Benefits and Risks of ART

Transcription

1 Benefits and Risks of ART Dr Paula Munderi WHO Training Course for Introducing Pharmacovigilance of HIV Medicines November 2009, Dar Es Salaam

2 Summary Progress in ART coverage WHO Progress Report Benefits of ART Survival Decreased Morbidity Decreased Transmission Vertical & Horizontal Principles of ART Measurement of efficacy Risks of ART linked to AEs and Toxicities Special Populations : Women & Children Epidemiology of Paediatric HIV Pregnancy and ART Co morbidities of specific concern : TB, HepB, Hep C, (Malaria) Programme implications Selection of ARVs in the PH approach ART principles & recommendations Current ART practice in LMIC What this means for countries Adherence : determinant of ART efficacy

3 Acknowledgements Sources of Slide Material Published data WHO progress report on access 2009 Jens Lundgren Lynne Moffenson WHO HQ HIV Dept (ATC team) DART study group

4 I Benefits of ART Improved Survival Reduced morbidity Reduced vertical transmission of HIV Possibly reduced horizontal transmission of HIV

5 Number of people receiving antiretroviral therapy in low and middle income countries, by region, Millions North Africa and the Middle East Europe and Central Asia East, South and South-East Asia Latin America and the Caribbean Sub-Saharan Africa End 2002 End 2003 End 2004 End 2005 End 2006 End 2007 End 2008

6 Reduced Death rates over time on ART Rate per 100 person years 0 1 years 17.9 [ ] 1 2 years 2.3 [ ] 2 3 years 1.2 [ ] Castelnuovo B, Manabe YC, Kiragga A et al CID 2009; 49:965 72

7 Survival impact of ART Proportion alive DART cohort ART: LCM: 2.2/100 PY CDM: 2.9/100 PY median CD4 86 at enrolment Entebbe Cohort (same community) NO ART available Years from enrolment into cohort median CD4 75 at enrolment 57.7/100 PY DART Study Group. IAS July 2009

8 Impact of ART on causes of death DART Study Group: XVI INTERNATIONAL AIDS CONFERENCE 2006 Pre-ART cohort: EC n = 516 PYO = 658 Oct 95 - Dec 00 Deaths (rate/100py) Post-ART cohort: DART n = 1015 PYO = 1819 Feb 03 - Jan 06 Deaths (rate/100py) Specific HIV-related causes 118 (17.9) 27 (1.5) Cryptococcus 64 (9.7) 4 (0.2) Cryptosporidium 18 (2.7) 2 (0.1) Tuberculosis 16 (2.4) 10 (0.5) HIV-related malignancy 11 (1.7) 6 (0.3) Bacteraemia 3 (0.5) 5 (0.3) CMV 4 (0.6) 0 (0) Severe anaemia 2 (0.3) 0 (0) Syndrome likely HIV related 176 (26.7) 18 (1.0) Wasting (+/- diarrhoea) 111 (16.9) 1 (0.1) Febrile event 48 (7.3) 12 (0.7) Neurological event 17 (2.6) 5 (0.3) Cause not HIV-related 4 (0.6) 6 (0.3) Unknown cause 82 (12.6) 11 (0.6) Total deaths 380 (57.7) 62 (0.3)

9 Malaria DART cohort

10 Vertical Transmission Maternal Viral Load in absence of ART % Transmission % 6% < % % % > Delivery Plasma HIV RNA Blattner W. XIII AIDS Conf, July 2000, Durban S Africa (LBOr4) WITS study,

11 Timing of vertical transmission for 30% 15 % 5% 10% Pregnancy Pre-natal DE LIV ER Y Breast-feeding Post-natal

12 Vertical Transmission at 6 weeks postpartum by ARV Regimen Botswana National Data Oct 2006 Nov 2007 Tlale J et al. IAS Mexico City Aug 2008 (Abs ThAC04) 15% Most Women Formula Feed Their Infants 10% 12.3% 5% 7.0% 4.7% 0% 0.7% 2.3% cart pre-preg cart during preg 3.3% AZT >4 wk +sdnvp AZT <4 wk +sdnvp sdnvp No ART

13 Vertical transmission of HIV 15-35% <1% Antenatal screen Maternal ART Neonatal ART C. section No breastfeeding

14 «Les personnes séropositives ne souffrant d aucune autre MST et suivant un traitement antirétroviral efficace ne transmettent pas le VIH par voie sexuelle» Commission fédérale pour les problèmes liés au sida (CFS), Commission d experts clinique et thérapie VIH et sida de l Office fédéral de la santé publique (OFSP) P Vernazza, B Hirschel, E Bernasconi, M Flepp. Bulletin des médecins suisses 2008;89: 5 Scientific basis: Effective ART undetectable HIV RNA Epidemiologic basis : vertical transmission is related to plasma HIV RNA e.g PMTCT

15 Longitudinal studies in HIV sero discordant couples Rwanda & Zambia 393 couples followed for 14 years no transmission from person on cart 8.6 % transmission with no cart 1 93 couples; in 41 +ve partner on cart 6 infections all in non treated 2 62 couples; Males +ve pregnancy desired no infection in female partner 3 2, 993 couples followed from HIV testing every 3 months person years 4 HIV infections from partners on cart 171 infections partners not on cart Incidence density of HIV transmission 4 0.7% on cart vs 3.4% off cart [RR = 0.21, CI: 0.08, 0.59] NB: HIV persists in semen and cervicovaginal fluid during effective cart

16 ARVs for Prevention PEP & PMTCT Universal Test & Treat combination ART Pre Exposure prophylaxis (PrEP) Tenofovir ARVs as vaginal microbicides Tenofovir Maraviroc

17 II Principles of ART Combination therapy Avoidance of resistance Importance of adherence

18 For sustained efficacy of ART... synergistic combinations of 3 active drugs usually from 2 different classes single or dual drug therapy only in PMTCT; low risk PEP the large number of possible combinations is only apparent cross resistance develops within classes Cross resistance may occur between NRTIs and NNRTIs preserving future treatment options is critical choice of initial regimen rational sequencing of combinations thereafter

19 Measurement of efficacy of ART When is treatment working? When has treatment failed Absence of clinical disease WHO clinical staging Recurrence of clinical illness WHO stage II/III/IV Immune restoration Rise in CD4 count Viral suppression Undetectable VL Fall in CD4 count to below 100 cells/mm 3 Detectable VL to >5000 copies/ml

20 Resistant virus Wild-type virus 10-20%

21 Resistant virus Wild-type virus Drug pressure 10-20%

22 Adherence Efficacy Nachega et al, Ann Intern Med, 2007

23 III Risks of ART Mainly related to toxicities

24 NB: Most ART Toxicities are... Predictable Clinically detectable Can be managed The key is patient and provider education!

25 Italian Cohort I C O N A Naive Antiretroviral Main reasons of discontinuation of first cart regimen within 1st year: ICONA cohort Toxicity Failure Non-adherence Other Continued Monforte et al. AIDS 1999

26 Reasons for change of a first combination ART regimen Reason N CD4 VL Unknown Other Choice Toxicities Failure p=0.27 p< N Median CD p= Median VL p= EuroSIDA: Mocroft et al, AIDS Research Hum Retro, 2005

27 ART Toxicity related deaths: 1 st year 1 Hepatotoxicity, 2 Lactic acidosis 2 nd year 1 Hepatotoxicity; 2 lactic acidosis; 1 pancreatitis Castelnuovo B, Manabe YC, Kiragga A et al CID 2009; 49:965 72

28 NB: Most ART Toxicities are... Predictable Clinically detectable Can be managed The key is patient and provider education!

29 IV Women & Children Pregnancy In utero & Perinatal exposure to ARVs cart in children

30 Incidence of Seroconversion in Pregnancy: Prevention of HIV in Pregnant Women is Critical Country Reference Incidence per 100 Pt Yrs Pregnancy Uganda Gray R et al. Lancet 2005;366: Botswana Lu L et al CROI Abs.94LB 1.3 ( ) Zimbabwe, Uganda South Africa Morrison CS et al. AIDS 2007;21:1027 Rehle T et al. S Afr Med J 2007;97: (0 12.9) South Africa Moodley D et al. AIDS 2009;23: ( )

31 43% of New Infant Infections in Botswana May be Due to Maternal Seroconversion in Pregnancy/PP Lu L et al. 16 th CROI, Montreal, Canada Feb 2009 Abs 94LB HIV diagnosed before or during ANC New maternal infection late pregnancy New maternal infection 1 yr postpartum # HIV+ women Estimated MTCT rate # infected infants 13, (incidence 1.3%) 4.7% (with PMTCT ARV) 450 (incidence 1.8%) 73% 36% Of the estimated 1,082 infant HIV infections in Botswana in 2007, 462 (43%) were due to incident cases of maternal HIV in pregnancy/pp

32 Prevention of HIV in Women, (Especially Young Women) Prevention of Unintended Pregnancies in HIV-Infected Women Prevention of Transmissio n from an HIV-Infected Woman to Her Infant Support for HIV-Infected Mother and Family Unintended Pregnancy Among HIV Infected Women 51% unintended pregnancies among women with HIV in Cote d Ivoire. 74% unintended pregnancies among women in HIV care in Rwanda. 84% unintended pregnancies among PMTCT clients in South Africa. 93% unintended pregnancies among women in HIV-ART care in Uganda. Desgrees du Lou Aet al. Int J STD AIDS 2002 Bangendanye, 3 rd Ped CLS 2007 Rochet T et al. JAMA 2006 Homsy J et al. PLosOne 2009

33 Incident pregnancy on ART DART cohort Age at enrolment yrs yrs yrs yrs All women <45 Incidence rate per 100 woman years <1 year 1 2 years 2 3 years 3 4 years >4 years Time since enrolment in DART

34 Increased plasma volume dilution effect Physiologic Changes During Pregnancy Can Affect Therapeutic Drug Administration Decreased in serum albumin increase in free fraction of drug Increased GFR 20 60% starting 1 st trimester change in drug clearance Changes in hepatic enzyme activity increase CYP34A, 2D6 = change in drug metabolism Decreased gastric acid secretion, prolonged gastric emptying and intestinal transit time decreased oral drug absorption

35 Pregnancy & Antiretroviral Pharmacokinetics NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Zidovudine NUCLEOTIDES Tenofovir AUC No No No No No No NNRTIs Efavirenz No data Etravirine No data Nevirapine No FUSION INHIBITORS Enfuvirtide No data PIs Atazanavir AUC Darunavir No data Fosamprenavir AUC? Indinavir AUC Lopinavir/rit AUC Nelfinavir AUC Ritonavir AUC Saquinavir AUC Tipranavir No data CCR5 CO-RECEPTOR ANTAGONISTS Maraviroc No data INTEGRASE INHIBITORS Raltegravir No data

36 Toxicity associations in pregnancy Maternal Foetal d4t / ddi lactic acidosis NEVIRAPINE hepatic toxicity EFAVIRENZ neural tube defects TENOFOVIR bone growth defects ZIDOVUDINE anaemia

37 Antiretroviral Pregnancy Registry 1/89 1/09 Prospective Cases ( % Birth Defect CDC general birth defect surveillance 2.7% ( %) 1 st trimester any ARV exposure 2.9% ( %) Atazanavir sulfate-containing (7/292) ABC-containing (18/608) AZT-containing (95/3108) 3TC-containing (93/3226) d4t-containing (19/754) Indinavir-containing (6/276) Nelfinavir-containing (37/1074) Nevirapine-containing (18/817) Ritonavir-containing (20/883) Lopinavir-containing (8/470) Tenofovir-containing (16/678) ddi-containing (16/365) 2.4% ( %) 3.0% ( %) 3.1% ( %) 2.9% ( %) 2.5% ( %) 2.2% ( %) 3.4% ( %) 2.2% ( %) 2.3% ( %) 1.7% ( %) 2.4% ( %) 4.4% ( %)

38 HIV negative but exposed children following in utero exposure to ARVs Clinically symptomatic mitochondrial dysfunction rare 0.3% 3 per 1,000 very rarely (0.07% 7 per 10,000) can be fatal Mild, clinically asymptomatic, but persistent hematologic abnormalities anaemia, neutropenia Transient elevations in lactic acid common with in utero exposure usually asymptomatic resolve within months

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40 ARV toxicities in treated children similar spectrum to adults Of particular importance in children: Metabolic abnormalities hyperlipidaemia glucose intolerance Fat redistribution Bone density & growth