DOES MATERNAL HSV2 INFECTION INCREASE RISK OF INTRAPARTUM TRANSMISSION OF HIV1

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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

2

• 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

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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
4
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
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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
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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

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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)

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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

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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, p0.002
• HSV-2 seropositivity per se not associated with
  increased transmission risk.
• Lancet 20013571149-53

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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 33121-4 . AIDS 2002162425-30)
• Possibly by increasing HIV-1 plasma viral load
  (Nagot et al CROI . 2006)

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Intra-partum transmission of HIV

• Maternal health
• Obstetric factors
• Infant prematurity
• Linear relationship between maternal plasma HIV-1
  viral load and risk of transmission

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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 20051851209-17)
• 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 (95CI 1.3-17.0). (Obst Gynec
  20051861341-8)

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Pre-ARV era MCTC rates

• ACTG 076 - 25.5 (95CI 18.8-32.5)
• European collaborative study - 14.4 (95 CI
  12.0-17.1)
• Sub-Saharan Africa 35-50

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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

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Seroprevalence of HSV-2 in Tanzania
JID 1999 17916-24
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DOES MATERNAL HSV-2 INFECTION INCREASE RISK OF
INTRA-PARTUM TRANSMISSION OF HIV-1?
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Zvitambo Study

• Randomised placebo controlled trial
• Aimed to discover if giving Vitamin A to mothers
  and babies in the immediate post-partum period
• improved infant mortality
• reduced risk of mother to child transmission of
  HIV-1 through breast feeding
• 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.

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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

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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
  intra-partum transmission of HIV-1
• women with serological evidence of active
  syphilis at delivery had an increased risk of
  intra-partum transmission.
• Case control study using archived sera

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Case control study design

• Cases 509 HIVve 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

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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.

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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).

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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
193 negative
162 low positive
1127 positive
4 indeterminate
Baseline FocusELISA
BIOELISA
Retested by Western blot BioELISA
Missing Pos Neg Ind
Total Missing 4 0 0
30 34 Pos 1 41
24 2 68 Neg 0
0 45 0 45 Ind 0
0 15 4 19 Total 5
41 84 36 166
Westernblot
68
60
Final baseline result
1195 positive
253 negative
34 low positive
4 indeterminate
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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.

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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,
  p0.01)
• Cases were more likely than controls to be HSV-2
  infected after adjusting for factors assocd with
  intra-partum transmission (adj OR1.50 95 CI
  1.09-2.08, p0.014)
• 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

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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, p0.15, adj OR 1.28 95 CI
  0.90-1.83, p0.17).
• HerpeSelect BioElisa only, (unadj OR 1.36 95
  CI 1.03-1.80, p0.03, adj OR 1.31 95 CI
  0.97-1.76, p0.08.

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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,
  p0.29 adj OR 1.44 95 CI 0.57-3.69, p0.44

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Effect of syphilis

• 52 of 1289 women had evidence of active syphilis
  at 6 weeks (4.0, 95 CI 3.0-5.1).
• Unadj OR of intra-partum transmission associated
  with syphilis 0.89 95 CI 0.49-1.59, p0.68
• Adj OR 0.63 95 CI 0.34-1.20, p0.16

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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

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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?