HIV & Serodiscordant couples • Dr Charlotte Bell • BSc, MBBS, DIP GUM, FRCP, FAchSHM • Consultant Sexual Health Physician • Royal Adelaide Hospital
Serodiscordant couples • ~50% of persons living with HIV and in a long-term sexual relationship have an HIV negative partner1 • Proportion of HIV positive women in stable heterosexual serodiscordant relationships ~ 47%2 • Mutual testing and disclosure 1Chemaitelly 2Eyawo
H, et al. STI 2012; 88: 51-57
O, et al. Lancet ID 2011; 11(4): 263-264
Prevention of Transmission • • • •
Condoms STI screening Male circumcision Post exposure prophylaxis following sexual exposure (PEP) • Pre-exposure Prophylaxis (PrEP) • Antiretroviral therapy (ART) for the positive partner
Condoms • Advantages – Protection vs STDs including HIV – Widely available
• Disadvantages – Unacceptable to some societies/religions – Single use devices – Latex allergies (rare)
Risk Group HIV – male having IVI with female HIV – female having RVI with male
Efficacy of Protection >94%
Strength of evidence HIGH: Cochrane metaanalysis suggests Best case popn benefit 94.2% True biological efficacy close to 100%
Why STI/ Genital infection Screening? • Increases susceptibility • Increases transmission
Heterosexual transmission of human immunodeficiency virus type 1 (HIV): interactions of conventional sexually transmitted diseases, hormonal contraception and HIV-1. Plummer FA. AIDS Res Hum Retroviruses. 1998 Apr;14 Suppl 1:S5-10.
Partners in Prevention HSV/HIV Transmission Study • Prospective cohort analysis of African couples • 2236 South & East African HIV serodiscordant couples • HIV + women gram stain every 3 months • HIV – men HIV testing every 3 months • BV independently associated with 3.17 fold increased risk of HIV transmission to uninfected male partners. Cohen C Plos Med 2012
BV & HIV Acquisition: a meta-analysis of published studies BV Well described increase in HIV acquisition to male partners
Loss of H202 (directly virucidal)
Activation of CD4 by alkaline pH Up-regulation of cytokines promoting local HIV replication
BV stimulates HIV expression on T cells/ monocytes
Partners share genital flora bacteria activating Langerhan’s cells CD4 T cells making the man more susceptible to HIV infection.
AIDS Jul 31 2008 22(12)1439 1501J.Atashil, Charles Poole et al 2008
Incidence and cofactors of acute HIV during pregnancy and postpartum. • Prospective cohort 1304 women • Women with a history of STI had almost 4 fold increase risk of acute HIV (OR 3.8, 95% CI 1.4-10.6) • Syphilis or BV at enrolment 10 & 3 fold increase risk respectively • Importance of STI screening CROI Boston, Kinuthia abstract 68, 2014.
Incidence and cofactors of acute HIV during pregnancy and postpartum
21st Conference on Retroviruses and Opportunistic Infections (CROI), Boston, abstract 68, 2014.
Male circumcision • 3 RCTs demonstrating male acquisition of HIV is reduced following circumcision1, 2, 3 • 60% reduction female to male transmission • Reduction in HIV incidence persists for many years following study participation4, 5 • ?benefit to HIV negative women (not shown to reduce HIV transmission from infected male to uninfected female6) 1Bailey
Lancet 2007; 2Gray Lancet 2007; 3Auvert PLoS 2005; 4Kong CROI 2011; 5Gray CROI 2012; 6Baeten AIDS 2010,
Impact of Circumcision • Rakai trail (783 control wives & 825 wives of circumcised men) • Female partners assessed for BV, TV & GUD baseline & 1 year • BV (OR0.6, 95% CI 38-94) & TV (OR0.52 95% CI .05-98) • BV, TV & GUD sig reduced a year later in wives of circumcised men. The effects of male circumcision on female partner’s genital tract symptoms and vaginal infections in a randomized trial in Rakai, Uganda. Dray et al Am Jour Obs Gynae 2009
Male circumcision and the incidence of syphilis : a prospective study • Prospective study 4716 HIV serodiscordant couples Kenya & Uganda . • 221 new Syphilis infections identified by a 4 fold increase in RPR & specific confirmatory test • MC associated with a decrease risk of incident syphilis in circumcised men 42% (p=0.017) & HIV + men 62% (p=0.013) • Women with circumcised partners were 59% less likely to acquire syphilis than women with uncircumcised partners (p=0.001) Male circumcision and the incidence of syphilis acquisition among male and female partners of HIV-1 serodiscordant heterosexual African couples: a prospective study International AIDS Conference, Melbourne, abstract MOPDC0103, 2014.
HIV incidence among women is associated with their partners' circumcision status in the township of Orange • Orange Farm SA circumcision has been scaled up to 53% 2007-2011 • During which time HIV prevalence decreased by 48% MC men • HIV incidence studies among women as a function of MC. • MC associated with a reduction of HIV incidence among 2452 women aged 15-29. • Women having only MC partners HIV prevalence rate 17.8% (162/910) versus 30.4% (469/1542) having had sex • The adjusted reduction of HIV incidence rate was 20.3% (95% CI: 5.8% to 33.8%). FRAE0105LB AIDS 2014 K Jean et al
Four Trials demonstrate PrEP efficacy in diverse geographic & Risk populations Study Population
PrEP agent
•Partners COPY TABLE PrEP FTC/ TDF
HIV Diagnosis PrEP 13
PrEP efficacy
Placebo 75%
study Heterosexual couples Kenya, Uganda N=4758
TDF
17
TDF2 study Heterosexuals Botswana N=1210
FTC/ TDF
10
26
62%
BTS IDU Thailand N=2413
TDF
17
33
49%
FTC/ TDF
36
64
44%
iPrEx MSM Brazil, Ecuador, Peru, South Africa, Thailand US (n=2499)
52
67%
Adherence & HIV Protection: oral PrEP % of blood samples with TDF detected
HIV protection efficacy in randomized comparison
HIV protection estimate with high adherence
81%
75%
90%
Heterosexuals Botswana N=1210
79%
62%
78%
BTS
67%
49%
70%-84%
iPrEx
51%
44%
92%
<30%
No HIV protection
N/A
Partners PrEP FTC/ TDF arm Heterosexual couples Kenya, Uganda N=4758
TDF2
IDU Thailand N=241 MSM
FEM-PrEP & VOICE
(TDF in blood)
(prescription refill)
(TDF in blood)
(TDF in blood)
When adherence was high HIV protection is consistent and high
The PARTNER study The PARTNER study (Partners of people on ART: a New Evaluation of the Risks) is a observational multicentre study, taking place in 75 European sites from 2010 to 2014 (Phase 1) and 2014-2017 (Phase 2) – Interim analysis no linked transmissions – 767 heterosex & gay couples couples – No cases VL<200 copies/ ml despite high levels of STIs (16% MSM & 5% hetero) Estimated number of condomless sex acts 44,400 A Rodger, T Bruun, V Cambiano, J Lundgren, et al. HIV Transmission Risk Through Condomless Sex If HIV+ Partner On Suppressive ART: PARTNER Study.CONFERENCE on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 153LB
HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm3 Randomization
Immediate ART CD4 350-550
Delayed ART CD4 <250
Primary Transmission Endpoint Virologically-linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death Cohen MS et al. NEJM 2011; 365: 493-505
HPTN 052: HIV-1 Transmission Total HIV-1 Transmission Events: 39
Unlinked or TBD Transmissions: 11
Linked Transmissions: 28
• 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm3
Immediat e Arm: 1
Delayed Arm: 27
• 23/28 (82%) transmissions in sub-Saharan Africa • 18/28 (64%) transmissions from female to male partners
p < 0.001
Putting All This Together HIV prevention effect with high adherence
ART for HIV prevention
PrEP for HIV Prevention
96%
90%
(HPTN 052 near perfect adherence)
(when TDF detected)
100%
(PARTNER study when viral load <200 copies/ ml)
Two incredibly powerful prevention strategieswhen used with adherence
Fundamental Principles of interventions for prevention of sexual HIV Transmission
HIV testing behaviour change condoms STI treatment
HIV testing behaviour change Condoms STI treatment
HIV transmission infectiousness
HIV acquisition susceptibility
HIV
Fertility Wishes • Couples want to have children • Studies of fertility desires and intentions have consistently shown that many women living with HIV want to have children. • Survey of 450 HIV+ women in the UK in 2011 – 75% stated they wanted more children – 45% said HIV did not affect their fertility intentions Fertility intentions of HIV-infected women in the United KingdomSusan Cliffeab, Claire L. Townsenda*, Mario Cortina-Borjaa & Marie-Louise Newellac pages 1093-1101. AIDS Care vol 23 n. 9 Sept 2011 1093-1101
HIV Excellent Prognosis & Low risk of MTCT
5 per 1000 births in UK & Ireland 2010-2011
n=4831 US adults email survey (2008)
HIV+ women internalize stigma around conception Women Living Positive Survey • n=700 HIV+ women on ARVs for 3+ yrs • 59-61% believed could have children if appropriate care • 59% believed society strongly urges not to have children – Caucasian (67%) vs. Hispanic (53%), (p < 0.05) – South (66%) vs. Northeast (52%) or Midwest (55%), (p < 0.05) – ID (62%) vs. FP/GP (62%) vs. NP or PA care (48%) (p < 0.05) Squires et al. (2011) AIDS patient care and STDs
Preconception counseling is not being addressed • Data suggests that reproductive counseling does not often occur until after conception – Study of 181 women: Only 31% reported a personalized discussion with their provider specific to their childbearing plans. – Of those who had a personalized discussion, most were initiated by the client rather than the provider.
•
S. Finocchario-Kessler, et al., AIDS Patient Care and STDS, 24(5), 317-23, 2010
How often are pregnancies planned? • 54% of HIV-positive women in Kenya said their last pregnancy was unplanned or unwanted1 • 40% of 981 pregnancies in Italian HIV positive women were unplanned2 • Only 51% of pregnancies between 2009 and 2010 at St Mary’s in London were planned (26% unplanned; 23% unclear)3 1Anand
et al AIDS 2009; 2 Baroncelli et al. 2009; 3 Fowler et al. BHIVA 2011
Preconception Care • Allows couples to plan a pregnancy that – Is well timed – Occurs in optimal health – Minimizes risks for perinatal transmission
• Optimising HIV care • Offering advice on how to get pregnant without transmitting HIV • Fertility screening • STI screening • Cost
Couples • • • • • • • • • •
Reproductive plans Reproductive/ gynae history Past medical history Discuss MTCT/ delivery/ breast feeding Medications/ ARV Genetic family history Substance use Folic acid 5mg/ iodine 150 mcg Psychosocial history Health environment
Investigations • Female:• HIV, Hepatitis B & C. Rubella, • day 2-6 only: E2, Progesterone, FSH, AMH • Baseline US • Male:• Semen analysis • HIV, hepatitis B & C, syphilis
HIV positive: Reproductive Options
HIV+ female and HIV- male • Insemination of partners sperm at ovulation • Natural conception (if effective viral suppression) +/- PrEP-C • Assisted reproduction (if fertility issues) • Adoption
â&#x20AC;˘ During the 24 hours after the LH surge ejaculate into a cup or into a condom without a spermicide
HIV + Woman HIV - Man • Home insemination with partner’s semen
• • • •
Suction semen into a syringe Place syringe in vagina Remain lying down for 20 minutes Return to having protected sex with condoms
HIV+ male and HIV- female • Sperm washing +/- IUI, IVF, ICSI • Natural conception (if effective viral suppression) +/- PrEP-C • Insemination of donor sperm at ovulation • Adoption
Sperm washing • HIV cannot attach to or infect spermatozoa due to lack of receptors • Centrifugation of ‘sperm’ performed in specialist units to remove HIV
Sperm washing • Sperm washing can be used in conjunction with assisted reproductive technologies – such as IUI, IVF, ICSI +/- ovulation induction – if additional fertility issues • Observational studies demonstrating safety and efficacy of sperm washing1, 2, 3 – 14% live birth rate per treatment cycle using intrauterine insemination (IUI) – 35% live birth rate for IVF or ICSI – No HIV transmissions 1Bujan
L et al. AIDS 2007 2Garrido N et al. Hum Reprod 2004 3Nicopoullos JD et al. Hum Fertil 2010
• 17 observational studies (no RCTs) involving more than 1700 HIV-serodiscordant couples undergoing sperm washing • 3900 IUI cycles and 738 IVF/ICSI cycles • No seroconversions • Pregnancy rates comparable to HIV-uninfected couples undergoing assisted reproduction Fertility and Sterility 2011; 95 (5): 1684-1690
Why not sperm washing? • Expensive – Ineligible for public funding – Unable to afford privately
• Inaccessible • Inconvenient • ‘Failure’ (up to 30% drop out before starting insemination; 30% do not complete) • Requests for ‘natural’ conception
Natural Conception • Increasing numbers of requests in both HIV concordant and HIV discordant couples (usually HIV + male) • Many reasons – Cost of sperm washing – Failure of sperm washing – Swiss Statement – PrEP?
Updated march 2014
Timed intercourse & PrEP in 46 heterosexual HIV discordant couples. HIV + male partners were receiving cART & VL <50. TDF at LH surge & 24 hours later None of the women HIV positive high pregnancy rates. Plateau of 75% after 12 attempts
Serodiscordance • If the man is HIV+ and the woman is HIV-, consider: – – – – –
Maximal viral suppression of the male Ovulation predictor kit/ timed insemination with washed sperm Intracytoplasmic sperm injection (ICSI) Ovulation predictor kit/timed intercourse Post-exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP) for female – Donor insemination/ adoption – Semen analysis – STI testing
HIV Concordant couples • Both partners on cART with maximal viral suppression • Periovulatory unprotected sex (with condoms at all other times) • Risk of superinfection negligible
US guidelines to reduce perinatal transmission
Acknowledgement Dr Nicky Mackie Consultant Physician & Honorary senior Clinical lecturer
The End