Abstract
Background:
The World Health Organisation recommends the use of syndromic management for patients presenting with genital ulcer disease (GUD) in developing countries. However, effective treatment guidelines depend on a current country-specific GUD etiological profile, which may change over time.
Methods:
From 2004–2006, we conducted a cross-sectional analysis of baseline data from patients presenting with GUD at a reference STI clinic in Lilongwe, Malawi. Participants were enrolled in a randomized clinical trial of acyclovir added to syndromic management and followed for up to 28 days. Serologies for HIV (using parallel rapid tests), herpes simplex virus type-2 (HSV-2) (using Focus HerpeSelect IgG2 ELISA) and syphilis (RPR confirmed by TPHA) were determined, with plasma HIV-1 RNA and CD4 count in HIV-positive patients. GUD etiology was determined by real-time multiplex-PCR from lesional swabs.
Results:
422 GUD patients (313 men, 74%) were enrolled. Overall seroprevalence of HIV-1, HSV-2, and syphilis were 61%, 72% and 5%, respectively. Ulcer etiology was available for 398 patients, and showed: HSV-2 67%, H. ducreyi 15%, T. pallidum 6%, lymphogranuloma venereum (LGV) 6%, mixed infections 14% and no etiology 20%. Most HSV-2 ulcers were recurrent (75%). Among all HSV-2 patients, HIV prevalence was high (67%) and HIV sero-prevalence was higher among patients with recurrent HSV-2 compared to patients with first episode HSV-2(78% vs 39%, p<0.001).
Conclusions:
HSV-2 ulcers are highly prevalent in this symptomatic population, and strongly associated with HIV. Unlike most locations in sub-Saharan Africa, H. ducreyi remains prevalent in this population and requires periodic monitoring and an appropriate treatment regimen.
Keywords: Genital ulcer disease (GUD), etiologies, Herpes simplex virus type-2 (HSV-2), HIV-1, Malawi
Brief Summary:
HSV-2 ulcers are highly prevalent and strongly associated with HIV in this symptomatic population. Unlike most locations in sub-Saharan Africa, H. ducreyi remains prevalent and requires monitoring and appropriate treatment.
INTRODUCTION
In recent years, the proportion of genital ulcer disease (GUD) due to bacterial pathogens has decreased dramatically in sub-Saharan Africa, while Herpes simplex virus type 2 (HSV-2) has become the most common cause of GUD [1] and is one of the most prevalent sexually transmitted infections (STI) worldwide [2, 3]. Prior HSV-2 infection significantly increases the risk of HIV acquisition by two- to three-fold [4]. HIV-1 and HSV-2 dually infected individuals, with or without symptomatic genital herpes, experience more frequent genital shedding of both viruses [5], thereby facilitating the risk of sexual transmission of each virus. These reciprocal and synergistic relationships suggest the importance of controlling HSV-2 for HIV prevention [6], although HSV-2 therapy trials have not had an effect on HIV acquisition or transmission. The shift in GUD etiologies has been accompanied by decreased cure rates which may undermine the confidence of patients and providers in the effectiveness of the syndromic approach to GUD management [7].
The prevalence of GUD etiologies such as syphilis and chancroid are important determinants of HIV transmission and STI regimens [8]. Given that many countries cannot conduct laboratory tests to determine those specific etiologies in routine practice, the World Health Organisation (WHO) recommends syndromic management for patients presenting with GUD in low-resource settings [9]. Traditionally, GUD management has consisted of antibiotics targeting Haemophilus ducreyi and Treponema pallidum [10], with treatments for other bacteria, such as the L1- L3 strains of Chlamydia trachomatis (lymphogranuloma venereum, LGV), and Klebsiella granulomatis (donovanosis) being added depending on local epidemiology. More recently, the WHO recommended the addition of acyclovir for the treatment of herpetic ulcers in countries with HSV-2 prevalence greater than 30% [9]. Many countries, including Malawi have added acyclovir to their GUD algorithms [11], although implementation has been incomplete due to lack of drug availability, lack of clinical re-training and conflicting local data.
WHO also advocates regular monitoring of STI syndrome etiologies to adjust treatment algorithms. To assist the Malawian Ministry of Health in monitoring and reviewing their algorithm for GUD and to provide regional data, we conducted a randomized controlled trial comparing adding acyclovir for episodic treatment of genital herpes to standard syndromic management. Episodic HSV-2 treatment with acyclovir added to syndromic management did not produce a significant clinical benefit in this African population, however among HIV-1/HSV-2 co-infected individuals, acyclovir reduced the frequency of lesional HIV-1 shedding and detection of seminal plasma HIV-1 RNA [12]. A secondary objective of this trial was to assess the prevalence of GUD etiologies among trial participants, and to assess the association with HIV serostatus.
METHODS
Study design
The study was an individually randomized double-blind placebo-controlled clinical trial of acyclovir 800 mg twice daily for 5 days added to syndromic management of GUD in Malawi. The protocol was approved by the National Health Sciences Research Committee in Malawi, and the ethics committees of the London School of Hygiene and Tropical Medicine, the University of North Carolina (UNC) and the Centres for Disease Control and Prevention (CDC).
Detailed procedures have been described elsewhere [12]. Briefly, consecutive adult patients aged 18 years and older, residing in Lilongwe and presenting with genital ulcers or vesicles at the Kamuzu Central Hospital (KCH) STI clinic between September 2004 and June 2006 were eligible for enrolment. Pregnant, lactating and menstruating women were excluded, as were previously enrolled participants.
Patients who provided written consent were interviewed using a standardized questionnaire and examined to obtain a detailed description of their ulcer(s). Prior history of self- treatment was obtained. The size of the largest ulcer on the external genitalia was measured using paper tapes, and the ulcer surface area (mm2) was calculated. Cotton-tipped sterile swabs were used to collect lesional fluids from the base of the largest ulcer to determine ulcer etiology and detect HIV-1 RNA. We did not collect swabs from blisters only. Ulcer swabs were stored at −20°C and kept frozen prior to lab testing. Additional genital samples included a cervical swab and a cervico-vaginal lavage (CVL) from women and a urine sample from men. Blood samples were also collected.
At the end of the baseline visit (day 0), participants were randomized to acyclovir or placebo, then received directly observed syndromic treatment following the Malawi Syndromic Management Guidelines for chancroid (ciprofloxacin 500 mg orally single dose) and syphilis (intramuscular injection of benzathine penicillin 2.4 million units single dose), STI and HIV counselling, partner notification slips and a supply of condoms. Participants were asked to return to the clinic on day 2 and/or day 4 (women only), and days 7, 14 and 28, though this manuscript focuses on results of the baseline visit only. Patients whose ulcers had not healed or remained symptomatic after seven days received second-line treatment with a single dose of azithromycin (1g orally). HIV-positive participants were counselled about their status and referred to the adjoining HIV treatment centre (Lighthouse Clinic) for further care. At the time of this study, the Malawi guidelines recommended patients with CD4 count below 200 cells/mm3 start antiretroviral treatment (ART) and all those patients were directly referred to the Lighthouse Clinic to determine eligibility.
Laboratory analyses
Blood serum samples were tested for HIV, HSV-2 and syphilis serologies. HIV-1 serostatus was determined at the clinic using two parallel rapid tests (Determine, Abbott Laboratories; and Uni-Gold, Trinity Biotech). Discordant results were resolved using an HIV ELISA (Genetics Systems) and these results were taken as final. HSV-2 serology was performed using HerpeSelect® IgG2 ELISA (Focus Technologies, Cypress Hill, CA, USA) with high sensitivity in African settings [13]. Syphilis serology was performed using a non-treponemal test (rapid plasma reagin [RPR], Macro-Vue, Becton-Dickinson, Sparks, Maryland, USA) with reactive samples confirmed by Treponema pallidum haemagglutination assay (Serodia-TPHA, Fujirebio, Tokyo, Japan).
Among HIV-1 seropositive participants, plasma HIV-1 RNA was quantified using Roche Amplicor HIV-1 Monitor Test, version 1.5 (Roche Diagnostic Systems, Branchburg, NJ, USA) with a lower limit of detection (LLOD) of 400 copies/mL. CD4 T-lymphocyte count was performed using standard fluorocytometry (FACScan, Becton-Dickinson, Sparks, Maryland, USA). All tests were performed at the UNC reference HIV/STI laboratory in Lilongwe.
Ulcer etiologies
DNA from the ulcer specimens was extracted using QIAamp DNA Mini Kit (Qiagen Inc.) and the ulcer etiologies were determined at the Reference Laboratory and Research Branch, Division of STD Prevention, CDC (Atlanta, GA). Real-time multiplex PCR was used for the molecular diagnosis of HSV-2, H ducreyi and T pallidum on TaqMan technology using a CDC in-house protocol. The assay was performed on a Rotor-Gene 3000 (Qiagen Inc.). First episode and first exposure HSV-2 ulcers were defined as presence of lesional HSV-2 DNA in patients with negative HSV-2 serology; recurrent HSV-2 ulcers were defined as presence of lesional HSV-2 DNA in patients with positive HSV-2 serology (regardless of prior GUD history). LGV diagnosis was based on a C trachomatis L1-L3 strain-specific real-time PCR assay developed by the CDC.
Other genital infections
Urine samples (men) and cervical swabs (women) were tested for Neisseria gonorrhoeae and Chlamydia trachomatis using Amplicor NG/CT® PCR (Roche Diagnostic Systems).
Statistical analyses
All analyses were carried out using SAS version 9.2 (The SAS Institute, Cary, NC) and Stata version 10.0 (Stata Corporation, College Station, TX). Categorical data were analyzed using chi-square tests, with Fisher’s exact test where appropriate. Comparisons of continuous data between two groups used the t-test if normally distributed and the Wilcoxon ranksum test otherwise. HIV-1 RNA quantities were log10 transformed for analyses.
RESULTS
Patients’ characteristics
Of 460 patients presenting with GUD at KCH/STI Clinic between September 2004 and June 2006, 422 (313 men [74%] and 109 women [26%]) were enrolled (Table 1). The median age in both men and women was 28 years. More men than women reported two or more sexual partners in the past year (60% vs 29%; p<0.001), and men were more likely than women to have a recent change of partner (50% vs 19%; p<0.001). Both sexes reported infrequent recent condom use (18% reported using a condom at last sex). About a third of patients reported experiencing prior GUD within the previous year. The reported median duration of the present ulcer was 6 to 7 days, with no difference by sex. Most lesions (69%) were multiple. Prevalence of N. gonorrhoeae was lower in men than women (6% vs. 15%, p=0.02). C. trachomatis was very low in both men and women, consistent with historical values from Malawi [14]. Among the HIV-1-infected patients, HIV-1 viral load was high overall (4.85 log10 copies/mL) with no difference in mean log viral loads between men and women (4.90 vs 4.74 log10 copies/mL, p=0.15). At the enrolment visit, fewer than 5% of HIV-infected participants were on ART and the median CD4 cell count was 232 cells/mm3.
Table 1:
Characteristics of patients presenting with genital ulcer disease in Lilongwe, Malawi 2004–061
| Total (N=422) | Women (N=109) | Men (N=313) | |
|---|---|---|---|
|
|
|||
| Median (IQR) | Median (IQR) | Median (IQR) | |
|
| |||
| Median age (IQR), years | 28 (24–33) | 28 (23–33) | 28 (25–33) |
| Median duration of ulcer (IQR), days | 7 (4–14) | 7 (4–14) | 6 (4–14) |
| Size of largest ulcer | |||
| Median size (IQR), mm2 | 28 (13–72) | 21 (13–50) | 28 (12–75) |
| Median age at first sex (IQR), years | 18 (15–19) | 18 (15–19) | 18 (15–20) |
| N (%) | N (%) | N (%) | |
|
|
|||
| Marital status | |||
| Single | 131 (31%) | 16 (15%) | 115 (37%) |
| Married | 226 (54%) | 62 (57%) | 164 (52%) |
| Separated/widowed/divorced | 65 (15%) | 31 (28%) | 34 (11%) |
| Education | |||
| Primary or less | 228 (54%) | 62 (56%) | 166 (53%) |
| More than primary | 194 (46%) | 47 (43%) | 147 (47%) |
| No. partners in last one year2 | |||
| 1 | 195 (46%) | 72 (71%) | 123 (40%) |
| ≥2 | 212 (50%) | 29 (29%) | 183 (60%) |
| Had new partner in last 3 months | |||
| Yes | 179 (42%) | 21 (19%) | 158 (50%) |
| No | 243 (58%) | 88 (81%) | 155 (50%) |
| Used a condom at last sex | |||
| Yes | 76 (18%) | 20 (18%) | 56 (18%) |
| No | 346 (82%) | 89 (82%) | 257 (82%) |
| Prior GUD within past year | |||
| Yes | 157 (37%) | 40 (37%) | 117 (37%) |
| No | 265 (63%) | 69 (63%) | 196 (63%) |
| Neisseria gonorrhoeae | |||
| Yes | 35 (8%) | 16 (15%) | 19 (6%) |
| No | 387 (92%) | 93 (85%) | 294 (94%) |
| Chlamydia trachomatis | |||
| Yes | 11 (3%) | 2 (2%) | 9 (3%) |
| No | 411 (97%) | 107 (98%) | 304 (97%) |
| Positive syphilis serology | |||
| Yes | 21 (5%) | 6 (5%) | 15 (5%) |
| No | 401 (95%) | 103 (95%) | 298 (95%) |
| Positive HSV-2 serology3 | |||
| Yes | 299 (72%) | 85 (81%) | 214 (69%) |
| No | 118 (28%) | 20 (19%) | 98 (31%) |
| Positive HIV-1 serology | |||
| Yes | 257 (61%) | 84 (77%) | 173 (55%) |
| No | 165 (39%) | 25 (23%) | 140 (45%) |
| Among HIV-positive patients | n=257 (61%) | n=84 (77%) | n=173 (55%) |
|
|
|||
| CD4+ lymphocyte count4 | |||
| Median count (IQR), cells/pL | 232 (128–400) | 173 (85–347) | 263 (152–408) |
| < 200 cells/μL | 138 (54%) | 33 (39%) | 105 (61%) |
| ≥ 200 cells/μL | 94 (37%) | 42 (50%) | 52 (30%) |
| Mean plasma HIV-1 RNA (CI), log10 copies/mL5 | 4.85 (4.75, 4.95) | 4.74 (4.55, 4.93) | 4.90 (4.78, 5.02) |
| Taking antiretroviral therapy | |||
| Yes | 12 (5%) | 7 (8%) | 5 (3%) |
| No | 245 (95%) | 77 (92%) | 168 (97%) |
CI, 95% confidence interval; GUD, genital ulcer disease; HSV-2, herpes simplex virus type 2; IQR, interquartile range.
Data missing for 8 women and 7 men
Data missing for 4 women and 1 man
Data missing for 9 women and 16 men
Data missing for 2 women and 4 men
HIV, HSV-2 and Syphilis serologies
Overall, 299/417 (72%) patients were HSV-2 seropositive, with lower prevalence in men compared to women (69% vs 81%; p=0.01); 61% were HIV-1 seropositive (55% in men vs 77% in women; p<0.001); and 21/422 (5%) had a positive syphilis serology (5% in men vs. 6% in women 6%, p=0.77).
GUD etiology
GUD etiology was obtained from 398 (94%) patients. HSV-2 ulcers were most prevalent (67%), either as a single agent (54%) or among ulcers with multiple etiologies (13%) Among the HSV-2 ulcers, the majority (75%) were recurrent or previously exposed. H. ducreyi remains a significant cause of GUD in Malawi (15%). The prevalence of T. pallidum and LGV were both 6% (Table 2). Of the 21 patients who were RPR and TPHA seropositive, 10 (45%) were multiplex PCR T. pallidum negative. Among these ten, nine (90%) were also positive for: HSV-2 alone (n=6), H. ducreyi alone (n=1), HSV-2 and H. ducreyi (n=1), or HSV-2 and LGV (n=1).
Table 2:
Prevalence of genital ulcer disease etiologies by sex1
| Total | Women | Men | |
|---|---|---|---|
|
|
|
||
| GUD Etiology2 | Total n=398 | Number (%) n=104 | Number (%) n=294 |
|
|
|
|
|
| Prevalence 3 | |||
| HSV-2 | 267 (67%) | 83 (80%) | 184 (63%) |
| HD | 60 (15%) | 13 (13%) | 47 (16%) |
| TP | 22 (6%) | 4 (4%) | 18 (6%) |
| LGV | 25 (6%) | 5 (5%) | 20 (7%) |
| Unknown | 79 (20%) | 15 (14%) | 64 (22%) |
| Single etiology: | 264 (66%) | 73 (70%) | 191 (65%) |
| HSV-2 | 216 (54%) | 68 (65%) | 148 (50%) |
| HD | 34 (9%) | 4 (4%) | 30 (10%) |
| TP | 10 (3%) | 1 (1%) | 9 (3%) |
| LGV | 4 (1%) | 0 (0%) | 4 (1%) |
| Mixed etiology: | 55 (14%) | 16 (15%) | 39 (13%) |
| HSV-2 + HD | 23 (6%) | 8 (8%) | 15 (5%) |
| HSV-2 + TP | 9 (2%) | 2 (2%) | 7 (2%) |
| HSV-2 + LGV | 19 (5%) | 5 (5%) | 14 (5%) |
| HD + TP | 2 (0.5%) | 1 (1%) | 1 (0.5%) |
| TP + LGV | 1 (0.5%) | 0 | 1 (0.5%) |
| HD + LGV | 1 (0.5 %) | 0 | 1 (0.5%) |
| HSV-2 Ulcers 4 | 263 (66%) | 80 (77%) | 183 (62%) |
| First episode | 67 (25%) | 10 (13%) | 57 (31%) |
| Recurrent | 196 (75%) | 70 (87%) | 126 (69%) |
Etiology data missing for 5 women and 19 men; Serology data missing for 1 woman and 4 men leaving a denominator of 371 in this table
HD, Haemophilus ducreyi; HSV-2, herpes simplex virus type 2; TP, Treponema pallidum; LGV, lymphogranuloma venereum
Indicates the presence of any positive result. These numbers will add up to more than 100% since there are some patients who have more than one etiology.
Categorized as first episode if results were HSV-antibody negative and HSV PCR positive; 4 people are missing antibody results.
GUD etiology by HIV sub-group and by gender
In HSV-2 infected patients, HIV prevalence was high (67%). HIV sero-positivity was significantly higher among patients with recurrent or previously exposed HSV-2 compared to patients with first episode and first exposure HSV-2 (78% vs 39%, p<0.001) (Table 3). Fewer HSV-2 infected men were HIV-positive than HSV-2 infected women (61% vs 81%, p=0.008).
Table 3:
Prevalence of HIV infection, by genital ulcer disease etiologies and sex*
| Total | Women | Men | ||||
|---|---|---|---|---|---|---|
|
|
|
|
||||
| GUD Etiology† | HIV+ (n=249) | Total (n=398) | HIV+ (n=81) | Total (n=104) | HIV+ (n=168) | Total (n=294) |
|
|
|
|
|
|||
| Prevalence ‡ | ||||||
| HSV-2 | 179 (67%) | 267 | 67 (81%) | 83 | 112 (61%) | 184 |
| HD | 30 (50%) | 60 | 10 (77%) | 13 | 20 (43%) | 47 |
| TP | 14 (64%) | 22 | 4 (100%) | 4 | 10 (56%) | 18 |
| LGV | 14 (56%) | 25 | 3 (60%) | 5 | 11 (55%) | 20 |
| Unknown | 43 (54%) | 79 | 8 (53%) | 15 | 35 (55%) | 64 |
| Single etiology § | 175 (66%) | 264 | 62 (85%) | 73 | 113 (59%) | 191 |
| HSV-2 | 150 (66%) | 216 | 57 (84%) | 68 | 93 (63%) | 148 |
| HD | 17 (50%) | 34 | 4 (100%) | 4 | 13 (43%) | 30 |
| TP | 6 (60%) | 10 | 1 (100 %) | 1 | 5 (56%) | 9 |
| LGV | 2 (50%) | 4 | 0 (0%) | 0 | 2 (50%) | 4 |
| Mixed etiology § | 31 (56%) | 55 | 11 (69%) | 16 | 20 (51%) | 39 |
| HSV-2 + HD | 12 (52%) | 23 | 5 (63%) | 8 | 7 (47%) | 15 |
| HSV-2 + TP | 6 (67%) | 9 | 2 (100%) | 2 | 4 (57%) | 7 |
| HSV-2 + LGV | 11 (58%) | 19 | 3 (60%) | 5 | 8 (57%) | 14 |
| HD + TP | 1 (50%) | 2 | 1 (100%) | 1 | 0 | 1 |
| TP + LGV | 1 (100%) | 1 | 0 | 0 | 1 (100%) | 1 |
| HD + LGV | 0 (0%) | 1 | 0 | 0 | 0 | 1 |
| HSV-2 Ulcers ** | 178 (68%) | 263 | 66 (83%) | 80 | 112 (61%) | 183 |
| First episode | 26 (39%) | 67 | 6 (60%) | 10 | 20 (35%) | 57 |
| Recurrent | 152 (78%) | 196 | 60 (86%) | 70 | 92 (73%) | 126 |
Etiology data missing for 5 women and 19 men; Serology data missing for 1 woman and 4 men leaving a denominator of 371 in this table
HD, Haemophilus ducreyi; HSV-2, herpes simplex virus type 2; TP, Treponema pallidum; LGV, lymphogranuloma venereum
Indicates the presence of any positive result
These categories do not include ulcers of unknown etiologies.
Categorized as first episode if results were HSV-antibody negative and HSV PCR positive; 4 people are missing antibody results.
DISCUSSION
In this cross sectional analysis of the etiology of genital ulcer disease (GUD) in Malawi, HSV-2 ulcers were the most prevalent presentation, including three quarters of recurrent HSV-2 ulcers. Ulcers caused by H. ducreyi (15%) remain prevalent in Malawi, but the prevalence of T. pallidum is low and has declined compared to past data [15, 16]. To date, LGV (6%) has largely been ignored (and untested) as a cause of GUD in this setting, and consequently has been treated less than optimally.
The prevalence and etiological distribution of GUD in sub-Saharan Africa over the past two decades has been influenced by the initiation and routine use of syndromic management and the persistent high prevalence of HIV in this population. Similar to the timeline in many developing countries, STI syndromic management was initiated in Malawi in the mid-90’s following etiologic studies that set the stage for the development of country specific algorithms [11]. The widespread use of this management approach that treats all genital ulcers for both syphilis and chancroid has contributed to a decline in the proportional prevalence of these treatable STIs in Malawi. Between 1992 and 2007 the proportion of GUD attributable to T. pallidum and H. ducreyi fell from 18% to 5% and 26% to 16% respectively [11]. Correspondingly, GUD caused by HSV-2 has increased from 23% in 1992 [17] to 67% in 2007 [12].
Where HIV-1 prevalence is high, the etiological profile of GUD often includes higher rates of HSV-2, as seen in our setting. While both initial and recurrent HSV-2 cases are associated with an increased risk of HIV-1 transmission and acquisition, patients with recurrent HSV-2 infections have a higher prevalence of HIV [4], which reflects both the cumulative increased risk of HIV acquisition facilitated by multiple episodes of GUD and the higher rate of recurrences associated with HIV-associated immunosuppression [22].
The WHO recommends adding episodic treatment with acyclovir to syndromic management in areas where the prevalence of herpetic ulcers is greater than 30% [9], based on a reduction in ulcer healing time found among patients who present early [23, 24], and because acyclovir reduces HIV viral shedding in HSV-2 ulcer lesions [12, 25] and in genital secretions [12, 23] among those dually infected. As a direct outcome of our study, the treatment of genital herpes has been added to the treatment of GUD in Malawi since 2007.
The 15% prevalence of H. ducreyi among GUD patients in Malawi is higher than in most other areas in sub-Saharan Africa. In Botswana, H. ducreyi prevalence decreased from 23% in 1993 to 1% in 2002 [7] (treating with a single intramuscular injection of Ceftriaxone 250mg), and was similarly low (1%) between 2002 and 2006, in Rakai, Uganda (treating with Ciprofloxacin 500 mg twice daily for 3 days + Erythromycin 500 mg PO, four times daily for 14 days) [26]. The relatively higher prevalence of H. ducreyi in Malawi may be related to the historic choice of treatment. In 1995, erythromycin 500 mg four times daily for seven days had a cure rate (>95%) comparable with ciprofloxacin 500 mg as a single dose [18]. Erythromycin was chosen for cost considerations, despite the risk of non-compliance due to gastro-intestinal side effects. This regimen was used until 2005 when the Malawi STI guidelines replaced the multi-dose eryrthromycin regimen with a single dose of ciprofloxacin. Another etiologic survey will be necessary to determine and monitor the effect of this regimen change on H. ducreyi prevalence.
This evaluation was the first to assess the presence of LGV in Malawi. The proportion of GUD attributable to LGV was higher than a recent assessment in Namibia (2%) [27] and an assessment of the trends among a mining community in South Africa, which ranged from 0.9% to 4.5% between 1986 and 1998 [28]. The prevalence in our population was similar to STI clinics in Bangkok (10%), Madagascar (8%) and Lesotho (7%) in the mid-to-late 1990’s [16, 25]. The standard treatment for LGV is doxycycline 100 mg twice daily for 21 days [29]. The current Malawi guidelines do not include LGV treatment in their GUD treatment algorithm, although patients returning with unhealed ulcers or other related symptoms at 7 days are treated with a single 1 g dose of azithromycin. The effectiveness of this regimen on LGV is unproven.
The presence of T. pallidum in Malawi is low and continues to decline. This decline may be due to almost two decades of systematically treating all presenting GUD with benzathine penicillin. Not only has the prevalence of genital ulcers due to T. pallidum declined from 18% (1992) [18] to 5% (2007) [11], but RPR seropositivity among women attending antenatal services country-wide declined from 7.0% in 1996 to 1.2% in 2010 [30]. While the rates of T. pallidum are at historic lows, the risk of resurgence, including an increase in congenital syphilis, would be too high to recommend removing syphilis treatment from the GUD syndromic treatment guidelines.
We were unable to identify a specific etiology for 20% of the patients with GUD, which is within the range of other similar evaluations [22, 26]. Unidentified ulcers could result from non-sexually transmitted etiologies or might represent older, healing sexually transmitted ulcers, perhaps co-infected with non STI agents.
Study participants were patients who presented for care at a semi-urban STI clinic in Malawi, so our work is generalizable to similar populations, but might not represent the distribution of GUD in the population. Patients who successfully self-treated their GUD or whose lesions would have spontaneously healed would be less likely to present to the clinic. This could include patients with ulcers too small or painless to notice, or indeed patients with recurrent HSV2 ulcers who may already know that their ulcers will heal with time alone. Patients with blisters only were excluded in the etiology analysis as swabs were not taken. The diagnostic tests have changed: the HSV-2 antigen detection method used in 1992 (EIA HERPCHECK) was less sensitive that the multiplex PCR used in subsequent years and could have contributed to the difference in prevalence found over time.
Nearly two decades of syndromic management of GUD appear to have contributed to a real reduction in the burden of some of the bacterial etiologies of GUD such as T. pallidum and H. ducreyi in Malawi, though the reduction in H. ducreyi has not been as pronounced as elsewhere due to suboptimal treatment. Although the WHO has attempted to respond to the burden of HSV/HIV co-infections by adding episodic acyclovir to the GUD algorithm, the failure of randomized clinical trials to show a benefit of suppressive HSV-2 therapy on acquisition and transmission of HIV hampers the implementation of episodic HSV-2 treatment at the country level. The clinical benefit of acyclovir for patients presenting with HSV ulcers is small but not debatable, however, more aggressive interventions would be required to prevent HIV transmission in this population. Broadly applied HIV testing and counselling and HIV and HSV-2 risk reduction counselling among all patients presenting with GUD and their sexual partners, in addition to the early initiation of ART when appropriate are, for now, the best prevention measures for persons co-infected with HSV-2 and HIV and those at risk of exposure.
Acknowledgments
We would like to thank all men and women who participated in this study, clinical staff at Kamuzu Central Hospital STI clinic and all staff involved in the study from University of North Carolina (UNC) Project teams, both at the Tidziwe Centre in Lilongwe and at Chapel Hill, NC. We would like to thank Debbie Kamwendo who supervised the laboratory analysis in Lilongwe and Kai-Hua Chi who performed all GUD testing at CDC in Atlanta, USA. We also thank members of the Data Safety and Monitoring Committee (Chair: Prof. Simon Cousens from the London School of Hygiene and Tropical Medicine, Dr Peter Leone from UNC, Chapel Hill, and the late Dr George Joaki from the UNC Project, Lilongwe). We would like to express our gratitude to the Malawi National STI Task Force chaired by the Reproductive Health Unit of the Ministry of Health who commissioned and supported this study.
Financial support:
The study was funded by the UK Department for International Development (DFID) through the Malawi National AIDS Commission, and by grants from the University of North Carolina at Chapel Hill, NC, USA. The views expressed are those of the authors and cannot be taken to reflect the official opinions of DFID, nor of the U.S. Centers for Disease Control and Prevention (CDC).
Footnotes
Conflict of interest: The authors declare they have no commercial or other association that might pose a conflict of interest (eg. pharmaceutical stock ownership, consultancy, advisory board membership, patents, or research funding)
Presentation: This work was presented as an oral presentation at the XVII International AIDS Conference, Mexico City, Mexico, 3rd-8th August 2008: Phiri S, Hoffman I, Weiss HA, et al. Impact of acyclovir on ulcer healing and HIV-1 lesional and genital shedding among patients with genital ulcer disease in Malawi: A randomized controlled trial. [Oral THAC0303].
Trial registration: The trial was registered with International Standard Randomised Controlled Trial Number Register # ISRCTN32121857.
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