impact of hsv-2 suppressive therapy with daily acyclovir on hiv-1 disease progression: a randomized...
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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 Diseases
U.S. National Institutes of Health
Rakai 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=220
Gender (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
0.00
0.20
0.40
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0 90 180 270 360 450 540 630 720
Prob
abili
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f ART
Elig
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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)
0.00
0.10
0.20
0.30
0.40
0.50
0 90 180 270 360 450 540 630 720
Placebo
TreatmentProb
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f ART
Elig
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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)
0.00
0.15
0.30
0.45
0.60
0.75
0 90 180 270 360 450 540 630 720
Placebo
TreatmentProb
abili
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f ART
Elig
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ty
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
Acknowledgments
NIAID/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