Transcript Peripartum Valacyclovir Improves Markers of HIV

Peripartum Valacyclovir Improves
Markers of HIV-1 Disease Progression in
Women Co-Infected with HSV-2:
A Randomized Trial
Alison C. Roxby, MD, MSc.
July 19, 2011
University of Washington / University of Nairobi
The Problem:
• 15.7 million women of
reproductive age are HIV-infected
• 4 – 9 lifetime pregnancies
per woman
• Lifetime risk of maternal
mortality: 1 in 22 women
• Worldwide, HIV is the leading
cause of death among women
of reproductive age
Interventions are needed to improve the health of
mothers with HIV
Research Rationale: Effect of HSV-2
suppression on HIV-1 progression
• Use of acyclovir or valacyclovir to suppress HSV-2
is associated with 0.25-0.40 log copies/ml
reduction in HIV-1 plasma RNA
• One trial of long-term acyclovir in co-infected
patients reduced HIV-1 disease progression by
16%
(Lingappa et al 2010 – Partners In Prevention)
Hypothesis
Will herpes suppressing agents improve
maternal health among co-infected women
in sub-Saharan Africa?
Valacyclovir in Pregnancy Study
Aim 1:
To determine whether herpes suppression
with valacyclovir will reduce HIV-1 RNA levels
in pregnant and postpartum women receiving
antiretrovirals for prevention of mother to
child transmission (PMTCT) of HIV-1
Valacyclovir in Pregnancy Study
Aim 2: To determine
whether herpes
suppression with
valacyclovir is
associated with
improved CD4 counts
and reductions in HIV-1
disease progression in
women followed for 12
months postpartum
Mathare North Health Centre, Nairobi
Study Design
• Double-blind, placebo-controlled, RCT
Intervention: 500 mg valacyclovir or placebo BID
• Pregnant women seeking antenatal care
• All women both HIV-1/HSV-2 seropositive
• All women with CD4 >250 cells/μl
• Enrolled/randomized to valacyclovir at 34
weeks gestation
• Followed for 1 year postpartum
Clinicaltrials.gov identifier: NCT00530777
Study Location
• Women were recruited and
followed at Mathare North
Health Center in Nairobi
• This clinic provides primary
health care and maternity
services on the edge of the
Mathare slum, home to
1,000,000 people
• About 300 women initiate
antenatal care each
month, and about 10% are
HIV positive
Mathare North VCT
Methods
Daniel Matemo, VIP Lab
Laboratory:
HIV-1 RNA and CD4
were measured at or before
34 weeks gestation,
6 months postpartum and
12 months postpartum
Clinical:
Clinical assessment of WHO stage was done monthly
Statistical:
Study arms were compared using chi-squared and t-tests to
determine adequacy of randomization
Viral loads and CD4 counts were compared using multivariate
linear regression controlling for baseline values
359 screened
149 ineligible
HSV-2 negative: 85 (24%)
CD4 < 250: 67 (19%)
WHO stage: 57 (16%)
Nairobi delivery/residence: 35 (10%)
210 eligible
62 not enrolled
148 enrolled
2 women lost before delivery
Modified Intention-to-treat analysis
74 randomized
to valacyclovir
74 randomized
to placebo
73 women
73 women
Baseline characteristics by study arm
Characteristic
at baseline
Valacyclovir
n=73
Placebo
n=73
Median (IQR)
or n (%)
Median (IQR)
or n (%)
25 (22-30)
25 (22-29)
No. of pregnancies
1 (1-3)
2 (1-2)
Education ≤ 8 years
43 (59%)
49 (67%)
Monthly rent (USD)
24 (19-33)
21 (13-33)
Employed
22 (30%)
18 (25%)
On ARVs for PMTCT
73 (100%)
68 (93%)
Stage 1
68 (93%)
62 (85%)
Stage 2
5 (7%)
11 (15%)
452 (351-560)
481 (340-598)
3.99 (3.30-4.41)
3.84 (3.43-4.45)
Age (years)
WHO Stage
CD4 count (cells/μL)
Log10 HIV-1 plasma RNA
level (copies/ml)
Maternal Mortality and Morbidity
Number of cases
All women (n=146)
Placebo (n=73)
Valacyclovir (n=73)
Stillbirth: 3
2
1
Cesarean section: 14
9
5
CD4 <250 cells/μl: 9
3
6
Tuberculosis: 6
4
2
Post-delivery hospitalization: 7
5
2
Malaria: 20
15
5
Diarrhea/colitis: 26
10
16
2
1
Perinatal Complications
Maternal Morbidity
Maternal Mortality
Number of deaths: 3
Effect of Valacyclovir on Plasma RNA
Mean HIV-1 RNA
(log10copies/ml)
Valacyclovir
Placebo
Difference
P*
Enrollment
3.89
3.87
-0.01
0.95
6 months
3.98
4.39
-0.42
<0.001
12 months
4.10
4.53
-0.40
0.001
HIV-1 RNA differences at one year, by study arm
Effect of Valacyclovir on CD4 Count
Mean CD4 Count
(cells/μl)
Valacyclovir
Placebo
Difference
P*
Enrollment
484
487
-3
0.92
6 months
631
612
17
0.72
12 months
638
565
73
0.03
CD4 differences at one year, by study arm
Adherence to study drugs
• Average mean adherence was 86% overall
• no difference between study arms
• Adherence was measured by pill count
Conclusions
• Valacyclovir consistently reduced HIV-1 RNA levels
by 0.40 log copies/ml in pregnant and postpartum
women
– This effect was noted despite short-courses of
antiretroviral therapy for PMTCT
• CD4 count was significantly different at 12 months
between study arms, with mean CD4 73 cells/μl
higher in the valacyclovir arm
Significance
Valacyclovir may be an additional tool to improve
outcomes among pregnant and postpartum women
• Modeling suggests that HIV viral load reductions of
this nature could lengthen time to development of
AIDS by 1.9 years in similar asymptomatic patients
(Baggaley 2009, Modjarrad 2008)
• Use of valacyclovir may be cost-effective in African
settings where access to ART continues to be
limited (Vickerman 2011)
Significance
• Safety data are conclusive that valacyclovir requires
no laboratory monitoring in pregnant or postpartum
women (IAS poster MOPE174)
• Consistent lowering of maternal HIV-1 plasma viral
load could reduce HIV-1 transmission to infants
during the breastfeeding period (IAS oral MOAC0201 )
Acknowledgements
Research Team:
PIs: Carey Farquhar (UW), James Kiarie (UoN)
Alison Drake,
Daniel Matemo, Francisca Ongecha-Owuor,
Barbra Richardson, Anna Wald,
Julie Overbaugh, Sandra Emery,
Grace John-Stewart
Funders:
National Institutes of Health (R03 HD 057773, R03 HD 057773-02S1, R01 AI076105)
Fogarty International Clinical Research Fellowship (Roxby, Ongecha-Owuor)
UW Royalty Research Fund & Puget Sound Partners Grant
Fogarty International Center International AIDS Research & Training Program
University of Washington CFAR
Mathare North Health Center
VIP Study Staff: Sarah Githuku, Jane Waithira, Winnie Nekesa, Wambui Karuoya,
Benetah Kendo, Jane Munuhe, and Samuel Kirichu
We thank the women and children who participated and made this research possible.