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IntroductionPregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies.DiscussionPregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias.ConclusionsPregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer.

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.

Background: The individual risk of severe outcomes following COVID-19 is poorly understood in populations with prior immunity. The lack of contemporary estimates limits support of timely diagnosis and antiviral treatment for individuals most likely to benefit. Objective: To determine the risk of severe outcomes following COVID-19 within strata of comorbidities, including patients without documented infection. Design: Population-based cohort study utilizing electronic medical records and g methods to account for selection bias in the documentation of COVID-19 illnesses. Setting: A large health system in northeastern United States Patients: Adults with increased risk conditions (90% vaccinated) and COVID-19 from June to December 2022. Measurements: Incidence of composite of inpatient admission within 14 days and death within 28 days of COVID-19 diagnosis. Results: An estimated 265,248 patients with at least one increased risk condition developed COVID-19, including 76,996 documented cases. Severe outcomes occurred in 3344 (1.3%) patients following COVID-19— 3147 (1.2%) hospitalizations and 376 (0.14%) deaths. In the absence of treatment, individuals with few increased risk conditions (MASS of 3 or less) accounted for 57% of infections and 0.7% developed severe outcomes. In contrast, 2.3% of patients with multiple increased risk conditions (MASS 4 or greater) or severe immunocompromise experienced severe outcomes, including 81% of deaths. The observed risk reduction with antiviral treatment was -0.1% (-0.2 to 0.02%), -0.6% (-0.9 to -0.4%), -1.3% (-2 to -1%), and -1.9% (-3 to -1%) for patients with MASS 3 or less, MASS 4 and 5, MASS 6 or greater, and severe immunocompromise, respectively. Limitations: Estimated number COVID-19 cases cannot be directly verified Conclusions: Individuals with multiple medical conditions remain at substantial risk for severe outcomes of COVID-19 and benefit from treatment. [ABSTRACT FROM AUTHOR]

Women and other people of childbearing potential living with HIV (WLHIV) have a higher risk of adverse birth outcomes than those without HIV (WWHIV). A higher risk of anemia in WLHIV could partially explain this disparity. Using a birth outcomes surveillance study in Botswana, we emulated target trials corresponding to currently available or feasible interventions on anemia. The first target trial evaluated 2 interventions: initiate multiple micronutrient supplementation (MMS), and MMS or iron and folic acid supplementation by 24 weeks gestation. The remaining target trials evaluated the interventions: eliminate anemia before pregnancy; and jointly eliminate anemia before pregnancy and initiate MMS. We estimated the observed disparity in adverse birth outcomes between WLHIV and WWHIV and compared the observed disparity measure (ODM) to the counterfactual disparity measure (CDM) under each intervention. Of 137 499 individuals (22% WLHIV), the observed risk of any adverse birth outcome was 26.0% in WWHIV and 34.5% in WLHIV (ODM, 8.5%; 95% confidence interval [CI], 7.9-9.1%). Counterfactual disparity measures (95% CIs) ranged from 6.6% (4.8-8.4%) for the intervention to eliminate anemia and initiate MMS to 8.4% (7.7%-9.1%) for the intervention to eliminate anemia only. Preventing anemia and expanding MMS may reduce HIV disparities in birth outcomes, but interventions with greater impact should be identified. [ABSTRACT FROM AUTHOR]

BackgroundClinical 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.MethodsIn 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.Findings47 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.InterpretationDecreasing 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.FundingNational Institutes of Health.

Purpose: Accurate identification of hepatic decompensation is essential for pharmacoepidemiologic research among patients with chronic liver disease. Methods: An algorithm using ≥ 1 inpatient or ≥ 2 outpatient International Classification of Diseases, 10th revision (ICD‐10) codes for hepatic decompensation was developed in Veterans Health Administration data from October 2015 through July 2019. Medical records were reviewed by hepatologists to confirm cases. The positive predictive value (PPV) of the coding algorithm for confirmed hepatic decompensation was calculated. Results: Hepatic decompensation was confirmed in 149/185 records meeting the algorithm (PPV 81%; 95% CI, 70%, 90%). The most common hepatic decompensation diagnosis was ascites. Only 56% of confirmed cases had an accompanying diagnosis code for cirrhosis. Conclusions: Our ICD‐10‐based coding algorithm identified hepatic decompensation with high PPV in Veterans Health Administration data. [ABSTRACT FROM AUTHOR]

ObjectiveTo illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART).DesignProspective 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.MethodsAntiretroviral-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.ResultsIn 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.ConclusionsOur 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.

ObjectiveTo illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART).DesignProspective 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.MethodsAntiretroviral-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.ResultsIn 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.ConclusionsOur 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.

SARS-CoV-2 infection during pregnancy was associated with maternal mortality and adverse birth outcomes in the pre-Omicron era, including a stillbirth rate of 5.6% in Botswana. We re-evaluated these outcomes in the Tsepamo Study during the Omicron era. We assessed maternal mortality and adverse birth outcomes for all singleton pregnancies from mid-November 2021 (the start of the Omicron era) to mid-August 2022 at nine Tsepamo sites, among individuals with documented SARS-CoV-2 screening PCR or antigen tests and known HIV status. Of 9,705 women routinely screened for SARS-CoV-2 infection at delivery (64% of deliveries at these sites), 373 (3.8%) tested positive. Women with HIV were as likely to test positive for SARS-CoV-2 (77/1833, 4.2%) as women without HIV (293/6981, 4.2%) (p = 1.0). There were 5 recorded maternal deaths (0.03%), one occurring in a woman with a positive SARS-CoV-2 test result. In contrast, maternal mortality was 3.7% and 0.1% in those with and without SARS-CoV-2, respectively, during the pre-Omicron era. In the Omicron era, there were no differences among infants exposed or unexposed to SARS-CoV-2 in overall adverse birth outcomes (28.1% vs 29.6%; aRR 1.0, 95%CI 0.8–1.1), severe adverse birth outcomes (11.9 vs 10.6%; aRR 1.1, 95%CI 0.8–1.5), preterm delivery (15.1% vs 14.9%; aRR 1.0, 95%CI 0.8–1.3), or stillbirth (1.9% vs 2.3%; aRR 0.8, 95%CI 0.4–1.7). Adverse outcomes among those exposed to both HIV and SARS-CoV-2 were similar to those exposed to HIV alone (31.2% vs. 33.1%; aRR 0.9, 95%CI 0.6–1.3; p = 0.5). Maternal mortality was far lower in Botswana during the Omicron era than in the pre-Omicron era, and adverse birth outcomes were no longer significantly impacted by exposure to SARS-CoV-2 either overall or with HIV co-exposure. Increased population immunity to SARS-CoV-2, less stress on the hospital systems in the Omicron era, and possible differences in viral pathogenicity may combine to explain these findings. [ABSTRACT FROM AUTHOR]

Background: Quitting smoking may lead to improvement in substance use, psychiatric symptoms, and pain, especially among high-risk populations who are more likely to experience comorbid conditions. However, causal inferences regarding smoking cessation and its subsequent benefits have been limited. Methods: We emulated a hypothetical open-label randomized control trial of smoking cessation using longitudinal observational data of HIV-positive and HIV-negative US veterans from 2003–2015 in the Veterans Aging Cohort Study. We followed individuals from the first time they self-reported current cigarette smoking (baseline). We categorized participants as quitters or non-quitters at the first follow-up visit (approximately 1 year after baseline). Using inverse probability weighting to adjust for confounding and selection bias, we estimated odds ratios for improvement of co-occurring conditions (unhealthy alcohol use, cannabis use, illicit opioid use, cocaine use, depressive symptoms, anxiety symptoms, and pain symptoms) at second follow-up (approximately 2 years after baseline) for those who quit smoking compared to those who did not, among individuals who had the condition at baseline. Results: Of 4,165 eligible individuals (i.e., current smokers at baseline), 419 reported no current smoking and 2,330 reported current smoking at the first follow-up. Adjusted odds ratios (95% confidence intervals) for associations between quitting smoking and improvement of each condition at second follow-up were: 2.10 (1.01, 4.35) for unhealthy alcohol use, 1.75 (1.00, 3.06) for cannabis use, 1.10 (0.58, 2.08) for illicit opioid use, and 2.25 (1.20, 4.24) for cocaine use, 0.78 (0.44, 1.38) for depressive symptoms, 0.93 (0.58, 1.49) for anxiety symptoms, and 1.31 (0.84, 2.06) for pain symptoms. Conclusions: While a causal interpretation of our findings may not be warranted, we found evidence for decreased substance use among veterans who quit cigarette smoking but none for the resolution of psychiatric conditions or pain symptoms. Findings suggest the need for additional resources combined with smoking cessation to reduce psychiatric and pain symptoms for high-risk populations. [ABSTRACT FROM AUTHOR]

INTRODUCTION Multiple studies have reported that tenofovir alafenamide (TAF) and dolutegravir (DTG) are associated with clinically significant weight gain, with risk of treatment?emergent obesity (body mass index, or BMI, >30) [...], : Introduction: Antiretrovirals such as dolutegravir (DTG) and tenofovir alafenamide (TAF) have been associated with excessive weight gain. The objective of this study was to understand the potential impact of ART?associated weight gain on pregnancy outcomes among women living with HIV. Methods: Using data from the Tsepamo birth outcomes surveillance study in Botswana, we evaluated the relationship between maternal weight (and weight gain) and severe birth outcomes (very preterm delivery 4000 g) and maternal hypertension. We estimated the relative risk of each outcome by baseline weight (first weight in pregnancy Results: Of 22,828 women on ART at conception with singleton deliveries between August 2014 and April 2020, 16,300 (71.4%) had a weight measured 90 kg) was associated with increased risk of macrosomia (aRR 3.24, 95% CI 2.36, 4.44) and maternal hypertension (aRR 1.79, 95% CI 1.62, 1.97). Baseline weight was not associated with stillbirth or early neonatal death. For all outcomes, second trimester weight gain showed weaker associations than did baseline weight. Duration of pre?pregnancy ART (years) was associated with higher baseline weight for DTG but not for EFV, and the risk of maternal hypertension by baseline weight category was higher for DTG than EFV for all strata. Conclusions: ART regimens associated with weight gain may reduce the number of women at risk for certain severe adverse pregnancy outcomes associated with low weight but increase the number at risk of macrosomia and maternal hypertension. Further research could determine whether weight?based ART treatment strategies improve maternal and child health.

Associations of incarceration with healthcare access and utilization among Black sexual minority men (BSMM) and differences in association among those with and without pre-incarceration symptoms of depression were measured. Secondary analysis using survey data from the longitudinal cohort HIV Prevention Trials Network 061 study was conducted among 1553 BSMM from six major U.S. cities from 2009 to 2011. We used modified log-binomial regression with robust standard errors to estimate associations of incarceration (reported at 6 month follow-up) on next six-month healthcare utilization and access (reported at the 12 month follow-up). We tested the significance of baseline depressive symptoms by incarceration interaction and reported differences in associations when observed. Participants with a history of incarceration were more likely to have depressive symptoms at baseline compared to those without. Recent incarceration was associated with almost twice the risk of mistrust in healthcare providers and emergency room utilization. Among men reporting depressive symptoms, a history of incarceration was associated with almost tripled risk of reporting providers do not communicate understandably. Among those with depression, one in five reported a missed visit regardless of incarceration status. [ABSTRACT FROM AUTHOR]