Characteristics of HIV-1 serodiscordant couples enrolled in a clinical trial of antiretroviral pre-exposure prophylaxis for HIV-1 prevention

Introduction

Stable heterosexual HIV-1 serodiscordant couples in Africa have high HIV-1 transmission rates and are a critical population for evaluation of new HIV-1 prevention strategies. The Partners PrEP Study is a randomized, double-blind, placebo-controlled trial of tenofovir and emtricitabine-tenofovir pre-exposure prophylaxis to decrease HIV-1 acquisition within heterosexual HIV-1 serodiscordant couples. We describe the trial design and characteristics of the study cohort.

Methods

HIV-1 serodiscordant couples, in which the HIV-1 infected partner did not meet national guidelines for initiation of antiretroviral therapy, were enrolled at 9 research sites in Kenya and Uganda. The HIV-1 susceptible partner was randomized to daily oral tenofovir, emtricitabine-tenofovir, or matching placebo with monthly follow-up for 24–36 months.

Results

From July 2008 to November 2010, 7920 HIV-1 serodiscordant couples were screened and 4758 enrolled. For 62% (2966/4758) of enrolled couples, the HIV-1 susceptible partner was male. Median age was 33 years for HIV-1 susceptible and HIV-1 infected partners [IQR (28–40) and (26–39) respectively]. Most couples (98%) were married, with a median duration of partnership of 7.0 years (IQR 3.0–14.0) and recent knowledge of their serodiscordant status [median 0.4 years (IQR 0.1–2.0)]. During the month prior to enrollment, couples reported a median of 4 sex acts (IQR 2–8); 27% reported unprotected sex and 14% of male and 1% of female HIV-1 susceptible partners reported sex with outside partners. Among HIV-1 infected partners, the median plasma HIV-1 level was 3.94 log₁₀ copies/mL (IQR 3.31–4.53) and median CD4 count was 496 cells/µL (IQR 375–662); the majority (64%) had WHO stage 1 HIV-1 disease.

Conclusions

Couples at high risk of HIV-1 transmission were rapidly recruited into the Partners PrEP Study, the largest efficacy trial of oral PrEP. (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00557245","term_id":"NCT00557245"}}NCT00557245)     

The Contribution of Family Planning towards the Prevention of Vertical HIV Transmission in Uganda

Background

Uganda has one of the highest total fertility rates (TFR) worldwide. We compared the effects of antiretroviral (ARV) prophylaxis for the prevention of mother-to-child HIV transmission (PMTCT) to that of existing family planning (FP) use and estimated the burden of pediatric HIV disease due to unwanted fertility.

Methodology/Principal Findings

Using the demographic software Spectrum, a baseline mathematical projection to estimate the current pediatric HIV burden in Uganda was compared to three hypothetical projections: 1) without ARV-PMTCT (to estimate the effect of ARV-PMTCT), 2) without contraception (effect of existing FP use), 3) without unwanted fertility (effect of unmet FP needs). Key input parameters included HIV prevalence, ARV-PMTCT uptake, MTCT probabilities, and TFR. We estimate that in 2007, an estimated 25,000 vertical infections and 17,000 pediatric AIDS deaths occurred (baseline projection). Existing ARV-PMTCT likely averted 8.1% of infections and 8.5% of deaths. FP use likely averted 19.7% of infections and 13.1% of deaths. Unwanted fertility accounted for 21.3% of infections and 13.4% of deaths. During 2008–2012, an estimated 131,000 vertical infections and 71,000 pediatric AIDS deaths will occur. The projected scale up of ARV-PMTCT (from 39%–57%) may avert 18.1% of infections and 24.5% of deaths. Projected FP use may avert 21.6% of infections and 18.5% of deaths. Unwanted fertility will account for 24.5% of infections and 19.8% of deaths.

Conclusions

Existing FP use contributes as much or more than ARV-PMTCT in mitigating pediatric HIV in Uganda. Expanding FP services can substantially contribute towards PMTCT.     

Interaction of nickel and manganese in accumulation and localization in leaves of the Ni hyperaccumulators Alyssum murale and Alyssum corsicum

The genus Alyssum contains >50 Ni hyperaccumulator species; many can achieve >2.5% Ni in dry leaf. In soils with normal Mn levels, Alyssum trichome bases were previously observed to accumulate Ni and Mn to high levels. Here we report concentration and localization patterns in A. murale and A. corsicum grown in soils with nonphytotoxic factorial additions of Ni and Mn salts. Four leaf type subsets based on size and age accumulated Ni and Mn similarly. The greatest Mn accumulation (10 times control) was observed in A. corsicum with 40 mmol Mn kg^?1 and 40 mmol Ni kg^?1 added to potting soil. Whole leaf Ni concentrations decreased as Mn increased. Synchrotron X-ray fluorescence mapping of whole fresh leaves showed localized in distinct high-concentration Mn spots associated with trichomes, Ni and Mn distributions were strongly spatially correlated. Standard X-ray fluorescence point analysis/mapping of cryofractured and freeze-dried samples found that Ni and Mn were co-located and strongly concentrated only in trichome bases and in cells adjacent to trichomes. Nickel concentration was also strongly spatially correlated with sulfur. Results indicate that maximum Ni phytoextraction by Alyssum may be reduced in soils with higher phytoavailable Mn, and suggest that Ni hyperaccumulation in Alyssum species may have developed from a Mn handling system.     

Chelator-buffered nutrient solution is ineffective in extracting Ni from seeds of Alyssum

Hyperaccumulator species of the genera Alyssum can accumulate 100 times more Ni than normal crops and are therefore used for phytomining and phytoextraction of nickel contaminated soils. Basic studies on the physiology and metal uptake mechanisms of these plants are needed to increase efficiency and uptake capacity of Nickel (Ni) by hyperaccumulators. Recent attempts to disclose if those hyperaccumulator species require higher Ni level than normal plants failed because of the high Ni content in the seeds (7000-9000 microg g(-1)). In this study, we attempted to use chelator buffered nutrient solution to deplete Ni from the seed/seed coat and to obtain low Ni seedlings of Alyssum cultivars to be used in physiology studies. HEDTA-buffered nutrient solution did not deplete Ni from the seeds, perhaps because Ni was mainly localized within the seedling embryonic tissues with greatest Ni enrichment in the cotyledons and hypocotyls. We could not observe any positive correlation between seed fitness and germination capacity with seed Ni content. Investigation of nickel localization in Alyssum seeds using synchrotron X-ray microfluorescence (micro-SXRF) showed that nickel is localized in the embryonic tissues with greatest Ni enrichment observed in the cotyledons and hypocotyl.     

Diagnostics to support elimination of lymphatic filariasis—Development of two target product profiles

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs and use-case analyses to be used by product developers. Here, we describe the development of two priority TPPs for LF diagnostics needed for making decisions for stopping mass drug administration (MDA) of a triple drug regimen and surveillance. Utilizing the WHO core TPP development process as the framework, the LF subgroup convened to discuss and determine attributes required for each use case. TPPs considered the following parameters: product use, design, performance, product configuration and cost, and access and equity. Version 1.0 TPPs for two use cases were published by WHO on 12 March 2021 within the WHO Global Observatory on Health Research and Development. A common TPP characteristic that emerged in both use cases was the need to identify new biomarkers that would allow for greater precision in program delivery. As LF diagnostic tests are rarely used for individual clinical diagnosis, it became apparent that reliance on population-based surveys for decision making requires consideration of test performance in the context of such surveys. In low prevalence settings, the number of false positive test results may lead to unnecessary continuation or resumption of MDA, thus wasting valuable resources and time. Therefore, highly specific diagnostic tools are paramount when used to measure low thresholds. The TPP process brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools.     

Genetic and immunologic characterization of a novel serotype 4, 15 strain of Neisseria meningitidis

The porin proteins of Neisseria meningitidis are important components of outer membrane protein (OMP) vaccines. The class 3 porin gene, porB, of a novel serogroup B, serotype 4, 15 isolate from Chile (Ch501) was found to be VR1-4, VR2-15, VR3-15 and VR4-15 by porB variable region (VR) typing. Rabbit immunization studies using outer membrane vesicles revealed immunodominance of individual PorB (class 3) VR epitopes. The predominant anti-Ch501 PorB response was directed to the VR1 epitope. Anti-PorB VR1 mediated killing was suggested by the bactericidal activity of Ch501 anti-sera against a type 4 strain not expressing PorA or class 5 OMPs. Studies that examine the molecular epidemiology of individual porB VRs, and the immune responses to PorB epitopes, may contribute to the development of broadly protective group B meningococcal vaccines.     

Redundant roles of four ZIP family members in zinc homeostasis and seed development in Arabidopsis thaliana

Zinc (Zn) is essential for normal plant growth and development. The Zn-regulated transporter, iron-regulated transporter (IRT)-like protein (ZIP) family members are involved in Zn transport and cellular Zn homeostasis throughout the domains of life. In this study, we have characterized four ZIP transporters from Arabidopsis thaliana (IRT3, ZIP4, ZIP6, and ZIP9) to better understand their functional roles. The four ZIP proteins can restore the growth defect of a yeast Zn uptake mutant and are upregulated under Zn deficiency. Single and double mutants show no phenotypes under Zn-sufficient or Zn-limited growth conditions. In contrast, triple and quadruple mutants show impaired growth irrespective of external Zn supply due to reduced Zn translocation from root to shoot. All four ZIP genes are highly expressed during seed development, and siliques from all single and higher-order mutants exhibited an increased number of abnormal seeds and decreased Zn levels in mature seeds relative to wild type. The seed phenotypes could be reversed by supplementing the soil with Zn. Our data demonstrate that IRT3, ZIP4, ZIP6, and ZIP9 function redundantly in maintaining Zn homeostasis and seed development in A. thaliana.