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Herpes Simplex Virus (HSV) Suppression with Valacyclovir Reduces Rectal and Blood Plasma HIV-1 Levels in HIV-1/HSV-2-Seropositive Men: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial

  1. Richard A. Zuckerman1,
  2. Aldo Lucchetti6,
  3. William L. H. Whittington2,
  4. Jorge Sánchez6,
  5. Robert W. Coombs2,3,
  6. Rosario Zuñiga6,
  7. Amalia S. Magaret3,
  8. Anna Wald2,3,4,5,
  9. Lawrence Corey2,3,5 and
  10. Dr. Connie Celum2,4
  1. 1 Section of Infectious Disease and International Health, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
  2. 2 Department of Medicine, University of Washington, Seattle
  3. 3 Department of Laboratory Medicine, University of Washington, Seattle
  4. 4 Department of Epidemiology, University of Washington, Seattle
  5. 5 Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle
  6. 6 Asociacion Civil Impacta Salud y Educacion, Lima, Peru
  1. Reprints or correspondence: Dr. Connie Celum University of Washington Harborview Medical Center Box 359927 325 9th Ave. Seattle WA 98104 (ccelum{at}u.washington.edu).

  1. Presented in part: 44th Annual Meeting of the Infectious Diseases Society of America, Toronto, 11–15 October 2006 (abstract LB-25).

 
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Abstract

Background. Herpes simplex virus type 2 (HSV-2) infection is common among human immunodeficiency virus (HIV)-infected persons, and HSV reactivation increases plasma and genital HIV-1 levels. We studied HIV-1 levels during HSV suppression in coinfected persons in a placebo-controlled crossover trial.

Methods. Twenty antiretroviral therapy (ART)—naive HIV-1/HSV-2—seropositive men who have sex with men in Lima, Peru, with CD4 cell counts >200 cells/μL were randomized to receive either valacyclovir at 500 mg twice daily or placebo for 8 weeks, after which they underwent a 2-week washout period and then received the alternative regimen for 8 weeks. Specimens included daily anogenital swabs (for HSV DNA polymerase chain reaction [PCR]), thrice weekly rectal mucosal secretions (for HIV-1 RNA and HSV DNA PCR) obtained by anoscopy, and weekly plasma (for HIV-1 RNA PCR). Outcomes were rectal and plasma HIV-1 RNA levels by treatment arm.

Results. HIV-1 was detected in 73% of 844 rectal and 99% of 288 plasma specimens. HSV was detected in 29% and 4% of mucocutaneous specimens obtained during placebo and valacyclovir administration, respectively (P< .001). Valacyclovir resulted in a 0.16 (95% confidence interval [CI], 0.07–0.25;P=.0008; 33% decrease) log10copies/mL lower mean within-subject rectal HIV-1 level and a 0.33 (95% CI, 0.23–0.42;P<.0001; 53% decrease) log10 copies/mL lower plasma HIV-1 level, compared with values for placebo.

Conclusions. Valacyclovir significantly reduces rectal and plasma HIV-1 levels in HIV-1/HSV-2-coinfected men. HSV suppression may provide clinical benefits to persons not receiving highly active ART as well as public health benefits.

Trial registration. ClinicalTrials.gov identifier: NCT00378976.

Most HIV-infected persons are also infected with herpes simplex virus type 2 (HSV-2) [1]. The risk of HIV-1 transmission is higher in HIV-1 serodiscordant couples when the source partner has reported recent genital ulcers [2]. Plasma and genital HIV-1 levels are increased during both symptomatic and asymptomatic HSV reactivations [3–6]. In vitro studies have demonstrated that HSV proteins increase HIV-1 expression [7–9], HSV coinfection of HIV-infected cells [10], and levels of proinflammatory cytokines during HSV reactivation, which increase HIV-1 replication [11]. These observations support the hypothesis that, by increasing HIV-1 replication, HSV may have clinical consequences for coinfected persons as well as public health consequences.

Proof-of-concept studies among HIV/HSV-coinfected persons are needed to assess whether HSV suppression consistently decreases HIV-1 levels in plasma and genital secretions. Daily suppressive therapy for HSV infection is highly effective in reducing both clinical and subclinical HSV reactivation in HIV—infected persons [12, 13]. A randomized trial in Burkina Faso recently showed that suppressive valacyclovir significantly reduced cervical and plasma HIV-1 levels [14]. This observation is consistent with a pooled analysis of 8 studies conducted in the 1990s of high-dose acyclovir in combination with mono- or dual-nucleoside antiretroviral therapy (ART), which indicated a survival benefit among HIV-infected persons who received acyclovir [15].

To evaluate the effect of HSV-2 suppression on anogenital and plasma HIV-1 levels among men, we conducted a randomized, double-blind, placebo-controlled crossover trial of daily valacyclovir among ART-naive HIV-1/HSV-2-coinfected men who have sex with men (MSM) with CD4 cell counts >200 cells/μL in Lima, Peru.

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Methods

Study Characteristics

Study design. A randomized, double-blind, placebo-controlled crossover trial of valacyclovir for HSV and HIV-1 suppression was conducted at the Asociacion Civil Impacta Salud y Education, a research organization in Lima. Eligible persons were MSM who were ⩾18 years old, were seropositive for HIV-1 and HSV-2, had no history of antiretroviral use, and had a CD4 cell count >200 cells/μL. Exclusion criteria included current or planned therapy with antiretrovirals or herpes antivirals (acyclovir, famciclovir, or valacyclovir), a history of adverse reactions to herpes antivirals, a history of seizures, a serum creatinine level >2.0 mg/dL, and hematocrit <30%.

The human experimentation guidelines of the US Department of Health and Human Services and the individual institutions were followed in the conduct of the clinical research. The institutional review boards of the University of Washington and the Asociacion Civil Impacta Salud y Education approved the protocol. Participants provided written informed consent and were compensated for travel and related expenses. Men with sexually transmitted infection (STI) syndromes at screening were treated with regimens recommended by the Peruvian Ministry of Health. At the time of the study, antiretrovirals were available in Peru in public clinics only for HIV-infected persons with CD4 cell counts <200 cells/μL or with an AIDS-related condition.

Study medication. Valacyclovir (500 mg orally twice daily) and matching placebo were supplied by GlaxoSmithKline. Subjects were randomly assigned 1:1 (valacyclovir to placebo) in blocks of 10. After 8 weeks of the initial treatment, each participant crossed over to the alternative treatment for 8 weeks, separated by a 2-week washout period with daily placebo. Medication was dispensed every 2 weeks, with pill counts performed at each visit. Open-label valacyclovir (1 g orally twice daily for 3 days) was dispensed for symptomatic herpes recurrences.

Study procedures. At enrollment, participants received counseling about genital herpes and training regarding study procedures, were administered a brief questionnaire, underwent a physical exam, and had blood and rectal secretions collected. Participants came to clinic 3 times a week during each treatment period. Anoscopy was performed at each visit to collect rectal secretions, with Snostrips (for HIV-1 polymerase chain reaction [PCR]) used first followed by a Dacron swab (for HSV DNA PCR), and blood was drawn weekly. Participants also collected daily swabs of genital and perianal skin at home for HSV DNA PCR [16, 17]. At each clinic visit, participants returned their collected specimens (stored at room temperature).

Specimen Collection And Laboratory Procedures

STI tests. At screening and as clinically indicated during the study, rectal specimens were collected for Neisseria gonorrhoeae culture, and urine was collected for gonococcal and chlamydial nucleic acid amplification tests (NAAT; Aptima; Gen-Probe). Peripheral blood was collected for syphilis serological tests (rapid plasma reagin [RPR] and HSV-2 antibody [HerpeSelect-2 ELISA; Focus Technologies]). Positive HSV-2 ELISAresults (by use of an index value cutoff of >3.5 to improve specificity) [18, 19] were confirmed by Western blot [20]. Gonorrhea cultures, HerpeSelect-2 ELISAs, and RPR tests were performed in Lima. Gonococcal and chlamydial NAATs and HSV Western blots were performed at the University of Washington.

Rectal specimens. Rectal mucosal specimens were obtained through an anoscope 3–4 cm above the squamocolumnar junction. For HIV-1 RNA, 3 Snostrips (Chauvin Pharmaceuticals) were saturated with rectal mucosal secretions and placed into 500μL of guanidinium solution (4 mol/L guanidinium thiocyanate, 25 mmol/L sodium citrate [pH 7], 0.5% N-lauroylsarcosine, and 0.1 mol/L 2-mercaptoethanol); for HSV DNA PCR, the swab was placed in transport medium. Specimens were frozen at -70°C within 8 h of collection. Samples were collected by 1 of 2 clinicians.

Blood specimens. Peripheral blood was collected into tubes containing EDTA (Becton Dickinson) and separated within 8 h into plasma and mononuclear cells by ficoll-hypaque gradient centrifugation. Lymphocyte subsets were determined by flow cytometry methods in Lima. Plasma aliquots were frozen at -70° C and transported to the University of Washington Retrovirology Laboratory.

HIV-1 RNA quantitation assays. HIV-1 RNA was quantified using the TaqMan real-time RNA PCR (rt-PCR) amplification assay [21] or the Amplicor HIV Monitor assay (Roche Molecular Systems). The rt-PCR assay was modified to include a second gag oligonucleotide probe with a 5′-carboxyfluorescein (FAM) reporter dye and a 3′-minor groove binder/nonfluorescent quencher (AR8: 6FAM-CTA TCC CAT TCT GC-3MGBNFQ) to enhance sensitivity. HIV-1 RNA external standards and positive and negative controls were included on each 96-well plate. To ensure that negative results were not due to loss during nucleic acid extraction or nonspecific inhibition of the PCR assay, 300 copies of an external synthetic sequence control (Gene Amplimer pAW 109 RNA [ABI catalogue N808–0037]) were added to and copurified with participant and control samples. Each PCR also contained 800 nmol/L each of the forward primer (GCC TGG GTT CCC TGT TCC) and reverse primer (CGA CGT ACC CCT GAC ATG G) and 100 nmol/L of the labeled pAW probe (VIC-CCA GGC CAA TGT CTC ACC AAG CTC TG-MGBNFQ). The laboratory was certified by the National Institute of Allergy and Infectious Diseases-sponsored Virology Quality Assurance Program to perform both assays.

HIV-1 RNA was consistently not detected in plasma from 3 of the 20 participants by the rt-PCR assay. The primer and probe binding regions of gag were sequenced from plasma aliquots from these 3 subjects. Mutations were detected in the gag-binding regions for the HXB2 and AR8 probes or the SK431 primer, likely accounting for the negative rt-PCR results. Plasma and rectal specimens from these 3 participants were subsequently tested with the Amplicor HIV Monitor assay, which yielded HIV-1 RNA; these results were included in the analysis. For the remaining men, baseline specimens were analyzed by both assays, and no significant quantitative differences were found.

For all specimens, vials were warmed, briefly mixed in a vortex mixer, and microfuged for 5 s at 12,000 g before 200μL of fluid was withdrawn for testing. Silica extraction to remove inhibitory factors was performed before PCR analysis of rectal samples. For the TaqMan assay, the lower limit of detection (LLOD) for HIV-1 quantitation in blood plasma was 120 (2.1 log10) HIV-1 RNA copies/mL; for the Amplicor HIV Monitor assay, the LLOD in plasma was 400 (2.6 log10) HIV-1 RNA copies/mL. Because of the small amount of fluid absorbed by the 3 rectal Snostrips (25 μL) and the dilution with guanadinium, LLODs were typically 6000 (3.8 log10) and 12,800 (4.1 log10) HIV-1 RNA copies/mL for the TaqMan and Amplicor HIV Monitor assays, respectively. For rectal specimens, further dilutional steps were performed for specimens when repeat testing was required; thus, the LLOD exceeded these values for 9.9% of specimens.

HSV DNA Assay

DNA was extracted from 200 μL of each specimen by use of the QIAamp 96 DNA Blood Kit (Qiagen) and was elutedinto 100 μL of AE buffer. A fluorescent probe-based rt-PCR (TaqMan; Applied Biosystems) assay was used to quantitate HSV, using 10βL of the extracted DNA for each PCR, with primers and probe sequences and PCR conditions as described eslewhere [22, 23]. To ensure that negative results were not due to nonspecific inhibition, each PCR also contained 50,000 copies of EXO DNA, 30 mmol/L of primers EXO186F and EXO315R, and 50 nmol/L of probe EXO-P, labeled at the 5′ end with VIC (Perkin-Elmer Cetus) and at the 3′ end with TAMRA [24]. All negative HSV PCR results required detection of EXO DNA. One positive control with 5000 copies of HSV was coprocessed with specimens. Specimens were processed in parallel with aliquots of 1×PBS. Wells without DNA also were included in each PCR run.

Statistical Methods

Sample size. The primary study end point was the effect of valacyclovir on rectal mucosal HIV-1 levels. On the basis of on our previous studies among MSM [25] and assuming a 10% dropout rate, we estimated that a sample size of 20 men would provide >80% power to detect a change of 0.3 log10 copies/mL in HIV-1 shedding in the rectum. A crossover design was used because of lower variability in HIV-1 RNA levels in plasma and rectal secretions on multiple observations from a person than between persons [25].

Statistical analysis. HSV shedding rate was computed by dividing the days with detectable HSV in swabs collected at home or in the clinic by the total days of swab collection. HSV shedding was measured on the basis of (1) daily external anogenital swabs and (2) clinic-obtained rectal mucosal swabs. Primary analyses involved overall HSV shedding rates (either external anogenital or rectal mucosal). All analyses were done on an intent-to-treat basis, excluding the first day of study drug administration from each arm. Investigators and technologists were unaware of treatment assignments, and unblinding occurred only after all laboratory assays were completed. For undetectable HIV-1 values, the midpoint between zero and the LLOD was used; HIV-1 values were log-transformed. HSV shedding was examined as a binary variable (detected vs. not detected).

Univariate nonlinear mixed-effects models with a Poisson link were used to compute the rate ratio comparing HIV-1 detection rates in each treatment arm. The mean quantity of HIV-1 in rectal Snostrips and plasma were compared by treatment arm. Potential predictors of HIV-1 level were evaluated using linear mixed-effect models. Because HIV-1 quantity is modeled on the log10 scale, coefficients (β) from models are exponentiated (10β) and compared with 1 to compute percent changes in HIV-1 quantity. Multivariate analysis with backward elimination using mixed-effects models were also performed to compare treatment arms after adjusting for CD4 cell count and HSV shedding, including interaction terms. Potential sequence effects were evaluated. Statistical analysis was performed using SAS for Windows (version 9.1).

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Results

Study population and protocol adherence. Of 63 men screened, 20 met the study entry criteria and were enrolled. The median age of participants was 31 years (range, 22–44 years), and the median CD4 cell count was 406 cells/μL (range, 23–869 cells/μL) (table 1). Of these 20 HIV-1/HSV-2-seropositive men, 4 (20%) reported prior genital or anal herpes episodes. Serological evidence of prior Treponema pallidum infection was detected in 8 men (40%), of whom 2 were treated for early syphilis on the basis of titers before enrollment; the other 6 were considered to have been treated adequately in the past. No rectal or urethral gonococcal or chlamydial infections were diagnosed during the study.

Figure 1.
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Figure 1.

Comparison of rectal (A) and plasma (B) HIV-1 levels between treatment arms, by individual participant. Boxes represent the mean HIV-1 level and brackets denote 1 SD for observations after the first day of each treatment. Undetectable HIV-1 levels were imputed to the midpoint between zero and the lower limit of detection (LLOD). For participants with mean values near the LLOD, the lower SD limit may span below the LLOD because of the effect of other values on the SD calculation. In panel A, for participants without detectable values in a given treatment arm, the marker is placed at the LLOD for that participant's values.

Figure 2.
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Figure 2.

Difference in mean plasma HIV level between the valacyclovir and placebo arms in 20 men who have sex with men enrolled in a randomized crossover trial, by CD4 cell count at screening. The figure shows a greater reduction in HIV levels at higher CD4 cell counts (P = .018).

Table 1.
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Table 1.

Characteristics of 20 men who have sex with men enrolled in a randomized, double-blind, placebo-controlled crossover trial of valacyclovir for the suppression of HIV-1 and herpes simplex virus type 2 (HSV-2).

Nineteen men (95%) completed the 18-week study; 1 participant withdrew after 14 weeks. Participants completed a median of 46 (range, 31–48) of 48 possible clinic visits. On the basis of pill counts, the men took a median of 96.2% (range, 65.8%–100%) of study drug dispensed. Study drug was well tolerated, with no reports of serious adverse events. Four men were treated with open-label valacyclovir for herpes recurrences during the study, of which 3 occurred during placebo administration. Overall, the analysis database included 2155 days with at least 1 genital and/or perianal swab collected for HSV DNA PCR, including 904 HSV swabs from anoscopy, 844 Snostrip samples for mucosal HIV-1 detection, and 288 plasma samples. Adherence with self-collection of anogenital swabs for HSV-2 DNA PCR was high, with a median 98.6% (range, 88.4%–100%) of expected swabs collected.

HSV detection in genital and rectal swabs. HSV DNA was detected in any anogenital specimen at least once for all study participants. Overall, HSV was detected in 29% of swabs during placebo administration, compared with 4% of swabs during valacyclovir administration (P<.001) (table 2). By participant, HSV detection ranged from 11% to 68% of all swabs obtained during placebo administration and from 0% to 26% of all swabs obtained during valacyclovir administration. Among rectal swabs obtained via anoscopy, HSV was detected in 25% of swabs obtained during placebo administration and in 3% of swabs obtained during valacyclovir administration (P < .001); the ranges of rectal swabs positive for HSV by participant were 0%–96% for placebo and 0%-17% for valacyclovir. The majority of HSV detection was asymptomatic, with only 4 symptomatic HSV recurrences.

Table 2.
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Table 2.

Rates of herpes simplex virus (HSV) and HIV-1 detection and mean log10 HIV-1 levels for 20 HIV-1/HSV-2-coinfected men who have sex with men.

Rectal HIV-1 levels. Overall, HIV-1 was detected in 620 (73%) of 844 rectal mucosal samples obtained from the 20 participants: 78% (333/427) of samples collected during placebo administration and in 69% (287/417) of samples collected during valacyclovir administration (P = .02) (table 2). The range by participant was 0%–100% in both the placebo and valacyclovir arms, with 2 participants having ⩽3 rectal specimens with detectable HIV, regardless of treatment arm. The mean HIV-1 levels in rectal secretions during placebo and valacyclovir administration were 5.00 (SD, 1.04) and 4.80 (SD, 1.04) log10 copies/mL, respectively (P < .001) (table 2).

In univariate analysis, the mean within-subject decrease in rectal HIV-1 levels during valacyclovir administration versus placebo administration was 0.16 log10 copies/mL (95% confidence interval [CI], 0.07–0.25 log10 copies/mL;P= .0008), a 31% decrease (table 3). Participant-level means and SDs for rectal HIV-1 levels for the treatment arms are displayed in figure 1A. No significant sequence effects between treatment arms were found (data not shown). No significant associations were noted for rectal HIV-1 shedding and CD4 cell counts (P = .11) or for detection of HSV shedding by either external anogenital or rectal mucosal swabs (P = .34). However, in analyzing only HSV swabs obtained by anoscope, rectal HSV detection was associated with an increase of 0.39 log10 copies/mL in the rectal Sno-strip HIV-1 level, a 150% increase (P < .0001); this association did not remain significant in a multivariate model that included treatment arm.

Table 3.
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Table 3.

Potential predictors of HIV-1 level in rectal mucosa and plasma, in univariate and multivariate models.

Plasma HIV-1 levels. HIV-1 RNA was detected in 284 (98.6%) of 288 plasma samples. Mean HIV-1 levels in plasma during placebo and valacyclovir administration were 4.50 (SD, 0.71) and 4.14 (SD, 0.71) log10 copies/mL, respectively (P < .001) (table 2). In univariate analysis, the mean within—subject decrease in plasma HIV-1 levels during valacyclovir administration versus placebo administration was 0.33 log10 copies/mL (95% CI, 0.23–0.42 log10 copies/mL;P < .0001), corresponding to a 53% decrease in the quantity of plasma HIV-1. Participant-specific means and SDs for plasma HIV-1 levels for the treatment arms are displayed in figure 1B. No significant sequence effects between treatment arms were found (data not shown). No univariate association between plasma HIV-1 level and CD4 cell counts was observed (P = .18). Univariately, the detection of HSV in rectal swabs was associated with an increase of 0.27 log10 copies/mL in HIV-1 level (P = .037); this association did not remain significant in a multivariate model that included treatment arm.

In multivariate analysis, the mean within-subject decrease in plasma HIV-1 levels during daily suppressive valacyclovir was 0.33 log10 copies/mL (P < .001). When CD4 cell count and treatment arm were included as an interaction term, there was a greater decrease in plasma HIV-1 levels for each 100-cell/mL increase in CD4 cell count for the valacyclovir arm (P = .018) (figure 2).

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Discussion

Our findings show that antiviral drugs that effectively suppress HSV reactivation significantly reduce plasma and mucosal HIV-1 RNA levels among HIV-1/HSV-2-coinfected MSM. In this proof-of-concept crossover trial with multiple observations per participant and intensive mucosal sampling, suppressive therapy with valacyclovir (500 mg twice daily) was associated with mean reductions of 31% in rectal and 53% in plasma HIV-1 levels. Importantly, we documented that the significant reduction in HSV detection coincided with the reduction in HIV-1 level, indicating that this effect on systemic and mucosal HIV-1 levels was mediated through HSV suppression. Our detection of HSV in samples from the distal rectum, where mucosal secretions were sampled to quantify rectal HIV-1 shedding, further suggests a direct association between anogenital HSV reactivation and HIV-1 replication. Thus, these findings support a substantial body of research in which HSV-2 enhanced HIV-1 replication in vitro and HSV-2 reactivation increased plasma and anogenital HIV-1 load in vivo, indicating that HSV-2 may enhance HIV-1 infectiousness in coinfected persons [2, 26–29].

The mean decrease in plasma HIV-1 level was 0.33 log10 copies/mL over the 2 months of HSV suppression, with a more pronounced effect among men with higher CD4 cell counts. Our findings are consistent with those of a recent trial in Burkina Faso in women, which demonstrated a mean reduction of 0.53 log10 copies/mL in plasma HIV level with valacyclovir suppression [14]. Natural history studies indicate that such a reduction in plasma HIV-1 levels may result in clinical benefits if associated with increased CD4 cell counts and delayed HIV disease progression [30, 31]. Comparable reductions in plasma HIV-1 levels (∼0.5 log10 copies/mL) with zidovudine monotherapy have translated into clinical benefit [32], although the benefit was attenuated by HIV rebound due to resistance to zidovudine. However, this would not be expected with antiherpes therapy, because it acts via suppression of a cofactor in HIV-1 up-regulation rather than directly on HIV-1 transcription. Interestingly, the Burkina Faso study, during which the study drug was administered for 3 months, noted an increased effect on HIV-1 over time, suggesting that longer duration of HSV-2 suppression may achieve greater reductions in HIV-1 levels. In comparison, the present crossover trial involved 2 months of administration for each arm, and no temporal effect in HIV-1 levels was observed (data not shown). Both trials showed an increased effect with a higher CD4 cell count.

HSV replication occurs in the anogenital mucosa, and the mechanisms by which HSV reactivation increases HIV-1 levels in plasma are not well understood. Increased levels of proinflammatory genital cytokines and chemokines were observed in a cross-sectional study of HIV-1/HSV-2—coinfected African women who were shedding HSV-2, compared with those in women who were not shedding HSV-2 [33]. Among HIV/HSV-2—coinfected MSM, anorectal HSV reactivation could directly increase HIV replication in the gut lymphoid tissue, which contains large numbers of CD4 lymphocytes, dendrocytes, and macrophages. The greater reduction in plasma HIV-1 than rectal HIV-1 levels during HSV suppression is likely a reflection of biological factors and greater variability in rectal HIV-1 measurement, given the small volumes collected by Snostrips and the dilution for sufficient volume for the HIV-1 RNA assays. Complex factors likely influence HIV replication in the gut—associated lymphoid tissue, which contains more CD4 T cells than lymph nodes or the peripheral blood [34]. Further studies, including immunological and virological analyses of rectal biopsy samples, will be required to understand the pathogenesis of anorectal HSV reactivation and HIV-1 replication.

Most HSV reactivations in this cohort were asymptomatic, so HSV interventions directed at decreasing HIV-1 levels will require the use of suppressive rather than episodic treatment. Given the small proportion who shed HSV-2 during valacyclovir administration in this trial, additional studies are needed to assess the effect of greater HSV-2 suppression on HIV replication. Valacyclovir, the hydrochloride salt of the L-valyl ester of acyclovir, is rapidly and completely metabolized to acyclovir, achieves higher plasma levels than do similar doses of acyclovir, and is very safe. Studies with comparable doses of acyclovir, which is available generically at lower cost, have demonstrated comparable efficacy to valacyclovir in suppressing HSV recurrences and shedding [35, 36]. Although acyclovir-resistant strains of HSV are observed among HIV-1- and HSV-2—infected persons [37–39], the prevalence remains low (<5%). Genital herpes lesions that are clinically refractory to acyclovir therapy because of acyclovir resistance are much less common [39, 40], and transmission of acyclovir-resistant strains is rare [41].

The limitations of the present study include our inability to precisely quantify lower levels of rectal HIV-1 and to detect rectal mucosal abnormalities not visualized on anoscopy. Adherence was assessed by pill count and self-report, which may not perfectly measure adherence, although the high rate of HSV suppression in the valacyclovir arm indicates very high adherence to study drug. The 8-week duration of treatment may have been too short to detect the maximal effect of HSV suppression on HIV levels. A longer trial is necessary to assess whether the reduction in HIV-1 levels translates to delayed HIV disease progression and clinical benefits from delayed time to highly active ART (HAART) initiation.

In summary, this randomized, double-blind, placebo-controlled crossover trial of valacyclovir in HIV-1/HSV-2-coinfected MSM with CD4 cell counts >200 cells/μL has demonstrated significant reductions in both mucosal and systemic HIV-1 levels during daily suppressive HSV therapy. Ongoing randomized trials will determine whether HSV suppression can reduce HIV-1 transmission and will address the potential for HSV suppression to delay HAART initiation. While awaiting those results regarding public health and clinical benefits of HSV suppression in HIV-1/HSV-2-coinfected persons, this study reinforces the need for HSV-2 serological testing among HIV-infected persons and the benefits of suppressive HSV therapy in those who have CD4 cell counts >200 cells/μL and are not receiving ART.

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Acknowledgments

We extend our grateful appreciation to the study participants. Additionally, we thank Shyla Sanchez and Julio Chamochumbi for study coordination and scheduling in Lima, Peru; Carmen Sanchez, Sofia Sanchez, and Dr. Jorge Vergara for clinical support and procedures for study participants; Drs. Jeffrey Ferris and Esmellin Perez for pharmacy support; Jerry Galea for technical support; Dr. Tuofu Zhu, Joan Dragavon, and the University of Washington Retrovirology Laboratory staff; and Stacy Selke, Dr. Meei-Li Huang, Dr. Rhoda Ashley-Morrow, and the University of Washington Virology Research Laboratories for support.

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Footnotes

  • Potential conflicts of interest: C.C. has received research grant support from the National Institutes of Health (NIH), the Bill and Melinda Gates Foundation, and GlaxoSmithKline (GSK) and has served on an advisory board for GSK. J.S. has received grant support from the NIH and GSK. A.W. has received grant support from the NIH, GSK, Antigenics, 3M, Roche, and Vical; she is a consultant for Novartis, PowderMed, and MediGene and is a speaker for Merck Vaccines. The University of Washington Virology Division Laboratories have received grant funding from GSK and Novartis to perform herpes simplex virus serologic assays and polymerase chain reaction assays for studies funded by these companies. L.C. directs these laboratories. He receives no salary support from these grants.

  • Financial support: GlaxoSmithKline (research grant R103); National Institutes of Health (Centers for AIDS Research Clinical Research and Laboratory Core Grants AI-27757 and AI-38858, R37 AI-42528, and HSV Program Project Grant AI-30731).

  • Received April 2, 2007.
  • Accepted April 27, 2007.
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References

  1. 1.↵
    1. Corey L,
    2. Wald A,
    3. Celum CL,
    4. Quinn TC
    . The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004;35:435-45.
    CrossRefMedlineWeb of Science
  2. 2.↵
    1. Gray RH,
    2. Wawer MJ,
    3. Brookmeyer R,
    4. et al
    . Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001;357:1149-range.
    CrossRefMedlineWeb of Science
  3. 3.↵
    1. Kreiss JK,
    2. Coombs R,
    3. Plummer F,
    4. et al
    . Isolation of human immunodeficiency virus from genital ulcers in Nairobi prostitutes. J Infect Dis 1989;160:380-range.
    Abstract/FREE Full Text
  4. 4.
    1. Mbopi Keou FX,
    2. Gresenguet G,
    3. Mayaud P,
    4. et al
    . Genital herpes simplex virus type 2 shedding is increased in HIV-infected women in Africa. AIDS 1999;13:536-7.
    CrossRefMedlineWeb of Science
  5. 5.
    1. Schacker TW,
    2. Ryncarz AJ,
    3. Goddard J,
    4. Diem K,
    5. Shaughnessy M,
    6. Corey L
    . Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA 1998;280:61-6.
    Abstract/FREE Full Text
  6. 6.↵
    1. McClelland RS,
    2. Wang CC,
    3. Overbaugh J,
    4. et al
    . Association between cervical shedding of herpes simplex virus and HIV-1. AIDS 2002;16:2425-30.
    CrossRefMedlineWeb of Science
  7. 7.↵
    1. Mosca J,
    2. Bednarik D,
    3. Raj N,
    4. et al
    . Herpes simplex virus type 1 can reactivate transcription of latent human immunodeficiency virus. Nature 1987;325:67-70.
    CrossRefMedline
  8. 8.
    1. Margolis D,
    2. Ostrove J,
    3. Straus S
    . HSV-1 activation of HIV-1 transcription is augmented by a cellular protein that binds near the initiator element. Virology 1993;192:370-4.
    CrossRefMedlineWeb of Science
  9. 9.↵
    1. Kucera L,
    2. Leake E,
    3. Iyer N,
    4. Raben D,
    5. Myrvik Q
    . Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) can coinfect and simultaneously replicate in the same human CD4+ cell: effect of coinfection on infectious HSV-2 and HIV-1 replication. AIDS Res Hum Retroviruses 1990;6:641-7.
    MedlineWeb of Science
  10. 10.↵
    1. Heng M,
    2. Heng S,
    3. Allen S
    . Coinfection and synergy of human immunodeficiency virus-1 and herpes simplex viurs-1. Lancet 1994;343:255-8.
    CrossRefMedlineWeb of Science
  11. 11.↵
    1. Moriuchi M,
    2. Moriuchi H,
    3. Williams R,
    4. Straus SE
    . Herpes simplex virus infection induces replication of human immunodeficiency virus type 1. Virology 2000;278:534-40.
    CrossRefMedlineWeb of Science
  12. 12.↵
    1. Schacker T,
    2. Hu HL,
    3. Koelle DM,
    4. et al
    . Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons: a double-blind, placebo-controlled trial. Ann Intern Med 1998;128:21-8.
    Abstract/FREE Full Text
  13. 13.↵
    1. DeJesus E,
    2. Wald A,
    3. Warren T,
    4. et al
    . Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis 2003;188:1009-16.
    Abstract/FREE Full Text
  14. 14.↵
    1. Nagot N,
    2. Ouedraogo A,
    3. Foulongne V,
    4. et al
    . Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007;356:790-9.
    CrossRefMedline
  15. 15.↵
    1. Ioannidis JPA,
    2. Collier AC,
    3. Cooper DA,
    4. et al
    . Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis ofrandomized individual patient data. J Infect Dis 1998;178:349-59.
    Abstract/FREE Full Text
  16. 16.↵
    1. Wald A,
    2. Zeh JE,
    3. Barnum G,
    4. Davis LG,
    5. Corey L
    . Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med 1996;124:8-15.
    Abstract/FREE Full Text
  17. 17.↵
    1. Wald A,
    2. Corey L,
    3. Cone R,
    4. Hobson A,
    5. Davis G,
    6. Zeh J
    . Frequent genital HSV-2 shedding in immunocompetent women. J Clin Invest 1997;99:1092-7.
    MedlineWeb of Science
  18. 18.↵
    1. Prince HE,
    2. Ernst CE,
    3. Hogrefe WR
    . Evaluation of an enzyme immunoassay system for measuring herpes simplex virus (HSV) type 1-specific and HSV type 2-specific IgG antibodies. J Clin Lab Anal 2000;14:13-6.
    CrossRefMedlineWeb of Science
  19. 19.↵
    1. Golden MR,
    2. Ashley-Morrow R,
    3. Swenson P,
    4. Hogrefe WR,
    5. Handsfield HH,
    6. Wald A
    . Herpes simplex virus type 2 (HSV-2) Western blot confirmatory testing among men testing positive for HSV-2 using the focus enzyme-linked immunosorbent assay in a sexually transmitted disease clinic. Sex Transm Dis 2005;32:771-7.
    CrossRefMedlineWeb of Science
  20. 20.↵
    1. Ashley RL,
    2. Militoni J,
    3. Lee F,
    4. Nahmias A,
    5. Corey L
    . Comparison of Western blot (Immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus types 1 and 2 in human sera. J Clin Microbiol 1988;26:662-7.
    Abstract/FREE Full Text
  21. 21.↵
    1. Li CC,
    2. Seidel KD,
    3. Coombs RW,
    4. Frenkel LM
    . Detection and quantification of human immunodeficiency virus type 1 p24 antigen in dried whole blood and plasma on filter paper stored under various conditions. J Clin Microbiol 2005;43:3901-5.
    Abstract/FREE Full Text
  22. 22.↵
    1. Jerome KR,
    2. Huang ML,
    3. Wald A,
    4. Selke S,
    5. Corey L
    . Quantitative stability of DNA after extended storage of clinical specimens as determined by real-time PCR. J Clin Microbiol 2002;40:2609-11.
    Abstract/FREE Full Text
  23. 23.↵
    1. Wald A,
    2. Huang ML,
    3. Carrell D,
    4. Selke S,
    5. Corey L
    . Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces: comparison with HSV isolation in cell culture. J Infect Dis 2003;188:1345-51.
    Abstract/FREE Full Text
  24. 24.↵
    1. Limaye AP,
    2. Huang ML,
    3. Leisenring W,
    4. Stensland L,
    5. Corey L,
    6. Boeckh M
    . Cytomegalovirus (CMV) DNA load in plasma for the diagnosis of CMV disease before engraftment in hematopoietic stem-cell transplant recipients. J Infect Dis 2001;183:377-82.
    Abstract/FREE Full Text
  25. 25.↵
    1. Zuckerman RA,
    2. Whittington WL,
    3. Celum CL,
    4. et al
    . Higher concentration of HIV RNA in rectal mucosa secretions than in blood and seminal plasma, among men who have sex with men, independent of antiretroviral therapy. J Infect Dis 2004;190:156-61.
    Abstract/FREE Full Text
  26. 26.↵
    1. Mole L,
    2. Ripich S,
    3. Margolis D,
    4. Holodniy M
    . The impact of active herpes simplex virus infection on human immunodeficiency virus load. J Infect Dis 1997;176:766-70.
    Abstract/FREE Full Text
  27. 27.
    1. Schacker T,
    2. Zeh J,
    3. Hu H,
    4. Shaughnessy M,
    5. Corey L
    . Changes in plasma human immunodeficiency virus type 1RNA associated with herpes simplex virus reactivation and suppression. J Infect Dis 2002;186:1718-25.
    Abstract/FREE Full Text
  28. 28.
    1. Freeman EE,
    2. Glynn JR
    . Factors affecting HIV concordancy in married couples in four African cities. AIDS 2004;18:1715-21.
    CrossRefMedlineWeb of Science
  29. 29.↵
    1. Ouedraogo A,
    2. Nagot N,
    3. Vergne L,
    4. et al
    . Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS 2006;20:2305-13.
    MedlineWeb of Science
  30. 30.↵
    1. Mellors JW,
    2. Munoz A,
    3. Giorgi JV,
    4. et al
    . Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997;126:946-54.
    Abstract/FREE Full Text
  31. 31.↵
    1. Rodriguez B,
    2. Sethi AK,
    3. Cheruvu VK,
    4. et al
    . Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 2006;296:1498-506.
    Abstract/FREE Full Text
  32. 32.↵
    1. Katzenstein DA,
    2. Hammer SM,
    3. Hughes MD,
    4. et al
    . The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med 1996;335:1091-8.
    CrossRefMedlineWeb of Science
  33. 33.↵
    1. Rebbapragada A,
    2. Wachihi C,
    3. Pettengell C,
    4. et al
    . Negative mucosal synergy between herpes simplex type 2 and HIV in the female genital tract. AIDS 2007;21:589-98.
    MedlineWeb of Science
  34. 34.↵
    1. Mattapallil JJ,
    2. Douek DC,
    3. Hill B,
    4. Nishimura Y,
    5. Martin M,
    6. Roederer M
    . Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005;434:1093-7.
    CrossRefMedline
  35. 35.↵
    1. Conant MA,
    2. Schacker TW,
    3. Murphy RL,
    4. Gold J,
    5. Crutchfield LT,
    6. Crooks RJ
    . Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS 2002;13:12-21.
    Abstract/FREE Full Text
  36. 36.↵
    1. Gupta R,
    2. Wald A,
    3. Krantz E,
    4. et al
    . Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. J Infect Dis 2004;190:1374-81.
    Abstract/FREE Full Text
  37. 37.↵
    1. Reyes M,
    2. Shaik NS,
    3. Graber JM,
    4. et al
    . Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics. Arch Intern Med 2003;163:76-80.
    Abstract/FREE Full Text
  38. 38.
    1. Sarisky RT,
    2. Bacon TH,
    3. Boon RJ,
    4. et al
    . Profiling penciclovir susceptibility and prevalence of resistance of herpes simplex virus isolates across eleven clinical trials. Arch Virol 2003;148:1757-69.
    CrossRefMedlineWeb of Science
  39. 39.↵
    1. Levin MJ,
    2. Bacon TH,
    3. Leary JJ
    . Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected patients. Clin Infect Dis 2004;39 Suppl 5:S248-57.
    CrossRefMedlineWeb of Science
  40. 40.↵
    1. Safrin S,
    2. Elbeik T,
    3. Phan L,
    4. et al
    . Correlation between response to acyclovir and foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1994;38:1246-50.
    Abstract/FREE Full Text
  41. 41.↵
    1. Kost R,
    2. Hill E,
    3. Tigges M,
    4. Straus S
    . Brief report: recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N Engl J Med 1993;329:1777-82.
    CrossRefMedlineWeb of Science
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  1. J Infect Dis. (2007) 196 (10): 1500-1508. doi: 10.1086/522523
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