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Impact of Acyclovir on Genital and Plasma HIV-1 RNA, Genital Herpes Simplex Virus Type 2 DNA, and Ulcer Healing among HIV-1–Infected African Women with Herpes Ulcers: A Randomized Placebo-Controlled Trial

  1. Philippe Mayaud1,
  2. Jérôme LeGoff3,4,
  3. Helen A. Weiss2,
  4. Gérard Grésenguet6,
  5. Khonde Nzambi7,
  6. Hicham Bouhlal3,
  7. Eric Frost8,
  8. Jacques Pépin8,
  9. Jean-Elie Malkin5,
  10. Richard J. Hayes2,
  11. David C. W. Mabey1,
  12. Laurent Bélec3 and
  13. for the ANRS 1212 Study Groupa
  1. 1Clinical Research Unit, Department of Infectious and Tropical Diseases, and
  2. 2Infectious Disease Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom;
  3. 3Université Paris Descartes, Equipe Immunité et Biothérapie Muqueuse, Unité INSERM Internationale U743 (Immunologie Humaine), Centre de Recherches Biomédicales des Cordeliers and Laboratoire de Virologie, Hôpital Européen Georges Pompidou,
  4. 4Université Paris Diderot, Laboratoire de Microbiologie, Hôpital Saint-Louis, and
  5. 5Centre Médical, Institut Pasteur, Paris, France;
  6. 6Centre National de Référence des Maladies Sexuellement Transmissibles et du SIDA de Bangui and Unité de Recherches et d’Intervention sur les Maladies Sexuellement Transmissibles et du SIDA, Faculté des Sciences de la Santé, Bangui, Central African Republic;
  7. 7West African Project To Combat AIDS and STIs, Accra, Ghana;
  8. 8Centre for International Health, University of Sherbrooke, Sherbrooke, Canada
  1. Reprints or correspondence: Philippe Mayaud, Clinical Research Unit, London School of Hygiene & Tropical Medicine, Keppel St., London WC1E 7HT, UK (philippe.mayaud{at}lshtm.ac.uk)
 
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Abstract

BackgroundLittle is known about the impact of episodic treatment of herpes on human immunodeficiency virus type 1 (HIV-1)

MethodsWomen from Ghana and the Central African Republic who had genital ulcers were enrolled in a randomized, double-blind, placebo-controlled trial of acyclovir plus antibacterials and were monitored for 28 days. Ulcer etiologies and detection of lesional HIV-1 RNA were determined by polymerase chain reaction (PCR). Cervicovaginal HIV-1 RNA and herpes simplex virus type 2 (HSV-2) DNA and plasma HIV-1 RNA were quantitated by real-time PCR. Primary analyses included 118 HIV-1–infected women with HSV-2 ulcers (54 of whom were given acyclovir and 64 of whom were given placebo)

ResultsAcyclovir had little impact on (1) detection of cervicovaginal HIV-1 RNA (risk ratio [RR], 0.96; 95% confidence interval [CI], 0.8–1.2) at day 7 of treatment, (2) the mean cervicovaginal HIV-1 RNA load (−0.06 log10 copies/mL; 95% CI, −0.4 to 0.3 log10 copies/mL) at day 7 of treatment, or (3) the plasma HIV-1 RNA load (+0.09 log10 copies/mL; 95% CI, −0.1 to 0.3 log10 copies/mL) at day 14 of treatment. At day 7, women receiving acyclovir were less likely to have detectable lesional HIV-1 RNA (RR, 0.70; 95% CI, 0.4–1.2) or cervicovaginal HSV-2 DNA (RR, 0.69; 95% CI, 0.4–1.3), had a lower quantity of HSV-2 DNA (−0.99 log10 copies/mL; 95% CI, −1.8 to −0.2 log10 copies/mL), and were more likely to have a healed ulcer (RR, 1.26; 95% CI, 0.9–1.9)

ConclusionEpisodic therapy for herpes reduced the quantity of cervicovaginal HSV-2 DNA and slightly improved ulcer healing, but it did not decrease genital and plasma HIV-1 RNA loads

Trial registrationClinicalTrials.gov identifier NCT00158483

Herpes simplex virus (HSV) type 2 (HSV-2), the most common cause of genital ulcer disease worldwide [1–3], is associated with the prevalence and incidence of human immunodeficiency virus (HIV) [4, 5]. Because of the high prevalence of HSV-2 in many parts of sub-Saharan Africa, a large proportion of HIV-infected individuals will be coinfected [1]. Several studies have demonstrated increased genital shedding of HIV-1 during symptomatic [6, 7] and asymptomatic [8–10] recurrences of herpetic episodes, suggesting that HSV-2 may increase replication of HIV type 1 (HIV-1), as has been supported by biological evidence [11]. Recent randomized trials have shown that HSV suppression decreases the detection and quantity of genital and plasma HIV-1 RNA in coinfected individuals [12–16]. Additional data on a possible causal role of HSV-2 in HIV transmission will emerge from an ongoing trial of the impact among HIV-serodiscordant couples of HSV suppressive therapy given to the HIV-infected partner [17]. Little is known, however, about the impact on HIV-1 of episodic antiherpetic therapy administered during symptomatic ulcerations

HIV infection alters the natural history of HSV-2 infection, and severely immunosuppressed coinfected patients may experience more frequent, severe, or prolonged symptomatic recurrences [18, 19]. Moreover, observational studies have shown transient increases in the plasma HIV load during symptomatic episodes of genital herpes [20]; these increases can be reduced by the use of antiherpetic therapy [21]. Among HIV-serodiscordant couples in Uganda, incident genital ulcer disease (mostly caused by HSV-2) in the HIV-infected partner was associated with a 4-fold increase in HIV transmission [22]. Thus, herpetic ulcers may contribute substantially to HIV transmission, and HSV treatment may reduce transmissibility

Management guidelines from the World Health Organization (WHO) recommend antiherpetic therapy for patients with genital ulcer disease for whom the proportion of ulcers caused by HSV-2 is ⩾30% [23]. However, herpes therapy is seldom used in resource-poor settings, and the impact of incorporating acyclovir into syndromic management has not been evaluated [3]. We present the results of what is, to our knowledge, the first trial of episodic antiherpetic therapy that used acyclovir in addition to standard syndromic genital ulcer disease treatment in Africa. The primary aim of the study was to assess the impact of this intervention on the detection and quantity of cervicovaginal HIV-1 RNA among HIV-1–infected women with herpetic ulcers. The secondary aims of the study were to evaluate the impact of the intervention on the detection of lesional HIV-1 RNA, the quantity of plasma HIV-1 RNA, the detection and quantity of cervicovaginal HSV-2 DNA, and the proportion of healed ulcers

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Methods

The Agence Nationale de Recherches sur le SIDA et les Hépatites (ANRS) 1212 trial was an individually randomized placebo-controlled trial of 400 mg of acyclovir given 3 times daily for 5 days, in accordance with standard recommendations [23–25], plus antibacterials for the syndromic management of genital ulcer disease. The study was approved by the research ethics committees of the Ministries of Health of Ghana and the Central African Republic and the London School of Hygiene & Tropical Medicine

Women with clinically confirmed ulcers or blisters in Accra and Kumasi (Ghana) and in Bangui (Central African Republic) were eligible for recruitment into the study if they were ⩾18 years of age and resided and planned to stay in Accra, Kumasi, or Bangui for 1 month. Exclusion criteria included menstruation; pregnancy (as determined by urine testing with Rapid HCG [Dectra Pharm]); contraindications to acyclovir (e.g., suspected renal impairment or allergy to acyclovir); and the presence of large ulcers (surface area, ⩾500 mm2), chronic ulcers (duration, >1 month), or perianal ulcers only, which prompted provision of open-label acyclovir. All women were offered voluntary HIV counseling. HIV serostatus was determined after consent was provided. Women who elected to know their HIV serostatus and who were eligible for highly active antiretroviral therapy (HAART) were referred to appropriate health care providers

Women who provided consent were interviewed and examined and had genital and blood samples collected. Study participants received directly observed single-dose syndromic treatment for chancroid (500 mg of ciprofloxacin given orally) and syphilis (2.4 million U of benzathine penicillin given intramuscularly), counseling about sexually transmitted infections and HIV, partner notification slips, and condoms. Participants were asked to return to the clinic on day 2 and/or day 4 (depending on the day of study enrollment) and on days 7, 14, and 28 (hereafter known as “D7,” “D14,” and “D28,” respectively). At each clinic visit, a pelvic examination was performed and genital samples collected. Genital sampling was deferred for menstruating women until 2 days after bleeding had ceased. During treatment, physicians assessed treatment adherence by pill counts, recorded and graded side effects and adverse events, and encouraged compliance. Participants whose ulcers had not improved by D14 of treatment (as defined by a <90% reduction in the surface area of the ulcer at D14, compared with that noted on day 0 [D0]) were given open-label acyclovir for 5 days

Participants were randomly assigned to receive acyclovir or placebo according to a 1:1 allocation scheme using block randomization (size, 10), in accordance with a random allocation list provided by the study drug manufacturer (Creapharm). Investigators and participants were blinded to treatment allocation through the use of prelabeled sequentially numbered treatment packs

Specimen collection and laboratory proceduresDetails about the sampling and testing procedures used have been published elsewhere [7]. In brief, at the enrollment clinic visit (D0) and at each follow-up visit, clinical characteristics were recorded, and the largest ulcer was measured using a disposable ruler. The surface area of the ulcer was estimated by multiplying its length by its width. For all participants, at D0 and at follow-up clinic visits, if the ulcer had not improved (if there was <75% reduction in the surface area of the largest ulcer at D7, compared with D0, and if there was <90% reduction in the surface area of the largest ulcer at D14, compared with D0), 2 dry Dacron swabs were collected from the base of the ulcer to determine ulcer etiology and test for lesional HIV-1 RNA (among HIV-positive patients). Lesional swab specimens were tested for HSV, Haemophilus ducreyi, Treponema pallidum, Klebsiella granulomatis and Chlamydia trachomatis lymphogranuloma venereum by use of molecular techniques [7]

At each clinic visit, a standardized 60-s cervicovaginal lavage specimen with 3 mL of phosphate-buffered saline fluid was collected, immediately processed, and stored [26]. Vaginal and cervical swab specimens were collected at enrollment (D0) for the diagnosis of vaginal and cervical infections [7]

At D0, blood samples were collected for the serologic diagnosis of HIV-1 (by use of 2 complementary enzyme-linked immunosorbent assays [ELISAs]), HSV (by use of specific immunoglobulin [Ig] G1 and IgG2 ELISAs for HSV-1 and HSV-2 [HerpeSelect; Focus Technologies] at the manufacturer’s recommended threshold of 1.1), and syphilis (by use of a rapid plasma reagin test, the results of which were confirmed by T. pallidum hemagglutination assay) [7, 27]. Serologic tests were performed again at D28 for those women who were initially found to be seronegative. In addition, among HIV-seropositive women, the CD4+ cell count was measured by FACScount (Becton Dickinson) at enrollment, and plasma HIV-1 RNA levels were measured on D0, D14, and D28

Detection and quantitation of HIV-1 RNA and HSV-2 DNA were performed in the acellular fraction of the cervicovaginal lavage specimen, and detection and quantitation of HIV-1 RNA in plasma were determined by real-time polymerase chain reaction (PCR) (detection threshold, 250 copies/mL) [28]. Lesional HIV-1 RNA was detected qualitatively by real-time PCR. To avoid possible misclassification of samples due to the presence of semen in the vagina, cervicovaginal lavage specimens were tested for the presence of the Y chromosome by means of PCR [7]

Study definitionsWe defined HIV-1 “infection” as detection of HIV-1 either in a cervicovaginal lavage specimen or serologically. A nonprimary first episode of genital HSV-2 infection was defined as detection of HSV-2 DNA in the lesion of or cervicovaginal lavage specimen obtained from women who were HSV-1 seropositive and HSV-2 seronegative. We used 2 definitions of ulcer healing at each clinic visit: (1) a ⩾90% reduction in the surface area of the largest ulcer, compared with its size at D0, and (2) the proportion of patients whose largest ulcer was ⩽10 mm2. Fully reepithelialized ulcers that were not measured were considered to be “healed” ulcers, according to both definitions

Statistical considerationsSample-size calculations were based on a previous study performed in Bangui [8]. Assuming 60% prevalence of cervicovaginal HIV-1 RNA in the placebo group, we estimated that enrollment of 450 women with genital ulcers would provide 90% power to detect a halving of detectable cervicovaginal HIV-1 RNA at D7 at the 95% significance level, under the assumption that 50% of women were HIV-1 infected and that 60% of these women had herpetic ulcers and with allowance for a 10% loss to follow-up. Under these assumptions, we aimed to enroll 135 HIV-1–infected women with lesional HSV-2 DNA

Women were enrolled and randomized irrespective of their HIV/HSV status, because this status was unknown at D0. However, the a priori–defined primary analysis group included only HIV-1–infected women with lesional HSV-2 DNA. The primary end point was D7 (i.e., the D7 clinic visit [visits on days 6–8 were included in this analysis]). Primary outcomes were the detection and quantitation of cervicovaginal HIV-1 RNA at D7. Secondary outcomes included the detection of lesional HIV-1 RNA at D7; quantitation of plasma HIV-1 RNA at D14 (visits on days 13–15 were included in this analysis) and D28 (visits on days 26–30 were included in this analysis); detection and quantitation of cervicovaginal HSV-2 DNA; and the proportion of ulcers healed at D7

Intention-to-treat analyses were conducted using Stata software (version 9.0; StataCorp). Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated by Poisson regression with robust standard errors [29], adjusting for detection of the outcome measurement at D0. The effects on viral loads among women with detectable virus were assessed by linear regression analysis, adjusting for mean viral loads at D0. Viral loads below the threshold of detection were assigned a value that was one-half the value of the threshold. We used generalized estimating equations (logistic or linear regression) to analyze data from all follow-up visits, adjusting for measurements at baseline. Cox regression was used to analyze the effect on rates of ulcer healing, with Kaplan-Meier survival curves showing the time to healing. All P values were 2-sided

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Results

Of 490 women who were assessed for study enrollment eligibility from May 2003 through October 2005, a total of 441 (90%) were enrolled and randomized to receive acyclovir (n=221) or placebo (n=220) (figure 1). Reported adherence was very high, with 99% of returning women in each group having taken all their pills by D7. Acyclovir was well tolerated, with no serious adverse events reported. Overall, 203 women (46%) were HIV-1 seropositive. Of the 3 HIV-seronegative women who had detectable cervicovaginal HIV-1 RNA (with no semen detected by Y chromosome PCR), 2 seroconverted at a subsequent visit (primary HIV infection). Of the 206 HIV-infected women, 118 (57%) had HSV-2 ulcers and were included in the primary analysis; 54 of these patients were treated with acyclovir, and 64 were given placebo (figure 1). Of these 118 women, 5 (4%) were HSV-2 seronegative and HSV-1 seropositive and were categorized as having a nonprimary first episode of genital HSV-2 infection

Figure 1
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Figure 1

Consolidated Standards of Reporting Trials flow diagram of eligibility, enrollment, and follow-up in the primary analysis group of the Agence Nationale de Recherches sur le SIDA et les Hépatites (ANRS) 1212 trial, which consisted of human immunodeficiency virus type 1 (HIV-1)–infected women with herpes simplex virus type 2 (HSV-2) ulcers. *Day 7 is the primary end point (defined as a visit occurring on days 6–8 after randomization). Eleven women in the control group and 6 women in the acyclovir treatment group were excluded from analyses because cervicovaginal lavage (CVL) specimens were not collected at this day 7 clinic visit, usually because of menstruation

Of the 118 HIV-1–infected women with HSV-2 ulcers, 12 (10%) were lost to follow-up by the clinic visit at D7, and an additional 17 women (14%) did not have a cervicovaginal lavage specimen analyzed at D7, usually because of menstruation. Therefore, 89 women (75%) (41 of whom were treated with acyclovir and 48 of whom were given placebo) were analyzed to determine the impact of acyclovir at the primary end point (figure 1). None of the women with primary HIV infection or a first episode of genital HSV-2 infection had a cervicovaginal lavage specimen analyzed at D7. Overall, 170 (79%) of 216 and 218 (85%) of 256 scheduled follow-up visits were completed in the acyclovir and placebo groups, respectively; 93 (79%) of 118 women were seen at D14, and 77 (65%) of 118 women were seen at D28

Demographic, behavioral, and clinical characteristics were generally similar between treatment groups (table 1). The mean age of the study participants was 31 years (range, 18–57 years). Almost one-half of the participants (52 [44%] of 118 women) reported having experienced genital ulcers in the year preceding their current episode, and most women (71 [60%] of 118 women) were currently experiencing ⩾2 ulcers, the largest having an average size of 120 mm2 (interquartile range [IQR], 50–198 mm2). The median duration of an ulcer before enrollment was 7 days (IQR, 4–15 days) in both groups. Women were generally immunosuppressed (median CD4 cell count, 190 cells/mm3; IQR, 84–520 cells/mm3), although a few (11 [9%] of 118 women) were receiving HAART. Women in the acyclovir group were more likely to have detectable plasma, lesional, and cervicovaginal HIV-1 RNA at baseline

Figure 2
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Figure 2

Detection of cervicovaginal human immunodeficiency virus type 1 (HIV-1) RNA and herpes simplex virus type 2 (HSV-2) DNA in HIV-1–infected women with HSV-2 ulcers in Ghana and the Central African Republic over time

Figure 3
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Figure 3

Rates of ulcer healing (as determined by Kaplan-Meier analysis) among 118 human immunodeficiency virus type 1–infected women with herpes simplex virus type 2 ulcers in Ghana and the Central African Republic. *P=.21 was estimated from Cox regression, with ulcer healing defined as a ⩾90% reduction in ulcer size. Nos. of patients at each visit are based on the no. of women whose ulcer size was recorded, which may be different from the no. of women who had cervicovaginal lavage specimens available, as shown in figure 1

Table 1
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Table 1

Baseline characteristics of the primary analysis group: 118 human immunodeficiency virus type 1 (HIV-1)–infected women with herpes simplex virus type 2 (HSV-2) ulcers in Ghana and the Central African Republic (CAR)

Impact on cervicovaginal, lesional, and plasma HIV-1 RNAThe proportion of women in the acyclovir group who had detectable cervicovaginal HIV-1 RNA decreased from 80% at D0 to 71% at D7, but there was no evidence of an impact of acyclovir on detectable cervicovaginal HIV-1 RNA, after adjusting for detection at D0 (RR, 0.96; 95% CI, 0.8–1.2) (table 2). There also was little reduction in the mean quantity of cervicovaginal HIV-1 RNA among women with detectable cervicovaginal HIV-1 RNA at D7 (−0.06 log10 copies/mL; 95% CI, −0.4 to 0.3 log10 copies/mL). Similarly, the repeated-measures (i.e., per-visit) analyses found little impact of acyclovir on either the detection or quantitation of cervicovaginal HIV-1 RNA (table 2 and figure 2)

Table 2
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Table 2

Effect of acyclovir among human immunodeficiency virus type 1 (HIV-1)–infected women with herpes simplex virus type 2 (HSV-2) ulcers, by treatment group

Table 2 also shows the impact of acyclovir on lesional HIV-1 RNA at D7 and on plasma HIV-1 RNA at D14. The proportion of women with detectable lesional HIV-1 RNA decreased in both groups, from 70% to 35% in the placebo group and from 76% to 27% in the acyclovir group (RR, 0.70; 95% CI, 0.4–1.2). There was no effect of acyclovir on the quantity of plasma HIV-1 RNA at D14 (+0.09 log10 copies/mL; 95% CI, −0.1 to 0.3 log10 copies/mL) or at D28 (0.01 log10 copies/mL; 95% CI, −0.3 to 0.4 log10 copies/mL) (data not shown)

Impact of acyclovir on cervicovaginal HSV-2 DNA and ulcer healingWomen receiving acyclovir were less likely to have detectable cervicovaginal HSV-2 at D7 than were women receiving placebo (RR, 0.69; 95% CI, 0.4–1.3) (table 2), and among those with detectable virus at D7, the quantity of virus was 1 log lower (−0.99 log10 copies/mL; 95% CI, −1.8 to −0.2 log10 copies/mL). There was also some impact of acyclovir on the detection of cervicovaginal HSV-2 DNA at day 2 or day 4 (RR, 0.73; 95% CI, 0.5–1.1) (data not shown). Differences were greater on the repeated-measures analyses (odds ratio [OR], 0.49 [95% CI, 0.3–0.9]; mean, −0.73 log10 copies/mL [95% CI, −1.1 to −0.4 log10 copies/mL]) (table 2 and figure 2)

There was some evidence that acyclovir improved ulcer healing, with 26 (55%) 47 ulcers healed at D7 in the acyclovir group compared with 26 (44%) of 59 ulcers healed in the placebo group (RR, 1.26; 95% CI, 0.9–1.9) and with similar data noted for those with small ulcers (27 [57%] of 47 vs. 25 [42%] of 59 ulcers, respectively; RR, 1.60 [95% CI, 1.0–2.5]) (table 2). Cox regression showed a weak effect of acyclovir on the rate of ulcer healing, which was defined as a ⩾90% reduction in ulcer size (hazard ratio [HR], 1.28; 95% CI, 0.9–1.9) (P=.21) (median time to healing, 7 vs. 8 days) (figure 3). Similar results were seen when ulcer healing was defined as a reduction in ulcer size to ⩽10 mm2 (HR, 1.35; 95% CI, 0.9–2.0) (P=.14) (median time to healing, 7 vs. 8 days)

At D7, according to ulcer duration before presentation (<7 days vs. ⩾7 days), there was no modification of the effect of acyclovir on genital HIV-1 RNA (P=.58) or ulcer healing (P=.88). However, acyclovir reduced genital HSV-2 DNA among those who presented late (RR, 0.38; 95% CI, 0.2–0.9) but not among those who presented within a week from the onset on an ulcer (RR, 1.55; 95% CI, 0.6–4.2) (P=.03)

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Discussion

We report what is, to our knowledge, the first randomized trial evaluating the impact of episodic antiviral therapy for HSV-2 added to syndromic management on HIV-1 outcomes among African women presenting with genital ulcer disease. In HIV-1–infected women with HSV-2 ulcers, there was no effect of acyclovir on cervicovaginal and plasma HIV-1, some evidence of reduction in lesional shedding of HIV-1 and of reduced frequency and quantity of cervicovaginal shedding of HSV-2, and only modest improvements in ulcer healing

The rationale for this study was multifold. First, epidemiologic and biological evidence has suggested an important role of HSV in enhancing HIV replication and, possibly, transmission. Clinical and subclinical reactivation of genital HSV-2 has been associated with increases in HIV-1 genital shedding [6–10, 30] and plasma HIV-1 loads [10, 20, 21], and observational studies of HSV episodic therapy have shown that acyclovir has a role in reducing lesional and plasma HIV-1 levels [6, 21]. Second, the strong association of HIV transmission with genital ulcer disease [31, 32] suggests that a substantial proportion of HIV transmissions may take place during clinical ulcer episodes, including in settings where the majority of ulcers are caused by HSV-2 [22]. Shortening the duration of ulcerative episodes may therefore have an appreciable effect on HIV transmission [31, 33]. Antibiotic treatment reduces HIV shedding in men with urethritis [34], and, in community randomized trials, it also reduces the incidence and prevalence of ulcer-causing infections [35, 36] as well as the incidence of HIV [37], although it is unclear whether the latter was mediated through an effect in reducing HIV susceptibility, HIV infectiousness, or both. Because the majority of ulcers in developing countries are caused by HSV-2 [3], particularly among HIV-positive patients, the World Health Organization recommends adding acyclovir to antibacterial syndromic management [23]. However, data on the effectiveness of this strategy in developing countries, where patients may present late (often with concomitant HIV infection), is lacking. Furthermore, few studies of episodic antiherpetic therapy provided to HIV-positive patients have been conducted, even in industrialized countries [6, 38]. Thus, we measured the impact of episodic HSV treatment in a pragmatic trial. Our results suggest that currently recommended HSV therapy does not dramatically improve ulcer healing, has only a modest effect on HSV-2 shedding, and could not inhibit the replication of HIV-1 in the genital tract or plasma

The estimated adherence to the study drug, as measured by pill counts, was very high, and the acyclovir dosage and duration of therapy used were the same as those specified in current treatment guidelines for recurrent genital herpetic ulceration [23, 25]. Given that only 15%–30% of orally administered acyclovir is absorbed [39, 40], it may be that this regimen, which has been studied mostly among HIV-uninfected patients, is insufficient to promote ulcer healing and reduce HSV-2 shedding (and, by implication, HIV-1 replication) among HIV-infected patients, many of whom have substantial immunosuppression. In an international multicenter trial conducted among HIV-infected patients, Conant et al. [38] did not find any difference in ulcer healing between patients taking 1000 mg of valacyclovir twice daily (>50% of which is absorbed) or 200 mg of acyclovir 5 times daily for 5 days, with a median time to healing of 5 days in both treatment groups. This was 2 days less than the median time to ulcer healing noted among women taking acyclovir in the present study. The fact that the level of immunosuppression among HIV-1–infected women in the present study was more pronounced than that noted in the study by Conant et al. [38] (by an average increase of 50 cells/mm3) may have contributed to slow reepithelialization. Prolonged therapy (duration, ⩾10 days) [25] or a higher dosage of antivirals may be necessary for more immunocompromised individuals

Early initiation of therapy (within 24–48 h of the onset of the lesion) is required for optimal control of HSV-2, because peak shedding of HSV-2 is generally observed within 24 h of the onset of the lesion [41]. Thus, the modest effect on HSV-2 genital shedding and ulcer healing noted in the present study may be partly attributable to the long delay before the start of acyclovir after the onset of lesions, although our subgroup analysis suggested a stronger effect of acyclovir on HSV-2 shedding among patients presenting >7 days after onset of the lesion. Such delays are probably representative of most resource-poor settings, where, given limited awareness and accessibility of medical services and herpes treatment, a selection process might have biased recruitment to patients with more severe cases, whereas more-immunocompetent patients preferentially wait for spontaneous resolution of their ulcer

The results of the present study indicate that management of herpetic clinical episodes was unable to reduce systemic and genital HIV-1 replication. By contrast, recent trials of daily suppressive antiviral therapy for HSV-2 in patients coinfected with HSV-2 and HIV have shown an effect on both genital and plasma HIV-1 RNA loads among asymptomatic patients [12–16], with some exceptions [42, 43], thereby confirming the causal relationship between HSV reactivation and HIV replication. The postulated mechanism of impact is that, by reducing reactivations of HSV-2, herpes-suppressive therapy is able to prevent HIV replication by disrupting direct viral interactions and, indirectly, by reducing the systemic and local immune activation induced by HSV-2 [11]. HSV-2 genital shedding is associated with increased levels of HIV-1 target cells (i.e., activated CD4 T lymphocytes and immature dendritic cells) within the genital mucosa [44, 45], and recent studies have shown that an HSV-2–specific cellular immune response persists in the genital mucosa after resolution of herpes lesions [46]. This response may increase replication of genital HIV-1 in HIV-1–infected individuals. In addition, recent ex vivo experiments have suggested that acyclovir may directly inhibit HIV replication in tissues coinfected with HSV and HIV [47]. However, our data suggest that such an effect may not be potent enough in vivo or is not sustained long enough to have a major impact

Our study had a number of limitations. It was designed as a pragmatic trial, in which unselected patients presenting with genital ulcers were randomized regardless of their HIV status and HSV status, because these could not be determined before randomization. Therefore, our primary analysis included only a subgroup of the randomized patients, and this resulted, by chance, in unbalanced groups for some baseline characteristics. In particular, women in the acyclovir group were more likely to have detectable plasma, lesional, and cervicovaginal HIV-1 RNA at baseline. As specified in our analysis plan, we adjusted for these baseline imbalances when estimating effect, but the direction of these imbalances may have led to underestimation of the true impact of the intervention. Our final sample size was also slightly smaller than that estimated by the power calculations (118 vs. 135 patients), and this fact, combined with an imbalance in numbers in each group, would have slightly reduced our power to detect significant differences. Finally, exclusion (for ethical reasons) of patients with more-severe herpetic ulcers may limit the generalizability of our findings, because such patients may more readily experience benefits from acyclovir therapy

In conclusion, our results indicate that, among HIV-infected women, the use of acyclovir in accordance with current recommendations for the management of genital ulcer disease due to HSV-2 had only a weak effect on the course of the ulcers and HSV-2 genital shedding, and it did not reduce systemic and genital HIV replication. Our results do not support the hypothesis that provider-initiated short-course acyclovir therapy effectively disrupts genital interactions between HIV-1 and HSV-2 or that such treatment has any profound effect on genital HIV-1 transmissibility. Trials of longer regimens or alternative antivirals, such as oral valacyclovir, would be useful to support the inclusion of herpes episodic therapy in the management of genital ulcer disease. Offering herpes-suppressive therapy to HIV-infected individuals presenting with genital ulcers might help reduce the frequency of clinical recurrences and the effect on transmission and progression of HIV-1

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Study Group Members

Members of the ARNS 1212 Study Group (by affiliation[s]) are as follows: L.B., H.B., Cécile Chemin, Maxime Lecerf, J.LeG., and Ali Si-Mohamed (Université Paris V, Equipe “Immunité et Biothérapie Muqueuse,” Unité INSERM Internationale U743 [“Immunologie Humaine”], Centre de Recherches Biomédicales des Cordeliers and Laboratoire de Virologie, Hôpital Européen Georges Pompidou, Paris, France); R.J.H., D.C.W.M., P.M., and H.A.W. (Clinical Research Unit, Department of Infectious and Tropical Diseases, and Infectious Disease Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom); G.G. and Jean-de-Dieu Longo (Centre National de Référence des Maladies Sexuellement Transmissibles et du SIDA de Bangui, & Unité de Recherches et d’Intervention sur les Maladies Sexuellement Transmissibles et du SIDA, Faculté des Sciences de la Santé, Bangui, Central African Republic); Thomas Agyarko-Poku, Comfort Asamoah-Adu, Agnes Dzokoto, and K.N. (West African Project to Combat AIDS and STDs, Accra, Ghana); Centre for International Health, University of Sherbrooke, Sherbrooke, Canada (Sylvie Deslandes, E.F., and J.P.); and J.-E.M. (Centre Médical, Institut Pasteur, Paris, France)

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Acknowledgments

We thank the women who participated in this study; the staff from the Centre National de Référence des Maladies Sexuellement Transmissibles et du SIDA (Bangui, Ghana); and the West African Project to Combat AIDS and STIs (Accra and Kumasi, Central African Republic). We also thank Michel Kazatchkine, Brigitte Bazin, and Séverine Blesson (Agence Nationale de Recherches sur le SIDA et les Hépatites) and Jamie Robinson (GlaxoSmithKline) for their support throughout the study. We are also grateful to members of the Data Monitoring Committee (Peter Smith [chair] and Tim Clayton [both from the London School of Hygiene & Tropical Medicine] and Anne Johnson [from the Royal Free Hospital, London]) and to Francis Ndowa (from the Reproductive Health Research Division, STI Unit, World Health Organization, Geneva) for their advice

Financial supportAgence Nationale de Recherches sur le SIDA et les Hépatites (ANRS), Paris (ANRS 1212); ANRS Clinical Monitor contract to H.B; GlaxoSmith Kline (GSK) Research & Development Department, Worldwide Epidemiology, Greenford, United Kingdom (GSK had no role in the manufacture and distribution of study drugs or on the review and analysis of trial results); and the United Kingdom Department for International Development–funded Research Programme Consortium on Research and Capacity Building on Sexual & Reproductive Health and HIV in Developing Countries

Supporting informationConsolidated Standards of Reporting Trials Checklist; Agence Nationale de Recherches sur le SIDA et les Hépatites 1212 Trial Plan of Analysis

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Footnotes

  • ↵Potential conflicts of interest: none reported

    Presented in part: Annual Conference of the International Union against Sexually Transmitted Infections, Versailles, France, 19–21 October 2006 (oral presentation)

    Financial support: Please see the Acknowledgments for information on financial support and supporting information

  • ↵Members of the study group are listed after the text

  • ↵The views presented in this manuscript are those of the authors and do not necessarily represent the official position of the United Kingdom Department of International Development

  • Received December 17, 2008.
  • Accepted February 25, 2009.
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  1. J Infect Dis. (2009) 200 (2): 216-226. doi: 10.1086/599991
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