Impact of HSV-2 suppressive therapy with daily acyclovir on HIV-1 disease progression: a

randomized placebo-controlled trial in Rakai, Uganda

Steven J. Reynolds, MD, MPH

National Institute of Allergy and Infectious DiseasesU.S. National Institutes of HealthRakai Health Sciences Program

Johns Hopkins University School of Medicine

Background

Despite the enormous success of ART scale up, of 22.5 million HIV infected individuals in sub-Saharan Africa, >85% are NOT yet on treatment 3.4 million do not have access 15.7 million are not yet eligible (pre-ART stage)

Strategies to delay HIV disease progression could offset some of the burden faced by countries continuing to scale up treatment with limited resources

Background: HSV-2 & HIV

HSV-2 most common cause of GUD, seroprevalence rates 70-90% among HIV-1 infected, HSV-2 reactivation common and known to increase HIV-1 replication

Results of 7 RCTs: daily acyclovir or valacyclovir reduced plasma

HIV-1 by 0.33 (95% CI; -0.56, -0.10) log10 copies/ml (AIDS, 2011; 25)

Valacyclovir has an even greater impact on HIV VL (IAS abstract B0106)

One study revealed a modest impact of daily suppressive acyclovir on disease progression, 16% reduction (J. Lingappa, Lancet 2010; 375)

Objective

To assess the impact of Acyclovir 400mg twice daily over 24 months versus placebo on:

Progression to CD4<250 cells/ul or WHO IV (primary endpoint)

Impact on HIV VL, GUD incidence, HSV-2 shedding (secondary endpoints)

Entebbe Airport

Rakai District

Methods: Study Design

440 HIV/HSV-2 co-infected participants with CD4 between 300-400 cells/ul randomized to either ACV 400mg twice daily or placebo

24 months follow-up, participants seen monthly for adherence assessment (pill-counts), examination for GUD if symptomatic, women provided self-administered vaginal swabs

Every 6 months, laboratory visit (CBC, CD4, HIV VL), quality of life survey and full physical examination

Methods: Analysis Survival analysis used to measure the impact of ACV

on HIV disease progression

Cox proportional hazards models adjusted for baseline VL, CD4 and gender

Mixed linear effects model used to measure the impact of ACV on HIV viral load trajectories

Secondary post-hoc analysis examined impact of ACV on disease progression among participants with low (<50000 copies/ml) versus high (>=50000 copies/ml) baseline HIV VL

Results

440 participants randomized between May 2007 and Nov 2008

14 (3.1%) subjects lost to follow-up during study

12 (2.7%) subjects died on study

Excellent follow-up, of those participants remaining on study, 99% of expected study visits completed

SAFE: No SAEs related to study treatment

Results: Baseline Characteristics

Characteristic Placebo n=220 Treatment n=220Gender (female) 161 (73%) 150 (68%)

Age 20-29 44 (20%) 46 (21%)

30-39 93 (42%) 93 (42%)

40-49 53 (24%) 54 (25%)

50+ 30 (14%) 26 (12%)

Median CD4 cells/ul 350 (321-372) 350 (373-375)

Log10VL (IQR) 4.44 (3.80, 5.05) 4.43 (3.85, 5.07)

Results

205 (46.7%) participants reached primary endpoint, (95 treatment and 110 placebo)

45 participants censored during follow-up due to: LTFU (14) ART initiation (17) death (12) missed last study visit (2)

Adherence, calculated in 3 month blocks, was high in both study arms ranging from 81%-95% participants achieving >90% study drug coverage

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Based on CD4 count and WHO Clinical staging

Figure 1 Cumulative probability of ART Eligibility

Total follow-up time (days)

Treatment

Placebo

AHR 0.73 (95% CI 0.56-0.97, p=0.029)

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Placebo

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Total follow-up time (days)

Enrolment viral load <50 000 copies/ml

Figure 2 Cumulative probability of ART Eligibility

AHR 0.90 (95% CI 0.54-1.5, p=0.688)

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Placebo

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Total follow-up time (days)

Enrolment viral load 50000+ copies/ml

Figure 3 Cumulative probability of ART Eligibility

AHR 0.62 (95% CI 0.43-0.96, p=0.03)

Results

Overall 27% reduction in HIV disease progression among participants treated with ACV 400mg twice daily versus placebo (AHR 0.73, 95% CI 0.56-0.97, p=0.029)

Greater impact observed among participants with higher baseline HIV VL, particularly among those with >50000 copies/ml (AHR 0.62; 95% CI 0.43-0.96, p=0.03)

Results: Impact on HIV VL

Annual rate of change of log10 VL copies/ml overall 0.169 (95% CI 0.032-0.305)

Placebo 0.402 (95% CI 0.212-0.592) ACV -0.061 (95% CI -0.250-0.129)

Difference: -0.463 (95% CI -0.731 -0.194, p=0.001) log10 VL copies/ml

Conclusion Acyclovir 400mg twice daily delayed disease

progression among HIV/HSV-2 co-infected individuals

Acyclovir reduced HIV VL by 0.463 log10 copies/ml consistent with earlier randomized trials

Treatment of chronic HSV-2 infection may be warranted in HIV infected individuals

Future studies of Valacyclovir (better bioavailability) are warranted and may have an even greater impact on HIV disease progression

AcknowledgmentsNIAID/NIHTom QuinnKevin NewellOliver Laeyendecker

Johns HopkinsRon GrayMaria Wawer

Rakai Health Sciences Program

David SerwaddaFred MakumbiIga BoazGertrude NakigoziGeorge MundoGodfrey KigoziNelson SewankamboDennis BuwemboTom LutaloFrancis BbosaFred NalugodaNoah KiwanukaPascal SsebowaVictor Ssempijja

Rakai Health Sciences Program Community ParticipantsDivision of Intramural Research NIAID/NIH & PEPFAR