Global, regional, and national burden of HIV and other sexually transmitted infections in older adults aged 60-89 years from 1990 to 2019: results from the Global Burden of Disease Study 2019.

BACKGROUND: Sexually active older adults are often more susceptible to HIV and other sexually transmitted infections (STIs) due to various health conditions (especially a weakened immune system) and low use of condoms. We aimed to assess the global, regional, and national burdens and trends of HIV and other STIs in older adults from 1990 to 2019. METHODS: We retrieved data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 on the incidence and disability-adjusted life-years (DALYs) of HIV and other STIs (syphilis, chlamydia, gonorrhoea, trichomoniasis, and genital herpes) for older adults aged 60-89 years in 204 countries and territories from 1990 to 2019. Estimated annual percentage changes in the age-standardised incidence and DALY rates of HIV and other STIs, by age, sex, and Socio-demographic Index (SDI), were calculated to quantify the temporal trends. Spearman correlation analysis was used to examine the relationship between age-standardised rates and SDI. FINDINGS: In 2019, among older adults globally, there were an estimated 77 327 (95% uncertainty interval 59 443 to 97 648) new cases of HIV (age-standardised incidence rate 7·6 [5·9 to 9·6] per 100 000 population) and 26 414 267 (19 777 666 to 34 860 678) new cases of other STIs (2607·1 [1952·1 to 3440·8] per 100 000). The age-standardised incidence rate decreased by an average of 2·02% per year (95% CI -2·38 to -1·66) for HIV and remained stable for other STIs (-0·02% [-0·06 to 0·01]) from 1990 to 2019. The number of DALYs globally in 2019 was 1 905 099 (95% UI 1 670 056 to 2 242 807) for HIV and 132 033 (95% UI 83 512 to 225 630) for the other STIs. The age-standardised DALY rate remained stable from 1990 to 2019, with an average change of 0·97% (95% CI -0·54 to 2·50) per year globally for HIV but decreased by an annual average of 1·55% (95% CI -1·66 to -1·43) for other STIs. Despite the global decrease in the age-standardised incidence rate of HIV in older people from 1990 to 2019, many regions showed increases, with the largest increases seen in eastern Europe (average annual change 17·84% [14·16 to 21·63], central Asia (14·26% [11·35 to 17·25]), and high-income Asia Pacific (7·52% [6·54 to 8·51]). Regionally, the age-standardised incidence and DALY rates of HIV and other STIs decreased with increases in the SDI. INTERPRETATION: Although the incidence and DALY rates of HIV and STIs either declined or remained stable from 1990 to 2019, there were regional and demographic disparities. Health-care providers should be aware of the effects of ageing societies and other societal factors on the risk of HIV and other STIs in older adults, and develop age-appropriate interventions. The disparities in the allocation of health-care resources for older adults among regions of different SDIs should be addressed. FUNDING: Natural Science Foundation of China, Fujian Province's Third Batch of Flexible Introduction of High-Level Medical Talent Teams, Science and Technology Innovation Team (Tianshan Innovation Team) Project of Xinjiang Uighur Autonomous Region, Cure Alzheimer's Fund, Helse Sør-Øst, the Research Council of Norway, Molecule/VitaDAO, NordForsk Foundation, Akershus University Hospital, the Civitan Norges Forskningsfond for Alzheimers Sykdom, the Czech Republic-Norway KAPPA programme, and the Rosa Sløyfe/Norwegian Cancer Society & Norwegian Breast Cancer Society.

Estimated economic burden of genital herpes and HIV attributable to herpes simplex virus type 2 infections in 90 low- and middle-income countries: A modeling study.

BACKGROUND: Economic losses due to herpes simplex infections in low- and middle-income countries (LMICs) are unknown. We estimated economic and quality-of-life losses due to genital herpes in 2019, in 90 LMICs, and from 2020 to 2030 in 45 countries in the World Health Organization (WHO) Africa. We additionally estimated economic losses due to human immunodeficiency virus (HIV) attributable to herpes simplex virus type 2 (HSV-2) infections. METHODS AND FINDINGS: We estimated genital herpes-related spending on treatment, wage losses due to absenteeism, and reductions in quality of life, for individuals aged 15 to 49 years, living with genital herpes. Had HSV-2 had contributed to the transmission of HIV, we estimated the share of antiretroviral treatment costs and HIV-related wage losses in 2019 that can be attributed to incident and prevalent HSV-2 infections in 2018. For the former, we used estimates of HSV-2 incidence and prevalence from the global burden of disease (GBD) study. For the latter, we calculated population attributable fractions (PAFs), using the classic (Levin's) epidemiological formula for polytomous exposures, with relative risks (RRs) reported in literature. To extend estimates from 2020 to 2030, we modeled the transmission of HSV-2 in 45 African countries using a deterministic compartmental mathematical model, structured by age, sex, and sexual activity, which was fitted to seroprevalence gathered from a systematic review and meta-regression analysis. In the 90 LMICs, genital herpes contributed to US$813.5 million in treatment and productivity losses in 2019 (range: US$674.4 to US$952.2 million). Given observed care-seeking and absenteeism, losses are in the range of US$29.0 billion (US$25.6 billion to US$34.5 billion). Quality-of-life losses in the amount of 61.7 million quality-adjusted life years (QALYs) are also possible (50.4 million to 74.2 million). The mean annual cost of treatment and wage losses per infection is US$183.00 (95% CI: US$153.60 to US$212.55); the mean annual cost of quality-of-life losses is US$343.27 (95% CI: 272.41 to 414.14). If HSV-2 has fueled the transmission of HIV, then seroprevalent HSV-2 cases in 2018 can account for 33.2% of the incident HIV infections in 2019, with an associated antiretroviral therapy (ART) cost of US$186.3 million (range: US$163.6 to US$209.5 million) and 28.6% of HIV-related wage losses (US$21.9 million; range: US$19.2 to US$27.4 million). In the WHO Africa region, the 3.9 million seroprevalent genital herpes cases from 2020 to 2030 contributed to US$700.2 million in treatment and productivity losses. Additionally, quality-of-life losses in the range of 88 million to 871 million QALYs are also possible. If HSV-2 has contributed to the transmission of HIV, then in 2020, the PAF of HIV due to prevalent HSV-2 will be 32.8% (95% CI: 26.7% to 29.9%) and due to incident infections will be 4.2% (95% CI: 2.6% to 3.4%). The PAF due to prevalent infections will decline to 31.0% by 2030 and incident infections to 3.6%. Though we have accounted for the uncertainty in the epidemiological and economic parameter values via the sensitivity analysis, our estimates still undervalue losses due to limiting to the 15- to 49-year-old population. CONCLUSIONS: Economic losses due to genital herpes in LMICs can be large, especially when considering the lifelong nature of the disease. Quality-of-life losses outweigh spending on treatment and reductions in productivity. If HSV-2 has contributed to the spread of HIV in LMICs, then nearly one third of antiretroviral costs and HIV-related wage losses can be attributed to HSV-2. Given the magnitude of the combined losses, a vaccine against HSV-2 must be a global priority.

Increasing incidence rates of sexually transmitted infections from 2010 to 2019: an analysis of temporal trends by geographical regions and age groups from the 2019 Global Burden of Disease Study.

BACKGROUND: World Health Organization announced its goal of ending sexually transmitted infection (STI) epidemics by 2030. To provide a reference for tailored prevention strategies, we analyzed trends and differences in STIs by geographical regions and age groups from 1990 to 2019. METHODS: Annual number of new infections and age-standardized incidence rates (ASRs) of syphilis, chlamydia, gonorrhea, trichomoniasis, and genital herpes were recorded from the 2019 Global Burden of Disease study. We quantified the temporal trends of STIs by calculating changes in new infections and estimated annual percentage changes (EAPCs) of ASR. RESULTS: The ASRs of syphilis, chlamydia, trichomoniasis, and genital herpes increased by 1.70% (95% confidence interval [CI], 1.62-1.78%), 0.29% (95% CI 0.04-0.54%), 0.27% (95% CI 0.03-0.52%), and 0.40% (95% CI 0.36-0.44%) per year from 2010 to 2019 worldwide, respectively, while that of gonorrhea did not. The American regions had the greatest increase in ASR for syphilis (tropical Latin America: EAPC, 5.72; 95% CI 5.11-6.33), chlamydia (high-income North America: EAPC, 1.23; 95% CI 0.73-1.73), and gonorrhea (high-income North America: EAPC, 0.77; 95% CI 0.12-1.41). Additionally, southern sub-Saharan Africa and East Asia had the greatest increase in ASR for trichomoniasis (EAPC, 0.88; 95% CI 0.57-1.20) and genital herpes (EAPC, 1.44; 95% CI 0.83-2.06), respectively. In the most recent years, the population with the greatest incidence of syphilis tended to be younger globally (25-29 years in 2010 vs. 20-24 years in 2019) but older in North Africa and Middle East (20-24 year vs. 25-29 years); with chlamydia tended to be older in southern sub-Saharan Africa (25-29 years vs. 30-34 years) but younger in Australasia (40-44 years vs. 25-29 years); with genital herpes tended to be older in high-income North America (20-24 years vs. 25-29 years) and South Asia (25-29 years vs. 30-34 years). CONCLUSIONS: Syphilis, chlamydia, trichomoniasis, and genital herpes showed a trend of increasing ASR from 2010 to 2019. The differences in trends by geographical regions and age groups point to the need for more targeted prevention strategies in key regions and populations.

Health-related quality of life in individuals with genital herpes: a systematic review.

BACKGROUND: There is a significant global burden of herpes simplex virus (HSV) related genital ulcer disease yet little is known about its impact on quality of life. This systematic review aimed to identify studies that quantitatively evaluated the effect of genital herpes on various aspects of health-related quality of life. METHODS: Six databases were searched (MEDLINE, EMBASE, NHS Economic Evaluation Database, Health Technology Assessment, Database of Abstracts of Reviews of Effects, Web of Science Core Collection) for primary quality of life and economic evaluations of genital herpes from January 1, 2000 to January 7, 2021. Qualitative studies or those without primary data were excluded. Two authors independently extracted data from the publications. The study's registration number with PROSPERO was CRD42021239410. FINDINGS: We identified 26 relevant publications: 19 presented primary quality of life data, and seven were economic evaluations. The primary studies presented a range of condition-specific tools for describing the quality of life in individuals with genital herpes, but only one study used a direct valuation that could be used to generate utility weights. All economic evaluations of HSV infection were from high-income country settings. Most (6 of 7) focused on neonatal HSV infection with utilities adopted from studies prior to 2000. INTERPRETATION: The extant literature on genital herpes-related quality of life is limited and requires updating. We recommend future studies be conducted in geographic- and population- diverse settings, and use preference-based condition-specific or generic-instruments to better inform economic modelling.

Healthcare resource utilisation pattern and costs associated with herpes simplex virus diagnosis and management: a systematic review.

OBJECTIVES: Little is known about the economic burden of herpes simplex virus (HSV) across countries. This article aims to summarise existing evidence on estimates of costs and healthcare resource utilisation associated with genital and neonatal HSV infection. DESIGN: Systematic literature review. DATA SOURCES: Seven databases were searched from inception to 31 August 2020. A focused search was performed to supplement the results. ELIGIBILITY CRITERIA: Studies which reported either healthcare resource utilisation or costs associated with HSV-related healthcare, including screening, diagnosis and treatment of genital HSV infection and neonatal herpes prevention and treatment. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed the risk of bias using the Larg and Moss's checklist. All data were summarised narratively. RESULTS: Out of 11 443 articles, 38 were included. Most studies (35/38, 94.6%) were conducted in high-income countries, primarily the United States, and were more often related to the prevention or management of neonatal herpes (n=21) than HSV genital ulcer disease (n=17). Most analyses were conducted before 2010. There was substantial heterogeneity in the reporting of HSV-related healthcare resource utilisation, with 74%-93% individuals who sought care for HSV, 11.6%-68.4% individuals who received care, while neonates with herpes required a median of 6-34 hospitalisation days. The costs reported were similarly heterogeneous, with wide variation in methodology, assumptions and outcome measures between studies. Cost for screening ranged from US$7-100, treatment ranged from US$0.53-35 for an episodic therapy, US$240-2580 yearly for suppressive therapy, while hospitalisation for neonatal care ranged from US$5321-32 683. CONCLUSIONS: A paucity of evidence exists on healthcare resource utilisation and costs associated with HSV infection, especially among low-income and middle-income countries. Future research is needed on costs and healthcare utilisation patterns to improve overall understanding of the global economic burden of HSV.

The Estimated Direct Lifetime Medical Costs of Sexually Transmitted Infections Acquired in the United States in 2018.

BACKGROUND: We estimated the lifetime medical costs attributable to sexually transmitted infections (STIs) acquired in 2018, including sexually acquired human immunodeficiency virus (HIV). METHODS: We estimated the lifetime medical costs of infections acquired in 2018 in the United States for 8 STIs: chlamydia, gonorrhea, trichomoniasis, syphilis, genital herpes, human papillomavirus (HPV), hepatitis B, and HIV. We limited our analysis to lifetime medical costs incurred for treatment of STIs and for treatment of related sequelae; we did not include other costs, such as STI prevention. For each STI, except HPV, we calculated the lifetime medical cost by multiplying the estimated number of incident infections in 2018 by the estimated lifetime cost per infection. For HPV, we calculated the lifetime cost based on the projected lifetime incidence of health outcomes attributed to HPV infections acquired in 2018. Future costs were discounted at 3% annually. RESULTS: Incident STIs in 2018 imposed an estimated $15.9 billion (25th-75th percentile: $14.9-16.9 billion) in discounted, lifetime direct medical costs (2019 US dollars). Most of this cost was due to sexually acquired HIV ($13.7 billion) and HPV ($0.8 billion). STIs in women accounted for about one fourth of the cost of incident STIs when including HIV, but about three fourths when excluding HIV. STIs among 15- to 24-year-olds accounted for $4.2 billion (26%) of the cost of incident STIs. CONCLUSIONS: Incident STIs continue to impose a considerable lifetime medical cost burden in the United States. These results can inform health economic analyses to promote the use of cost-effective STI prevention interventions to reduce this burden.

Lifetime Medical Costs of Genital Herpes in the United States: Estimates From Insurance Claims.

BACKGROUND: The purpose of this study was to estimate the lifetime direct medical costs per incident case of genital herpes in the United States. METHODS: We used medical claims data to construct a cohort of people continuously enrolled in insurance for at least 48 consecutive months between 2010 and 2018. From this cohort, we identified initial genital herpes diagnoses as well as the cost of related clinical visits and medication during the 36 months after an initial diagnosis. Lifetime costs beyond 36 months were estimated based on treatment use patterns observed in the 36 months of follow-up. RESULTS: The present value of lifetime direct medical costs of genital herpes was estimated to be $972 per treated case or $165 per infection (2019 dollars), not including costs associated with prevention or treatment of neonatal herpes. The clinical visit at which genital herpes was first diagnosed accounted for 27% of lifetime costs. Subsequent clinical visits and medications related to genital herpes accounted for an additional 13% and 60% of lifetime costs, respectively. CONCLUSIONS: The results from this study can inform cost-effectiveness analysis of genital herpes control interventions as well as help quantify the cost burden of sexually transmitted infections in the United States.

Herpes Simplex Virus Serotyping in Pregnant Women With a History of Genital Herpes and an Outbreak in the Third Trimester of Pregnancy: A Cost-Effectiveness Analysis.

OBJECTIVE: To estimate whether serotyping women with a history of genital herpes simplex virus (HSV) and an outbreak during the third trimester of pregnancy is cost effective compared with no serotyping. METHODS: We designed a decision-analytic model using TreeAge Pro software to assess an approach of routine HSV serotyping in a theoretical cohort of 63,582 women (an estimate of the number of women in the United States with a history of genital HSV and an outbreak during the third trimester of pregnancy). Outcomes included mild, moderate, and severe neonatal HSV, neonatal death, costs, and quality-adjusted life-years (QALYs) for both the woman and neonate. Probabilities, utilities, and costs were derived from the literature, and we used a willingness-to-pay threshold of $100,000 per QALY. Sensitivity analyses were performed to assess the robustness of the results. RESULTS: In our theoretical cohort, HSV serology screening resulted in 519, 8, and 15 cases of mild, moderate, and severe neonatal HSV, whereas no serology screening resulted in 745, 65, and 85 cases, respectively. Thus, HSV serology screening led to 226, 57, and 70 fewer cases of mild, moderate, and severe neonatal HSV, respectively, as well as 91 fewer neonatal deaths. Additionally, serology screening saved $61 million and gained 7,900 QALYs, making it a dominant strategy. Univariate sensitivity analysis demonstrated that serology screening was cost effective until the chance of progression from neonatal HSV infection to disease despite empiric antiviral treatment was greater than 23%. CONCLUSION: Serology screening in pregnant women with an outbreak in the third trimester of pregnancy and a history of genital HSV resulted in improved outcomes and decreased costs.

Genotype-Informed Versus Empiric Management Of VirEmia (GIVE MOVE): study protocol of an open-label randomised clinical trial in children and adolescents living with HIV in Lesotho and Tanzania.

BACKGROUND: Globally, the majority of people living with HIV have no or only limited access to HIV drug resistance testing to guide the selection of antiretroviral drugs. This is of particular concern for children and adolescents, who experience high rates of treatment failure. The GIVE MOVE trial assesses the clinical impact and cost-effectiveness of routinely providing genotypic resistance testing (GRT) to children and adolescents living with HIV who have an unsuppressed viral load (VL) while taking antiretroviral therapy (ART). METHODS: GIVE MOVE is an open-label randomised clinical trial enrolling children and adolescents (≥6 months to <19 years) living with HIV with a VL ≥400 copies/mL (c/mL) while taking first-line ART. Recruitment takes place at sites in Lesotho and Tanzania. Participants are randomised in a 1:1 allocation to a control arm receiving the standard of care (3 sessions of enhanced adherence counselling, a follow-up VL test, continuation of the same regimen upon viral resuppression or empiric selection of a new regimen upon sustained elevated viremia) and an intervention arm (GRT to inform onward treatment). The composite primary endpoint is the occurrence of any one or more of the following events during the 36 weeks of follow-up period: i) death due to any cause; ii) HIV- or ART-related hospital admission of ≥24 h duration; iii) new clinical World Health Organisation stage 4 event (excluding lymph node tuberculosis, stunting, oral or genital herpes simplex infection and oesophageal candidiasis); and iv) no documented VL <50 c/mL at 36 weeks follow-up. Secondary and exploratory endpoints assess additional health-related outcomes, and a nested study will assess the cost-effectiveness of the intervention. Enrolment of a total of 276 participants is planned, with an interim analysis scheduled after the first 138 participants have completed follow-up. DISCUSSION: This randomised clinical trial will assess if the availability of resistance testing improves clinical outcomes in children and adolescents with elevated viremia while taking ART. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov ( NCT04233242 ; registered 18.01.2020). More information: www.givemove.org .

Cost analysis of treatment strategies for the control of HSV-2 infection in the U.S.: A mathematical modeling-based case study.

Infection of Herpes Simplex Virus type 2 (HSV-2) is a lifelong sexually transmitted disease. According to the Center for Disease Control and Prevention (CDC), 11.9% of the United States (U.S.) population was infected with HSV-2 in 2015-2016. The HSV-2 pathogen establishes latent infections in neural cells and can reactivate causing lesions later in life, a strategy that increases pathogenicity and allows the virus to evade the immune system. HSV-2 infections are currently treated by Acyclovir only in the non-constitutional stage, marked by genital skin lesions and ulcers. However, patients in the constitutional stage expressing mild and common (with other diseases) symptoms, such as fever, itching and painful urination, remain difficult to detect and are untreated. In this study, we develop and analyze a mathematical model to study the transmission and control of HSV-2 among the U.S. population between the ages of 15-49 when there are options to treat individuals in different stages of their pathogenicity. In particular, the goals of this work are to study the effect on HSV-2 transmission dynamics and to evaluate and compare the cost-effectiveness of treating HSV-2 infections in both constitutional and non-constitutional stages (new strategy) against the current conventional treatment protocol for treating patients in the non-constitutional stage (current strategy). Our results distinguish model parameter regimes where each of the two treatment strategies can optimize the available resources and consequently gives the long-term reduced cost associated with each treatment and incidence. Moreover, we estimated that the public health cost of HSV-2 with the proposed most cost-effective treatment strategy would increase by approximately 1.63% in 4 years of implementation. However, in the same duration, early treatment via the new strategy will reduce HSV-2 incidence by 42.76% yearly and the reproduction number will decrease to 0.84 from its current estimate of 2.5. Thus, the proposed new strategy will be significantly cost-effective in controlling the transmission of HSV-2 if the strategy is properly implemented.

An Assessment of Risk Factors for Herpes Simplex Virus Type 2 Infection in Malawian Women Using 2 Classifications for the HerpeSelect 2 Test.

BACKGROUND: The HerpeSelect 2 ELISA IgG test for herpes simplex virus type 2 (HSV-2) infection is widely used, convenient, and inexpensive. However, it has been shown to have lower specificity among populations in Sub-Saharan Africa compared with HSV-2 tests regarded as criterion standards. METHODS: In 2016, we collected blood and survey data from 248 women participating in a community-based cohort study in rural Malawi (the Umoyo wa Thanzi project). Using multinomial logistic regression accounting for village-level clustering, we examined unadjusted associations between select demographic and sexual risk factors and HSV-2 serostatus. Because increasing the index value cutpoint for a positive result improves specificity, we coded HSV-2 serostatus in 2 ways: the manufacturer's recommended cutpoints (<0.9, negative; 0.9-1.1, indeterminate; >1.1, positive) and modified cutpoints with improved specificity (<0.9, negative; 0.9-3.5, indeterminate; >3.5, positive). We aimed to investigate whether associations between select risk factors and HSV-2 serostatus varied under the 2 approaches. RESULTS: The prevalence of HSV-2 in this sample was 67% under the manufacturer's cutpoint and 22% under the modified cutpoint. Under both cutpoints, age, household size, number of marriages, and number of pregnancies were associated with HSV-2-positive serostatus. Using modified cutpoints, current bacterial vaginosis (odds ratio [OR], 3.17; 95% confidence interval [CI], 1.35-7.47), partner concurrency (OR, 4.88; 95% CI, 2.54-9.37) and unsure about partner concurrency (OR, 1.91; 95% CI, 1.08-3.38) were associated with HSV-2 seropositivity. Household size, education, and marital status were the only variables significantly associated with indeterminate HSV-2 serostatus using the modified cutpoints. CONCLUSION: HSV-2-focused interventions informed by identifying individuals likely to have or acquire HSV-2 must be aware that different target populations may emerge depending on which cutpoints are adopted.

Menstrual cups and cash transfer to reduce sexual and reproductive harm and school dropout in adolescent schoolgirls: study protocol of a cluster-randomised controlled trial in western Kenya.

BACKGROUND: Adolescent girls in sub-Saharan Africa are disproportionally vulnerable to sexual and reproductive health (SRH) harms. In western Kenya, where unprotected transactional sex is common, young females face higher rates of school dropout, often due to pregnancy, and sexually transmitted infections (STIs), including HIV. Staying in school has shown to protect girls against early marriage, teen pregnancy, and HIV infection. This study evaluates the impact of menstrual cups and cash transfer interventions on a composite of deleterious outcomes (HIV, HSV-2, and school dropout) when given to secondary schoolgirls in western Kenya, with the aim to inform evidence-based policy to improve girls' health, school equity, and life-chances. METHODS: Single site, 4-arm, cluster randomised controlled superiority trial. Secondary schools are the unit of randomisation, with schoolgirls as the unit of measurement. Schools will be randomised into one of four intervention arms using a 1:1:1:1 ratio and block randomisation: (1) menstrual cup arm; (2) cash transfer arm, (3) cups and cash combined intervention arm, or (4) control arm. National and county agreement, and school level consent will be obtained prior to recruitment of schools, with parent consent and girls' assent obtained for participant enrolment. Participants will be trained on safe use of interventions, with all arms receiving puberty and hygiene education. Annually, the state of latrines, water availability, water treatment, handwashing units and soap in schools will be measured. The primary endpoint is a composite of incident HIV, HSV-2, and all-cause school dropout, after 3 years follow-up. School dropout will be monitored each term via school registers and confirmed through home visits. HIV and HSV-2 incident infections and risk factors will be measured at baseline, mid-line and end-line. Intention to treat analysis will be conducted among all enrolled participants. Focus group discussions will provide contextual information on uptake of interventions. Monitoring for safety will occur throughout. DISCUSSION: If proved safe and effective, the interventions offer a potential contribution toward girls' schooling, health, and equity in low- and middle-income countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT03051789 , 15th February 2017.

Clinical evaluation and cost analysis of a Trioplex real-time PCR assay for the detection and differentiation of herpes simplex virus 1 and 2 in cutaneous and mucocutaneous lesions.

PURPOSE: Herpes simplex virus (HSV) is a common lifelong sexually transmitted infection. HSV-1 typically manifests as oral cold sores, while HSV-2 is more traditionally associated with sexual transmission and infection. We have developed a real-time PCR (Trioplex) for the simultaneous detection of HSV-1 and -2 and the bacterial phage internal control (IC) MS2. METHODOLOGY: To determine the performance of the Trioplex method and resolve discrepancies, 178 clinical specimens from cutaneous and mucocutaneous sources were tested using 3 different methods; virus culture with direct fluorescent antibody (DFA) immunostaining, Trioplex and a commercially available HSV analyte-specific reagent (ASR). RESULTS: HSV Trioplex was significantly more sensitive than virus culture (89 and 67 % HSV 1/2, respectively) and comparable to the commercial assay (P<0.001). Cost analysis revealed that the Trioplex reduced cost by 80  % compared to cell culture. CONCLUSIONS: The implementation of the HSV Trioplex improved the detection turnaround time from 3-10 days to 2.5 h, thus streamlining Herpes detection, improving sensitivity and reducing laboratory costs.

Cash transfers and HIV/HSV-2 prevalence: A replication of a cluster randomized trial in Malawi.

INTRODUCTION: In this paper we perform a replication analysis of "Effect of a cash transfer programme for schooling on prevalence of HIV and herpes simplex type 2 in Malawi: a cluster randomised trial" by Sarah Baird and others published in "The Lancet" in 2012. The original study was a two-year cluster randomized intervention trial of never married girls aged 13-22 in Malawi. Enumeration areas were randomized to either an intervention involving cash transfer (conditional or unconditional of school enrollment) or control. The study included 1708 Malawian girls, who were enrolled at baseline and had biological testing for HIV and herpes simplex virus type 2 (HSV-2) at 18 months. The original findings showed that in the cohort of girls enrolled in school at baseline, the intervention had an effect on school enrollment, sexual outcomes, and HIV and HSV-2 prevalence. However, in the baseline school dropout cohort, the original study showed no intervention effect on HIV and HSV-2 prevalence. METHODS: We performed a replication of the study to investigate the consistency and robustness of key results reported. A pre-specified replication plan was approved and published online. Cleaned data was obtained from the original authors. A pure replication was conducted by reading the methods section and reproducing the results and tables found in the original paper. Robustness of the results were examined with alternative analysis methods in a measurement and estimation analysis (MEA) approach. A theory of change analysis was performed testing a causal pathway, the effect of intervention on HIV awareness, and whether the intervention effect depended on the wealth of the individual. RESULTS: The pure replication found that other than a few minor discrepancies, the original study was well replicated. However, the randomization and sampling weights could not be verified due to the lack of access to raw data and a detailed sample selection plan. Therefore, we are unable to determine how sampling influenced the results, which could be highly dependent on the sample. In MEA it was found that the intervention effect on HIV prevalence in the baseline schoolgirls cohort was somewhat sensitive to model choice, with a non-significant intervention effect for HIV depending on the statistical model used. The intervention effect on HSV-2 prevalence was more robust in terms of statistical significance, however, the odds ratios and confidence intervals differed from the original result by more than 10%. A theory of change analysis showed no effect of intervention on HIV awareness. In a causal pathway analysis, several variables were partial mediators, or potential mediators, indicating that the intervention could be working through its effect on school enrollment or selected sexual behaviors. CONCLUSIONS: The effect of intervention on HIV prevalence in the baseline schoolgirls was sensitive to the model choice; however, HSV-2 prevalence results were confirmed. We recommend that the results from the original published analysis indicating the impact of cash transfers on HIV prevalence be treated with caution.

Executive function associated with sexual risk in young South African women: Findings from the HPTN 068 cohort.

PURPOSE: Heightened sexual risk in adolescence and young adulthood may be partially explained by deficits in executive functioning, the set of cognitive processes used to make reasoned decisions. However, the association between executive function and sexual risk is understudied among adolescent girls and young women, particularly in low- and middle-income countries. METHODS: In a cohort of 853 young women age 18-25 in rural Mpumalanga province, South Africa, we evaluated executive function with three non-verbal cognitive tests: I. a rule-finding test, II. a trail-making test, and III. a figure drawing test. Using log-binomial regression models, we estimated the association between lower executive function test scores and indicators of sexual risk (unprotected sex acts, concurrent partnerships, transactional sex, and recent HSV-2 infection). RESULTS: In general, young women with lower executive function scores reported higher frequencies of sexual risk outcomes, though associations tended to be small with wide confidence intervals. Testing in the lowest quintile of Test I was associated with more unprotected sex [aPR (95% CI): 1.4 (1.0, 1.8)]. Testing in the lowest quintile of Test II was associated with more concurrent relationships and transactional sex [aPR (95% CI): 1.6 (1.1, 2.5) and 1.7 (1.3, 2.4), respectively], and testing in the lowest four quintiles of Test III was associated with more concurrent relationships [aPR (95% CI): 1.7 (1.0, 2.7)]. CONCLUSIONS: These results demonstrate an association between low executive function and sexual risk in South African young women. Future work should seek to understand the nature of this association and whether there is promise in developing interventions to enhance executive function to reduce sexual risk.

HIV and herpes simplex virus type 2 epidemiological synergy: misguided observational evidence? A modelling study.

OBJECTIVES: To investigate whether observational studies of HIV and herpes simplex virus type 2 (HSV-2) infections have the capacity to assess the HIV/HSV-2 epidemiological synergy. METHODS: An individual-based Monte Carlo model was used to simulate HIV/HSV-2 epidemics in two scenarios: no HIV/HSV-2 biological interaction and HSV-2 seropositivity enhancing HIV acquisition. Cross-sectional observational studies were simulated by sampling individuals from the population to assess resulting crude and adjusted ORs of the HIV/HSV-2 association. Meta-analyses were conducted to estimate the pooled mean ORs. Impact of under-reporting of sexual behaviour and miscapture of high-risk individuals was assessed through sensitivity analyses. RESULTS: Assuming no HIV/HSV-2 biological interaction, the crude HIV/HSV-2 OR ranged between 1.38 and 9.93, with a pooled mean of 6.45 (95% CI 5.81 to 7.17). Adjustment for the number of sexual partners over last year, over lifetime and for both partner numbers simultaneously reduced the mean OR to 5.45 (95% CI 4.90 to 6.06), 3.70 (95% CI 3.32 to 4.12) and 3.54 (95% CI 3.17 to 3.94), respectively. Assuming HIV/HSV-2 biological interaction, the crude OR ranged between 3.44 and 9.95, with a pooled mean of 8.05 (95% CI 7.14 to 9.07). The adjustments reduced the mean OR to 7.00 (95% CI 6.21 to 7.90), 3.76 (95% CI 3.32 to 4.25) and 3.68 (95% CI 3.25 to 4.17), respectively. Under-reporting of partners reduced the confounder-adjustment effects. Miscapture of high-risk individuals considerably lowered the estimated ORs. CONCLUSIONS: It is difficult to control for sexual-behaviour confounding in observational studies. The observed HIV/HSV-2 association appears more consistent with two infections sharing the same mode of transmission, rather than with HSV-2 enhancing HIV acquisition.

[Neonatal herpes: Epidemiology, clinical manifestations and management. Guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF)]. / Herpès néonatal : épidémiologie, manifestations cliniques et prise en charge. Recommandations pour la pratique clinique du Collège national des gynécologues obstétriciens français (CNGOF).

OBJECTIVES: To describe the epidemiology of neonatal herpes and its risk factors, clinical and paraclinic manifestations, propose guidelines for a newborn at risk of neonatal herpes, describe treatment modalities, describe post-natal transmission and its prevention. METHODS: Bibliographic search from Medline, Cochrane Library databases and research of international clinical practice guidelines. RESULTS: Neonatal herpes is rare (about 20 cases per year in France) and mainly due to HSV 1 (level of evidence LE3). The main risk factors for mother-to-child transmission are maternal primary episode of genital herpes close to delivery and serotype HSV 1 (LE3). There are three clinical forms of neonatal herpes : SEM infection for skin, eyes and mucosa, central nervous system (CNS) associated infection, and the disseminated infection. Neurological mortality and morbidity depend on the clinical form and the HSV serotype (LE3). In most of the case of neonatal herpes, the mothers have no history of genital herpes (LE3). Fever and vesicular rash may be absent at the time of diagnosis (LE3). In case of suspicion of neonatal herpes, different samples (blood and cerebrospinal fluid) for HSV PCR must be carried out to confirm the diagnosis (Professional consensus). Any newborn suspected of neonatal herpes should be treated with intravenous aciclovir (Grade A) prior to the results of HSV PCR (Professional consensus). In case of maternal genital herpes at delivery, the management of an asymptomatic newborn depends on the evaluation of the risk of transmission. In case of maternal reactivation (low risk of transmission), HSV PCR samples are taken at 24hours of life and the newborn must be follow closely until results. In the case of maternal primary episode or non-primary infection first episode (high risk of transmission), the samples are taken at 24hours of life and intravenous treatment with aciclovir is started (Professional consensus). The treatment of neonatal herpes is based on intravenous aciclovir (60mg/kg/day divided into 3 injections) (Grade C). The duration of the treatment depends on the clinical form (14 days for the SEM infection, 21 days for the other forms) (Professional consensus). A relay with aciclovir per os (300mg/m2/day) for 6 months is recommended to improve the neurological outcome and reduce the risk of reactivation (grade B). Post-natal transmission is mainly due to HSV 1. The rules for the prevention of post-natal transmission must be known by parents and family, but also by nursing staff (Professional consensus). Breastfeeding is not contraindicated in cases of maternal herpes, except if there is herpetic lesion on the nipple (Professional consensus). Parents of newborns at risk for neonatal herpes should receive information on the clinical signs to be monitored at home after hospital discharge (Professional consensus). CONCLUSIONS: Neonatal herpes is a rare disease with a high morbidity and mortality. The management of a newborn at risk requires good coordination between the obstetric and pediatric teams and parent's information.

A high resolution melting (HRM) technology-based assay for cost-efficient clinical detection and genotyping of herpes simplex virus (HSV)-1 and HSV-2.

Genital herpes can be caused by two very similar viruses, herpes simplex virus (HSV)-1 or HSV-2. These two HSV types cannot be distinguished clinically, but genotyping is recommended in the first-episodes of genital herpes to guide counselling and management. Quantitative polymerase chain reaction (qPCR) is the preferred diagnostic method for HSV typing. However, commercial qPCR methods use expensive fluorescent labeled probes for detection. Furthermore, most low-cost methods are not able to differentiate between HSV-1 and -2. The aim of this study was to develop a high resolution melting (HRM) technology-based assay for sensitive HSV-1 and HSV-2 detection and genotyping. Using a panel of 46 clinical specimens, the performance of the HRM assay was compared to two commercial HSV tests: the HRM assay detected HSV in all 23 positive samples, with no false positive results (100% concordance with HSV I/II Real-TM assay). Additionally, the HRM assay correctly genotyped both HSV types in a subset of these clinical samples, as determined by the Realstar HSV PCR Kit. The HSV HRM assay provides a cost-effective alternative method to conventional more expensive assays and can be used in routine clinical specimens, in cases where it is particularly necessary to detect and distinguish HSV-1 from -2.

Herpes simplex virus 1 and 2 educational assessment of young adults in rural southwest Virginia.

PURPOSE: Herpes simplex virus 2 (HSV-2) causes genital herpes, one of the most common sexually transmitted infections (STIs) in the U.S. HSV-1, commonly associated with cold sores, is increasing as a cause of genital herpes. Abstinence-only sexual health classes, commonly taught in Virginia, generate young adults who are under-educated in sexual health, increasing STI risks. College students in southwest Virginia were surveyed to assess comprehensiveness of high school health education regarding HSV-1 and HSV-2 and to identify students' preferred methods for STI education. METHODS: To obtain data on knowledge of HSV, comprehensiveness of sexual health education in high school, and preferred learning methods, 237 college students participated in an online questionnaire and 28 students were interviewed using structured interviews. RESULTS: Questionnaire and interview data indicated that Family Life Education classes need to include more comprehensive information on prevention, viral transmission, and differences between HSV-1 and HSV-2. The majority of total respondents (both the questionnaire and interview) (65%) reported non-comprehensive high school sexual health education. The majority of interview (79%) and questionnaire (55%) respondents wished they had learned more about herpes and other STIs in high school. Education preferences of both interviewed and surveyed respondents included interactive internet programs or games, more realistic lectures, and learning about STIs later in high school when students reported greater sexual activity. CONCLUSION: Our results indicate that more comprehensive sexual health education is needed and wanted by students in southwest Virginia. More relevant educational programs should be implemented for VA high school students utilizing technology and interactive methods to improve student engagement in sexual health education. IMPLICATIONS AND CONTRIBUTION: These studies provide information on knowledge of herpes simplex viruses among college students, comprehensiveness of sexual health education received in high schools, and preferred methods to learn about HSV and other STIs. These studies inform the facilitation of improved health education practices and programs for high school and college students.