Decreasing plasma HIV-1 RNA in infected persons can prevent transmission to susceptible partners.1–6 However, at the end of 2010, it was estimated that less than half of those who met the WHO guidelines for initiation of antiretroviral therapy (ART) were receiving antiretroviral medications.7 While the gap between the goal of universal access and the realities of the current levels of antiretroviral coverage exists, alternative strategies to decrease plasma HIV-1 RNA, with the goal of reducing transmission and delaying HIV-1 disease progression, will remain important.
Standard-dose herpes simplex virus (HSV) suppressive therapy (acyclovir 400 mg or valacyclovir 500 mg twice daily) among persons coinfected with HIV-1 and HSV-2 reduced plasma HIV-1 RNA levels by 0.25–0.53 log10 copies per milliliter in several randomized controlled trials,8–15 and acyclovir modestly slows HIV-1 progression in patients not receiving ART.16,17 Postulated mechanisms by which anti-HSV therapy lowers plasma HIV-1 RNA levels include decreasing proinflammatory cytokines,18 decreasing HIV-1 transcriptional activation by HSV-encoded proteins,18,19 and direct inhibition of HIV-1 reverse transcriptase.20,21 In one study, high-dose valacyclovir (1.5 g twice daily) was associated with a decline in plasma HIV-1 RNA by 1.23 log10 copies per milliliter,22 suggesting a dose–response relationship. To investigate whether the reduction in plasma HIV-1 RNA with increasing doses of anti-HSV therapy is mediated by greater HSV suppression, we conducted a randomized, open-label crossover trial of high-dose valacyclovir compared with standard-dose acyclovir in HSV-2/HIV-1 coinfected persons in which we measured the effect of therapy on both plasma HIV-1 RNA and genital HSV shedding.
We recruited HIV-1/HSV-2 coinfected patients in Seattle, Washington, between January 2008 and June 2010. Inclusion criteria were age 18 years or older, detectable plasma HIV-1 RNA, the intention to remain in the area, and no current or planned initiation of ART during the study. Exclusion criteria were previous adverse reaction to acyclovir, valacyclovir, or famciclovir, current or planned open-label use of antivirals with anti-HSV activity, including ganciclovir, foscarnet, and cidofovir, active or prior cytomegalovirus (CMV) disease, history of seizures, creatinine >1.5 mg/dL, serum transaminases >3 times the upper limit of normal, hematocrit <30%, absolute neutrophil count (ANC) <1000/μL, platelet count <75,000/μL, history of thrombotic microangiopathy, and pregnancy.
Participants underwent randomization in a 1:1 ratio to receive open-label acyclovir 400 mg twice daily or valacyclovir 1000 mg twice daily. The randomization sequence, developed by the study statistician (A. Magaret), was implemented using sealed study kits. After 12 weeks on therapy, participants underwent a 2-week washout period and then crossed over to the alternative treatment arm for 12 weeks.
Clinical and Laboratory Procedures
At the screening visit, HSV-2 seropositivity was determined by Western blot.23 HIV-1 Western blot, plasma HIV-1 RNA polymerase chain reaction (PCR), CD4 count, serum creatinine, transaminases, complete blood count, and for women, a urine pregnancy test were also performed. Testing for Neisseria gonorrhoeae and Chlamydia trachomatis was performed by culture of rectal swabs from men and by nucleic acid amplification testing of urine samples from men and cervical swabs from women; participants who tested positive were treated and became eligible for enrollment 14 days after completing therapy.
Participants provided daily self-collected genital and perianal swabs for HSV PCR using previously described methods24,25 and maintained a diary of genital symptoms for the first 4 weeks of each treatment period.26 DNA from 200 μL of PCR buffer surrounding each swab was extracted with a QIAamp 96 DNA Blood Kit (Qiagen Inc., Valencia, CA) following the manufacturer's recommendations. HSV gB–specific Taqman quantitative real-time PCR was performed using QuantiTect multiplex PCR master mix (Qiagen) on a 7900HT sequencing detection system. The sequences of HSV gB primers and probe were previously described.27 An internal control was included in each reaction to monitor for false-negative results due to inhibition of the PCR assay.28 We reported as positive those samples in which ≥150 copies of HSV DNA per milliliter were detected.29 Weekly plasma samples were collected for HIV-1 RNA quantification by a TaqMan RT-PCR assay.30 The lower limit of quantification was 50 copies of HIV-1 RNA per milliliter. Participants who, on screening, had detectable plasma HIV-1 RNA below the limit of quantification were retained in the analysis. Plasma CMV DNA was also quantified by a CMV-specific TaqMan PCR assay; we reported samples in which ≥50 copies of CMV DNA per milliliter were detected as positive.28 Laboratory staff were not aware of treatment assignments. At each visit, we assessed symptoms of genital herpes reactivation, medication tolerance, and adherence by pill counts. At the end of each study arm, serum creatinine, CD4 count, and complete blood count of the participants were measured. Throughout the study, condoms, risk reduction, and adherence counseling were provided.
To more precisely assess the kinetics of plasma HIV-1 RNA decline after initiation of valacyclovir, beginning in April 2010, we invited participants, including those who already completed the study, to participate in a substudy which measured plasma HIV-1 RNA 1 day before, at initiation, and at 6, 24, 48, and 72 hours after initiating valacyclovir.
Sample Size Calculation and Statistical Analysis
We estimated that a sample size of 29 participants would be required to detect a 0.25 log10 copies per milliliter difference10,11 in plasma HIV-1 RNA between the study arms, and a sample size of 38 participants, with 4 weeks of daily genital swabs per treatment arm, would be required to detect a decrease in the HSV shedding rate from 4%, the rate expected on standard suppressive therapy,13 to 1%, with 80% power, at a 2-sided type I error rate of 5%. We have recently validated a more accurate method of sample size computation for crossover shedding studies.31 This rigorously validated calculation, which accounts for person-to-person variability in shedding over time, required 26 participants to detect a 50% reduction in genital HSV shedding.
The co-primary end points of the study were the plasma HIV-1 RNA level and genital HSV shedding rate during high-dose valacyclovir compared with standard-dose acyclovir administration. Secondary end points included days with genital herpes lesions and the quantity of HSV-2 DNA from genital swabs during shedding episodes on each arm. Plasma HIV-1 RNA and genital HSV DNA levels were log10 transformed to stabilize variance. The genital shedding rate was defined as the number of swabs with HSV divided by the number of swabs collected. A genital shedding episode was defined as a consecutive series of positive genital swabs separated by at least 2 negative swabs. Analyses were modified intent to treat, including those participants who contributed at least 1 specimen on both arms. The first day of treatment and all washout days were excluded from analysis. Participants who initiated ART were censored at that time.
Linear mixed models were used to compare plasma HIV-1 RNA and HSV-2 DNA quantity from genital swabs by treatment arm. We explored whether the effect of valacyclovir compared with acyclovir on plasma HIV-1 RNA levels was modified, in separate models, by baseline plasma HIV-1 RNA level, CD4 count, or detection of CMV viremia by testing the significance of interaction terms. Genital HSV-2 shedding rates were compared by treatment arm using random effects Poisson regression. The Wilcoxon signed-rank test was used to compare the total number of genital shedding episodes, days with genital HSV-2 lesions, and drug adherence rate by treatment arm. Cox regression analysis, accounting for multiple episodes per participant,32 was used to compare the episode duration by treatment arm. Period effects on plasma HIV-1 RNA and genital HSV-2 shedding rates were assessed by testing the significance of session adjusted for treatment arm. Carryover effects were evaluated by testing the interaction of treatment and session. Correlation of drug adherence on each treatment arm with change in mean plasma HIV-1 RNA levels from baseline and genital HSV-2 shedding rates was evaluated with Spearman correlation coefficients.
First-phase viral decay slopes were determined for substudy participants, for whom plasma HIV-1 RNA levels were assessed more frequently over the first 3 days of valacyclovir treatment. Previous studies of HIV-1 viral decay after antiretroviral administration have observed an initial static phase before the exponential decline in the first phase of viral decay.33–35 Viral decay slopes, determined by linear regression using robust variance estimates in clusters, consequently included data points beginning at 24 hours.
The protocol was approved by the University of Washington Human Subjects Review Committee, and the participants gave written informed consent. The University of Washington investigators wrote the protocol, conducted the study, analyzed the data, and prepared the article for publication. This trial is registered with ClinicalTrials.gov, number NCT00527618.
Of the 49 persons screened, 15 were found to be ineligible for reasons including lack of HSV-2 infection (n = 5), plans to initiate ART (n = 3), and undetectable plasma HIV-1 RNA (n = 3). Of the 34 persons enrolled, 3 (8.8%) participants were treated for Chlamydia, including 1 participant who was treated for both Chlamydia and Gonorrhea, before enrollment. Six participants did not contribute to both arms of the study. Thus, the final analysis set included 28 participants, of whom 12 (43%) initiated acyclovir and 16 (57%) initiated valacyclovir first (Fig. 1). The mean age of participants was 44 (range: 24–46); 18 (64%) were white and 23 (82%) were men (Table 1). Overall, from participants during treatment with acyclovir or valacyclovir, we obtained and analyzed 594 plasma samples for HIV-1 RNA quantification, for 570 of which we were also able to measure CMV DNA, and 1425 genital swabs for HSV DNA quantification.
Effect of Study Drug on Plasma HIV-1 RNA
Twenty-seven participants had plasma HIV-1 RNA levels available for analysis, as samples for 1 participant were persistently inhibited. Of these participants, 23 (85%) had a mean plasma HIV-1 RNA level lower on valacyclovir than acyclovir (Figs. 2, 3). Plasma HIV-1 RNA during treatment was 0.27 log10 copies per milliliter lower (95% CI: −0.41 to −0.14 log10 copies per milliliter; P < 0.001) on valacyclovir compared with acyclovir (Table 2). Sixteen (59%) of 27 participants on valacyclovir and 5 (20%) of 25 participants on acyclovir achieved a decrease in mean plasma HIV-1 RNA by ≥0.25 log10 copies per milliliter relative to baseline. No association between genital HSV shedding and plasma HIV-1 RNA was detected. When the genital HSV shedding rate on drug was included in the model, there was no change in the results: plasma HIV-1 RNA during treatment was 0.27 log10 copies per milliliter lower on valacyclovir compared with acyclovir (95% CI: −0.41 to −0.14 log10 copies per milliliter; P < 0.001). We found no evidence that the baseline HIV-1 RNA level, CD4 count, or detection of CMV viremia modified the effect of valacyclovir compared with acyclovir on plasma HIV-1 RNA (Table 2). Because the mean plasma HIV-1 RNA was higher in participants who started in the valacyclovir arm, evaluation for period effect was adjusted for baseline plasma HIV-1 RNA on each drug arm; no period (P = 0.27) or carryover (P = 0.39) effects were found. One participant received interferon and ribavirin during the acyclovir arm for hepatitis C treatment. When this participant was excluded from the analysis, plasma HIV-1 RNA during treatment was 0.31 log10 copies per milliliter lower (95% CI: −0.43 to −0.19 log10 copies per milliliter; P < 0.001) on valacyclovir compared with acyclovir. Two participants in the analysis had plasma HIV-1 RNA below the limit of quantification (<50 copies per milliliter); when these participants were excluded, the results were similar.
Effect of Study Drug on Genital HSV Shedding
Twenty-eight participants collected swabs of genital skin and mucosa during both study arms. The HSV shedding rate did not differ between the study arms: HSV was detected on 55 (7.8%) of 707 days on valacyclovir and 59 (8.2%) of 718 days on acyclovir (relative risk: 0.95; 95% CI: 0.66 to 1.37; P = 0.78). There were 19 HSV shedding episodes on acyclovir and 18 on valacyclovir. No significant difference was seen in the episode duration by treatment arm (P = 0.68). The median quantity of HSV-2 DNA for positive samples was 3.0 log10 copies per milliliter on both arms (range: acyclovir, 2.2–6.4 log10 copies per milliliter; valacyclovir, 2.2–6.8 log10 copies per milliliter; P = 0.67). Genital lesions were present on 7 (1.0%) of 772 days, occurring in only 1 participant during the valacyclovir arm, compared with 27 (4.0%) of 750 days, occurring in 2 participants during the acyclovir arm (P = 0.16). Ninety-three percent of the participants did not report any genital lesion throughout the study, and 94% of all shedding episodes were asymptomatic. There was a significant period effect such that rates of HSV-2 shedding were 76% (range: 60%–85%) lower during the second treatment arm compared with the first treatment arm regardless of the treatment given (P < 0.001). There was no significant drug carryover (P = 0.58). When the participant receiving interferon and ribavirin was excluded from analysis, we still found no significant difference in the rate of HSV detection on valacyclovir compared with acyclovir (relative risk: 0.82; 95% CI: 0.55 to 1.23; P = 0.33).
Effect of Study Drug on Plasma CMV DNA
CMV DNA was detected in 6 plasma samples from 5 participants during treatment with acyclovir and 6 samples from 2 participants during treatment with valacyclovir. The mean quantity of CMV DNA for positive samples was 2.00 log10 copies per milliliter during acyclovir and 1.99 log10 copies per milliliter during valacyclovir treatment.
Ten participants completed the substudy, during which plasma was collected for HIV-1 RNA more frequently for the first 72 hours after valacyclovir initiation. Two participants had plasma HIV-1 RNA <50 copies per milliliter at the time of valacyclovir initiation and were excluded from analysis. The remaining 8 participants were all men. The mean age was 47 years (range: 29–66 years). At enrollment, the mean CD4 count was 410 cells/μL (range: 242–714 cells/μL), and the mean plasma HIV-1 RNA level was 4.10 log10 copies per milliliter (range: 3.57–4.97 log10 copies per milliliter). Seven of the 8 participants experienced a decline in plasma HIV-1 RNA between 24 and 72 hours (see Figure S1, Supplemental Digital Content, http://links.lww.com/QAI/A415). On average, plasma HIV-1 RNA decreased by −0.20 log10 copies per milliliter per day (95% CI: −0.38 to −0.19 log10 copies per milliliter per day).
Adherence to Study Drug
The median adherence rate was 93% on valacyclovir (range: 34%–100%) and 96% on acyclovir (range: 75%–100%; P = 0.23). We did not find a correlation between drug adherence and genital HSV shedding on valacyclovir (r = 0.02) or acyclovir (r = −0.16) nor between adherence and the change in mean plasma HIV-1 RNA from baseline on valacyclovir (r = −0.10) or acyclovir (r = 0.06). One participant took additional doses of acyclovir for 3 days during the acyclovir arm. Two participants used valacyclovir during the acyclovir arm, one for 12 days and the other for 9 days. Both acyclovir and valacyclovir were taken by 1 participant during the washout period, stopping the day before starting the valacyclovir arm. All participants were included in the analysis according to their assigned treatment group.
One participant developed neutropenia during the acyclovir arm, with a nadir ANC of 570 cells/μL, thought to be related to concomitant interferon use. With cessation of interferon therapy, the ANC normalized and remained normal during 12 weeks of high-dose valacyclovir. One participant developed urticaria after 2.5 weeks of valacyclovir and was discontinued from the study; this participant was not included in the analysis because he did not participate in the acyclovir arm. Two participants with depression developed exacerbations during the valacyclovir arm, one of whom was hospitalized for 2 weeks and did not follow-up during this period. Both participants were included in the analysis.
In our study, valacyclovir, dosed at 1000 mg twice daily, reduced plasma HIV-1 RNA levels by 0.27 log10 copies per milliliter more than standard-dose acyclovir (400 mg twice daily) in HIV-1/HSV-2–seropositive persons not on ART. We did not, however, find a difference in the rate of genital HSV shedding between the 2 arms, and the decrease in plasma HIV-1 RNA was unchanged after adjusting for genital HSV reactivation, suggesting that the differential effect of high-dose valacyclovir on HIV-1 RNA is not mediated by greater HSV-2 suppression.
The absence of differential effect of high-dose valacyclovir compared with standard-dose acyclovir on genital HSV shedding contrasts with the suggestion of greater efficacy of valacyclovir 500 mg twice daily compared with standard-dose acyclovir in another study of HIV-1–infected patients.36 It is consistent, however, with a previous study of immunocompetent hosts that showed no difference in HSV suppression by valacyclovir 500 mg twice daily compared with standard-dose acyclovir.26
The median adherence rate was 93% during the valacyclovir arm and 96% during the acyclovir arm. Imperfect adherence would be expected to attenuate the effect size; the genital HSV shedding rate found in this study, however, was comparable to the rates of 4%–14% found in previous studies of HIV-1/HSV-2 coinfected persons treated with HSV suppressive therapy.13,37,38 No correlation was found between adherence and HSV shedding or reduction in plasma HIV-1 RNA.
Recent studies have raised the question of whether acyclovir directly inhibits HIV-1 replication. After phosphorylation of acyclovir by kinases of human herpesviruses20 and possibly cellular kinases,39 and further phosphorylation by cellular kinases, acyclovir triphosphate may competitively inhibit HIV-1 reverse transcriptase as a guanosine-5′-triphosphate analog chain terminator.20,21 Previous studies of HSV suppressive therapy with standard-dose acyclovir and valacyclovir have demonstrated a similar decrease in plasma HIV-1 RNA (0.25–0.53 log10 copies per milliliter) compared with the response seen with 24 weeks of zidovudine monotherapy.40 If acyclovir is a reverse transcriptase inhibitor, the development of reverse transcriptase resistance mutations with acyclovir monotherapy would be expected. Such resistance has been seen in vitro with the development of V75I, T69N, and M184I reverse transcriptase mutations.21 These mutations have not been recognized in patients treated with prolonged administration of suppressive doses of acyclovir and valacyclovir in the absence of ART.41,42 The decrease in plasma HIV-1 RNA as a result of suppressive acyclovir therapy has also been sustained over 24 months,41 which would be unexpected with acyclovir monotherapy, or any other reverse transcriptase inhibitor when given alone. A potential explanation for this discrepancy is that, in vivo, the fitness cost associated with these resistance mutations may outweigh the survival advantage of acyclovir resistance when acyclovir is provided at standard suppressive doses.41,42
The rate of decline of plasma HIV-1 RNA in the first week of treatment with high-dose valacyclovir is smaller than for a potent reverse transcriptase inhibitor such as tenofovir, where the first-phase viral decay slope is 0.32–0.39 log10 copies per milliliter per day when provided as monotherapy.33 We also found considerable variability among the participants in the decline in plasma HIV-1 RNA achieved with valacyclovir and acyclovir, in contrast to patients treated with antiretrovirals. Consequently, the mechanism of in vivo anti-HIV-1 effect has yet to be clarified.
A recent study found that HIV progression was delayed preferentially among patients receiving suppressive acyclovir with plasma HIV-1 RNA ≥50,000 copies per milliliter.17 Although we did not find that baseline plasma HIV-1 RNA ≥50,000 vs. <50,000 log10 copies per milliliter modified the effect of valacyclovir compared with acyclovir on plasma HIV-1 RNA, inference is limited by the small number of participants in our study with plasma HIV-1 RNA ≥50,000 log10 copies per milliliter. If persons with a high plasma HIV-1 viral load do experience a greater decline in plasma HIV-1 RNA with anti-HSV therapy, it is possible that the relatively low mean baseline plasma HIV-1 RNA in this study (3.89 log10 copies per milliliter compared with 4.0–4.6 log10 copies per milliliter in other studies of the effect of anti-HSV therapy on plasma HIV-1 RNA)8–13,22,43 may have contributed to the decreased effect size observed in comparison to previous studies.8–13 As most previous trials occurred in developing countries, however, many other differences between the populations may impact the effect of anti-HSV therapy on plasma HIV-1 RNA.
Despite decreasing plasma HIV-1 RNA by 0.25 log10 copies per milliliter, standard-dose acyclovir was not found to decrease HIV-1 transmission.10 We do not know the optimal dose of anti-HSV therapy to decrease plasma HIV-1 RNA, but it appears that there is a dose–response relationship based on this study and the recent publication by Mugwanya et al,22 where a 50% higher dose of valacyclovir (1.5 g twice daily) was associated with a 0.62 log10 copies per milliliter reduction in plasma HIV-1 RNA compared with standard-dose acyclovir. The higher dose of valacyclovir may be required for it to act as a more potent antiretroviral21 or for it to adequately suppress the effect of other herpesviruses on upregulating HIV-1 transcription. We explored whether the difference in plasma HIV-1 RNA achieved with high-dose valacyclovir vs. acyclovir was greater among the participants in whom CMV viremia was detected compared with the participants in whom it was not; the difference was not statistically significant. Inference is limited by the small number of participants with CMV viremia during the study and reliance on CMV viremia as a surrogate for CMV reactivation. To further investigate the potential role of CMV, plasma HIV-1 RNA on acyclovir and high-dose valacyclovir could be compared in CMV-seronegative and CMV-seropositive persons, but we acknowledge that enrollment into such a study would be challenging.
Whether the greater decline in HIV-1 RNA achieved by high-dose valacyclovir would translate into a more substantial delay of HIV progression than was observed with acyclovir,16,17 or would provide sufficiently potent reduction that could reduce HIV-1 transmission, is not known. Mathematical modeling has suggested that a decrease in mean plasma HIV-1 RNA by 0.74 log10 copies per milliliter could decrease heterosexual HIV-1 transmission by 50%.44 Although the provision of ART to all HIV-positive persons irrespective of CD4 count is the ideal approach to reduce HIV-1 transmission because treatment decreases transmission by at least 96%,1 at the end of 2010, it was estimated that less than half of those who met the WHO guidelines for initiation of ART (CD4 < 350 cells/μL) were receiving antiretroviral medications,7 and few national HIV treatment guidelines currently recommend universal ART.45 Until we can successfully expand ART access, high-dose valacyclovir, if demonstrated to decrease HIV transmission by persons not yet eligible for ART, could offer a provisional means to decrease the number of new HIV infections. Future studies, in persons on ART with suppressed plasma HIV-1 RNA, could also assess whether high-dose anti-HSV therapy could reduce genital HIV-1 RNA shedding, which may be a potential transmission risk in persons with suppressed plasma viral load.46
Our findings are limited by high loss to follow-up, which is especially problematic in crossover studies and decreases power. HIV-1–infected patients with detectable plasma HIV-1 RNA are becoming increasingly difficult to enroll in studies in developed countries where antiretrovirals are available and prescribed early in the course of HIV-1 disease to decrease associated morbidity and mortality, prevent transmission to sexual partners, and reduce community viral load.47 Because persons who remain viremic and not on treatment are often those with psychosocial comorbidities, such as serious mental illness, substance abuse, and poverty,48–50 maintaining high adherence to study protocol has become challenging in this population. As we collected swabs on a daily basis, we may have underestimated the frequency of shedding by missing episodes <24 hours in duration,25 although this would be expected to similarly affect both arms. The crossover design of this trial, with each participant serving as their own control, increased efficiency and decreased potential confounding. This design also mitigated potential ramifications of the period effect that we found for HSV-2 shedding rates, because in the second treatment period, each group received a different drug.
By simultaneous measurement of daily genital HSV DNA in each participant, this study demonstrates that the incremental reduction in plasma HIV-1 RNA achieved by high-dose valacyclovir compared with standard-dose acyclovir is not mediated by greater genital HSV suppression. Further research is needed to determine the characteristics that modify the effect of anti-HSV therapy on HIV-1 RNA and to determine the potential population-level impact of high-dose valacyclovir on HIV-1.
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HIV; viral load; HSV; valacyclovir; acyclovir
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