Alison Drake

International AIDS Society Conference

July 18, 2011

Valacyclovir suppression reduces breast milk and plasma HIV-1 RNA postpartum:

results of a randomized clinical trial

Abstracts at IAS 2011

Oral Abstract Session

Maternal Health and Paediatric OutcomesTUAB0202: Tuesday 2:30 – 4:00, MR 4

Poster ExhibitionsMOPE174: Monday 12:30 – 2:30TUPE268: Tuesday 12:30 – 2:30

MTCT in non-breastfeeding populations

Pregnancy Delivery Postpartum

ZDV sdNVP Maternal ZDV + 3TC (1 wk)Maternal HAART

Postnatal Tx rate

(6 mo)

1 - 2%1 - 2%Maternal HAART

MTCT in breastfeeding populations

Pregnancy Delivery Postpartum

ZDV sdNVP Maternal ZDV + 3TC (1 wk)Maternal HAART or Infant NVP

Postnatal Tx rate

(6 mo)

8 - 10%3 - 5%Maternal HAART

Cessation of BF

MTCT in breastfeeding populations

Access to ARVs for PMTCT not universal53% coverage in low- and middle- income countries (WHO 2010)

Alternative strategies needed to reduce postnatal transmission

Pregnancy Delivery Postpartum

ZDV sdNVP Maternal ZDV + 3TC (1 wk)Maternal HAART or Infant NVP

Postnatal Tx rate

(6 mo)

8 - 10%3 - 5%Maternal HAART

Cessation of BF

HSV-2 infection in HIV-1 infected women

Prevalence 75% to > 95%

Suppressive therapyReduces plasma HIV-1 RNA 0.25 - 0.5 log0.18 log greater reduction with valacyclovir (Ludema 2011)

Effect on breast milk HIV-1 RNA or MTCT unknown

AimsTo evaluate the effect of valacyclovir suppressive

therapy administered during late pregnancy and for 12 months postpartum on:

Plasma HIV-1 RNA levels

Breast milk HIV-1 RNA detection and levels

Study designInclusion criteriaProceduresHIV-1/HSV-2 seropositive≥ 18 years of ageHAART ineligible

CD4 > 250 cells/mm3

Seeking ANC in Nairobi, KenyaDeliver and remain in Nairobi

12 months postpartum

Double blind RCT 500 mg valacyclovir

or placebo bidPMTCT ARVs

ZDV + sdNVP

28-32wk 34wk 38wk 2wk 6wk 14wk 6mo 12mo

Study design

Pregnancy

Delivery

Postpartum

ScreenEnroll &

Randomize

Inclusion criteriaProceduresHIV-1/HSV-2 seropositive≥ 18 years of ageHAART ineligible

CD4 > 250 cells/mm3

Seeking ANC in Nairobi, KenyaDeliver and remain in Nairobi

12 months postpartum

Blood & breast milk

Double blind RCT 500 mg valacyclovir

or placebo bidPMTCT ARVs

ZDV + sdNVP

74 valacyclovir

74 placebo

73 included

in analysis

73 included

in analysis1 LTFU 1 LTFU

April 2008 – June 2009

359 screened

211 eligible

148 enrolled

Screening, enrollment, and follow-up

* not mutually exclusive

Ineligible *85 HSV-267 CD4

70 HAART24 Residence

Baseline and infant characteristicsMedian (IQR) or Mean* (95% CI) or n (%)

Characteristic Valacyclovir (n=73) Placebo (n=73)

Age (years) 25 (22 - 30) 25 (22 - 29)

Reported history of GUD 10 (14) 13 (18)

CD4 count (cells/mm3) 452 (351 - 560) 481 (340 - 598)

WHO stage 1 68 (93) 62 (85)

Plasma HIV-1 RNA (log10 copies/mL)* 3.89 (3.66 - 4.11) 3.87 (3.67 - 4.06)

Initiated ZDV by enrollment 73 (100) 68 (93)

Infant received sdNVP 67/72 (93) 70/71 (96)

Breastfeeding (reported at 2 weeks) 67/72 (93) 66/66 (100)

23

45

67

log

10

co

pie

s/m

L

0 4 8 12

Months postpartum

Postpartum plasma HIV-1 RNA levels

PlaceboValacyclovir

23

45

67

log

10

co

pie

s/m

L

0 4 8 12

Months postpartum

Postpartum plasma HIV-1 RNA levels

PlaceboValacyclovir

23

45

67

log

10

co

pie

s/m

L

0 4 8 12

Months postpartum

Postpartum plasma HIV-1 RNA levels

PlaceboValacyclovir

23

45

67

log

10

co

pie

s/m

L

0 4 8 12

Months postpartum

Postpartum plasma HIV-1 RNA levels

PlaceboValacyclovirp

2wk PVL 2- 6 wk rate of ∆ 3.10 2.08 2.83 1.48 0.11 <0.001

0.60 lower (95% CI 0.92 – 0.28)

23

45

67

log

10

co

pie

s/m

L

0 4 8 12

Months postpartum

Postpartum plasma HIV-1 RNA levels

PlaceboValacyclovirp

6 wk – 12 mo rate of ∆ Mean (95% CI) difference0.030.02 0.51 lower (0.73 – 0.30)0.3 <0.001

HIV-1 RNA detection in breast milk

RR 0.81 RR 0.70* RR 0.54* RR 0.84 RR 0.900

.2.4

.6.8

% w

ith H

IV-R

NA

de

tect

ed

2 week 6 week 14 week 6 month 12 monthPostpartum visit

Placebo Valacyclovir* p<0.05

23

45

6

log

10

co

pie

s/m

L

0 4 8 12

Months postpartum

Breast milk HIV-1 RNA levels

PlaceboValacyclovir

Breast milk Plasma Median (IQR)

6 wk 14 wk2.42 (1.70 – 3.35) 1.70 (1.70 – 2.96)1.70 (1.70 – 2.57) 1.70 (1.70 – 1.70)

23

45

6

log

10

co

pie

s/m

L

0 4 8 12

Months postpartum

Breast milk and plasma HIV-1 RNA levels

PlaceboValacyclovir

Median (IQR) 6 wk 14 wk2.42 (1.70 – 3.35) 1.70 (1.70 – 2.96)1.70 (1.70 – 2.57) 1.70 (1.70 – 1.70)

Breast milk Plasma

HR = 1.45(95% CI: 0.41 - 5.12)

0.00

0.10

0.20

Pro

bab

ility

of H

IV-1

tran

smis

sion

72 67(3) 66(0) 64(0) 64(0) 61(1) 41(2)Valacyclovir71 67(1) 64(2) 61(1) 60(0) 59(0) 43(0)Placebo

Number at risk

0 60 120 180 240 300 360

Age (days)

Risk of infant HIV-1 transmission

n = 6

n = 4

Conclusions

Valacyclovir reduced Early breast milk HIV-1 RNA detectionPlasma HIV-1 RNA 0.51 log

Plasma results consistent with other trials

Impact of valacyclovir on MTCT may differ from heterosexual transmission Prolonged exposure to bodily fluids 0.4 log lower viral load associated with reduced risk of

postnatal MTCT (Neveu 2011)

Implications

Valacyclovir is an appealing intervention

Valacyclovir suppressive therapy, in conjunction with PMTCT ARVs, should be evaluated as an intervention to reduce postnatal MTCT and improve maternal health

Acknowledgments

University of Washington Carey Farquhar Alison Roxby Anna Wald Grace John-Stewart Barbra Richardson Julie Overbaugh Jane Hitti Sandy Emery

University of Nairobi James Kiarie Francisca Ongecha-Owuor

Funding

NIH R03 5R03HD057773-02

NIH ARRA 5R03HD057773-02S1

University of Washington CFAR

P30 AI027757

CFAR STD Pre-doctoral Training Grant 5T32AI007140-33

Puget Sound Partners for Global Health

UW Royalty Research Fund

Study participants

Mathare staff

DSMB

GlaxoSmithKline