Search

Background The ALVAC/gp120 + MF59 vaccines in the HIV Vaccine Trials Network (HVTN) 702 efficacy trial did not prevent human immunodeficiency virus-1 (HIV-1) acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition. Methods Among 1893 HVTN 702 female vaccinees, 60 HIV-1–seropositive cases and 60 matched seronegative noncases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks after fourth and fifth immunizations. Cox proportional hazards models assessed prespecified responses as predictors of HIV-1 acquisition. Results The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs 40%, P = .03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs 100%, P Conclusions HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T cells with HIV-1 acquisition. Clinical Trials Registration . NCT02968849.

Motivation A single monoclonal broadly neutralizing antibody (bnAb) regimen was recently evaluated in two randomized trials for prevention efficacy against HIV-1 infection. Subsequent trials will evaluate combination bnAb regimens (e.g. cocktails, multi-specific antibodies), which demonstrate higher potency and breadth in vitro compared to single bnAbs. Given the large number of potential regimens, methods for down-selecting these regimens into efficacy trials are of great interest. Results We developed Super LeArner Prediction of NAb Panels (SLAPNAP), a software tool for training and evaluating machine learning models that predict in vitro neutralization sensitivity of HIV Envelope (Env) pseudoviruses to a given single or combination bnAb regimen, based on Env amino acid sequence features. SLAPNAP also provides measures of variable importance of sequence features. By predicting bnAb coverage of circulating sequences, SLAPNAP can improve ranking of bnAb regimens by their potential prevention efficacy. In addition, SLAPNAP can improve sieve analysis by defining sequence features that impact bnAb prevention efficacy. Availabilityand implementation SLAPNAP is a freely available docker image that can be downloaded from DockerHub (https://hub.docker.com/r/slapnap/slapnap). Source code and documentation are available at GitHub (https://github.com/benkeser/slapnap and https://benkeser.github.io/slapnap/).

Summary Doubly robust estimators are widely used to draw inference about the average effect of a treatment. Such estimators are consistent for the effect of interest if either one of two nuisance parameters is consistently estimated. However, if flexible, data-adaptive estimators of these nuisance parameters are used, double robustness does not readily extend to inference. We present a general theoretical study of the behaviour of doubly robust estimators of an average treatment effect when one of the nuisance parameters is inconsistently estimated. We contrast different methods for constructing such estimators and investigate the extent to which they may be modified to also allow doubly robust inference. We find that while targeted minimum loss-based estimation can be used to solve this problem very naturally, common alternative frameworks appear to be inappropriate for this purpose. We provide a theoretical study and a numerical evaluation of the alternatives considered. Our simulations highlight the need for and usefulness of these approaches in practice, while our theoretical developments have broad implications for the construction of estimators that permit doubly robust inference in other problems.

Background Bedaquiline and delamanid are newly available drugs for treating multidrug-resistant tuberculosis (MDR TB); however, there is limited data guiding their use and no comparison studies. Methods We conducted a prospective observational study among patients with MDR TB in Georgia receiving a bedaquiline or delamanid-based treatment regimen. Monthly sputum cultures, minimal inhibitory concentration testing, and adverse event monitoring were performed. Primary outcomes were culture conversion rates and clinical outcomes. Targeted maximum likelihood estimation (TMLE) and superlearning were utilized to produce a covariate-adjusted proportion of outcomes for each regimen. Results Among 156 patients with MDR TB, 100 were enrolled and 95 were receiving a bedaquiline (n=64) or delamanid (n=31) based regimen. Most were male (82%) and the median age was 38 years. Rates of previous treatment (56%) and cavitary disease (61%) were high. The most common companion drugs included linezolid, clofazimine, cycloserine and a fluoroquinolone. Median effective drugs received among patients on bedaquiline (4, IQR 4-4) and delamanid (4, IQR 3.5-5) based regimens were similar. Rates of acquired drug resistance were significantly higher among patients receiving delamanid versus bedaquiline (36% vs. 10%, p Conclusions Among patients with MDR TB, bedaquiline-based regimens were associated with higher rates of sputum culture conversion and favorable outcomes and a lower rate of acquired drug resistance versus delamanid-based regimens.

Background Bedaquiline and delamanid are new and much-needed treatment options for drug-resistant tuberculosis (TB); however, there are limited data guiding their use and no direct comparison of the two drugs. We thus sought to compare the clinical outcomes of patients with drug-resistant tuberculosis receiving either a bedaquiline- or delamanid-based treatment regimen. Methods This is a prospective observational study among patients with drug-resistant pulmonary TB in the country of Georgia from 2015 to 2017. Patients receiving bedaquiline or delamanid were eligible to be enrolled. Monthly sputum cultures and MIC testing on Mycobacterium tuberculosis isolates were performed. Clinical outcomes included time to culture conversion, rate of acquired drug resistance and treatment outcomes. Results Among 156 patients with MDR-TB who were approached, 100 were enrolled, and 95 were receiving a bedaquiline (n = 64) or delamanid (n = 31) based regimen and included in the study. Patients receiving bedaquiline or delamanid were similar with regards to age, BMI, substance use, comorbidities, rate of cavitary disease, and extensively drug-resistant (XDR) TB. Rates of additional Class A drug use including linezolid (78 vs. 81%) and a fluoroquinolone (39 vs. 36%) were similar and the mean effective drugs received per group was 4 (IQR 3–4, P = 0.33). Median drug duration was 171 days for bedaquiline and 182 days for delamanid; no patient discontinued due to QTC prolongation. Adjusted cumulative culture conversion rates at 60 days (64% vs. 48%, P = 0.14) and 180 days (95% vs. 77%, P = 0.02) were higher in patients receiving bedaquiline compared with delamanid (see figure). Rates of acquired drug resistance were higher in patients receiving delamanid compared with bedaquiline (35 vs. 12%, P < 0.01). Lastly, patients receiving a bedaquiline-based regimen had higher rates of favorable outcomes as compared with patients receiving delamanid (94% vs. 67%, P < 0.01). Conclusion Patients receiving bedaquiline- and delamanid-based treatment regimens for drug-resistant TB had similar characteristics and those receiving bedaquiline had better clinical outcomes. Our results provide an important first comparison of bedaquiline vs. delamanid containing regimens. Disclosures All Authors: No reported Disclosures.