Sexually Transmitted Diseases:
Modern Management of Genital Ulcer Disease—Frappez Fort et Frappez Vite
Lewis, David FRCP(UK), PHD*†‡§¶
From the *Sexually Transmitted Infections Reference Centre, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa; †Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; ‡Division of Medical Microbiology, University of Cape Town, Cape Town, South Africa; §Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; and ¶African Regional Office of the International Union against Sexually Transmitted Infections, Johannesburg, South Africa
Correspondence: David Lewis, FRCP(UK), PhD, STI Reference Centre, National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, South Africa. E-mail: email@example.com.
Received for publication March 28, 2010, and accepted April 11, 2010.
Genital herpes infections, caused by herpes simplex viruses types 1 (HSV-1) and 2 (HSV-2), are characterized by viral latency, asymptomatic shedding, blister formation and genital ulcer disease (GUD).1 Globally, HSV-2 is the predominant cause of genital herpes, although there has been a recent upsurge in genital HSV-1 infections in Europe and North America.2 Based on seroprevalence data, it was estimated that 536 million individuals of reproductive age were living with HSV-2 infection in 2003, the highest estimates being within sub-Saharan Africa and eastern Asia.3 Although genital herpes accounts for the majority of GUD worldwide, the global disease burden is more difficult to estimate as not all infections are symptomatic. Continued transmission of both HSV types is facilitated by the frequency of atypical disease, the occurrence of asymptomatic shedding and the large number of infected individuals who remain unaware of their diagnosis.1
As genital herpes is the most common GUD worldwide, the risk of human immunodeficiency virus type 1 (HIV-1) attributable to HSV-2 is likely to be high.4 A wealth of evidence exists to support the concept of epidemiologic synergy between HIV-1 and HSV-2 infections.5 The seroprevalence of HSV-2 is characteristically higher in those living with HIV-1.5 Data from monogamous HIV-1 discordant couples in the Rakai community sexually transmitted disease (STD) intervention trial suggest that HSV-2 seropositive HIV-uninfected individuals have a fivefold greater per-contact risk of acquiring HIV-1 compared to HSV-2 seronegative individuals.6 Mucosal HIV-1 shedding occurs more often and at higher copy numbers during episodes of asymptomatic HSV-2 shedding and symptomatic genital herpes.5,7 Some studies have also reported rises in plasma HIV-1 RNA in association with genital HSV-2 lesions and, in keeping with this, acyclovir suppressive therapy given to HIV-1 and HSV-2 dually infected individuals reduces plasma HIV-1 load and modestly delays HIV-1 disease progression.5,8,9
In 2003, in recognition of the important link between the HSV-2 and HIV-1 epidemics, the World Health Organization (WHO) published STI treatment guidelines which recommended that acyclovir should be included as a first-line GUD therapy in all countries where the relative prevalence of HSV-2 as an etiological agent was 30% or higher.10 As Corbell et al illustrate in this issue of Sexually Transmitted Diseases, 4 years on from publication of these STI treatment guidelines, several African countries had failed to effectively implement the WHO's recommendation for acyclovir to be prescribed to patients with GUD. They report that some countries had not revised their own national STI treatment guidelines accordingly, and among those that had, there were significant problems highlighted with drug procurement and distribution, drug stock-outs and regulatory requirements in respect of whether nurses were able to prescribe acyclovir.11 The explanations underlying these findings are likely to be multifactorial, in keeping with the complexity of health systems and the challenges of delivering health care in resource-poor settings. Possible solutions, as suggested by Corbell et al include strengthening of public-private partnerships to provide accessible and affordable STI care, and provision of technical and financial assistance to low-income countries to strengthen the public sector drug procurement and supply chains for acyclovir.
On a positive note, the situation has changed significantly in South Africa since Corbell et al performed their survey. In 2008, acyclovir was recommended for first-line treatment of genital ulceration in revisions of both the National STI Guidelines and the Primary Health Care Standard Treatment Guidelines and Essential Medicines List.12,13 These guideline changes were only made possible through presentation to the National Department of Health's Essential Drugs Programme's Primary Healthcare Sub-Committee of in-country data from a randomized controlled trial (RCT), which highlighted both the high burden of HSV-2 among genital ulcers and the benefits of episodic acyclovir therapy in terms of both ulcer healing and reduction in HIV-1 lesional shedding.14,15 This case example illustrates quite clearly the reluctance of countries to blindly follow WHO global recommendations without a local evidence base and situational analysis. In the interest of cost-effectiveness and timely operations, it is better for neighboring countries to work together and make use of relevant regional data and expertise rather than perform situational analyses on a country by country basis. A regional framework for prevention and management of STIs has been prepared by the Southern African Development Community (SADC), a key regional organization consisting of 15 member states, which contains revised STI guidelines including the addition of acyclovir as first-line therapy for GUD syndromic management. These regional guidelines will be reviewed, and hopefully be approved, by SADC ministers in April 2010.
Changing the guideline is, of course, only the first step in a long process. To institute the changes effectively, (i) dissemination of the guideline and training around the new recommendations are required for all healthcare workers to ensure compliance with the new recommendations, (ii) effective drug procurement and coordinated distribution to the treatment facilities are crucial to avoid stock-outs, and (iii) public education regarding the importance of presenting early to clinical facilities with genital ulceration is essential to ensure a public health benefit. Perhaps the biggest challenge facing us is to change the mind-set of health care workers themselves and convince them of the importance of prescribing acyclovir to patients with GUD. Much of today's dogma and scepticism relating to relative ineffectiveness of episodic therapy for genital herpes arose from the early episodic therapy trials, which failed to differentiate between acquisition and recurrent disease episodes and demonstrated only minimal benefit from acyclovir in recurrent disease.16
Importantly, these early trials were also conducted in populations with low prevalence of HIV-1 infection and so are less relevant to countries in the midst of an HIV/AIDS epidemic, where the natural history of HSV-2 infection has been radically altered by frequent recurrences and extended symptomatic episodes. Recently, episodic acyclovir treatment RCTs have been repeated in sub-Saharan Africa to reassess the benefit of an episodic 5-day course of acyclovir (400 mg, 8-hourly) in treating GUD in the context of a high HIV-1 prevalence. The South African RCT, undertaken among men with GUD demonstrated a statistically significant decrease in time to healing in the acyclovir compared to the placebo arm.14 As expected, the study demonstrated increased effectiveness of acyclovir in 3 groups of individuals, namely those with acquisition episodes, those HIV-1-infected men with herpetic ulcers and those who presented early. In keeping with these findings, Mayaud et al reported that episodic therapy with a similar acyclovir regimen, compared to placebo, resulted in decreased lesional detection of HIV-1 and improved ulcer healing among a smaller group of HIV-1-infected women with herpetic ulcers from Ghana and the Central African Republic.17
One way to improve the cost and improve compliance for resource-poor settings is to shorten the duration of treatment and use generic antiviral drugs. Several studies have now reported success with shorter courses of treatment with acyclovir, valacyclovir, and famciclovir.18–22 The 2006 Centers for Disease Control and Prevention (CDC) STD treatment guidelines now include both a shortened 3-day valacyclovir regimen and the 1-day ultrashort famciclovir treatment regimen for the treatment of recurrent genital herpes.23
Evidence has now accumulated that antiviral drugs for genital herpes are more effective when given within 24 hours of the onset disease manifestations.16, 24–26 Patients frequently attend late for GUD treatment as exemplified by the median time from symptom development to clinic presentation was 5 days (treatment arm, IQR: 3–7 days) and 6 days (placebo arm, IQR: 4–10 days) in the recent South African RCT.14 To educate patients with blisters and/or GUD to come for acyclovir treatment within 24 hours is probably an unrealistic challenge for any country's health system. Empowering patients by provision of advance treatment courses for home-based use is surely the logical way to manage most recurrent herpes cases, because it optimizes the chances of early commencement of treatment, gives an opportunity to abort lesions at the vesicular stage and so maintain mucosal barrier integrity, and reduces patient attendances at overstretched health care centers.
Paul Ehrlich, one of the founding fathers of infectious disease chemotherapy, coined the expression frappez fort et frappez vite (hit hard and hit fast) which perfectly describes the approach required to treat GUD effectively and potentially impact on HIV transmission. Early treatment with a combination of effective anti-infective against all key GUD pathogens, including HSV-1/HSV-2, is required to abort lesion formation and hasten ulcer healing. To achieve this will require effective advocacy at country and regional levels by influential organizations and key opinion leaders, translation of scientific data into public health messages easily understood by programme managers and policy-makers, more effective management of the supply chain, improved patient access to antiherpes medication, and education of the general public on the importance of early presentation to clinical services.
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