Toxicity of stavudine- and nevirapine-containing antiretroviral treatment regimens:

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: • Stavudine (d4T) • Lamivudine (3TC) • Nevirapine (NVP)

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

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

5. 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 Methods (1): Setting

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

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

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

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

10. Results (3): Risk factors • Skin toxicity: non-significant • Hepatotoxicity • BMI ≤20 kg/m2 • Abnormal baseline liver tests • No association with baseline CD4 count and sex

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

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

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

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

19. Implications for MSF? • 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 • ART programs need alternatives • tenofovir (TDF) or abacavir (ABV) • at present prohibitively expensive

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

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

25. NVP-related toxicity

26. D4T-related toxicity

27. Incidence of neuropathy

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

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

31. Definition • Technical investigations: CT/DEXA/MRI (Golden Standard) • Clinical • “Lipodystrophy Case Definition Study” Questionnaire • Validated vs “golden standard” • Anthropometrics • 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 l’infirmière 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) • Lipodystrophy: 34 % • Isolated lipoatrophy: 10 % • Isolated lipohypertrophy: 5 % • Mixed presentation: 19 % • Moderate/severe > 60-70 % • “Body changes disturbing” > 50 % • Cohort on d4T (severe lipoatrophy): • Substitution of lipoatrophie for 6.7 % • Incidence of 43/1000 py • 20 % by 3 years on ART

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

36. Toxicity of ARVs (South-Afr)

37. Toxicity of ARVs (South-Afr)