Andrew G. Allmon’s research while affiliated with University of North Carolina at Chapel Hill and other places

Background Point-of-care (POC) early infant diagnosis (EID) provides same-day results and the potential for immediate initiation of antiretroviral therapy (ART). Methods We conducted a pragmatic trial at six public clinics in Zambia. HIV-exposed infants were individually randomized to either: (a) POC EID – on-site testing with the Alere q HIV-1/2 Detect or (b) enhanced standard of care (SOC) EID – off-site testing at a public laboratory. HIV-infected infants were referred for ART and followed for 12 months. Our primary outcome was defined as alive, in care, and virally suppressed at 12 months. Results Between March 2016 and November 2018, we randomized 4,000 HIV-exposed infants to POC (n=1,989) or SOC (n=2,011). All but two infants in the POC group received same-day results, while the median time to result in the SOC group was 27 (IQR: 22-30) days. Eighty-one (2%, 95% CI: 1.6–2.5%) infants were diagnosed with HIV. Although ART initiation was high, there were 15 (19%) deaths, 15 (19%) follow-up losses, and 31 (38%) virologic failures. By 12 months, only 20 of 81 (25%, 95% CI: 15–34%) HIV-infected infants were alive, in care, and virally suppressed: 13 (30%, 95% CI: 16–43%) infants in the POC group vs. 7 (19%, 95% CI: 6–32%) in the SOC group (RR: 1.56, 95% CI: 0.7–3.50). Conclusions POC EID eliminated diagnostic delays and accelerated ART initiation but did not translate into definitive improvement in 12-month outcomes. In settings where centralized EID is well functioning, POC EID is unlikely to improve pediatric HIV outcomes.

Oral treprostinil has recently been shown to delay disease progression in patients with pulmonary arterial hypertension (PAH) in a long-term outcomes study. The potential advantages of an oral formulation have resulted in patients transitioning from inhaled to oral treprostinil. The current study reports a retrospective analysis of patients who transitioned from treatment with inhaled to oral treprostinil. A multicenter retrospective chart review was conducted for 30 patients with pulmonary hypertension that transitioned from inhaled to oral treprostinil. Data were collected from inhaled treprostinil initiation and patients were followed until discontinuation of oral treprostinil or the end of the observation period. Persistence was calculated using Kaplan-Meier estimates. Prior to transition to oral treprostinil, patients had received inhaled treprostinil for a median of 643 (IQR: 322, 991) days and 52% of patients were New York Heart Association (NYHA)/World Health Organization (WHO) Functional Class III. For patients that cross titrated between formulations, the median time to complete the cross titration was 24 (IQR: 1, 57) days. At 16- and 24-weeks post transition, oral treprostinil persistence was 86% and 76%, respectively. Persistence was 59% at 52 weeks post transition. Clinical stability for the majority of patients at first follow-up post transition was suggested based on available NYHA/WHO Functional Classification. Transitions from inhaled to oral treprostinil appeared safe and tolerable in the short-term. Additional prospective studies are needed to fully evaluate the safety and efficacy of transitions from inhaled to oral treprostinil.

The 2015 European Society of Cardiology/European Respiratory Society treatment guidelines recommend frequent risk assessment in pulmonary arterial hypertension utilizing risk variables. Our objectives were: (1) to investigate the impact of inhaled treprostinil on risk stratification using the French noninvasive approach and REVEAL 2.0, and (2) to analyze the prognostic utility of both risk stratification methods in the predominantly New York Heart Association/World Health Organization functional class III/IV cohorts of TRIUMPH and BEAT. A post hoc analysis was performed to assess risk at baseline and follow-up at Week 12 in the TRIUMPH cohort (n = 148) and at Week 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort (n = 73). Overall survival, clinical worsening-free survival, and pulmonary arterial hypertension-related hospitalization-free survival were all assessed in the pooled TRIUMPH and inhaled treprostinil naïve placebo BEAT cohorts based on risk group/strata at Week 12/16 follow-up. Inhaled treprostinil improved REVEAL 2.0 risk stratum (OR: 2.38, 95% CI: 1.09–5.19, p = 0.0298) and REVEAL 2.0 score (p = 0.0008) compared to placebo in the TRIUMPH cohort at Week 12. REVEAL 2.0 risk stratum and the number of low-risk criteria by the French approach improved at Weeks 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort. Combining cohorts, REVEAL 2.0 risk stratification at follow-up was prognostic for clinical worsening-free, pulmonary arterial hypertension hospitalization-free, and overall survival, whereas the number of low-risk criteria was not. These post-hoc pooled analyses suggest inhaled treprostinil improves risk status and indicates that the REVEAL 2.0 calculator may be more suitable than the French noninvasive method for evaluating short-term clinical change in the New York Heart Association/World Health Organization functional class III/IV population.

High-dimensional low sample size (HDLSS) data sets emerge frequently in many biomedical applications. A common task for analyzing HDLSS data is to assign data to the correct class using a classifier. Classifiers which use two labels and a linear combination of features are known as binary linear classifiers. The direction-projection-permutation (DiProPerm) test was developed for testing the difference of two high-dimensional distributions induced by a binary linear classifier. This paper discusses the key components of the DiProPerm test, introduces the diproperm R package, and demonstrates the package on a real-world data set.

Antiretroviral therapy (ART) requires lifelong daily oral therapy. While patient characteristics associated with suboptimal ART adherence and persistence have been described in cohorts of HIV-infected persons, these factors are poor predictors of individual medication taking behaviors. We aimed to create and test instruments for the estimation of future ART adherence and persistence for clinical and research applications. Following formative work, a battery of 148 items broadly related to HIV infection and treatment was developed and administered to 181 HIV-infected patients. ART adherence and persistence were assessed using electronic monitoring for 3 months. Perceived confidence in medication taking and self-reported barriers to adherence were strongest in predicting non-adherence over time. Barriers to adherence (e.g., affordability, scheduling) were the strongest predictors of non-adherence, as well as 3- and 7-day non-persistence. A ten-item battery for prediction of these outcomes (www.med.unc.edu/ncaidstraining/adherence/for-providers) and a 30-item battery reflective of underlying psychological constructs can help identify and study individuals at risk for suboptimal ART adherence and persistence.

Serial limiting dilution (SLD) assays are used in many areas of infectious disease related research. This paper presents SLDAssay, a free and publicly available R software package and web tool for analyzing data from SLD assays. SLDAssay computes the maximum likelihood estimate (MLE) for the concentration of target cells, with corresponding exact and asymptotic confidence intervals. Exact and asymptotic goodness of fit p-values, and a bias-corrected (BC) MLE are also provided. No other publicly available software currently implements the BC MLE or the exact methods. For validation of SLDAssay, results from Myers et al. (1994) are replicated. Simulations demonstrate the BC MLE is less biased than the MLE. Additionally, simulations demonstrate that exact methods tend to give better confidence interval coverage and goodness-of-fit tests with lower type I error than the asymptotic methods. Additional advantages of using exact methods are also discussed.

Background While rates of sustained virologic response (SVR) following HCV treatment with Direct Acting Antivirals (DAAs) surpass 90% in trials and some more ‘real world’ settings, some patients, such as those with substance use disorders, will be challenged to adhere to HCV care. Methods To assess the feasibility of two strategies for financially incentivizing adherence to HCV care, patients with a substance use history prescribed 12-weeks of a sofosbuvir-containing regimen were randomized to either fixed or lottery-based monetary incentives for attending clinic appointments, pill count adherence >90%, and SVR achievement. Electronic medication monitoring provided an objective measure of DAA adherence. Results Fifty-nine participants were randomized to the lottery (n=31) or fixed incentive (n=28) arms. All 31 (100%) in the lottery arm and 24 of 28 (86%) in the fixed arm completed 12 weeks of therapy. By intent-to-treat, 93% in the lottery arm and 92% in the fixed arm achieved SVR (estimated difference: 0.5%, 95% CI -17.5, 18.8). Overall, 92% of scheduled visits were attended without significant differences between arms. The mean adherence ratio (days with ≥1 bottle opening:monitored days) was 0.91 for lottery and 0.92 for fixed arms. Conclusions In this pilot, fixed- and lottery-based financial incentives were successfully implemented and accepted by patients with a substance use history. High levels of HCV therapy and care adherence, as well as rates of SVR, were observed. Financial incentives may be useful to support treatment adherence in patients with substance use disorders and should be tested in a larger randomized controlled trial.

Background: Quantifying tissue drug concentrations can yield important information during drug development, but complicates pharmacokinetic study design. Mucosal fluids collected by direct aspiration(cervicovaginal fluid; CVF) or swab(rectal fluid; RF) might be used as tissue concentration surrogates, but these relationships are not well characterized. Methods: Forty-nine healthy women, given a single oral dose of tenofovir, maraviroc, emtricitabine, or raltegravir at 50% to 200% of the treatment dose, provided 13 plasma, 12 CVF, 12 RF and one cervical, vaginal and rectal tissue biopsy over 48hrs. Relationships between these paired samples were characterized by linear and multiple linear regression. Adjusted r values were used to select the final predictive models. Results: CVF exposure increased linearly with dose for all antiretrovirals (r≥0.23, p≤0.02) except raltegravir (r=0.08, p=0.19). In RF, only emtricitabine increased linearly with dose (r=0.27, p=0.01). For all antiretrovirals, CVF and RF concentrations significantly correlated with mucosal tissue concentrations (female genital tract r≥0.37, rectal tissue r≥0.50; p≤0.001). In the final multivariate models, plasma and fluid concentrations were both associated with FGT concentrations for all antiretrovirals (r≥0.81; p<0.001). The same was noted for rectal tissue (r≥0.58; p<0.001) except for tenofovir, for which RF alone was predictive of tissue concentration (r=0.91; p<0.001). Conclusions: Mucosal fluids were positively correlated with tissue concentrations, and including plasma concentrations improved the regression models in most cases. Dose linearity in CVF, but not RF, suggests a saturation process in lower gastrointestinal tract tissue. These findings suggest that mucosal fluid and plasma concentrations may be used for qualitative inference of tissue concentrations for these antiretrovirals.