Access to Treatment in Africa Ergebnisse und Herausforderungen aus dem Programm DREAM Dieter Wenderlein Gemeinschaft Sant‘Egidio Universitätsklinikum Würzburg

Das Programm DREAM der Gemeinschaft Sant’Egidio (Drug Resource Enhancement against AIDS and Malnutrition) Comprehensive approach: - VCT - Antiretrovirale Therapie (HAART) - Prävention der Mutter-Kind-Übertragung von HIV (PMTCT) - Nahrungsmittelhilfen - Aufklärung - Fortbildung von “AktivistInnen” zu Multiplikatoren - Trainingskurse, Fortbildung von medizinischem Personal

DREAM in Afrika 10 Länder in Subsahara-Afrika 18 Labore zur HIV/AIDS-Diagnostik 31 Therapiezentren: 6 in staatlichen Gesundheitseinrichtungen 22 in kirchlichen Gesundheitseinrichtungen Bisher wurden 100.000 Patienten mit HIV aufgenommen 65.000 Patienten in ART genommen, darunter 6.000 Kinder 14.000 Kinder in PMTCT geboren Derzeit 1.300 Schwangerschaften in PMTCT

Einige Charakteristika von DREAM: Komplette Einbindung aller Aktivitäten in die nationalen Gesundheitssysteme - Kostenlose Versorgung der HIV-Patienten - Ausschließlich afrikanische Mitarbeiter in den Therapiezentren Intensive Mitarbeit von AktivistInnen / Community Health Workers - Klinische Studien u.a. zu PMTCT (Stillzeit), Adhärenz, Risikofaktoren für Sterblichkeit, Diagnostik (realtime PCR)

PMTCT Schwangere CD4<350 Therapieindikation HAART Schwangere CD4>350 HAART (AZT/3TC/NVP) ab der 25. SSW bis zum Ende der Stillzeit (je nach nationaler Leitlinie 6-12 Monate) Exclusive Breastfeeding bis 6 Monate, nach 6 Monaten complementary feeding Lebensmittelhilfen , Moskitonetze Neugeborenes - ARVs je nach nationaler Leitlinie (NVP SD, NVP für 4-6 Wochen, ev. mit AZT/3TC) - Realtime PCR nach 1-2 Monaten, 12 Monaten, 18 Monate AB-Test - HAART im Falle der Seropositivität

Methods: Prospective observational cohort study Live-born infants of HIV-1-infected women receiving medical care HIV-1 testing at 1, 6 and 12 months of age Women with CD4<350: HAART indefinitely Women with CD4>350: HAART ante- and postnatally for the first 6 months Exclusiv breastfeeding for 6 months

Results: 341 infants enrolled at birth 313 mother-infant pairs (92%) completed 6 months of follow-up 283 (83%) completed 12 months of follow-up HIV-1 diagnosis was ascertained in 287 infants (84%) including 4 who died. All 8 transmission occured at women with baseline CD4 > 350 6 of 8 transmissions in women with baseline VL > 4log 6 of 8 transmissions in women with less than 3 months antepartum HAART The 2 transmissions after 6 months occured in women who did non continue HAART

Two mothers (0. 6%) and 11 infants (3 Two mothers (0.6%) and 11 infants (3.2%) died; 7 infants (64%) died after weaning Country rate (Mozambique) Maternal mortality 587/100.000 1000/100.000 Infant mortality 33/1.000 101/1.000

Favorable pregnancy outcomes with reduction of abortion, stillbirth, and prematurity rates in a large cohort of HIV+ women in Southern Africa receiving highly active antiretroviral therapy (HAART) for prevention of mother-child-transmission (PMTCT) M.C. Marazzi et al. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Capetown, 19.-22.07.2009 Cohort: 3.273 HIV+ pregnant women from centers in Malawi and Mozambique from 7/2005 to 12/2008 Regimen: NVP-based HAART at 14 wks (if eligible for own health) or 25 wks gestation until 6 months postpartum. Abortion and stillbirths: Defined as fetal death at < or ≥ 32 wks gestation.

Results: Median baseline CD4 count: 357/mm3 Median baseline viral load: 4Log c/ml Median pregnancy duration: 39.1 wks Median time of pre-delivery HAART: 83 days (CL95%53-108). Maternal mortality: 1.2% Significantly associated with HAART: 7.4% if no HAART vs. 0.7 HAART ≥ 90 days before delivery CD4 threshold (3.2% vs. 0.7% if ≥ 200; p< 0.001). Abortion and stillbirth: 25.7% (18/70) in women with no HAART 4.3% (125/2,909) in women receiving HAART for >30 days (p< 0.001). Low birth weight:1.5% not associated with HAART duration or CD4 count.

Prematurity: Strongly associated with short/absent HAART: 70.8% reduction overall (Mantel-Heanszel OR=0.16; CL95%:0.12-0.21) and within each CD4 strata. Body Mass Index (OR 0.27; CL95% 0.15-0.50) and VL at delivery (OR 1.44; CL95% 1.22-1.70) strongly associated with prematurity by multivariate analysis. CD4 count Pre-delivery HAART (days) Premature delivery (N.) % OR >500 <30 >30 TOTAL 43/77 121/712 164/789 55.8 17.0 20.8 0.16 0.10-0.26 351-500 27/56 94/661 121/717 48.2 14.2 16.9 0.18 0.10-0.31 201-350 45/63 124/779 169/842 71.4 15.9 20.1 0.08 0.04-0.13 ≤200 10/32 85/497 95/529 31.3 17.1 18.0 0.45 0.21-0.99

J Acquir Immune Defic Syndr. 2011 May 4. [Epub ahead of print] Palombi L et. al. Limited Risk of Drug Resistance after Discontinuation of Antiretroviral Prophylaxis for the Prevention of Breastfeeding Transmission of HIV. J Acquir Immune Defic Syndr. 2011 May 4. [Epub ahead of print] Evaluated cohort: 70 HIV-infected pregnant women CD4>350/mm3 2 treatments sites in Malawi (Lilongwe, Blantyre) PMTCT Regime: AZT 300mg + 3TC 150mg + NVP 200mg BID Starting in week 25 of gestational age (or as soon as possible after that) until 6 months postpartum 3 week tail of AZT 300mg+3TC 150mg Plasma sample collected Baseline before drug administration (genotyping) Delivery Months 1, 3, 6 postpartum 1-2 months after drug discontinuation (genotyping) 6 months after drug discontinuation (genotyping)

Median duration of HAART during pregnancy: 63 days Median total duration of HAART: 240 days Median time from interruption of all drugs and testing: 60 days (interquartile range, 58-64) Results: 5 women had NNRTI mutations after HAART discontinuation (7.1%, 95% CI 1.11-13.17)  Risk of developing resistance mutations in compliant women who receive ARV prophylaxis and interrupt drugs 6 months after delivery is limited, after all with a long tail of 3 weeks The HIV-RNA level at the moment of drug discontinuation was significantly higher (P = 0.02) in women subsequently developing mutations. 2 had the same mutation archived in baseline HIV-DNA. Only 2 women with undetectable viral load during treatment had presence of resistance after drug discontinuation. These women had archived resistance at baseline

3 women had, at least once, detectable viral load and presence of mutations during treatment (K103N+G190A, K101E, K103N+Y188C) Presence of mutations after drug discontinuation associated with previous emergence of resistance during treatment (underlying the importance of drug adherence in these patients) Six months after drug discontinuation (month 12) there was persistence of mutations only when the mutations were previously archived in baseline HIV-DNA. None of the infants born to these women was infected with HIV.

Probleme - Herausforderungen   Leichter gesagt als getan: WHO Leitlinien 2009 (z.B. Rapid advice: Use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants, WHO November 2009) - Einsatz von EFV zu Beginn der Schwangerschaft - Breiter Einsatz von NVP bei HIV-exposed children (“from birth until 6 weeks of age”, “from birth until one week after all exposure to breast milk has ended”) - PI/r bleiben weiterhin second line 2. Unzureichender Zugang zu den nötigen diagnostischen Methoden: - Abdeckung mit CD4-Bestimmung unzureichend - Referenzlabore für Viruslast-Bestimmung, Realtime PCR (dried blood spot!) - Referenzlabore mit Möglichkeit der Resistenztestung 3. Systeme zum Monitoring der Adhärenz Optimierung des Patientenflusses von VCT zu Treatment - Defaulter tracing von Patienten lost to follow up - Einsatz von AktivistInnen, Community Health Workers, Support Groups

4. Schnelle Ausweitung und Optimierung der Qualität von HAART - zu niedrige Raten auf HIV getesteter Personen - HAART als Prävention („Test and treat“) 5. Schnelle Ausweitung und Optimierung der Qualität von PMTCT - zu niedrige Raten auf HIV getesteter schwangerer Frauen - HAART auch für Schwangere ohne Therapieindikation bis zum Ende der Stillzeit (Option B des Rapid advice Use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants - Richtiges Abstillen (kein abrupt weaning) - Richtige Ernährung des Kindes nach Stillzeit (Wasserqualität) 6. Finanzierungssicherheit (donor fatigue)

Vielen Dank!