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Resistances: The evidencesResistances: The evidences

The point of view of an epidemiologistThe point of view of an epidemiologist

PMTCT Programmes: What needs to change?

MSF Expert Round Table - Geneva - June 23-24, 2008

Pr François DABIS

Francois.dabis@isped.u-bordeaux2.fr

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Towards Universal Access

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The challenge of the PMTCT cascade in Africa and The challenge of the PMTCT cascade in Africa and elsewhere (Stringer, Bull WHO 2008)elsewhere (Stringer, Bull WHO 2008)

ANC antenatal care

VCT voluntary counselling and testing

ARV antiretroviral prophylaxis or treatment (HAART) for the prevention of peripartum transmission

Prevention of the breastfeeding transmission

(A)Attend institutional

antenatal care

(B)Be offered VCT

(C)Accept VCT

(D)Obtain results

(E)Agree to ARVprophylaxis

(F)Adhere to ARV

prophylaxis

(G)Adhere to infant

ARV doses

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1°) The progress and challenges of PMTCT1°) The progress and challenges of PMTCTduring pregnancy and labor in 2008during pregnancy and labor in 2008

• Peripartum transmission is amenable to fully suppressive antiretroviral (ARV) combinations for women in need for their own health and also to relatively simple ARV interventions using ZDV, 3TC, and NVP either alone or in combinations: short-courses or single-dose regimens

• However short-course and single-dose ARV regimens are– partially efficacious,– at the expense of acquisition of viral resistance,– and insufficiently used (single-dose nevirapine most often)

… and they do not cover the breastfeeding period +++

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Six-week-MTCT riskSix-week-MTCT risk in women in women notnot requiring HAART* and who requiring HAART* and who receive short-course ARV prophylaxisreceive short-course ARV prophylaxis

Côte d’Ivoire experienceCôte d’Ivoire experience(ANRS Ditrame Lancet 1999 & Ditrame Plus AIDS 2005)(ANRS Ditrame Lancet 1999 & Ditrame Plus AIDS 2005)

10,9%3,6% 3,5%

0%

10%

20%

30%

40%

50%

% M

TC

T a

t 6

Wks

* do not meet WHO criteria if: WHO stage 3 and CD4 >350or stage 1-2 and CD4 >200

scAZT scAZT+ sc(AZT+3TC) sdNVP + sdNVP

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The selected use of HAART: Abidjan MTCT-PlusThe selected use of HAART: Abidjan MTCT-Plus(Tonwe-Gold, PLOS Medicine 2007;4:e257-)(Tonwe-Gold, PLOS Medicine 2007;4:e257-)

• 107 women starting HAART antenatally for their own health:

– >95% ZDV + 3TC + NVP– 189 CD4+/mm3 in median– 30.9% at WHO stage 3-4– Initiating treatment at 30 weeks, 74 days until delivery

• Week-4 transmission risk (RNA PCR): 1.0% [0-3.1%]

• 37% of HAART-treated women started formula feeding, 63% opted for early weaning

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Frequency of nevirapine resistance in women after single-dose nevirapine use to prevent HIV-1 peripartum transmission

Meta-analysis summary estimate(Arrive E, Ghent Group - Int J Epidemiol 2007)

35.7% [23.0% - 50.6%]

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Clinical significance of NVP resistance for Clinical significance of NVP resistance for subsequent HAART subsequent HAART in mothersin mothers? Trials under way? Trials under way

• In Abidjan, no difference of immunological response in women, previously exposed to sdNVP or not, after 12 months of HAART initiated >12 months later (Coffie, CID 2008).

A finding consistent with Thailand study (Jourdain, NEJM, 2004) and with Zambia recent findings (Chi AIDS 2007)

• Poorer virological response (<50 copies) at 6 and 18 months when women were exposed previously to sdNVP in Thailand (Lallemant, IAS 2005). But no difference with the threshold of 400 copies.

Confirmed in Côte d’Ivoire (Coffie, CID 2008) & Botswana (Lockman, NEJM 2007) & South Africa (Coovadia, CROI 2006) and in multi-country African study (Weidle P. CROI 2008)

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Clinical treatment failure* in HAART-treated women previously Clinical treatment failure* in HAART-treated women previously exposed** or not to sdNVP in Lusaka, Zambiaexposed** or not to sdNVP in Lusaka, Zambia

(Chi B. AIDS 2007; 21: 957-64)(Chi B. AIDS 2007; 21: 957-64)* increasing WHO stage, CD4 drop below baseline, death ** median 16 months* increasing WHO stage, CD4 drop below baseline, death ** median 16 months

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The risk of NVP resistance after exposureThe risk of NVP resistance after exposureto sdNVP-based PMTCT can be reducedto sdNVP-based PMTCT can be reduced

• A short-course “tail” of Combivir (3-7 days postpartum) following sdNVP alone is efficient (Mc Intyre J. IAS 2007, unpublished) and in the 2006 WHO guidelines

Also following scZDV + sdNVP (Chaix ML. JID 2006)

• A single-dose or short-course of TDF+FTC (Truvada®) will also yield some benefit

– Reducing the risk of NVP resistance by half (25 to 12%) with a single-dose of TFD300/FTC200 after scZDV + sdNVp (Chi B. Lancet 2007)

– Reducing the risk of NVP resistance to 0 (upper limit of 95% CI: 9.5%) with a single-dose of 2 x TDF300/FTC200 + 7 days post-partum « tail » of 1 x TDF300/FTC200 daily after scZDV + sdNVP (Arrive E. CROI 2008)

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The risk of 3TC resistance can be high after exposureThe risk of 3TC resistance can be high after exposureto 3TC-based short-course PMTCT for >4 weeks and to 3TC-based short-course PMTCT for >4 weeks and

induce poorer response of maternal treatmentinduce poorer response of maternal treatment

• French ANRS 075 trial (Mandelbrot JAMA 2001)

• Côte d’Ivoire ANRS 1201 Ditrame Plus trial (Chaix ML. JID 2006 and Coffie CID 2008)

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2°) Prevention of breast milk HIV transmission 2°) Prevention of breast milk HIV transmission in 2008 in 2008

An unresolved issue in AfricaAn unresolved issue in Africa

• Greatest protection of breastfeeding against infant mortality is in first 6 months of life

• Risk of breast milk HIV transmission is associated with duration, modalities of breastfeeding and with maternal HIV disease

• Formula feeding and abrupt weaning raise programmatic concerns in settings where there are risks of malnutrition, morbidity & mortality from unsafe preparation

± Becquet (Côte d’Ivoire) PLOS Medicine 2007

+++ Kuhn (Zambia) NEJM 2008

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18-month postnatal transmission of HIV among children diagnosed uninfected at 4 weeks of age

Stratified by maternal antenatal CD4 count Pooled analysis of Vertical Transmission Study (South Africa,

2001-07) and Ditrame Plus Trial (Côte d’Ivoire, 2001-05). N=1151 Antenatal maternal CD4 count (cells/ml)

N Number of children

HIV-infected through breastfeeding

HIV postnatal transmission

(%)

95% confidence

interval

< 200 119 15 15.3 9.5-24.2 ³ 200 1032 57 6.2 4.9-8.0

< 250 181 20 11.0 5.3-16.2 ³ 250 970 52 5.4 3.5-6.5

< 350 353 38 12.6 9.3-16.9 ³ 350 798 34 4.8 3.4-6.6

< 200 119 15 15.3 9.5-24.2 200-349 234 23 11.3 7.6-16.5 350-500 320 18 6.3 4.9-9.1 ³ 500 478 16 3.7 2.3-6.0

(Adapted from Becquet R. CROI 2008)(Adapted from Becquet R. CROI 2008)

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The challenge of PMTCT by ARVsThe challenge of PMTCT by ARVsduring breastfeeding in 2008during breastfeeding in 2008

• So far, postnatal ARV interventions have targeted either the breastfeeding women or the neonates for short periods of time– with a partial efficacy,– and at the expense of acquisition of viral resistance

• Recently completed or ongoing studies :– postnatal ARV interventions for the breastfeeding women– postnatal ARV interventions for the breastfed neonates

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Thomas CROI 2008, De Vincenzi CROI 2008, Tonwe-Gold PLoS Med 2007, Marazzi CROI 2008

ARV interventions for the breastfeeding women (a)

Study Maternal ARV

regimen Infant regimen

MTCT risk according to baseline maternal CD4 count

Kisumu trial, Kenya

ZDV/3TC+NVP

NVP single dose for infants

Among women with CD4<250:

4.3% at 1 Mo (1.8-10.0) 6.7% at 12 Mo (3.2-13.9)

Among women with

CD4>250: 3.8% at 1 Mo (2.2-6.3)

5.5% at 12 Mo (3.6-8.4)

Kesho-Bora trial, Burkina Faso - Kenya

ZDV/3TC+NVP

NVP single dose for infants

Among women with CD4<200:

6.4% at 12 Mo (0.3-12.4)

MTCT-Plus, Côte d'Ivoire

ZDV/3TC+NVP

NVP single dose + 1 week of ZDV

for infants

Among women eligible for ARV therapy:

1.0% at 1 Mo (0.0-3.1) 3.3% at 12 Mo (0.0-6.9)

Dream cohort, Mozambique

ZDV/3TC+NVP

NVP single dose for infants

Among women eligible for ARV therapy:

1.2% at 1 Mo 2.8% at 12 Mo

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KIBS Maternal HAART Prophylaxis Study (Kisumu)KIBS Maternal HAART Prophylaxis Study (Kisumu)Evaluation of ARV Resistance in InfantsEvaluation of ARV Resistance in Infants

Zeh C et al. 15Zeh C et al. 15thth CROI, Boston, MA, 2008 Abs 84LB CROI, Boston, MA, 2008 Abs 84LB

• 29/502 infant (5.8%) were infected.

• 24/29 infants (83%) were infected prior to 6 months (during period of prophylaxis).

• Maternal HAART regimen for 24 infants:

– 14 (58%) NVP and 10 (42%) NFV

• Resistance was identified in 16 (67%) infants:

– 43% (6/14) infants of moms on NVP

– 100% (10/10) infants of moms on NFV

• Resistance not generally present on first viral test but emerged in the breastfeeding infant of mothers on HAART by week 14-24.

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ARV interventions for the breastfeeding women (b)

The MITRA-PLUS trial, Tanzanie (Kilewo C. IAS 2007, Sydney)

• Non randomized trial (N= 501)

• HAART among breastfeeding women:

ZDV + 3TC + NVP / NFV

• Median CD4: 416

• Breastfeeding 98% at 6 weeks, 77% at 5 months

• Transmission at 6 weeks 4.1%

Transmission t 6 months 5.0%

• 5.5% rash (all with CD4 >200)

• The AMATA trial, Rwanda (to be discussed in this meeting)

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Increased resilience to the development of drug-resistance with modern boosted protease inhibitor-based HAART

(Lima VD. JID 2008; 198: 51-8)

• British Columbia Center for Excellence Cohort (N = 2350)

• Investigated temporal trends in HAART use among previously naïve patients and the emergence of resistance after a median of 4.8 years of treatment

• 18% women; 50% >200 CD4 at baseline• After adjustment on many baseline variables, and

compared to non-boosted PI-based HAART regimens, the OR of viral resistance was – 1.09 (95% CI: 0.84 - 1.42) for NNRTI-based HAART– 0.42 (95% CI: 0.28 - 0.62) for ritonavir-boosted PI-

based HAART

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LIMA VD, et al. JID 2008; 198:51-8.LIMA VD, et al. JID 2008; 198:51-8.

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sont requis pour visionner cette image.

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1.1. Prevention of MTCT during pregnancy remains Prevention of MTCT during pregnancy remains challenging in most ressource-limited settingschallenging in most ressource-limited settings HAART for maternal indications MUST be promoted HAART for maternal indications MUST be promoted

2. Summary of ongoing research on maternal- or infant-only ARV interventions for preventing postnatal transmission:

– Preliminary results shed some light on the limits of the maternal-only approach of MTCT prevention including the risk of resistance for the infant

– The administration of ARV drugs to breastfed infants as a post-exposure prophylaxis needs to be maintained all over the breastfeeding exposure

3. Question: Will it be necessary– To offer the best possible HAART to all pregnant, delivering and

breastfeeding women?

– to combine ARVs in women and children?

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ARV interventions for the breastfed neonates (a)

• PEPI trial, Malawi (Kumwenda, NEJM 2008)– Infant daily NVP or sc(NVP+ZDV) from birth until 14 weeks of age– 9-month HIV transmission or death: 11% (extended NVP), 12%

(extended NVP+ZDV)– What about viral resistance in infants?– 1/3 children breastfed beyond 9 months of age: what about postnatal

HIV transmission beyond that age?

• Multicentric SWEN trial (Sastry & Moorthty, CROI 2008)– Infant daily NVP from birth until 6 weeks of age vs. NVP single-dose– 6-month HIV transmission: 7% (not different from NVPsd arm)– 6-month HIV transmission or death: 8% – 92% of NVP viral resistance in HIV-infected infants in the extended

NVP arm

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ARV interventions for the breastfed neonates (b)

• MITRA cohort study, Tanzania (Kilewo, JAIDS 2008)

– Infant daily 3TC from birth until 6 months of age

– 6-week HIV transmission: 3.8%

– 6-month HIV transmission: 4.9%

– 6-month HIV transmission or death: 8.5%

– … But very short breastfeeding duration: median=18 weeks,only 15% of the children still breastfed at 6 months of age