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Estimated mortality on HIV treatment among active patients and patients lost to follow-up in 4 provinces of Zambia: Findings from a multistage sampling-based survey

Ve, 12/01/2018 - 23:00

by Charles B. Holmes, Izukanji Sikazwe, Kombatende Sikombe, Ingrid Eshun-Wilson, Nancy Czaicki, Laura K. Beres, Njekwa Mukamba, Sandra Simbeza, Carolyn Bolton Moore, Cardinal Hantuba, Peter Mwaba, Caroline Phiri, Nancy Padian, David V. Glidden, Elvin Geng

Background

Survival represents the single most important indicator of successful HIV treatment. Routine monitoring fails to capture most deaths. As a result, both regional assessments of the impact of HIV services and identification of hotspots for improvement efforts are limited. We sought to assess true mortality on treatment, characterize the extent under-reporting of mortality in routine health information systems in Zambia, and identify drivers of mortality across sites and over time using a multistage, regionally representative sampling approach.

Methods and findings

We enumerated all HIV infected adults on antiretroviral therapy (ART) who visited any one of 64 facilities across 4 provinces in Zambia during the 24-month period from 1 August 2013 to 31 July 2015. We identified a probability sample of patients who were lost to follow-up through selecting facilities probability proportional to size and then a simple random sample of lost patients. Outcomes among patients lost to follow-up were incorporated into survival analysis and multivariate regression through probability weights. Of 165,464 individuals (64% female, median age 39 years (IQR 33–46), median CD4 201 cells/mm3 (IQR 111–312), the 2-year cumulative incidence of mortality increased from 1.9% (95% CI 1.7%–2.0%) to a corrected rate of 7.0% (95% CI 5.7%–8.4%) (all ART users) and from 2.1% (95% CI 1.8%–2.4%) to 8.3% (95% CI 6.1%–10.7%) (new ART users). Revised provincial mortality rates ranged from 3–9 times higher than naïve rates for new ART users and were lowest in Lusaka Province (4.6 per 100 person-years) and highest in Western Province (8.7 per 100 person-years) after correction. Corrected mortality rates varied markedly by clinic, with an IQR of 3.5 to 7.5 deaths per 100 person-years and a high of 13.4 deaths per 100 person-years among new ART users, even after adjustment for clinical (e.g., pretherapy CD4) and contextual (e.g., province and clinic size) factors. Mortality rates (all ART users) were highest year 1 after treatment at 4.6/100 person-years (95% CI 3.9–5.5), 2.9/100 person-years (95% CI 2.1–3.9) in year 2, and approximately 1.6% per year through 8 years on treatment. In multivariate analysis, patient-level factors including male sex and pretherapy CD4 levels and WHO stage were associated with higher mortality among new ART users, while male sex and HIV disclosure were associated with mortality among all ART users. In both cases, being late (>14 days late for appointment) or lost (>90 days late for an appointment) was associated with deaths. We were unable to ascertain the vital status of about one-quarter of those lost and selected for tracing and did not adjudicate causes of death.

Conclusions

HIV treatment in Zambia is not optimally effective. The high and sustained mortality rates and marked under-reporting of mortality at the provincial-level and unexplained heterogeneity between regions and sites suggest opportunities for the use of corrected mortality rates for quality improvement. A regionally representative sampling-based approach can bring gaps and opportunities for programs into clear epidemiological focus for local and global decision makers.

From macro- to microfactors in health: Social science approaches in research on sexually transmitted infections

Me, 10/01/2018 - 23:00

by Ruth Kutalek, Elena Jirovsky, Igor Grabovac

Ruth Kutalek and colleagues share their Perspective on Kipruto Chesang and colleagues' qualitative study of beliefs and practices among healthcare providers managing STIs in Kenya and discuss the value of this type of research for addressing biosocial challenges.

The WHO 2016 verbal autopsy instrument: An international standard suitable for automated analysis by InterVA, InSilicoVA, and Tariff 2.0

Me, 10/01/2018 - 23:00

by Erin K. Nichols, Peter Byass, Daniel Chandramohan, Samuel J. Clark, Abraham D. Flaxman, Robert Jakob, Jordana Leitao, Nicolas Maire, Chalapati Rao, Ian Riley, Philip W. Setel, on behalf of the WHO Verbal Autopsy Working Group

Background

Verbal autopsy (VA) is a practical method for determining probable causes of death at the population level in places where systems for medical certification of cause of death are weak. VA methods suitable for use in routine settings, such as civil registration and vital statistics (CRVS) systems, have developed rapidly in the last decade. These developments have been part of a growing global momentum to strengthen CRVS systems in low-income countries. With this momentum have come pressure for continued research and development of VA methods and the need for a single standard VA instrument on which multiple automated diagnostic methods can be developed.

Methods and findings

In 2016, partners harmonized a WHO VA standard instrument that fully incorporates the indicators necessary to run currently available automated diagnostic algorithms. The WHO 2016 VA instrument, together with validated approaches to analyzing VA data, offers countries solutions to improving information about patterns of cause-specific mortality. This VA instrument offers the opportunity to harmonize the automated diagnostic algorithms in the future.

Conclusions

Despite all improvements in design and technology, VA is only recommended where medical certification of cause of death is not possible. The method can nevertheless provide sufficient information to guide public health priorities in communities in which physician certification of deaths is largely unavailable.The WHO 2016 VA instrument, together with validated approaches to analyzing VA data, offers countries solutions to improving information about patterns of cause-specific mortality.

Sexually transmitted infections in the era of antiretroviral-based HIV prevention: Priorities for discovery research, implementation science, and community involvement

Me, 10/01/2018 - 23:00

by Jeanne M. Marrazzo, Julia C. Dombrowski, Kenneth H. Mayer

Jeanne M. Marrazzo and colleagues join PLOS Medicine's Collection on the prevention, diagnosis, and treatment of STIs with a Perspective on HIV research imperatives in our time of effective viral suppression and pre-exposure prophylaxis.

Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Ma, 09/01/2018 - 23:00

by Iris Broce, Celeste M. Karch, Natalie Wen, Chun C. Fan, Yunpeng Wang, Chin Hong Tan, Naomi Kouri, Owen A. Ross, Günter U. Höglinger, Ulrich Muller, John Hardy, International FTD-Genomics Consortium , Parastoo Momeni, Christopher P. Hess, William P. Dillon, Zachary A. Miller, Luke W. Bonham, Gil D. Rabinovici, Howard J. Rosen, Gerard D. Schellenberg, Andre Franke, Tom H. Karlsen, Jan H. Veldink, Raffaele Ferrari, Jennifer S. Yokoyama, Bruce L. Miller, Ole A. Andreassen, Anders M. Dale, Rahul S. Desikan, Leo P. Sugrue

Background

Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.

Methods and findings

Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders—namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)—and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal.

Conclusions

We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

Association between intake of less-healthy foods defined by the United Kingdom's nutrient profile model and cardiovascular disease: A population-based cohort study

Gi, 04/01/2018 - 23:00

by Oliver T. Mytton, Nita G. Forouhi, Peter Scarborough, Marleen Lentjes, Robert Luben, Mike Rayner, Kay Tee Khaw, Nicholas J. Wareham, Pablo Monsivais

Background

In the United Kingdom, the Food Standards Agency-Ofcom nutrient profiling model (FSA-Ofcom model) is used to define less-healthy foods that cannot be advertised to children. However, there has been limited investigation of whether less-healthy foods defined by this model are associated with prospective health outcomes. The objective of this study was to test whether consumption of less-healthy food as defined by the FSA-Ofcom model is associated with cardiovascular disease (CVD).

Methods and findings

We used data from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort study in adults (n = 25,639) aged 40–79 years who completed a 7-day diet diary between 1993 and 1997. Incident CVD (primary outcome), cardiovascular mortality, and all-cause mortality (secondary outcomes) were identified using record linkage to hospital admissions data and death certificates up to 31 March 2015. Each food and beverage item reported was coded and given a continuous score, using the FSA-Ofcom model, based on the consumption of energy; saturated fat; total sugar; sodium; nonsoluble fibre; protein; and fruits, vegetables, and nuts. Items were classified as less-healthy using Ofcom regulation thresholds. We used Cox proportional hazards regression to test for an association between consumption of less-healthy food and incident CVD. Sensitivity analyses explored whether the results differed based on the definition of the exposure. Analyses were adjusted for age, sex, behavioural risk factors, clinical risk factors, and socioeconomic status. Participants were followed up for a mean of 16.4 years. During follow-up, there were 4,965 incident cases of CVD (1,524 fatal within 30 days). In the unadjusted analyses, we observed an association between consumption of less-healthy food and incident CVD (test for linear trend over quintile groups, p < 0.01). After adjustment for covariates (sociodemographic, behavioural, and indices of cardiovascular risk), we found no association between consumption of less-healthy food and incident CVD (p = 0.84) or cardiovascular mortality (p = 0.90), but there was an association between consumption of less-healthy food and all-cause mortality (test for linear trend, p = 0.006; quintile group 5, highest consumption of less-healthy food, versus quintile group 1, HR = 1.11, 95% CI 1.02–1.20). Sensitivity analyses produced similar results. The study is observational and relies on self-report of dietary consumption. Despite adjustment for known and reported confounders, residual confounding is possible.

Conclusions

After adjustment for potential confounding factors, no significant association between consumption of less-healthy food (as classified by the FSA-Ofcom model) and CVD was observed in this study. This suggests, in the UK setting, that the FSA-Ofcom model is not consistently discriminating among foods with respect to their association with CVD. More studies are needed to understand better the relationship between consumption of less-healthy food, defined by the FSA-Ofcom model, and indices of health.

Pelvic inflammatory disease risk following negative results from chlamydia nucleic acid amplification tests (NAATs) versus non-NAATs in Denmark: A retrospective cohort

Ma, 02/01/2018 - 23:00

by Bethan Davies, Katy M. E. Turner, Thomas Benfield, Maria Frølund, Berit Andersen, Henrik Westh, on behalf of the Danish Chlamydia Study , Helen Ward

Background

Nucleic Acid Amplification Tests (NAATs) are the recommended test type for diagnosing Chlamydia trachomatis (chlamydia). However, less sensitive diagnostic methods—including direct immunofluorescence (IF) and enzyme-linked immunoassay (ELISA)—remain in use in lower resourced settings. We estimate the risk of pelvic inflammatory disease (PID) following undiagnosed infection in women tested with non-NAATs and estimate the health gain from using accurate diagnostic tests.

Methods and findings

We used Denmark’s national Chlamydia Study dataset to extract all chlamydia tests performed in women aged 15–34 years (1998–2001). Tests were categorised as non-NAAT (IF/ELISA) or NAAT and limited to each woman’s first test in the study period. We linked test data to hospital presentations for PID within 12 months from the Danish National Patient Register. The study included 272,105 women with a chlamydia test, just under half (44.78%, n = 121,857) were tested using NAATs. Overall, 6.38% (n = 17,353) tested positive for chlamydia and 0.64% (n = 1,732) were diagnosed with PID within 12 months. The risk of PID following a positive chlamydia test did not differ by test type (NAAT 0.81% [95% CI 0.61–1.00], non-NAAT 0.78% [0.59–0.96]). The risk of PID following a negative test was significantly lower in women tested with NAATs compared to non-NAATs (0.55% [0.51–0.59] compared to 0.69% [0.64–0.73]; adjusted odds ratio (AOR) 0.83 [0.75–0.93]). We estimate that 18% of chlamydia infections in women tested with a non-NAAT were undiagnosed and that the risk of progression from undiagnosed chlamydia infection to PID within 12 months was 9.52% (9.30–9.68). Using non-NAATs could lead to an excess 120 cases of PID per 100,000 women tested compared to using NAATs. The key limitations of this study are under ascertainment of PID cases, misclassification bias in chlamydia and PID exposure status, bias to the association between clinical presentation and test type and the presence of unmeasured confounders (including other sexually transmitted infection [STI] diagnoses and clinical indication for chlamydia test).

Conclusion

This retrospective observational study estimates the positive impact on women’s reproductive health from using accurate chlamydia diagnostic tests and provides further evidence for restricting the use of inferior tests. Women with a negative chlamydia test have a 17% higher adjusted risk of PID by 12 months if they are tested using a non-NAAT compared to a NAAT.

What about drinking is associated with shorter life in poorer people?

Ma, 02/01/2018 - 23:00

by Jürgen Rehm, Charlotte Probst

In a Perspective, Jürgen Rehm and Charlotte Probst examine the links between socioeconomic status, alcohol use, and cardiovascular mortality and discuss implications for policy.

Life course socioeconomic position, alcohol drinking patterns in midlife, and cardiovascular mortality: Analysis of Norwegian population-based health surveys

Ma, 02/01/2018 - 23:00

by Eirik Degerud, Inger Ariansen, Eivind Ystrom, Sidsel Graff-Iversen, Gudrun Høiseth, Jørg Mørland, George Davey Smith, Øyvind Næss

Background

Socioeconomically disadvantaged groups tend to experience more harm from the same level of exposure to alcohol as advantaged groups. Alcohol has multiple biological effects on the cardiovascular system, both potentially harmful and protective. We investigated whether the diverging relationships between alcohol drinking patterns and cardiovascular disease (CVD) mortality differed by life course socioeconomic position (SEP).

Methods and findings

From 3 cohorts (the Counties Studies, the Cohort of Norway, and the Age 40 Program, 1987–2003) containing data from population-based cardiovascular health surveys in Norway, we included participants with self-reported information on alcohol consumption frequency (n = 207,394) and binge drinking episodes (≥5 units per occasion, n = 32,616). We also used data from national registries obtained by linkage. Hazard ratio (HR) with 95% confidence intervals (CIs) for CVD mortality was estimated using Cox models, including alcohol, life course SEP, age, gender, smoking, physical activity, body mass index (BMI), systolic blood pressure, heart rate, triglycerides, diabetes, history of CVD, and family history of coronary heart disease (CHD). Analyses were performed in the overall sample and stratified by high, middle, and low strata of life course SEP. A total of 8,435 CVD deaths occurred during the mean 17 years of follow-up. Compared to infrequent consumption (p = 0.002; middle versus high), 1.23 (95% CI 0.96, 1.58, p = 0.10; low versus high), and 0.96 (95% CI 0.76, 1.21, p = 0.73; low versus middle). In the group with data on binge drinking, 2,284 deaths (15 years) from CVDs occurred. In comparison to consumers who did not binge during the past year, HRs among frequent bingers (≥1 time per week) were 1.58 (95% CI 1.31, 1.91) overall, and 1.22 (95% CI 0.84, 1.76), 1.71 (95% CI 1.31, 2.23), and 1.85 (95% CI 1.16, 2.94) in the strata, respectively. HRs for effect modification were 1.36 (95% CI 0.87, 2.13, p = 0.18; middle versus high), 1.63 (95% CI 0.92, 2.91, p = 0.10; low versus high), and 1.32 (95% CI 0.79, 2.20, p = 0.29; low versus middle). A limitation of this study was the use of a single measurement to reflect lifetime alcohol consumption.

Conclusions

Moderately frequent consumers had a lower risk of CVD mortality compared with infrequent consumers, and we observed that this association was more pronounced among participants with higher SEP throughout their life course. Frequent binge drinking was associated with a higher risk of CVD mortality, but it was more uncertain whether the risk differed by life course SEP. It is unclear if these findings reflect differential confounding of alcohol consumption with health-protective or damaging exposures, or differing effects of alcohol on health across socioeconomic groups.

Sexually transmitted infections—Research priorities for new challenges

Me, 27/12/2017 - 23:00

by Nicola Low, Nathalie J. Broutet

In an Editorial, Guest Editors Nicola Low and Nathalie Broutet discuss the Collection on sexually transmitted infections in the context of research priorities in the field.

Healthcare provider perspectives on managing sexually transmitted infections in HIV care settings in Kenya: A qualitative thematic analysis

Me, 27/12/2017 - 23:00

by Kipruto Chesang, Sureyya Hornston, Odylia Muhenje, Teresa Saliku, Joy Mirjahangir, Amanda Viitanen, Helgar Musyoki, Christine Awuor, George Githuka, Naomi Bock

Background

The burden of sexually transmitted infections (STIs) has been increasing in Kenya, as is the case elsewhere in sub-Saharan Africa, while measures for control and prevention are weak. The objectives of this study were to (1) describe healthcare provider (HCP) knowledge and practices, (2) explore HCP attitudes and beliefs, (3) identify structural and environmental factors affecting STI management, and (4) seek recommendations to improve the STI program in Kenya.

Methods and findings

Using individual in-depth interviews (IDIs), data were obtained from 87 HCPs working in 21 high-volume comprehensive HIV care centers (CCCs) in 7 of Kenya’s 8 regions. Transcript coding was performed through an inductive and iterative process, and the data were analyzed using NVivo 10.0. Overall, HCPs were knowledgeable about STIs, saw STIs as a priority, reported high STI co-infection amongst people living with HIV (PLHIV), and believed STIs in PLHIV facilitate HIV transmission. Most used the syndromic approach for STI management. Condoms and counseling were available in most of the clinics. HCPs believed that having an STI increased stigma in the community, that there was STI antimicrobial drug resistance, and that STIs were not prioritized by the authorities. HCPs had positive attitudes toward managing STIs, but were uncomfortable discussing sexual issues with patients in general, and profoundly for anal sex. The main barriers to the management of STIs reported were low commitment by higher levels of management, few recent STI-focused trainings, high stigma and low community participation, and STI drug stock-outs. Solutions recommended by HCPs included formulation of new STI policies that would increase access, availability, and quality of STI services; integrated STI/HIV management; improved STI training; increased supervision; standardized reporting; and community involvement in STI prevention. The key limitations of our study were that (1) participant experience and how much of their workload was devoted to managing STIs was not considered, (2) some responses may have been subject to recall and social desirability bias, and (3) patients or clients of STI services were not interviewed, and therefore their inputs were not obtained. While considering these limitations, the number and variety of facilities sampled, the mix of staff cadres interviewed, the use of a standardized instrument, and the consistency of responses add strength to our findings.

Conclusions

This study showed that HCPs understood the challenges of, and solutions for, improving the management of STIs in Kenya. Commitment by higher management, training in the management of STIs, measures for reducing stigma, and introducing new policies of STI management should be considered by health authorities in Kenya.

Internet-accessed sexually transmitted infection (e-STI) testing and results service: A randomised, single-blind, controlled trial

Me, 27/12/2017 - 23:00

by Emma Wilson, Caroline Free, Tim P. Morris, Jonathan Syred, Irrfan Ahamed, Anatole S. Menon-Johansson, Melissa J. Palmer, Sharmani Barnard, Emma Rezel, Paula Baraitser

Background

Internet-accessed sexually transmitted infection testing (e-STI testing) is increasingly available as an alternative to testing in clinics. Typically this testing modality enables users to order a test kit from a virtual service (via a website or app), collect their own samples, return test samples to a laboratory, and be notified of their results by short message service (SMS) or telephone. e-STI testing is assumed to increase access to testing in comparison with face-to-face services, but the evidence is unclear. We conducted a randomised controlled trial to assess the effectiveness of an e-STI testing and results service (chlamydia, gonorrhoea, HIV, and syphilis) on STI testing uptake and STI cases diagnosed.

Methods and findings

The study took place in the London boroughs of Lambeth and Southwark. Between 24 November 2014 and 31 August 2015, we recruited 2,072 participants, aged 16–30 years, who were resident in these boroughs, had at least 1 sexual partner in the last 12 months, stated willingness to take an STI test, and had access to the internet. Those unable to provide consent and unable to read English were excluded. Participants were randomly allocated to receive 1 text message with the web link of an e-STI testing and results service (intervention group) or to receive 1 text message with the web link of a bespoke website listing the locations, contact details, and websites of 7 local sexual health clinics (control group). Participants were free to use any other services or interventions during the study period. The primary outcomes were self-reported STI testing at 6 weeks, verified by patient record checks, and self-reported STI diagnosis at 6 weeks, verified by patient record checks. Secondary outcomes were the proportion of participants prescribed treatment for an STI, time from randomisation to completion of an STI test, and time from randomisation to treatment of an STI. Participants were sent a £10 cash incentive on submission of self-reported data. We completed all follow-up, including patient record checks, by 17 June 2016. Uptake of STI testing was increased in the intervention group at 6 weeks (50.0% versus 26.6%, relative risk [RR] 1.87, 95% CI 1.63 to 2.15, P < 0.001). The proportion of participants diagnosed was 2.8% in the intervention group versus 1.4% in the control group (RR 2.10, 95% CI 0.94 to 4.70, P = 0.079). No evidence of heterogeneity was observed for any of the pre-specified subgroup analyses. The proportion of participants treated was 1.1% in the intervention group versus 0.7% in the control group (RR 1.72, 95% CI 0.71 to 4.16, P = 0.231). Time to test, was shorter in the intervention group compared to the control group (28.8 days versus 36.5 days, P < 0.001, test for difference in restricted mean survival time [RMST]), but no differences were observed for time to treatment (83.2 days versus 83.5 days, P = 0.51, test for difference in RMST). We were unable to recruit the planned 3,000 participants and therefore lacked power for the analyses of STI diagnoses and STI cases treated.

Conclusions

The e-STI testing service increased uptake of STI testing for all groups including high-risk groups. The intervention required people to attend clinic for treatment and did not reduce time to treatment. Service innovations to improve treatment rates for those diagnosed online are required and could include e-treatment and postal treatment services. e-STI testing services require long-term monitoring and evaluation.

Trial registration

ISRCTN Registry ISRCTN13354298.

The vaginal microbiome and sexually transmitted infections are interlinked: Consequences for treatment and prevention

Me, 27/12/2017 - 23:00

by Janneke H. H. M. van de Wijgert

In a Perspective for our Collection on STI research, Janneke van de Wijgert discusses the latest on how the vaginal microbiota predisposes women to acquisition of STIs and discusses future potential for clinical intervention.

Dual-strain genital herpes simplex virus type 2 (HSV-2) infection in the US, Peru, and 8 countries in sub-Saharan Africa: A nested cross-sectional viral genotyping study

Me, 27/12/2017 - 23:00

by Christine Johnston, Amalia Magaret, Pavitra Roychoudhury, Alexander L. Greninger, Daniel Reeves, Joshua Schiffer, Keith R. Jerome, Cassandra Sather, Kurt Diem, Jairam R. Lingappa, Connie Celum, David M. Koelle, Anna Wald

Background

Quantitative estimation of the extent to which the immune system’s protective effect against one herpes simplex virus type 2 (HSV-2) infection protects against infection with additional HSV-2 strains is important for understanding the potential for HSV-2 vaccine development. Using viral genotyping, we estimated the prevalence of HSV-2 dual-strain infection and identified risk factors.

Methods and findings

People with and without HIV infection participating in HSV-2 natural history studies (University of Washington Virology Research Clinic) and HIV prevention trials (HIV Prevention Trials Network 039 and Partners in Prevention HSV/HIV Transmission Study) in the US, Africa, and Peru with 2 genital specimens each containing ≥105 copies herpes simplex virus DNA/ml collected a median of 5 months apart (IQR: 2–11 months) were included. It is unlikely that 2 strains would be detected in the same sample simultaneously; therefore, 2 samples were required to detect dual-strain infection. We identified 85 HSV-2 SNPs that, in aggregate, could determine whether paired HSV-2 strains were the same or different with >90% probability. These SNPs were then used to create a customized high-throughput array-based genotyping assay. Participants were considered to be infected with more than 1 strain of HSV-2 if their samples differed by ≥5 SNPs between the paired samples, and dual-strain infection was confirmed using high-throughput sequencing (HTS). We genotyped pairs of genital specimens from 459 people; 213 (46%) were men, the median age was 34 years (IQR: 27–44), and 130 (28%) were HIV seropositive. Overall, 272 (59%) people were from the US, 59 (13%) were from Peru, and 128 (28%) were from 8 countries in Africa. Of the 459 people, 18 (3.9%) met the criteria for dual-strain infection. HTS and phylogenetic analysis of paired specimens confirmed shedding of 2 distinct HSV-2 strains collected at different times in 17 pairs, giving an estimated dual-strain infection prevalence of 3.7% (95% CI = 2.0%–5.4%). Paired samples with dual-strain infection differed by a median of 274 SNPs in the UL_US region (range 129–413). Matching our observed dual-strain infection frequency to simulated data of varying prevalences and allowing only 2 samples per person, we inferred the true prevalence of dual-strain infection to be 7%. In multivariable analysis, controlling for HIV status and continent of origin, people from Africa had a higher risk for dual-strain infection (risk ratio [RR] = 9.20, 95% CI = 2.05–41.32), as did people who were HIV seropositive (RR = 4.06, 95% CI = 1.42–11.56).

Conclusions

HSV-2 dual-strain infection was detected in 3.7% of paired samples from individual participants, and was more frequent among people with HIV infection. Simulations suggest that the true prevalence of dual-strain infection is 7%. Our data indicate that naturally occurring immunity to HSV-2 may be protective against infection with a second strain. This study is limited by the inability to determine the timing of acquisition of the second strain.

Re-emerging and newly recognized sexually transmitted infections: Can prior experiences shed light on future identification and control?

Me, 27/12/2017 - 23:00

by Kyle Bernstein, Virginia B. Bowen, Caron R. Kim, Michel J. Counotte, Robert D. Kirkcaldy, Edna Kara, Gail Bolan, Nicola Low, Nathalie Broutet

How do we spot the next sexually transmitted infection? Kyle Bernstein and colleagues look for lessons from past discovery.

Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: An evaluation from multi-country surveys and stakeholder interviews

Me, 27/12/2017 - 23:00

by Stephen Nurse-Findlay, Melanie M. Taylor, Margaret Savage, Maeve B. Mello, Sanni Saliyou, Manuel Lavayen, Frederic Seghers, Michael L. Campbell, Françoise Birgirimana, Leopold Ouedraogo, Morkor Newman Owiredu, Nancy Kidula, Lee Pyne-Mercier

Background

Benzathine penicillin G (BPG) is the only recommended treatment to prevent mother-to-child transmission of syphilis. Due to recent reports of country-level shortages of BPG, an evaluation was undertaken to quantify countries that have experienced shortages in the past 2 years and to describe factors contributing to these shortages.

Methods and findings

Country-level data about BPG shortages were collected using 3 survey approaches. First, a survey designed by the WHO Department of Reproductive Health and Research was distributed to 41 countries and territories in the Americas and 41 more in Africa. Second, WHO conducted an email survey of 28 US Centers for Disease Control and Prevention country directors. An additional 13 countries were in contact with WHO for related congenital syphilis prevention activities and also reported on BPG shortages. Third, the Clinton Health Access Initiative (CHAI) collected data from 14 countries (where it has active operations) to understand the extent of stock-outs, in-country purchasing, usage behavior, and breadth of available purchasing options to identify stock-outs worldwide. CHAI also conducted in-person interviews in the same 14 countries to understand the extent of stock-outs, in-country purchasing and usage behavior, and available purchasing options. CHAI also completed a desk review of 10 additional high-income countries, which were also included. BPG shortages were attributable to shortfalls in supply, demand, and procurement in the countries assessed. This assessment should not be considered globally representative as countries not surveyed may also have experienced BPG shortages. Country contacts may not have been aware of BPG shortages when surveyed or may have underreported medication substitutions due to desirability bias. Funding for the purchase of BPG by countries was not evaluated. In all, 114 countries and territories were approached to provide information on BPG shortages occurring during 2014–2016. Of unique countries and territories, 95 (83%) responded or had information evaluable from public records. Of these 95 countries and territories, 39 (41%) reported a BPG shortage, and 56 (59%) reported no BPG shortage; 10 (12%) countries with and without BPG shortages reported use of antibiotic alternatives to BPG for treatment of maternal syphilis. Market exits, inflexible production cycles, and minimum order quantities affect BPG supply. On the demand side, inaccurate forecasts and sole sourcing lead to under-procurement. Clinicians may also incorrectly prescribe BPG substitutes due to misperceptions of quality or of the likelihood of adverse outcomes.

Conclusions

Targets for improvement include drug forecasting and procurement, and addressing provider reluctance to use BPG. Opportunities to improve global supply, demand, and use of BPG should be prioritized alongside congenital syphilis elimination efforts.

Cell salvage and donor blood transfusion during cesarean section: A pragmatic, multicentre randomised controlled trial (SALVO)

Ma, 19/12/2017 - 23:00

by Khalid S. Khan, Philip A. S. Moore, Matthew J. Wilson, Richard Hooper, Shubha Allard, Ian Wrench, Lee Beresford, Tracy E. Roberts, Carol McLoughlin, James Geoghegan, Jane P. Daniels, Sue Catling, Vicki A. Clark, Paul Ayuk, Stephen Robson, Fang Gao-Smith, Matthew Hogg, Doris Lanz, Julie Dodds, on behalf of the SALVO study group

Background

Excessive haemorrhage at cesarean section requires donor (allogeneic) blood transfusion. Cell salvage may reduce this requirement.

Methods and findings

We conducted a pragmatic randomised controlled trial (at 26 obstetric units; participants recruited from 4 June 2013 to 17 April 2016) of routine cell salvage use (intervention) versus current standard of care without routine salvage use (control) in cesarean section among women at risk of haemorrhage. Randomisation was stratified, using random permuted blocks of variable sizes. In an intention-to-treat analysis, we used multivariable models, adjusting for stratification variables and prognostic factors identified a priori, to compare rates of donor blood transfusion (primary outcome) and fetomaternal haemorrhage ≥2 ml in RhD-negative women with RhD-positive babies (a secondary outcome) between groups. Among 3,028 women randomised (2,990 analysed), 95.6% of 1,498 assigned to intervention had cell salvage deployed (50.8% had salvaged blood returned; mean 259.9 ml) versus 3.9% of 1,492 assigned to control. Donor blood transfusion rate was 3.5% in the control group versus 2.5% in the intervention group (adjusted odds ratio [OR] 0.65, 95% confidence interval [CI] 0.42 to 1.01, p = 0.056; adjusted risk difference −1.03, 95% CI −2.13 to 0.06). In a planned subgroup analysis, the transfusion rate was 4.6% in women assigned to control versus 3.0% in the intervention group among emergency cesareans (adjusted OR 0.58, 95% CI 0.34 to 0.99), whereas it was 2.2% versus 1.8% among elective cesareans (adjusted OR 0.83, 95% CI 0.38 to 1.83) (interaction p = 0.46). No case of amniotic fluid embolism was observed. The rate of fetomaternal haemorrhage was higher with the intervention (10.5% in the control group versus 25.6% in the intervention group, adjusted OR 5.63, 95% CI 1.43 to 22.14, p = 0.013). We are unable to comment on long-term antibody sensitisation effects.

Conclusions

The overall reduction observed in donor blood transfusion associated with the routine use of cell salvage during cesarean section was not statistically significant.

Trial registration

This trial was prospectively registered on ISRCTN as trial number 66118656 and can be viewed on http://www.isrctn.com/ISRCTN66118656.

Estimated clinical impact of the Xpert MTB/RIF Ultra cartridge for diagnosis of pulmonary tuberculosis: A modeling study

Gi, 14/12/2017 - 23:00

by Emily A. Kendall, Samuel G. Schumacher, Claudia M. Denkinger, David W. Dowdy

Background

The Xpert MTB/RIF (Xpert) assay offers rapid and accurate diagnosis of tuberculosis (TB) but still suffers from imperfect sensitivity. The newer Xpert MTB/RIF Ultra cartridge has shown improved sensitivity in recent field trials, but at the expense of reduced specificity. The clinical implications of switching from the existing Xpert cartridge to the Xpert Ultra cartridge in different populations remain uncertain.

Methods and findings

We developed a Markov microsimulation model of hypothetical cohorts of 100,000 individuals undergoing diagnostic sputum evaluation with Xpert for suspected pulmonary TB, in each of 3 emblematic settings: an HIV clinic in South Africa, a public TB center in India, and an adult primary care setting in China. In each setting, we used existing data to project likely diagnostic results, treatment decisions, and ultimate clinical outcomes, assuming use of the standard Xpert versus Xpert Ultra cartridge. Our primary outcomes were the projected number of additional unnecessary treatments generated, the projected number of TB deaths averted, and the projected number of unnecessary treatments generated per TB death averted, if standard Xpert were switched to Xpert Ultra. We also simulated alternative approaches to interpreting positive results of the Ultra cartridge’s semi-quantitative trace call. Extensive sensitivity and uncertainty analyses were performed to evaluate the drivers and generalizability of projected results. In the Indian TB center setting, replacing the standard Xpert cartridge with the Xpert Ultra cartridge was projected to avert 0.5 TB deaths (95% uncertainty range [UR]: 0, 1.3) and generate 18 unnecessary treatments (95% UR: 10, 29) per 1,000 individuals evaluated—resulting in a median ratio of 38 incremental unnecessary treatments added by Ultra per incremental death averted by Ultra compared to outcomes using standard Xpert (95% UR: 12, indefinite upper bound). In the South African HIV care setting—where TB mortality rates are higher and Ultra’s improved sensitivity has greater absolute benefit—this ratio improved to 7 unnecessary treatments per TB death averted (95% UR: 2, 43). By contrast, in the Chinese primary care setting, this ratio was much less favorable, at 372 unnecessary treatments per TB death averted (95% UR: 75, indefinite upper bound), although the projected number of unnecessary treatments using Xpert Ultra was lower (with a possibility of no increased overtreatment) when using specificity data only from lower-burden settings. Alternative interpretations of the trace call had little effect on these ratios. Limitations include uncertainty in key parameters (including the clinical implications of false-negative results), the exclusion of transmission effects, and restriction of this analysis to adult pulmonary TB.

Conclusions

Switching from the standard Xpert cartridge to the Xpert Ultra cartridge for diagnosis of adult pulmonary TB may have different consequences in different clinical settings. In settings with high TB and HIV prevalence, Xpert Ultra is likely to offer considerable mortality benefit, whereas in lower-prevalence settings, Xpert Ultra will likely result in considerable overtreatment unless the possibility of higher specificity of Ultra in lower-prevalence settings in confirmed. The ideal use of the Ultra cartridge may therefore involve a more nuanced, setting-specific approach to implementation, with priority given to populations in which the anticipated prevalence of TB (and HIV) is the highest.

Antiretroviral therapy and population mortality: Leveraging routine national data to advance policy

Ma, 12/12/2017 - 23:00

by Amitabh B. Suthar, Till Bärnighausen

In a Perspective, Amitabh Suthar and Till Bärnighausen discuss progress made so far in reducing HIV-related mortality in South Africa and keys towards further population mortality reductions going forward.

Estimating the impact of antiretroviral treatment on adult mortality trends in South Africa: A mathematical modelling study

Ma, 12/12/2017 - 23:00

by Leigh F. Johnson, Margaret T. May, Rob E. Dorrington, Morna Cornell, Andrew Boulle, Matthias Egger, Mary-Ann Davies

Background

Substantial reductions in adult mortality have been observed in South Africa since the mid-2000s, but there has been no formal evaluation of how much of this decline is attributable to the scale-up of antiretroviral treatment (ART), as previous models have not been calibrated to vital registration data. We developed a deterministic mathematical model to simulate the mortality trends that would have been expected in the absence of ART, and with earlier introduction of ART.

Methods and findings

Model estimates of mortality rates in ART patients were obtained from the International Epidemiology Databases to Evaluate AIDS–Southern Africa (IeDEA-SA) collaboration. The model was calibrated to HIV prevalence data (1997–2013) and mortality data from the South African vital registration system (1997–2014), using a Bayesian approach. In the 1985–2014 period, 2.70 million adult HIV-related deaths occurred in South Africa. Adult HIV deaths peaked at 231,000 per annum in 2006 and declined to 95,000 in 2014, a reduction of 74.7% (95% CI: 73.3%–76.1%) compared to the scenario without ART. However, HIV mortality in 2014 was estimated to be 69% (95% CI: 46%–97%) higher in 2014 (161,000) if the model was calibrated only to HIV prevalence data. In the 2000–2014 period, the South African ART programme is estimated to have reduced the cumulative number of HIV deaths in adults by 1.72 million (95% CI: 1.58 million–1.84 million) and to have saved 6.15 million life years in adults (95% CI: 5.52 million–6.69 million). This compares with a potential saving of 8.80 million (95% CI: 7.90 million–9.59 million) life years that might have been achieved if South Africa had moved swiftly to implement WHO guidelines (2004–2013) and had achieved high levels of ART uptake in HIV-diagnosed individuals from 2004 onwards. The model is limited by its reliance on all-cause mortality data, given the lack of reliable cause-of-death reporting, and also does not allow for changes over time in tuberculosis control programmes and ART effectiveness.

Conclusions

ART has had a dramatic impact on adult mortality in South Africa, but delays in the rollout of ART, especially in the early stages of the ART programme, have contributed to substantial loss of life. This is the first study to our knowledge to calibrate a model of ART impact to population-level recorded death data in Africa; models that are not calibrated to population-level death data may overestimate HIV-related mortality.