Transcript Impact of HSV-2 suppressive therapy with daily acyclovir

Impact of HSV-2 suppressive therapy with
daily acyclovir on HIV-1 disease
progression: a randomized placebocontrolled 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 selfadministered 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
Figure 1 Cumulative probability of ART Eligibility
0.40
0.20
Placebo
Treatment
0.00
Probability of ART Eligibility
0.60
Based on CD4 count and WHO Clinical staging
0
90
180
270
360
450
540
Total follow-up time (days)
AHR 0.73 (95% CI 0.56-0.97, p=0.029)
630
720
Figure 2 Cumulative probability of ART Eligibility
0.40
0.30
0.20
0.10
Placebo
Treatment
0.00
Probability of ART Eligibility
0.50
Enrolment viral load <50 000 copies/ml
0
90
180
270
360
450
540
Total follow-up time (days)
AHR 0.90 (95% CI 0.54-1.5, p=0.688)
630
720
Figure 3 Cumulative probability of ART Eligibility
0.60
0.45
0.15
0.30
Placebo
Treatment
0.00
Probability of ART Eligibility
0.75
Enrolment viral load 50000+ copies/ml
0
90
180
270
360
450
540
Total follow-up time (days)
AHR 0.62 (95% CI 0.43-0.96, p=0.03)
630
720
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/NIH
Tom Quinn
Kevin Newell
Oliver Laeyendecker
Johns Hopkins
Ron Gray
Maria Wawer
Rakai Health Sciences
Program
David Serwadda
Fred Makumbi
Iga Boaz
Gertrude Nakigozi
George Mundo
Godfrey Kigozi
Nelson Sewankambo
Dennis Buwembo
Tom Lutalo
Francis Bbosa
Fred Nalugoda
Noah Kiwanuka
Pascal Ssebowa
Victor Ssempijja
Rakai Health Sciences Program Community Participants
Division of Intramural Research NIAID/NIH & PEPFAR