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      The global and regional burden of genital ulcer disease due to herpes simplex virus: a natural history modelling study

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          Abstract

          Introduction

          Herpes simplex virus (HSV) infection can cause painful, recurrent genital ulcer disease (GUD), which can have a substantial impact on sexual and reproductive health. HSV-related GUD is most often due to HSV type 2 (HSV-2), but may also be due to genital HSV type 1 (HSV-1), which has less frequent recurrent episodes than HSV-2. The global burden of GUD has never been quantified. Here we present the first global and regional estimates of GUD due to HSV-1 and HSV-2 among women and men aged 15–49 years old.

          Methods

          We developed a natural history model reflecting the clinical course of GUD following HSV-2 and genital HSV-1 infection, informed by a literature search for data on model parameters. We considered both diagnosed and undiagnosed symptomatic infection. This model was then applied to existing infection estimates and population sizes for 2016. A sensitivity analysis was carried out varying the assumptions made.

          Results

          We estimated that 187 million people aged 15–49 years had at least one episode of HSV-related GUD globally in 2016: 5.0% of the world’s population. Of these, 178 million (95% of those with HSV-related GUD) had HSV-2 compared with 9 million (5%) with HSV-1. GUD burden was highest in Africa, and approximately double in women compared with men. Altogether there were an estimated 8 billion person-days spent with HSV-related GUD globally in 2016, with 99% of days due to HSV-2. Taking into account parameter uncertainty, the percentage with at least one episode of HSV-related GUD ranged from 3.2% to 7.9% (120–296 million). However, the estimates were sensitive to the model assumptions.

          Conclusion

          Our study represents a first attempt to quantify the global burden of HSV-related GUD, which is large. New interventions such as HSV vaccines, antivirals or microbicides have the potential to improve the quality of life of millions of people worldwide.

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          Most cited references94

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          Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda.

          The probability of HIV-1 transmission per coital act in representative African populations is unknown. We aimed to calculate this probability overall, and to estimate how it is affected by various factors thought to influence infectivity. 174 monogamous couples, in which one partner was HIV-1 positive, were retrospectively identified from a population cohort in Rakai, Uganda. Frequency of intercourse and reliability of reporting within couples was assessed prospectively. HIV-1 seroconversion was determined in the uninfected partners, and HIV-1 viral load was measured in the infected partners. Adjusted rate ratios of transmission per coital act were estimated by Poisson regression. Probabilities of transmission per act were estimated by log-log binomial regression for quartiles of age and HIV-1 viral load, and for symptoms or diagnoses of sexually transmitted diseases (STDs) in the HIV-1-infected partners. The mean frequency of intercourse was 8.9 per month, which declined with age and HIV-1 viral load. Members of couples reported similar frequencies of intercourse. The overall unadjusted probability of HIV-1 transmission per coital act was 0.0011 (95% CI 0.0008-0.0015). Transmission probabilities increased from 0.0001 per act at viral loads of less than 1700 copies/mL to 0.0023 per act at 38 500 copies/mL or more (p=0.002), and were 0.0041 with genital ulceration versus 0.0011 without (p=0.02). Transmission probabilities per act did not differ significantly by HIV-1 subtypes A and D, sex, STDs, or symptoms of discharge or dysuria in the HIV-1-positive partner. Higher viral load and genital ulceration are the main determinants of HIV-1 transmission per coital act in this Ugandan population.
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            Genital herpes.

            Genital herpes is the main cause of genital ulcers worldwide; the prevalence of herpes simplex virus (HSV) type 2 infections in the general population ranges from 10% to 60%. Most genital herpes is caused by HSV-2, although HSV-1 accounts for about half of new cases in developed countries. The risk of HIV acquisition is three times higher in people with HSV-2. Neonatal herpes is an uncommon but serious complication of genital herpes. Most genital HSV-2 infections are unrecognised and undiagnosed; infected individuals, even with mild symptoms, shed HSV, and can infect sexual partners. Since clinical diagnosis is neither sensitive nor specific, virological and type-specific serological tests should be used routinely. Oral antiviral drugs for HSV infections are safe and effective and can be used both to treat episodes and to prevent recurrences. Antiviral treatment of the infected partners and condom use reduce the risk of sexual transmission of HSV-2.
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              Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

              Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.) 2010 Massachusetts Medical Society
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                Author and article information

                Journal
                BMJ Glob Health
                BMJ Glob Health
                bmjgh
                bmjgh
                BMJ Global Health
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2059-7908
                2020
                8 March 2020
                : 5
                : 3
                : e001875
                Affiliations
                [1 ]departmentPopulation Health Sciences, Bristol Medical School , University of Bristol , Bristol, UK
                [2 ]departmentDepartment of Medicine , University of Washington , Seattle, Washington, USA
                [3 ]Virology Research Clinic , Seattle, Washington, USA
                [4 ]departmentVaccine and Infectious Diseases Division , Fred Hutchinson Cancer Research Center , Seattle, Washington, USA
                [5 ]departmentBristol Veterinary School , University of Bristol , Bristol, UK
                [6 ]departmentDepartment of Infectious Disease Epidemiology , Imperial College London , London, UK
                [7 ]departmentDepartment of Reproductive Health and Research , World Health Organization , Geneve, Switzerland
                Author notes
                [Correspondence to ] Dr Katharine Jane Looker; katharine.looker@ 123456bristol.ac.uk
                Author information
                http://orcid.org/0000-0002-3375-0807
                Article
                bmjgh-2019-001875
                10.1136/bmjgh-2019-001875
                7061890
                32201620
                c54b5d1b-7bb0-43d2-9963-554771c0cc8b
                © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:  https://creativecommons.org/licenses/by/4.0/.

                History
                : 29 July 2019
                : 24 October 2019
                : 10 November 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004423, World Health Organization;
                Categories
                Original Research
                1506
                Custom metadata
                unlocked

                epidemiology,infections, diseases, disorders, injuries

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