Mapping male circumcision for HIV prevention efforts in sub-Saharan Africa

Background HIV remains the largest cause of disease burden among men and women of reproductive age in sub-Saharan Africa. Voluntary medical male circumcision (VMMC) reduces the risk of female-to-male transmission of HIV by 50–60%. The World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) identified 14 priority countries for VMMC campaigns and set a coverage goal of 80% for men ages 15–49. From 2008 to 2017, over 18 million VMMCs were reported in priority countries. Nonetheless, relatively little is known about local variation in male circumcision (MC) prevalence. Methods We analyzed geo-located MC prevalence data from 109 household surveys using a Bayesian geostatistical modeling framework to estimate adult MC prevalence and the number of circumcised and uncircumcised men aged 15–49 in 38 countries in sub-Saharan Africa at a 5 × 5-km resolution and among first administrative level (typically provinces or states) and second administrative level (typically districts or counties) units. Results We found striking within-country and between-country variation in MC prevalence; most (12 of 14) priority countries had more than a twofold difference between their first administrative level units with the highest and lowest estimated prevalence in 2017. Although estimated national MC prevalence increased in all priority countries with the onset of VMMC campaigns, seven priority countries contained both subnational areas where estimated MC prevalence increased and areas where estimated MC prevalence decreased after the initiation of VMMC campaigns. In 2017, only three priority countries (Ethiopia, Kenya, and Tanzania) were likely to have reached the MC coverage target of 80% at the national level, and no priority country was likely to have reached this goal in all subnational areas. Conclusions Despite MC prevalence increases in all priority countries since the onset of VMMC campaigns in 2008, MC prevalence remains below the 80% coverage target in most subnational areas and is highly variable. These mapped results provide an actionable tool for understanding local needs and informing VMMC interventions for maximum impact in the continued effort towards ending the HIV epidemic in sub-Saharan Africa

SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

Mapping male circumcision for HIV prevention efforts in sub-Saharan Africa

Background HIV remains the largest cause of disease burden among men and women of reproductive age in sub-Saharan Africa. Voluntary medical male circumcision (VMMC) reduces the risk of female-to-male transmission of HIV by 50–60%. The World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) identified 14 priority countries for VMMC campaigns and set a coverage goal of 80% for men ages 15–49. From 2008 to 2017, over 18 million VMMCs were reported in priority countries. Nonetheless, relatively little is known about local variation in male circumcision (MC) prevalence. Methods We analyzed geo-located MC prevalence data from 109 household surveys using a Bayesian geostatistical modeling framework to estimate adult MC prevalence and the number of circumcised and uncircumcised men aged 15–49 in 38 countries in sub-Saharan Africa at a 5 × 5-km resolution and among first administrative level (typically provinces or states) and second administrative level (typically districts or counties) units. Results We found striking within-country and between-country variation in MC prevalence; most (12 of 14) priority countries had more than a twofold difference between their first administrative level units with the highest and lowest estimated prevalence in 2017. Although estimated national MC prevalence increased in all priority countries with the onset of VMMC campaigns, seven priority countries contained both subnational areas where estimated MC prevalence increased and areas where estimated MC prevalence decreased after the initiation of VMMC campaigns. In 2017, only three priority countries (Ethiopia, Kenya, and Tanzania) were likely to have reached the MC coverage target of 80% at the national level, and no priority country was likely to have reached this goal in all subnational areas. Conclusions Despite MC prevalence increases in all priority countries since the onset of VMMC campaigns in 2008, MC prevalence remains below the 80% coverage target in most subnational areas and is highly variable. These mapped results provide an actionable tool for understanding local needs and informing VMMC interventions for maximum impact in the continued effort towards ending the HIV epidemic in sub-Saharan Africa

<i>In vitro</i> trypanocidal activity of SCYX-7158.

<p><b>a</b>, Parasite viability, as indicated by ATP content, following continuous exposure of <i>T. b. brucei</i> 427 to SCYX-7158 at the indicated concentrations and times. Data are mean ± s.d. <b>b</b>, Irreversibility of trypanocidal effect. <i>T. b. brucei</i> 427 were exposed to the indicated concentrations of SCYX-7158 for the time indicated, then were sedimented by centrifugation and resuspended in drug-free media. Parasite viability was measured at 72 h by the resazurin method as described in the <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001151#s2" target="_blank">Methods</a> section.</p

Chemical structures of compounds.

<p>Chemical structures of compounds.</p

SCYX-7158 exhibits excellent plasma exposure across species.

<p>Male CD-1 mice, Sprague-Dawley rats, cynomolgus monkeys or male beagle dogs were administered a single oral dose of SCYX-7158 at a dose of 25 mg/kg (mouse, rat) or 10 mg/kg (monkey, dog). Blood samples were collected and analyzed as described in the <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001151#s2" target="_blank">Methods</a> section. Data points for mouse and rat represent a single animal at each time point; data points for cynomolgus monkey and dog represent the mean of three animals at each time point. The MIC line (red hashed line) is defined as the lowest concentration of compound that completely inhibits visible parasite growth, determined by visual inspection of 96-well test plates after 72 h incubation.</p

Time vs. concentration curves for SCYX-7158 following administration to mice infected with <i>T. b. brucei</i> TREU667.

<p>Female Swiss Webster mice were administered 7 daily doses of SCYX-7158 at the indicated doses. Blood (solid lines) and brain (dashed lines) samples were collected after the last dose and analyzed as described in the <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001151#s2" target="_blank">Methods</a> section. Data points represent a single mouse at each time point. The MIC line (red hashed line) is defined as the lowest concentration of compound that completely inhibits visible parasite growth, determined by visual inspection of 96-well test plates after 72 h incubation.</p

<i>In vitro</i> activity of SCYX-7158.

<p><i>In vitro</i> activity of SCYX-7158.</p

<i>In vitro</i> physicochemical and ADME properties of SCYX-7158.

<p><i>In vitro</i> physicochemical and ADME properties of SCYX-7158.</p