Transcript Epidemiologic Study Designs [M.Tevfik DORAK]

Effect of High-Dose HSV-2 Suppressive
Therapy on Plasma HIV-1 RNA levels: a
randomized, cross over trial
6th IAS conference, Rome, Italy
17-20th July, 2011
Kenneth K. Mugwanya
Co-Investigators:
Jared Baeten, MD, PhD
Nelly Mugo, MBChB, M.Med., MPH
Elizabeth Irungu, MBChB
Kenneth Ngure, BSN, MPH
Connie Celum, MD, MPH
Background
Standard-dose HSV-2 suppressive therapy (acyclovir 400 mg twice daily)
reduces plasma HIV-1 levels by 0.25-0.50 log10 copies/mL.
If greater HIV suppression can be achieved with higher dose HSV-2 suppression,
there may be a role for HSV-2 suppression to delay HIV disease progression
and/or reduce HIV transmission.
Methods
Randomized, open label, crossover trial, 32 HIV-1/HSV-2 dually-infected
Not on ART, CD4 >250, detectable PVL: Kenya
HSV-2 suppression regimens: valacyclovir 1.5 gm Vs. acyclovir 400 mg both
twice daily for 12 wks, then a 2 wk wash-out, and then the alternative for 12 wks.
PVL were measured weekly, with additional time points at day 1,2,& 3 postdrug initiation, and at day 3 post-drug termination.
Safety: AST, ALT, Creatinine, CBC, CD4 at screening and end of each drug period
Participants provided written informed consent. (ClinicalTrials.gov number NCT01026454)
Results
At Enrollment:
17 (53%) were women
Median age was 37 years (range 23-60)
Median CD4 count: 441 cells/ µL (range 283-977)
Mean plasma HIV levels: 4.10 log10 copies/mL (SD: 0.75).
Follow-up: mean plasma HIV-1 levels
Valacyclovir arm: 2.94 log10 copies/mL, (95% CI: 2.65, 3.24)
Acyclovir arm: 3.56 log10 copies/mL, (95% CI: 3.26, 3.85)
Mean difference between the study arms:
0.62 log10 copies/mL lower in VAL. arm (95% CI -0.68, -0.55; p<0.001)
Valacyclovir Vs. Baseline PVL levels prior to HSV-2 suppression:
1.23 log10 copies/mL decrease (95% CI, -1.38, -1.07; p <0.001)
Drug adherence and safety:
Participants took a median of 99.4% of tablets dispensed
lab. safety profiles were similar in both arms
Plasma HIV-1 levels by treatment arm
Early post-drug initiation kinetics:
Day 1, 2, & 3
4.4
Acyclovir
4.2
Wash-out period:
Day 3, Weeks 1 & 2 post-drug termination
Valacyclovir
Mean plasma viral load (log10 copies/mL)
4
3.8
3.6
3.4
3.2
3
2.8
2.6
2.4
End of study drug medication
2.2
2
0
Day 1
Day 2
Day 3
Follow-up time (days)
Week 1
2
3
4
5
6
7
8
9
Follow-up time (weeks)
10
11
12
12+3
days
13
14
Conclusions
High dose valacyclovir was safe and significantly reduced
plasma HIV-1 levels by an average of 0.6 log10 copies/mL
compared to standard dose acyclovir, and a net >1 log10
copies/mL decrease compared to baseline HIV-1 levels prior to
HSV-2 suppression.
Given the constraints on ART programs and preference of some
HIV-1 infected individuals to delay ART initiation, the potential
for high dose HSV-2 suppression to delay ART initiation warrants
further evaluation.
Acknowledgements
Study participants
The Bill and Melinda Gates Foundation (grant 26469)
US National Institutes of Health (grant R01 AI083034)
GlaxoSmithKline for study drug donation
 Dr Ruth Wamae, and the staff at the Thika Partners Clinic
The Immunology Lab. at the University of Nairobi for HIV-1 PCR testing
The Clinical Trials Lab. University of Nairobi for additional lab. Testing
Dr. Larry Corey, University of Washington
Dr. Anna Wald, University of Washington
Dr. Meredith Potochnic, University of Washington