DOES MATERNAL HSV-2
INFECTION INCREASE RISK OF
INTRA-PARTUM TRANSMISSION
OF HIV-1?
Frances M Cowan, Jean Humphrey,
Robert Ntozini, Kuda Mutasa, Peter Iliff
• Herpes simplex virus type 2 infection
• Role of HSV-2 on sexual acquisition and
transmission of HIV
• How HSV-2 might effect intra-partum HIV
transmission
• Zvitambo study
• Nested case control study to examine the
role of HSV-2 in MTCT of HIV
• Implications
Herpes simplex virus type 2 - the
cause of genital herpes
Sexually transmitted
Commonest cause of genital ulceration
Infection may be symptomatic (65%) or
asymptomatic (35%)
Only one third of those infected are
aware of diagnosis
Following infection the virus becomes
latent, periodically reactivating to
cause recurrences.
HIV and HSV-2 co-infection results in
more frequent and severe recurrences
Aciclovir suppresses genital herpes
reactivation
What explains the variability in rates of
HIV infection in Africa?
• 4 Cities Study
– 2 cities in West Africa (low HIV
prevalence)
- 2 cities in East Africa (high HIV
prevalence)
AIDS 2001; 15: S15-30
Yaounde
HIV-1: 7% W, 3.6% M
HSV-2: 51% W, 27% M
Cotonou
HIV-1: 2.8% W, 2.8% M
HSV-2: 30% W, 12% M
Kisumu
HIV-1: 29% W, 18% M
HSV-2: 68% W 35% M
Ndola
HIV-1: 32% W, 24% M
HSV-2: 55% W, 36% M
What explains the variability in rates of
HIV infection in Africa?
• Circumcision
• HSV-2 infection
 Sexual behavior not very different
AIDS 2001; 15: S15-30
HSV-2 and sexual
acquisition of HIV-1
• Sexual acquisition of HIV-1 is likely increased by
presence of HSV-2 infection (AIDS 2006)
• Meta-analysis of 19 studies suggests that prevalent
HSV-2 infection increases risk of acquisition in men
(adjusted RR 2.7 [95% CI 1.9-3.9]) and women (aRR 3.1
[95% CI 1.7-5.6].
• Studies looking at effect of incident HSV-2 infection are
less methodologically sound.
• Intervention trials ongoing to see if suppressing HSV-2
infection with antiviral drugs can reduce this risk. (HPTN
039 and Mwanza Herpes Trial)
Effect of HSV-2 on sexual
transmission of HIV
• Much less data than for acquisition
• Very few studies on HIV transmission overall
• Relatively few events observed
• Risk factors: high viral load, more advanced HIV
disease or primary disease, Genital Ulcer
Disease
• Only one study which has looked at effect of
HSV-2 on sexual transmission of HIV
HSV-2 and sexual
transmission of HIV-1
• Genital ulceration increases risk of
transmission five fold
Per contact risk = 0.0062 vs 0.0012 for those
without genital ulceration, p=0.002
• HSV-2 seropositivity per se not associated
with increased transmission risk.
Lancet 2001;357:1149-53
How does HSV-2 facilitate sexual
HIV-1 transmission?
• Increased genital shedding of HIV from
both clinical and sub-clinical HSV-2 lesions
(JAIDS 2003; 33:121-4 . AIDS
2002;16:2425-30)
• Possibly by increasing HIV-1 plasma viral
load (Nagot et al CROI . 2006)
Intra-partum transmission of HIV
• Maternal health
• Obstetric factors
• Infant prematurity
• Linear relationship between maternal
plasma HIV-1 viral load and risk of
transmission
Intra-partum transmission - 2
• Role of STIs in intra-partum transmission unclear.
• Presumptive treatment of bacterial STIs does not reduce
risk of intra-partum transmission.
(Am J Ob Gyn 2005;185:1209-17)
• No data on whether HSV-2 infection increases risk
of intra-partum transmission of HIV-1
• Clinical genital herpes during pregnancy is associated
with increased transmission risk (adj OR 4.8 (95%CI 1.317.0). (Obst Gynec 2005;186:1341-8)
Pre-ARV era MCTC rates
• ACTG 076 - 25.5% (95%CI 18.8-32.5)
• European collaborative study - 14.4%
(95% CI 12.0-17.1%)
• Sub-Saharan Africa 35-50%
Rates of HSV-2 vary globally
• NHANES 3 - 22% of adults in the USA
infected. Higher rates among women and
African-American women.
• European studies show sero-prevalences
of 2-6% (higher in Eastern Europe)
• Rates in sub-Saharan Africa are high
Seroprevalence of HSV-2 in
Tanzania
80
70
60
50
HSV-2
prevelance 40
(%)
30
Female
Male
20
10
0
15
16
17
18
19
2024
25- 30- >35
29 34
Age (years)
JID 1999; 179:16-24
DOES MATERNAL HSV-2
INFECTION INCREASE RISK OF
INTRA-PARTUM TRANSMISSION
OF HIV-1?
Zvitambo Study
Randomised placebo controlled trial
Aimed to discover if giving Vitamin A to mothers
and babies in the immediate post-partum
period
i) improved infant mortality
ii) reduced risk of mother to child transmission of
HIV-1 through breast feeding
iii) reduced the risk of women acquiring HIV-1 in
the year after delivery.
Recruitment took place in Harare, Zimbabwe from
November 1997 to January 2000.
Trial design
• 14,110 mother-baby pairs recruited
• Included 4,495 HIV-1 positive mothers
• HIV-1 positive mothers and their babies
had blood taken at baseline, 6 weeks, 3
months then 3 monthly for 2 years
• Where available specimens were archived
from each visit
Objectives of nested
case control study
To see if:
• women with prevalent HSV-2 infection at
delivery had an increased risk of intra-partum
transmission of HIV-1;
• women who acquired HSV-2 antibodies within 6
weeks of delivery had an increased risk of intrapartum transmission of HIV-1;
• women with serological evidence of active
syphilis at delivery had an increased risk of intrapartum transmission.
• Case control study using archived sera
Case control study design
Cases: 509 HIV+ve women whose babies
were presumed HIV infected intra-partum
(baby HIV PCR-negative at delivery and
PCR-positive at 6 weeks)
Controls: 1018 HIV-positive women whose
babies remained PCR-negative at 1 year
Power
If 80% of controls group are co-infected with
HSV-2, the study had > 90% power to detect a
50% increase in the risk of intra-partum
transmission.
If incidence of HSV-2 is 1% in the control arm
the study has 80% power to show that incident
HSV-2 increases the risk of intra-partum by a
factor >3.
Testing strategy
• Maternal serum taken within 96 hours of delivery was
tested for HSV-2 antibody
– HerpeSelect (Focus Diagnostics)
– Low +ves / indeterminates re-tested using
HerpeSelect
– Those remained LP/Ind re-tested using western blot (11%)
– Those remained LP/Ind re-tested using Biokit Elisa
– Random sample of positives and negatives retested using
western blot and Biokit Elisa
• 6 week samples were tested for HSV-2 if HSV-2
seronegative at delivery and for syphilis (RPR and
TPHA).
HSV-2 Testing Flowchart: determination of baseline HSV-2 result
1527 women selected
(509 cases and 1018 controls)
18 cases and 23 controls
insufficient baseline sample
Baseline
FocusELISA
1127
193
162
4
positive
negative
low positive
indeterminate
BIOELISA
Retested by:
Western blot &
BioELISA
W
es
ter
nb
lot
Missing
4
1
0
0
5
Missing
Pos
Neg
Ind
Total
Pos
0
41
0
0
41
Neg
0
24
45
15
84
Ind
30
2
0
4
36
Total
34
68
45
19
166
68
60
Final baseline
result
1195
253
34
4
positive
negative
low positive
indeterminate
Results
• Overall 82.5% [95% CI 80.6-84.5] of (HIV
positive) women were HSV-2 antibody
positive
• Baseline Characteristics
– Cases were less educated, and had more
signs of advanced HIV-1 disease (lower CD4
count, lower haemoglobin, higher viral load,
smaller arm circumference) and to have to
lower birth weight babies than controls.
Effect of prevalent HSV-2 infection
• Cases were more likely than controls to be HSV-2
infected (unadj OR 1.49 [95% CI 1.10-2.02, p=0.01])
• Cases were more likely than controls to be HSV-2
infected after adjusting for factors assocd with intrapartum transmission (adj OR1.50 [95% CI 1.09-2.08,
p=0.014])
• The proportion of HIV-1 intra-partum transmission
potentially attributable to maternal HSV-2 infection at
time of delivery was 28.4% [95% CI 7.3-44.7]
Sensitivity analyses
• Re-analysing data using differing testing
algorithms for HSV-2 diagnosis did not change
direction of effect but did alter significance of
results
• HerpeSelect + WB only (unadj OR 1.27 [95% CI
0.91-1.77], p=0.15, adj OR 1.28 [95% CI 0.901.83], p=0.17).
• HerpeSelect + BioElisa only, (unadj OR 1.36
[95% CI 1.03-1.80], p=0.03, adj OR 1.31 [95%
CI 0.97-1.76], p=0.08].
Effect of ‘incident’ HSV-2 infection
• 27 / 158 women who were HSV-2 negative
at delivery had ‘seroconverted’ to HSV-2
by 6 weeks (17.3%, 95% CI 11.3-23.3)
• ‘Sero-conversion’ was associated with an
increased risk of HIV-1 transmission
although not significant (unadj OR 1.59
[95% CI 0.67-3.73, p=0.29]; adj OR 1.44
[95% CI 0.57-3.69, p=0.44]
Effect of syphilis
• 52 of 1289 women had evidence of active
syphilis at 6 weeks (4.0%, 95% CI 3.05.1).
• Unadj OR of intra-partum transmission
associated with syphilis = 0.89 [95% CI
0.49-1.59, p=0.68]
• Adj OR 0.63 [95% CI 0.34-1.20, p=0.16]
Conclusion
• HSV-2 is common among HIV positive women of
child bearing age in Zimbabwe
• Maternal HSV-2 is associated with an increased
the risk of intra-partum transmission of HIV
• Maternal seroconversion to HSV-2 is common
and needs to be better defined.
• Syphilis is not associated with an increased risk
of intra-partum transmission of HIV
Implications
• Adding HSV-2 interventions to existing PMTCT
programmes might further reduce intra-partum
transmission of HIV
• Unlikely to be worthwhile if using HAART but
may have a significant impact where PMTCT
uses nevaripine only approach
• Trial of adding suppressive aciclovir to
nevaripine only PMTCT may be warranted?