulative exposure may provide a better indication of the clinical benefit of enhanced depression treatment protocols delivered in HIV care settings. Methods: Women living with HIV (WLWH), naive to antiretroviral therapy, from the Women's Interagency HIV Study were followed from their first visit in or after 1998 for up to 10 semiannual visits (5 years). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. An area-under-the-curve approach was used to translate CES-D scores into a time-updated measure of cumulative days with depression (CDWD). We estimated the effect of CDWD on all-cause mortality using marginal structural Cox proportional hazards models. Results: Overall, 818 women contributed 3292 woman-years over a median of 4.8 years of follow-up, during which the median (interquartile range) CDWD was 366 (97-853). Ninety-four women died during follow-up (2.9 deaths/100 woman-years). A dose-response relationship was observed between CDWD and mortality. Each additional 365 days spent with depression increased mortality risk by 72% (hazard ratio, 1.72; 95% confidence interval, 1.34-2.20). Conclusions: In this sample of WLWH, increased CDWD elevated mortality rates in a dose-response fashion. More frequent monitoring and enhanced depression treatment protocols designed to reduce CDWD may interrupt the accumulation of mortality risk among WLWH.

Association of Increased Chronicity of Depression With HIV Appointment Attendance, Treatment Failure, and Mortality Among HIV-Infected Adults in the United States.

Importance: Depression commonly affects adults with HIV and complicates the management of HIV. Depression among individuals with HIV tends to be chronic and cyclical, but the association of this chronicity with HIV outcomes (and the related potential for screening and intervention to shorten depressive episodes) has received little attention. Objective: To examine the association between increased chronicity of depression and multiple HIV care continuum indicators (HIV appointment attendance, treatment failure, and mortality). Design, Setting, and Participants: The study comprised an observational clinical cohort of 5927 patients with 2 or more assessments of depressive severity who were receiving HIV primary care at 6 geographically dispersed US academic medical centers from September 22, 2005, to August 6, 2015. Main Outcomes and Measures: Missing a scheduled HIV primary care visit, detectable HIV RNA viral load (≥75 copies/mL), and all-cause mortality. Consecutive depressive severity measures were converted into a time-updated measure: percentage of days with depression (PDD), following established methods for determining depression-free days. Results: During 10 767 person-years of follow-up, the 5927 participants (5000 men, 926 women, and 1 intersex individual; median age, 44 years [range, 35-50 years]) had a median PDD of 14% (interquartile range, 0%-48%). During follow-up, 10 361 of 55 040 scheduled visits (18.8%) were missed, 6191 of 28 455 viral loads (21.8%) were detectable, and the mortality rate was 1.5 deaths per 100 person-years. Percentage of days with depression showed a dose-response relationship with each outcome. Each 25% increase in PDD led to an 8% increase in the risk of missing a scheduled appointment (risk ratio, 1.08; 95% CI, 1.05-1.11), a 5% increase in the risk of a detectable viral load (risk ratio, 1.05; 95% CI, 1.01-1.09), and a 19% increase in the mortality hazard (hazard ratio, 1.19; 95% CI, 1.05-1.36). These estimates imply that, compared with patients who spent no follow-up time with depression (PDD, 0%), those who spent the entire follow-up time with depression (PDD, 100%) faced a 37% increased risk of missing appointments (risk ratio, 1.37; 95% CI, 1.22-1.53), a 23% increased risk of a detectable viral load (risk ratio, 1.23; 95% CI, 1.06-1.43), and a doubled mortality rate (hazard ratio, 2.02; 95% CI, 1.20-3.42). Conclusions and Relevance: Greater chronicity of depression increased the likelihood of failure at multiple points along the HIV care continuum. Even modest increases in the proportion of time spent with depression led to clinically meaningful increases in negative outcomes. Clinic-level trials of protocols to promptly identify and appropriately treat depression among adults living with HIV should be conducted to understand the effect of such protocols on shortening the course and preventing the recurrence of depressive illness and improving clinical outcomes.

Self-disclosure of HIV status, disclosure counseling, and retention in HIV care in Cameroon.

Poor retention in care is common among HIV-positive adults in sub-Saharan Africa settings and remains a key barrier to HIV management. We quantify the associations of disclosure of HIV status and referral to disclosure counseling with successful retention in care using data from three Cameroon clinics participating in the Phase 1 International epidemiologic Databases to Evaluate AIDS Central Africa cohort. Of 1646 patients newly initiating antiretroviral therapy between January 2008 and January 2011, 43% were retained in care following treatment initiation. Self-disclosure of HIV status to at least one person prior to treatment initiation was associated with a minimal increase in the likelihood of being retained in care (risk ratio [RR] = 1.14; 95% confidence interval (CI): 0.94, 1.38). However, referral to disclosure counseling was associated with a moderate increase in retention (RR = 1.37; 95% CI: 1.21, 1.55) and was not significantly modified by prior disclosure status (p = .3). Our results suggest that while self-disclosure may not significantly improve retention among patients receiving care at these Cameroon sites, counseling services may play an important role regardless of prior disclosure status.

Learning from the private sector: towards a keener understanding of the end-user for microbicide introduction planning.

INTRODUCTION: In planning for the introduction of vaginal microbicides and other new antiretroviral (ARV)-based prevention products for women, an in-depth understanding of potential end-users will be critically important to inform strategies to optimize uptake and long-term adherence. User-centred private sector companies have contributed to the successful launch of many different types of products, employing methods drawn from behavioural and social sciences to shape product designs, marketing messages and communication channels. Examples of how the private sector has adapted and applied these techniques to make decisions around product messaging and targeting may be instructive for adaptation to microbicide introduction. DISCUSSION: In preparing to introduce a product, user-centred private sector companies employ diverse methods to understand the target population and their lifestyles, values and motivations. ReD Associates' observational research on user behaviours in the packaged food and diabetes fields illustrates how 'tag along' or 'shadowing' techniques can identify sources of non-adherence. Another open-ended method is self-documentation, and IDEO's mammography research utilized this to uncover user motivations that extended beyond health. Mapping the user journey is a quantitative approach for outlining critical decision-making stages, and Monitor Inclusive Markets applied this framework to identify toilet design opportunities for the rural poor. Through an iterative process, these various techniques can generate hypotheses on user drop-off points, quantify where drop-off is highest and prioritize areas of further research to uncover usage barriers. Although research constraints exist, these types of user-centred techniques have helped create effective messaging, product positioning and packaging of health products as well as family planning information. These methods can be applied to microbicide acceptability testing outside of clinical trials to design microbicide marketing that enhances product usage. CONCLUSIONS: The introduction of microbicide products presents an ideal opportunity to draw on the insights from user-centred private sector companies' approaches, which can complement other methods that have been more commonly utilized in microbicide research to date. As microbicides move from clinical trials to real-world implementation, there will be more opportunities to combine a variety of approaches to understand end-users, which can lead to a more effective product launch and ultimately greater impact on preventing HIV infections.