Predicting the long-term impact of antiretroviral therapy scale-up on population incidence of tuberculosis.

OBJECTIVE: To investigate the impact of antiretroviral therapy (ART) on long-term population-level tuberculosis disease (TB) incidence in sub-Saharan Africa. METHODS: We used a mathematical model to consider the effect of different assumptions about life expectancy and TB risk during long-term ART under alternative scenarios for trends in population HIV incidence and ART coverage. RESULTS: All the scenarios we explored predicted that the widespread introduction of ART would initially reduce population-level TB incidence. However, many modelled scenarios projected a rebound in population-level TB incidence after around 20 years. This rebound was predicted to exceed the TB incidence present before ART scale-up if decreases in HIV incidence during the same period were not sufficiently rapid or if the protective effect of ART on TB was not sustained. Nevertheless, most scenarios predicted a reduction in the cumulative TB incidence when accompanied by a relative decline in HIV incidence of more than 10% each year. CONCLUSIONS: Despite short-term benefits of ART scale-up on population TB incidence in sub-Saharan Africa, longer-term projections raise the possibility of a rebound in TB incidence. This highlights the importance of sustaining good adherence and immunologic response to ART and, crucially, the need for effective HIV preventive interventions, including early widespread implementation of ART

An assessment of the eye care workforce in Enugu State, south-eastern Nigeria

<p>Abstract</p> <p>Background</p> <p>The availability and distribution of an appropriate eye care workforce are fundamental to reaching the goals of "VISION 2020: The right to sight", the global initiative for the elimination of avoidable blindness launched jointly by the World Health Organization and the International Agency for the Prevention of Blindness with an international membership of nongovernmental organizations, professional associations, eye care institutions and corporations. Periodic evaluation of these parameters is important in the journey towards achieving these goals. The objectives of the study were to determine the availability and distribution of human resources for eye care delivery in Enugu Urban, south-eastern Nigeria.</p> <p>Methods</p> <p>The study was designed as a cross-sectional descriptive survey, the setting for which was all public and privately owned eye care facilities in Enugu Urban, Enugu State, south-eastern Nigeria, in October 2006. The health map of Enugu Urban and the hospital register of the Public Health Department of the Enugu State Ministry of Health were used to identify the eye health care facilities in Enugu Urban. A structured, pretested, researcher-administered questionnaire was used to capture data on cadre and distribution of the eye care personnel in these facilities.</p> <p>Relevant population data were obtained from the Enugu Regional Office of the National Population Commission. Descriptive statistical analysis was used to generate percentages and proportions. Eye care personnel-to-population ratios were calculated and compared to World Health Organization recommendations.</p> <p>Results</p> <p>Out of Enugu State's population of three million, Enugu Urban accounts for 22%. The population of Enugu Urban is distributed between the three-component Local Government Areas comprising Enugu North (31%), Enugu South (30%) and Enugu East (39%). There are 45 eye care facilities (public: 31 (69%); private: 14 (31%)) employing 252 eye care workers (public: 226 (90%); private: 26 (10%)) aged 18 to 63 (mean = 36.1 years, SD = 2 years) comprising males (36: 14%) and females (216: 86%), giving a male-to-female sex ratio of 1:6. The available eye care workforce is unevenly distributed between Enugu North (128: 51%), Enugu South (65: 26%) and Enugu East (59: 23%) Local Government Areas.</p> <p>Conclusion</p> <p>Using broad and crude World Health Organization standards for minimum provider-to-population ratios, there is a sufficient eye care workforce in Enugu Urban. However, the maldistribution of the workforce creates a major barrier to uptake of eye care services. Policy modifications could reverse this maldistribution.</p

HIV Infection Linked to Injection Use of Oxymorphone in Indiana, 2014-2015

BACKGROUND: In January 2015, a total of 11 new diagnoses of human immunodeficiency virus (HIV) infection were reported in a small community in Indiana. We investigated the extent and cause of the outbreak and implemented control measures. METHODS: We identified an outbreak-related case as laboratory-confirmed HIV infection newly diagnosed after October 1, 2014, in a person who either resided in Scott County, Indiana, or was named by another case patient as a syringe-sharing or sexual partner. HIV polymerase (pol) sequences from case patients were phylogenetically analyzed, and potential risk factors associated with HIV infection were ascertained. RESULTS: From November 18, 2014, to November 1, 2015, HIV infection was diagnosed in 181 case patients. Most of these patients (87.8%) reported having injected the extended-release formulation of the prescription opioid oxymorphone, and 92.3% were coinfected with hepatitis C virus. Among 159 case patients who had an HIV type 1 pol gene sequence, 157 (98.7%) had sequences that were highly related, as determined by phylogenetic analyses. Contact tracing investigations led to the identification of 536 persons who were named as contacts of case patients; 468 of these contacts (87.3%) were located, assessed for risk, tested for HIV, and, if infected, linked to care. The number of times a contact was named as a syringe-sharing partner by a case patient was significantly associated with the risk of HIV infection (adjusted risk ratio for each time named, 1.9; P<0.001). In response to this outbreak, a public health emergency was declared on March 26, 2015, and a syringe-service program in Indiana was established for the first time. CONCLUSIONS: Injection-drug use of extended-release oxymorphone within a network of persons who inject drugs in Indiana led to the introduction and rapid transmission of HIV. (Funded by the state government of Indiana and others.)

Tuberculosis Incidence Rates during 8 Years of Follow-Up of an Antiretroviral Treatment Cohort in South Africa: Comparison with Rates in the Community

BACKGROUND: Although antiretroviral therapy (ART) is known to be associated with time-dependent reductions in tuberculosis (TB) incidence, the long-term impact of ART on incidence remains imprecisely defined due to limited duration of follow-up and incomplete CD4 cell count recovery in existing studies. We determined TB incidence in a South African ART cohort with up to 8 years of follow-up and stratified rates according to CD4 cell count recovery. We compared these rates with those of HIV-uninfected individuals living in the same community. METHODOLOGY/PRINCIPAL FINDINGS: Prospectively collected clinical data on patients receiving ART in a community-based cohort in Cape Town were analysed. 1544 patients with a median follow-up of 5.0 years (IQR 2.4-5.8) were included in the analysis. 484 episodes of incident TB (73.6% culture-confirmed) were diagnosed in 424 patients during 6506 person-years (PYs) of follow-up. The TB incidence rate during the first year of ART was 12.4 (95% CI 10.8-14.4) cases/100PYs and decreased to 4.92 (95% CI 3.64-8.62) cases/100PYs between 5 and 8 years of ART. During person-time accrued within CD4 cell strata 0-100, 101-200, 201-300, 301-400, 401-500, 501-700 and ≥700 cells/µL, TB incidence rates (95% CI) were 25.5 (21.6-30.3), 11.2 (9.4-13.5), 7.9 (6.4-9.7), 5.0 (3.9-6.6), 5.1 (3.8-6.8), 4.1 (3.1-5.4) and 2.7 (1.7-4.5) cases/100PYs, respectively. Overall, 75% (95% CI 70.9-78.8) of TB episodes were recurrent cases. Updated CD4 cell count and viral load measurements were independently associated with long-term TB risk. TB rates during person-time accrued in the highest CD4 cell count stratum (>700 cells/µL) were 4.4-fold higher that the rate in HIV uninfected individuals living in the same community (2.7 versus 0.62 cases/100PYs; 95%CI 0.58-0.65). CONCLUSIONS/SIGNIFICANCE: TB rates during long-term ART remained substantially greater than rates in the local HIV uninfected populations regardless of duration of ART or attainment of CD4 cell counts exceeding 700 cells/µL

Social Transmission and the Spread of Modern Contraception in Rural Ethiopia

Socio-economic development has proven to be insufficient to explain the time and pace of the human demographic transition. Shifts to low fertility norms have thus been thought to result from social diffusion, yet to date, micro-level studies are limited and are often unable to disentangle the effect of social transmission from that of extrinsic factors. We used data which included the first ever use of modern contraception among a population of over 900 women in four villages in rural Ethiopia, where contraceptive prevalence is still low (<20%). We investigated whether the time of adoption of modern contraception is predicted by (i) the proportion of ever-users/non ever-users within both women and their husbands' friendships networks and (ii) the geographic distance to contraceptive ever-users. Using a model comparison approach, we found that individual socio-demographic characteristics (e.g. parity, education) and a religious norm are the most likely explanatory factors of temporal and spatial patterns of contraceptive uptake, while the role of person-to-person contact through either friendship or spatial networks remains marginal. Our study has broad implications for understanding the processes that initiate transitions to low fertility and the uptake of birth control technologies in the developing world

Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya

IntroductionGlobally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies.MethodsHealthy women ages 18–34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition.ResultsAmong 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36–90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded &gt;2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was &lt;10 ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and −27.1% to −20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased &gt;50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml [95% CI 473, 726] and 87 pg/ml [95% CI 64, 119], respectively).ConclusionTFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR.Clinical Trial RegistrationNCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382

Role of AMP-Activated Protein Kinase on Steroid Hormone Biosynthesis in Adrenal NCI-H295R Cells

Regulation of human androgen biosynthesis is poorly understood. However, detailed knowledge is needed to eventually solve disorders with androgen dysbalance. We showed that starvation growth conditions shift steroidogenesis of human adrenal NCI-H295R cells towards androgen production attributable to decreased HSD3B2 expression and activity and increased CYP17A1 phosphorylation and 17,20-lyase activity. Generally, starvation induces stress and energy deprivation that need to be counteracted to maintain proper cell functions. AMP-activated protein kinase (AMPK) is a master energy sensor that regulates cellular energy balance. AMPK regulates steroidogenesis in the gonad. Therefore, we investigated whether AMPK is also a regulator of adrenal steroidogenesis. We hypothesized that starvation uses AMPK signaling to enhance androgen production in NCI-H295R cells. We found that AMPK subunits are expressed in NCI-H295 cells, normal adrenal tissue and human as well as pig ovary cells. Starvation growth conditions decreased phosphorylation, but not activity of AMPK in NCI-H295 cells. In contrast, the AMPK activator 5-aminoimidazole-4-carboxamide (AICAR) increased AMPKα phosphorylation and increased CYP17A1-17,20 lyase activity. Compound C (an AMPK inhibitor), directly inhibited CYP17A1 activities and can therefore not be used for AMPK signaling studies in steroidogenesis. HSD3B2 activity was neither altered by AICAR nor compound C. Starvation did not affect mitochondrial respiratory chain function in NCI-H295R cells suggesting that there is no indirect energy effect on AMPK through this avenue. In summary, starvation-mediated increase of androgen production in NCI-H295 cells does not seem to be mediated by AMPK signaling. But AMPK activation can enhance androgen production through a specific increase in CYP17A1-17,20 lyase activity

Basis for treatment of tuberculosis among HIV-infected patients in Tanzania: the role of chest x-ray and sputum culture

BACKGROUND: Active tuberculosis (TB) is common among HIV-infected persons living in tuberculosis endemic countries, and screening for tuberculosis (TB) is recommended routinely. We sought to determine the role of chest x-ray and sputum culture in the decision to treat for presumptive TB using active case finding in a large cohort of HIV-infected patients. METHODS: Ambulatory HIV-positive subjects with CD4 counts ≥ 200/mm3 entering a Phase III TB vaccine study in Tanzania were screened for TB with a physical examination, standard interview, CD4 count, chest x-ray (CXR), blood culture for TB, and three sputum samples for acid fast bacillus (AFB) smear and culture. RESULTS: Among 1176 subjects 136 (12%) were treated for presumptive TB. These patients were more frequently male than those without treatment (34% vs. 25%, respectively; p = 0.049) and had lower median CD4 counts (319/μL vs. 425/μL, respectively; p < .0001). Among the 136 patients treated for TB, 38 (28%) had microbiologic confirmation, including 13 (10%) who had a normal CXR and no symptoms. There were 58 (43%) treated patients in whom the only positive finding was an abnormal CXR. Blood cultures were negative in all patients. CONCLUSION: Many ambulatory HIV-infected patients with CD4 counts ≥ 200/mm3 are treated for presumptive TB. Our data suggest that optimal detection requires comprehensive evaluation, including CXR and sputum culture on both symptomatic and asymptomatic subjects.National Institutes of Health (A1 45407); Fogarty International Center (D43-TW006807