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

Ndola

HIV-1: 32% W, 24% M

HSV-2: 55% W, 36% M

Yaounde

HIV-1: 7% W, 3.6% M

HSV-2: 51% W, 27% M

Kisumu

HIV-1: 29% W, 18% M

HSV-2: 68% W 35% M

Cotonou

HIV-1: 2.8% W, 2.8% M

HSV-2: 30% W, 12% 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 foldPer 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 1.3-17.0). (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

0

10

20

30

40

50

60

70

80

HSV-2 prevelance

(% )

15 16 17 18 19 20-24

25-29

30-34

>35

Age (years)

FemaleMale

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 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

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).

1527 women selected(509 cases and 1018 controls)

Baseline FocusELISA

1127 positive

193 negative

4indeterminate

162 low positive

Retested by: Western blot & BioELISA

1195positive

253negative

4 indeterminate

34low positive

Final baseline result

Missing Pos Neg Ind TotalMissing 4 0 0 30 34Pos 1 41 24 2 68Neg 0 0 45 0 45Ind 0 0 15 4 19Total 5 41 84 36 166

W es ter

nb lot

BIOELISA

18 cases and 23 controls insufficient baseline sample

6860

HSV-2 Testing Flowchart: determination of baseline HSV-2 result

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 intra-partum 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 0.90-1.83], 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 3.0-5.1).

• 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?