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Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus
Global Health Sciences Literature Digest
Published March 26, 2007
Journal Article

Nagot N, Ouedraogo A, Foulongne V, Konate I, Weiss HA, Vergne L, Defer MC, Djagbare D, Sanon A, Andonaba JB, Becquart P, Segondy M, Vallo R, Sawadogo A, Van de Perre P, Mayaud P; ANRS 1285 Study Group. Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus. N Engl J Med. 2007 Feb 22;356(8):790-9.

Objective

To assess the effect of valacyclovir on the presence and quantity of genital and plasma HIV-1 RNA and genital herpes simplex virus-2 (HSV-2) DNA during treatment and to evaluate the effect over time.

Study Design

Randomized double-blinded placebo-controlled trial. Eligible women were randomly assigned to either the treatment or the placebo group using a 1:1 allocation scheme with block randomization of 10 patients using a random-allocation list independently provided by the study drug manufacturer. Women were enrolled in the baseline phase of the study between August 2004 and January 2005.

Setting

Bobo-Dioulasso, Burkina Faso.

Participants

Women were recruited from the Yerelon cohort of high-risk women, from local organizations of people living with HIV/AIDS, and from the University Hospital in Bobo-Dioulasso, Burkina Faso. Women who were at least 16 years of age, had serum antibodies to both HSV-2 and HIV-1, and were not eligible for HAART could enroll in the study. Women who had significant renal impairment or hypersensitivity to acyclovir; were breastfeeding, pregnant or desired to become pregnant in the next six months; or had a medical indication for HSV suppressive therapy were not eligible to participate. A total of 190 women were screened, of whom 150 met inclusion criteria. Two declined to participate, four were lost to follow-up, and four did not meet eligibility criteria. A total of 140 women were randomized, and 136 (68 in each group) were included in the analysis. Two women in each group were excluded due to enrollment errors.

Intervention

Women were followed for a total of 24 weeks: 12 weeks before randomization (the baseline phase) and 12 weeks after randomization (the treatment phase). The baseline phase consisted of six visits every other week. At the scheduled sixth visit, eligibility criteria were reassessed and eligible subjects were randomized to receive either valacyclovir (500 mg twice daily) or identically packaged placebo for 12 weeks. Women were then seen for a total of six additional visits every other week, starting two weeks after randomization. At each visit, swabs were collected for diagnosis of vaginal infections and cervicovaginal lavage enriched by cervical swabbing was performed for the detection and quantitation of genital HIV-1 RNA and HSV-2 DNA. Blood samples were drawn on alternate visits for the quantitation of plasma HIV-1. Women who became pregnant discontinued the study drug but were invited to continue regular follow-up procedures. Women with genital ulcers were initially treated with antibiotics according to national guidelines. After seven days, non-healing ulcers were treated with open-label acyclovir (200 mg five times daily for 5 days). The assigned study drug was not discontinued.

Primary Outcomes

Primary outcomes were the presence, frequency, and quantity of genital HIV-1 RNA during the treatment phase. Secondary outcomes included the presence and quantity of plasma HIV-1 RNA, as well as genital HSV-2 DNA and genital ulcers during the treatment phase. Analysis was performed using a modified intention-to-treat approach, in which the data for pregnant women (five) were censored at the time of the first positive urine test. Adjustment was made for the pre-randomization, baseline-phase genital HIV-1 RNA and HSV-2 DNA levels to allow for the variability of shedding for each of these outcomes respectively.

Results

At baseline, there were no major differences between the study groups with regard to demographic, behavioral and clinical characteristics. The mean age was 32 years, median CD4 count was 446 cells per cubic millimeter, and mean plasma HIV-1 RNA level was 4.44 log10 copies per milliliter at enrollment. However, the mean quantity of plasma HIV-1 RNA and the proportion of visits with detectable genital HIV-1 were higher in the placebo group during the entire baseline phase. Approximately 92% of possible visits were completed, and pill counts revealed adherence of 97.2%. Using summary-measures analysis, valacyclovir therapy was found to be associated with a significant decrease in the frequency of genital HIV-1 RNA (odds ratio [OR] 0.41; 95% confidence interval [CI], 0.21 – 0.80) and in the mean quantity of the virus (log10 copies per milliliter, -0.29; 95% CI, -0.44 to -0.15). However, there was no significant decrease in the proportion of women who had detectable HIV-1 RNA at least once (risk ratio, 0.93; 95% CI, 0.81 – 1.07). HSV suppressive therapy also reduced the mean plasma HIV-1 RNA level by 0.53 log10 copies per milliliter (05% CI, -0.72 to -0.35). Repeated-measures analysis showed that these effects became significantly stronger during the three months of follow-up. Additionally, valacyclovir was highly effective in lowering the detection and frequency of genital HSV-2 DNA.

Conclusions

The authors concluded that HSV suppression therapy significantly reduces genital and plasma HIV-1 RNA levels in dually infected women and that the findings have important implications for HIV control.

Quality Rating

Based on the Jadad criteria for rating randomized controlled trials, this study received a quality rating of 5 out of a possible 5 points. One point was given for describing the randomization, one for adequate randomization, one for double-blinding, one for appropriate blinding, and one for description of loss to follow-up.

In Context

The effect of acyclovir on plasma HIV-1 RNA has been observed previously among 12 patients who were sero-positive for HSV-2 and HIV-1.(1) Acyclovir is unlikely to have a direct pharmacologic effect on HIV-1,(2) and hence the most plausible explanation is that HSV suppressive therapy prevents clinical and sub-clinical reactivations responsible for an increased HIV-1 viral load. A trial of similar design conducted among women qualifying for HAART showed that valacyclovir could have a further effect on the residual shedding of HIV-1 despite good systemic control, which supports an effect of HSV-2 on independent mucosal HIV-1 replication.(3) The effect of valacyclovir on clinical episodes of HSV-2 seen in this study was similar to that reported in previous suppressive-treatment trials among co-infected women.(4,5)

Programmatic Implications

The statistically significant reduction in plasma and genital HIV-1 RNA levels associated with valacyclovir treatment suggests that sustained forms of HSV-2 control may reduce HIV-1 transmission. The additional finding that the effects of valacyclovir steadily increased over time suggests that a longer duration of treatment may lead to a greater reduction in HIV-1 RNA levels. These conclusions, however, assume that a reduction in plasma and genital HIV-1 RNA levels is a proxy for decreased transmissibility.(6,7) Additional studies with sero-conversion outcomes are needed to determine if the results found in this trial translate into a meaningful clinical effect.

References

  1. Schacker T, Zeh J, Hu H, Shaughnessy M, Corey L. Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. J Infect Dis 2002 Dec 15;186(12):1718-25.
  2. Collier AC, et al. Lack of effect on survival of high-dose acyclovir and zidovudine compared with zidovudine alone for acquired immunodeficiency syndrome. Antiviral Ther 1998;3:25-32. (No abstract available.)
  3. Ouedraogo A, Nagot N, Vergne L, Konate I, Weiss HA, Defer MC, et al. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS 2006 Nov 28;20(18):2305-13.
  4. DeJesus E, Wald A, Warren T, Schacker TW, Trottier S, Shahmanesh M, Hill JL, Brennan CA; Valacyclovir International HSV Study Group. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis. 2003 Oct 1;188(7):1009-16. Erratum in: J Infect Dis 2003 Nov 1;188(9):1404.
  5. Schacker T, Hu HL, Koelle DM, Zeh J, Saltzman R, Boon R, 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 Jan 1;128(1):21-8.
  6. Celum CL, Robinson NJ, Cohen MS. Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis 2005 Feb 1;191 Suppl 1:S107-14. Review.
  7. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000 Mar 30;342(13):921-9.