1. Toxicity of stavudine- and nevirapine-containing antiretroviral treatment regimens: incidence and risk factors after 3 years in a large cohort in Rwanda Johan van Griensven

2. Background (1) 90% of ART regimens in low-income countries use fixed dose combination of: 90% of ART regimens in low-income countries use fixed dose combination of: Stavudine (d4T) Stavudine (d4T) Lamivudine (3TC) Lamivudine (3TC) Nevirapine (NVP) Nevirapine (NVP)

3. Background (2) Long-term toxicity well-described in high- income countries Long-term toxicity well-described in high- income countries Stavudine (d4T) Stavudine (d4T) Abandoned for reasons of toxicity Abandoned for reasons of toxicity First choice in low-income countries First choice in low-income countries Nevirapine (NVP) Nevirapine (NVP) significant morbidity/mortality significant morbidity/mortality contra-indicated for higher CD4 counts (> 250) contra-indicated for higher CD4 counts (> 250)

4. Objectives Assess incidence, timing and risk factors of toxicity with D4T and NVP in Rwanda Assess incidence, timing and risk factors of toxicity with D4T and NVP in Rwanda

5. Methods (1): Setting ART program in 2 urban health centers, Kigali 3,417 patients started on ART by Dec 07 Open cohort: 90% in care by 2 years of ART Diagnostic tools available ARV KMK ARV KNN

6. Methods (2) Study population Study population N= 2,970 N= 2,970 2,667 started stavudine-based regimen (90.6%) 2,667 started stavudine-based regimen (90.6%) 2,694 started nevirapine-based regimen (89.6%) 2,694 started nevirapine-based regimen (89.6%) Side-effects/toxicity Side-effects/toxicity WHO definitions (grading) WHO definitions (grading) Symptomatic hyperlactatemia/lactic acidosis Symptomatic hyperlactatemia/lactic acidosis Lipoatrophy Lipoatrophy

7. Methods (3) Side-effects/toxicity Side-effects/toxicity WHO definitions (grading) WHO definitions (grading) Symptomatic hyperlactatemia/lactic acidosis Symptomatic hyperlactatemia/lactic acidosis Lipoatrophy Lipoatrophy Probabilities of time to first severe toxicity requiring treatment change (KM) Probabilities of time to first severe toxicity requiring treatment change (KM) related to NVP and D4T related to NVP and D4T A risk factor analysis A risk factor analysis multivariate Cox proportional hazards modelling multivariate Cox proportional hazards modelling

8. WHO stage WHO stage stage I (6.5%) stage I (6.5%) stage II (28.4%) stage II (28.4%) stage III (56.6%) stage III (56.6%) stage IV (8.5%) stage IV (8.5%) Baseline CD4 count: 162 cells/µL Baseline CD4 count: 162 cells/µL Median time on ART: 1.5 years Median time on ART: 1.5 years Results (1): baseline characteristics

9. Results (2): NVP toxicity Severe toxicity (drug-substitution): 6.4% (170) Severe toxicity (drug-substitution): 6.4% (170) Rash: 4.9% (130) Rash: 4.9% (130) Hepatitis: 1.5% (40) Hepatitis: 1.5% (40) Early toxicity Early toxicity Within first 6 months of treatment for 90 % Within first 6 months of treatment for 90 % Not clearly different from what reported in high and low-income countries Not clearly different from what reported in high and low-income countries

10. Results (3): Risk factors Skin toxicity: non-significant Skin toxicity: non-significant Hepatotoxicity Hepatotoxicity BMI 20 kg/m 2 BMI 20 kg/m 2 Abnormal baseline liver tests Abnormal baseline liver tests No association with baseline CD4 count and sex No association with baseline CD4 count and sex

11. Results (4): Risk factors for severe toxicity Similar findings from several other African studies Similar findings from several other African studies Contrasts with findings from high income countries Contrasts with findings from high income countries Female sex Female sex CD4 count > 250 cells/µL CD4 count > 250 cells/µL

12. Results (5): Stavudine toxicity Neuropathy: 7.6% (206) Neuropathy: 7.6% (206) Lactic acidosis (SH/LA): 3.2% (85) Lactic acidosis (SH/LA): 3.2% (85) Lipoatrophy (body fat changes): 6.7% (180) Lipoatrophy (body fat changes): 6.7% (180) Total: 16.6% (448) Total: 16.6% (448) Similar findings from other African countries Similar findings from other African countries

13. Results (6): Stavudine toxicity

14. Results (7): Stavudine toxicity

15. Results (8): Lipoatrophy

16. Results (9): Risk factors Neuropathy Lactic acidosis Lipoatrophy Higher age (>35 years) ++ Advanced WHO stage ++ Female sex ++++++ Higher baseline BMI ++++++

17. Conclusion (1) Toxicity of NVP similar to high-income countries Toxicity of NVP similar to high-income countries Different risk factors? Different risk factors? Risk factors different ? Risk factors different ? Different from rich countries Different from rich countries Allergy vs toxicity ? Allergy vs toxicity ? Implications for ART initiation and PMTCT protocols Implications for ART initiation and PMTCT protocols Safe to give NVP when high baseline CD4 counts ? Safe to give NVP when high baseline CD4 counts ?

18. Conclusion (2) D4T has severe, long-term toxicity D4T has severe, long-term toxicity Main concern is Main concern is lactic acidosis: mortality lactic acidosis: mortality Lipoatrophhy: acceptance and adherence ? Lipoatrophhy: acceptance and adherence ?

19. Implications for MSF? Risk factors could help identify patients at higher risk of drug toxicity Risk factors could help identify patients at higher risk of drug toxicity Develop diagnostic and treatment paths with few diagnostic tools to ensure pro-active management Develop diagnostic and treatment paths with few diagnostic tools to ensure pro-active management ART programs need alternatives ART programs need alternatives tenofovir (TDF) or abacavir (ABV) tenofovir (TDF) or abacavir (ABV) at present prohibitively expensive at present prohibitively expensive

20. Acknowledgements Health Centres Kinyinya and Kimironko Health Centres Kinyinya and Kimironko MSF team Rwanda (2002-2007) MSF team Rwanda (2002-2007) Ministry of Health Rwanda Ministry of Health Rwanda

24. Diagnostic tool: Accutrend 226 $/machine 2.3 $/test Interfering factors: Exercise Hydratation Nutrition ? Infections malaria, TB ? Asymptomatic hyperlactatemia Action threshold ? Clinical evaluation

25. NVP-related toxicity

26. D4T-related toxicity

27. Incidence of neuropathy Severe neuropathy Total Rwanda 7.6 % - SA (Durban) 6.9 % SA (CapeT) 5.9 % - Kenya (slum) 3 % 23 % Uganda 9.3 % (subst 17 %) 36 %

28. Hyperlactatemia/lactic acidosis Rwanda Rwanda Substitution for 3.2 % of patients on d4T Substitution for 3.2 % of patients on d4T IR 20/1000 patient years IR 20/1000 patient years 6 % by 3 years on ARV 6 % by 3 years on ARV South-Africa South-Africa Soweto: 30/1000 patient years (CID, 2007) Soweto: 30/1000 patient years (CID, 2007) Durban: 30/1000 patient years Durban: 30/1000 patient years Cape Town: 19/1000 patient years Cape Town: 19/1000 patient years Botswana (CID, 2007), Uganda (JAIDS 2007) Botswana (CID, 2007), Uganda (JAIDS 2007)

29. Acidose lactique/hyperlactatemie South-Africa (Clin Infect Dis, 2007) – Soweto South-Africa (Clin Infect Dis, 2007) – Soweto Symptomatic hyperlactatemia: Symptomatic hyperlactatemia: 20/1000 py 20/1000 py Mortality 0 % Mortality 0 % Lactic acidosis: Lactic acidosis: 10/1000 py 10/1000 py Mortality 30 % Mortality 30 % South-Africa – Durban South-Africa – Durban 37/1000 py 37/1000 py

31. Definition Technical investigations: CT/DEXA/MRI (Golden Standard) Technical investigations: CT/DEXA/MRI (Golden Standard) Clinical Clinical Lipodystrophy Case Definition Study Questionnaire Lipodystrophy Case Definition Study Questionnaire Validated vs golden standard Validated vs golden standard Anthropometrics Anthropometrics Rwanda: screening for long-term side-effects integrated in routine care Rwanda: screening for long-term side-effects integrated in routine care

32. 1. Evaluation par le patient Au visage 0 - + un peu moyen beaucoup Au cou 0 - + un peu moyen beaucoup Au seins 0 - + un peu moyen beaucoup Au ventre 0 - + un peu moyen beaucoup Aux fesses 0 - + un peu moyen beaucoup Aux bras 0 - + un peu moyen beaucoup Au jambes 0 - + un peu moyen beaucoup 2. Evaluation par linfirmière Au visage 0 - + un peu moyen beaucoup Au cou 0 - + un peu moyen beaucoup Au seins 0 - + un peu moyen beaucoup Au ventre 0 - + un peu moyen beaucoup Aux fesses 0 - + un peu moyen beaucoup Aux bras 0 - + un peu moyen beaucoup Au jambes 0 - + un peu moyen beaucoup Depuis quand ces changements ont-ils commencé ?.….jours/semaine(s)/mois/année(s)

33. Symptômes associés (arguments pour acidose lactique) ? Depuis quand ? Paresthésie non un peu moyen beaucoup …..jours/sem/mois/années Nausée non un peu moyen beaucoup …..jours/sem/mois/années Vomissement non un peu moyen beaucoup …..jours/sem/mois/années Diarrhée non un peu moyen beaucoup …..jours/sem/mois/années Inappétence non un peu moyen beaucoup …..jours/sem/mois/années Douleur non un peu moyen beaucoup …..jours/sem/mois/années abdominal Gonflement non un peu moyen beaucoup …..jours/sem/mois/années abdominal Dyspnée non un peu moyen beaucoup …..jours/sem/mois/années repos effort Fatigue non un peu moyen beaucoup …..jours/sem/mois/années Perte de poids…. kg en ….. jours/sem/mois Augmentation de poids…. kg en ….. jours/sem/mois Autres symptômes…………………………………………… Quand est-ce que ces symptôms ont-ils commencé ? …..jours/sem/mois/années

34. Frequency of lipodystrophie Cross-sectional evaluation (> 1 an sous ARV, n=409) Cross-sectional evaluation (> 1 an sous ARV, n=409) Lipodystrophy: 34 % Lipodystrophy: 34 % Isolated lipoatrophy: 10 % Isolated lipoatrophy: 10 % Isolated lipohypertrophy: 5 % Isolated lipohypertrophy: 5 % Mixed presentation: 19 % Mixed presentation: 19 % Moderate/severe > 60-70 % Moderate/severe > 60-70 % Body changes disturbing > 50 % Body changes disturbing > 50 % Cohort on d4T (severe lipoatrophy): Cohort on d4T (severe lipoatrophy): Substitution of lipoatrophie for 6.7 % Substitution of lipoatrophie for 6.7 % Incidence of 43/1000 py Incidence of 43/1000 py 20 % by 3 years on ART 20 % by 3 years on ART

35. Until recently rarely reported Until recently rarely reported First report coming from MSF Rwanda First report coming from MSF Rwanda CROI, Feb 2006 CROI, Feb 2006 South-Africa South-Africa Prospective cohort study (George) Prospective cohort study (George) 43 % lipodystrophy by 2 years onARV 43 % lipodystrophy by 2 years onARV Cape Town, 2007 Cape Town, 2007 9 % substituted d4T for La by 3 ans of ARV 9 % substituted d4T for La by 3 ans of ARV Implementers meeting (2006), Durban: Implementers meeting (2006), Durban: Substitution for lipoatrophy: 73/1000 py Substitution for lipoatrophy: 73/1000 py Rwanda (KIST): Rwanda (KIST): Prevalence of 70 % by 3 years Prevalence of 70 % by 3 years Incidence of La in Africa ?

36. Toxicity of ARVs (South-Afr)