Acquisition of HIV infection in children born to

HIV infected mothers

Marie-Louise Newell

European Collaborative StudyGhent Group on HIV infection in women and children Institute of Child Health, UCL United Kingdom

HIV infection in pregnant women and their children

Epidemiology of vertically-acquired HIV infection

Interventions to prevent acquisition of infection in children

Adverse effects of exposure to ART Consequences of prevention of MTCT

policy decisions

Vertically-acquired HIV infection Need for ART in children

Size of the problem• Worldwide an estimated 1800

infants acquire HIV infection each day, nearly always through vertical transmission before, during or after delivery

• Nearly all live in sub-Saharan Africa where, in several countries with antenatal prevalences of 30% or more, declining trends in infant and child mortality are being reversed

UN targets specified in 2001: 20% reduction in newly infected children by 2005 and 50% by 2010

Antenatal prevalence

Estimated annual number of births to infected women globally: 2,834,772• Sub-Saharan Africa: 2,285,372 • Asia: 445,217• China: 17,369• Europe: 17,596• USA: 24,871• South America: 44,347

Mother-to-child transmission

• Without specific interventions, the estimated MTCT rate is 15-40%

• Differences between populations are associated with maternal characteristics (HIV RNA viral load, CD4 cell count, clinical disease progression), circumstances around delivery (vaginal delivery) and in particular with infant feeding

Infected children

Mother-to-child transmission

HIV infection in women

Prevention of MTCT of HIV-1

In utero/ intra-partum: Lowering maternal viral load with ARTIntra-partum:Avoiding exposure to maternal secretions by elective CS deliveryPer exposure ARV prophylaxis for infantPost-partum: Refraining from breastfeedingMaternal ART to reduce VL Per exposure ARV prophylaxis for infant

• Elective CS and not breastfeeding not feasible, affordable or safe • Peripartum antiretroviral therapy, mostly ZDV or sdNVP, substantially and significantly reduces MTCT risk• Longer (from 28 or 32 weeks gestation) and/or combination ART (ZDV+3TC+sdNVP) further reduces MTCT rates • Revised WHO guidelines (July 2005) suggest where feasible ZDV from 28 weeks plus sdNVP and, where possible, 7 days ZDV+3TC for the mother, and sdNVP plus 7 days ZDV for the infant

Resource-limited settings

Mums-to-be shun HIV tests

Malawian health officials are deeply concerned at the reluctance of pregnant women to go for HIV tests, even though those who test positive are given anti-Aids drugs

Many men still do not want their wives to be tested. Some pregnant women have resorted to undergoing HIV tests without the knowledge of their husbands, for fear of being abandoned if found positive. "I couldn't tell him because he would have beaten me or even left me"

BBC news May 2005

PMTCT programmatic experience

• Fewer than 10% of infected women worldwide are estimated to benefit from PMTCT

• Even with complete coverage of an effective peripartum ART intervention, an estimated 300,000 children will acquire infection through breastfeeding

Potential consequences of changes in antenatal prevalence, PMTCT coverage or breastfeeding

on the annual number of vertical infections

Antenatal prevalence % reduction30% to 20%

PMTCT50% sdNVP 21%

50% sdNVP+50% ZDV+sdNVP 35%

100% ZDV+sdNVP

Infant feeding100% BF for 6 mths

50% FF and 50% 6m BF 39%

Newell, Unicef et al 2005

33%

42%

33%

Adverse events possibly associated with ART during pregnancy and early life are as yet inadequately quantified

Antenatal ART can thus substantially and dramatically reduce the risk of MTCT from already infected women and has been a main element in PMTCT programmes worldwide, however evidence from resource-rich countries where ART use is widespread suggests that that benefit may come with a cost

Exposure to HAART from before and early pregnancy: complications and outcome

• Risk of premature delivery ECS, AIDS 2004; 18: 2337-2339

• Associated increased perinatal and neonatal mortality

• ART-associated mitochondrial abnormalities with clinical symptoms in a small number of uninfected exposed children in the first 18 months of life remain a cause for concern

Haematological effects of ART exposure

Decreased neutrophil levels following in utero and neonatal exposure to ART prophylaxis in uninfected children until at least 8 years of age – clinical implications are not yet clarified (le Chenadec, AIDS 2003, ECS AIDS 2004)

01

23

45

6C

D8

co

unts

*10

^9/L

0 1 2 3 4 5 6 7 8age (years)

No ART exposure ART exposure

white childrenART exposure in fetal or early neonatal life has also been associated with reduced total lymphocyte levels, but not with risk of lymphopenia, until at least 8 years of age, with evidence of a duration and intensity of ART exposure effect

ART could potentially cause medium to long-term adverse events in the large number of uninfected children born to HIV infected mothers

These events are likely to be rare, may be sub-clinical and difficult to detect and may not present until later life

Use of ART in PMTCT may also have adverse effects for the mother: drug resistance*, especially following single dose NVP or other monotherapy, may jeopardise future treatment options

HAART initiated before or in early pregnancy may be associated with adverse pregnancy outcome

* See TuPe 5.2 P15

Children with vertically-acquired HIV infection in resource-poor

countries

MorbidityMortalityTreatment

Aids 'kills one in three'

The high death rates due to HIV/AIDS highlight the urgency to accelerate the implementation of the comprehensive plan for the treatment and prevention of HIV and AIDS

MRC South Africa April 2005

In six sub-Saharan Africa AIDS is contributing to one- to two- thirds of all under five deaths: Botswana, Lesotho, South Africa, Namibia, Swaziland and Zimbabwe

Mortality in children born to HIV infected mothers

• Mortality in children under 5 years of age is approximately three times higher in children of HIV infected than of uninfected mothers

• HIV negative children born to HIV infected mothers have higher morbidity and mortality than infants born to uninfected mothers

• Deaths of HIV infected, but not of HIV uninfected mothers or of fathers, has been associated with increased child mortality

Child survival in settings with a high HIV prevalence

• In a pooled analysis based on individual data from seven RCT evaluating interventions to reduce MTCT in sub-Saharan Africa where prolonged breastfeeding is the norm, 3500 children were included, of which nearly 700 were infected

• About 5% of uninfected and 35% of infected children will die before age one year, and 7.5% and 52.5% by two years of age

• Uninfected and infected children whose mother had died were 2 - 3.5 times more likely to die than those whose mothers survived

Newell et al, Lancet 2004

Estimated progression to serious disease or death by period of birth

Children born after 1998

Children born before 1994

ECS, unpublished 2005

Progression to AIDS or death at one year of age:

≈ 20% pre-1994 (no ART)

10% 1994-1998 (mono or dual therapy)

0% post-1998 (HAART)

Children born 1994-1998

0 5 10 15

0.0

0.2

0.4

0.6

0.8

1.0

ECS, unpublished 2005

Paediatric ART eligibility criteria

• WHO stage 4• WHO stage 3: all children under 18 mths; for

children over 18 months treat with CD4 guidance especially for TB, LIP, OHL and thrombocytopenia

• WHO stages 1 and 2 only with evidence of severe immunological disease progression (on the basis CD4% or TLC)

• Children < 18 mths in whom an HIV diagnosis has not yet been confirmed – start treatment on a presumptive diagnosis of stage 4 disease

• Co-trimoxazole prophylaxisWHO, July 2005

Delivery of ART for children

• Globally, UNAIDS/WHO/UNICEF estimates that 660,000 children less than 15 years of age are eligible for ART on clinical grounds (600,000 in sub-Saharan Africa)

• This includes 270,000 infants less than 18 months

• An estimated 4 million children should receive cotrimoxazole prophylaxis, early diagnosis allowing cessation in children who are uninfected would reduce this to 2.1m

Boerma et al, 2005

Newell et al 2005

Effect of Cotrimoxazole and ART availability on the number of vertically-infected children eligible for ART

0

5,000

10,000

15,000

20,000

25,000

30,000

1 2 3 4 5 6 7 8 9 10

age in yearsART for the over-1s Cotrim Cotrim plus ART for over 1's

Cotrim and ART from birth No Cotrim, No ART

Concluding remarkso Prevention of infection in women of

child-bearing ages should be high priority in all programmes

o Little or no counselling for women who are negative in pregnancy

o PMTCT: VCT barriers and only partial uptake of even simple interventions

o ART for PMTCT may impact on future therapy options

o ART for infected children – finally getting the attention it deserves

HIV infection in women

PMTCT

Infected children