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Challenges in HIV Treatment and Care in a Resource Constrained Environnement

Challenges in HIV Treatment and Care in a Resource Constrained Environnement. Serge Paul Eholié Xavier Anglaret. Affiliation: ANRS research site in Côte d’Ivoire Infectious Disease Department, Treichville University Hospital, Abidjan Inserm U897, ISPED, Bordeaux University. INTRODUCTION.

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Challenges in HIV Treatment and Care in a Resource Constrained Environnement

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  1. Challenges in HIV Treatment and Care in a Resource Constrained Environnement Serge Paul Eholié Xavier Anglaret • Affiliation: • ANRS research site in Côte d’Ivoire • Infectious Disease Department, Treichville University Hospital, Abidjan • Inserm U897, ISPED, Bordeaux University

  2. INTRODUCTION • In 1998-2001, pilot programs gave evidencethat ART couldbefeasible and effective in resourcelimited settings: • UNAIDS Initiative (Uganda, Côte d’Ivoire, Chile, Vietnam) • Countries (Senegal) or NGOS (MSF) initiatives • From 2000 to 2010, large programs confirmedthat ART wasfeasible and effective in resourcelimited settings: • As of june 2010, approx 6.6 million people on ART in low- and middle-income countries (4.5 millions in sub-Saharan Africa); • With success in Scaling program and decentralization, almost 19 000 health facilities implemented; • With extensive evidence that ART reduces morbidity and mortality in routine conditions.

  3. Successes of ART in low and middle income settings

  4. SUCCESSES However, challenges remain!!!!

  5. Challenges to ensure the successof ART programs in low- and middle-income countries * Increase coverage * Ensure financing sustainability * Reduce AIDS and HIV non-AIDS morbidity, and mortality * Implement 2010 WHO guidelines * Improve assessment of programs efficacy * Improve prevention, diagnosis, and management of adverse events * Improve retention * Ensure comprehensive HIV care

  6. CHALLENGE 1 Coverage

  7. COVERAGE, December 2009: 36% in LMICIntraregional differences Towards universal access: Scaling up priority HIV/AIDS interventions in the health sector. Progress report 2010

  8. Challenge 2:Financing sustainability 80-95% of funds are from international donors Achilles’ heel of ART programs Courtesy of PM Girard Source Hecht R, Lancet 2010

  9. CHALLENGE 3 REDUCE MORBIDITY AND MORTALITY

  10. Countries *Zambia, Stringer JSA, JAMA 2006 * Senegal, Etard JF, AIDS 2006 * Zimbabwe, Erisktrup C, JAIDS 2007 * Haiti, Tuboi H, JAIDS 2009 * Honduras, Tuboi H, JAIDS 2009 Mortality rate 7% 23.1% 29.5% 12.4% 10.1% ART Mortality

  11. Risk factors for mortality • Male sex • Clinical stage, WHO 3-4, CDC C • Body Mass Index <18-19 Kg/m2 • Haemoglobin<10g/dl • CD4 <200 cells/mm3 • Viral load >5 log10 copies/ml Stringer JF JAMA 2006, Etard JF AIDS 2006, Erisktrup C JAIDS 2007, Moh R AIDS 2007, Tuboi SH JAIDS 2009, Mills EJ AIDS 2011, Toure AIDS 2008, Lawn AIDS 2009

  12. 200-350 CD4/mL < 200 CD4/mL Mortalityreduction 75% Severe P, N Engl J Med 2010

  13. Challenge 3: REDUCE MORBIDITY AND MORTALITY • Certainly start ART earlier… but how much earlier ? • < 350 CD4 : minimal threshold worldwide1 • < 500 CD4 : minimal threshold in increasing number of rich countries2,3 • > 500 CD4: ongoing randomized trials (START, Temprano4…) 2) Improve access to care, diagnosis and treatment of comon morbity (TB, bacterial diseases…) 1-WHO, Antiretroviral Therapy for HIV infections in adults and adolescents, Recommandations, 2010, h http://www.who.int ttp://www.who.int 2- Prise en Charge Me´dicale des Personnes Infecte´es par le VIH Ministry of Health France, 2008. http://www.sante-sports.gouv.fr/ 3- Panel on Antiretroviral Guidelines for Adults, and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS, USA,2009 4- Temprano study ANRS 12 136, clinicaltrials.govNCT00495651

  14. Challenges 4 IMPLEMENT 2010 WHO GUIDELINES

  15. Main changes in WHO 2010 Guidelines • Start earlier: CD4 < 350/mm3 or WHO stage 3,4 (vs. 200 CD4orWHO stage 4 or WHO stage 3 & 200-350) • First line regimen: • Include viral load in routine monitoring • Second line regimen: WHO, AntiretroviralTherapy for HIV infections in adults and adolescents, Recommandations, 2010, h http://www.who.int ttp://www.who.int

  16. Main changes in WHO 2010 Guidelines WHO, AntiretroviralTherapy for HIV infections in adults and adolescents, Recommandations, 2010, h http://www.who.int ttp://www.who.int 1) Start earlier: CD4 < 350/mm3 or WHO stage 3,4 (vs. 200 CD4orWHO stage 4 or WHO stage 3 & 200-350) • First line regimen: • Include viral load in routine monitoring • Second line regimen:

  17. ART at 350 CD4 vs. 200 CD4 Where to find patients at earlier stage of HIV disease ?

  18. ART at 350 CD4 vs. 200 CD4 • Find patients with higher CD4 counts?? • Increase Voluntary Counseling and Testing (VCT) • Facilitate or strenghten the link between VCT centers and ART clinics • Anticipate and face an increase in the number of patients on ART • Demonstrate cost effectiveness/acceptability to governments and donors

  19. 8 countries:3 EasternAfrica, 3 SouthernAfrica, 1 Western Africa, 1 Central Africa 267 sites (ICAP centers) 121 404 patients Median CD4 136 cells/l Nash D, AIDS 2011

  20. ART at 350 CD4 vs. 200 CD4 • Find patients wiht higher CD4 counts • Change the paradigm • Target HIV negative patients • Increase Voluntary Counseling and Testing (VCT) • Facilitate or strenghten the link between VCT centers and ART clinics • Anticipate and face an increase in the number of patients on ART • Demonstrate cost effectiveness/acceptability to governments and donors

  21. ART at 350 CD4 vs. 200 CD4 • Find asymptomatic patients • Change the paradigm • Target HIV negative patients • Increase Voluntary Counseling and Testing (VCT) • Facilitate or strenghten the link between VCT centers and ART clinics • Anticipate and face an increase in the number of patients on ART • Demonstrate cost effectiveness/acceptability to governments and donors

  22. Whydon’tphysicians test for HIV? A review of the US littérature. Burke RC, AIDS 2007 Insufficient time Consent process Lack of knowledge/training Language Lack of patient acceptance Pre-test counselling requirements Competingpriorities Inadequatereimbursement Prenatal 24 barriers Othermedical settings 23 barriers Much of the failure to expand HIV Testing guidelines are related to physicians

  23. Standard of Care and Intervention periods in a routine HIV Testing Cohort in an out patient department, Durban, SA Bassett IV, JAIDS 2007 We need a pro-active approach!!!!

  24. ART at 350 CD4 vs. 200 CD4 • Findasymptomatic patients • Change the paradigm • Target HIV negative patients • IncreaseVoluntaryCounseling and Testing (VCT) • HIV testingisgeneralmedicine (« it’s all HCW business ») • Makerapid tests available • Facilitate or strenghten the linkbetween VCT centers and ART clinics • Anticipate and face an increase in the number of patients on ART • Demonstratecosteffectiveness/acceptability to governments and donors

  25. ART at 350 CD4 vs. 200 CD4 • Find asymptomatic patients • Change the paradigm • Target HIV negative patients • Increase Voluntary Counseling and Testing (VCT) • HIV testing is general medicine (« it’s all care workers business ») • Make rapid tests available • Facilitate or strenghten the link between VCT centers, Ante Natal Clinic and ART clinics • Anticipate and face an increase in the number of patients on ART • Demonstrate cost effectiveness/acceptability to governments and donors

  26. ART at 350 CD4 vs. 200 CD4 • Find asymptomatic patients • Change the paradigm • Target HIV negative patients • Increase Voluntary Counseling and Testing (VCT) • HIV testing is general medicine (« it’s all care workers business ») • Make rapid tests available • Facilitate or strenghten the link between VCT centers and ART clinics • Anticipate and face an increase in the number of patients on ART • Demonstrate cost effectiveness/acceptability to governments and donors

  27. Source: Konde-Lule J, AIDS Care 2010 < 350 vs <200 = 59% increase in demand of services

  28. Patients Volume, HumanResourcesLevels and Attrition from HIV Treatment Programs in Central Mozambique Lambdin BH, JAIDS 2011 Staff burden : do not forget those who deliver the pills ! (200-300 patients/day or more !!!!)

  29. ART at 350 CD4 vs. 200 CD4 • Find asymptomatic patients • Change the paradigm • Target HIV negative patients • Increase Voluntary Counseling and Testing (VCT) • HIV testing is general medicine (« it’s all care workers business ») • Make rapid tests available • Facilitate or strenghten the link between VCT centers and ART clinics • Anticipate and face an increase in the number of patients on ART • Set up or strenghten task shifting • Demonstrate cost effectiveness/acceptability to governments and donors

  30. ART at 350 CD4 vs. 200 CD4 • Find asymptomatic patients • Change the paradigm • Target HIV negative patients • Increase Voluntary Counseling and Testing (VCT) • HIV testing is general medicine (« it’s all care workers business ») • Make rapid tests available • Facilitate or strenghten the link between VCT centers and ART clinics • Anticipate and face an increase in the number of patients on ART • Set up or strenghten task shifting • * Demonstrate benefits and cost effectiveness for acceptability by governments and donors

  31. Benefits on morbidity, mortality and transmission Source: Stover J, AIDS Research and Treatment2011 Costeffectiveness: Walensky R, Ann Intern Med 2009

  32. Main changes in WHO 2010 Guidelines 1) Start earlier : CD4 < 350/mm3 or WHO stage 3,4 (vs. 200 CD4orWHO stage 4 or WHO stage 3 & 200-350) 2) First line regimen: • Include viral load in routine monitoring • Switch when VL>5,000 copies/ml (vs. >10,000 copies/ml in 2006 guidelines) • Second line • Stop ABC+ DDI. • AZT/TDF+XTC+ATVr/LPVr • Start as soon as possible in case of tuberculosis and HVB

  33. Challenges for first line regimen Cost, efficacy, cost-effectiveness and tolerance issues • Costs • Phase out d4T • Choice between AZT and TDF • Haematological toxicity, LD (AZT) • Renal safety, bone mineral toxicity (TDF) • Choice between efavirenz and nevirapine • Percentage of young women, pregnancy (NVP) • One pill, once a day, TB co-morbidity (EFV) • Availabililty of fixed drug combination * Paediatric formulation

  34. Phase out stavudine : issues • Lingering stocks of d4T - 30 countries have implemented d4T phase out plan (12/2009) - 60% first line started with d4T (12/2009) • Finance constraints • TDF or ZDV first line 2-3 times as high as d4T regimen • … at a time when we still need to scale up the number of people initiating ART • Need for : - Further drug price reductions (AZT and TDF) - Increase funds for ART programme Renaud-Thery F, AIDS Res and treatment 2011

  35. Bendavid E, AIDS 2011 WHO MEETING REPORT. Short-TermPriorities for Antiretroviral Drug Optimization, London UK, 18-19 avril 2011.

  36. Prevalence of Renal dysfunction in HIV-seropositive untreated patients in Sub saharan Africa * Nigeria (n=400) Emen CP, Nephrol Dial Transplant 2008 * South Africa (n= 1322) Brennan A, AIDS 2011 * Zambia (n=24 596) Mulenga BL, AIDS 2008 * Msango L (n=335) AIDS 2011 38% 35.7% 33.7% 63.6% HIV is THE kidney killer (not tenofovir)

  37. Incidence of severe renal dysfunctionDART (n=3316)  eGFR < 30ml/mn *Median time to severe renal dysfunction14 weeks IQR [4-52] * TDF 41/2469 (1.7%) * NVP (Open-label) 4/247 (1.6%) * ABC (Nora Study) 3/300 (1.0%) * NVP (Nora Study) 4/300 (1.3%) Reid A, Clin Infect Dis. 2008 P=0.94 *Zambia, 30/960 (3.2%), M12 (Chi BH, JAIDS 2010) * Lesotho, 31/566 (5.5%), M12 (Bygrave H, Plos One 2011)

  38. Follow WHO guidelines for tenofovir prescription * Creatinine dosage (creatinine clearance calculation) * Proteinuria with urines sticks

  39. Main changes in WHO 2010 Guidelines WHO, AntiretroviralTherapy for HIV infections in adults and adolescents, Recommandations, 2010, h http://www.who.int ttp://www.who.int 1) Start earlier : CD4 < 350/mm3 or WHO stage 3,4 2)°First line: 3) Include viral load in routine monitoring • Second line

  40. Case for routine use of viral load • Best tool to assess adherence • Maintain first line therapy • Earlier switch to second line  limit NRTI and NNRTI cumulative resistance; • Cost effectiveness

  41. Status at 12 months of ART : Messou E, JAIDS 2010

  42. Case for routine use of viral load • Best tool to assess adherence • Maintain first line therapy • Earlier switch to second line  limit NRTI and NNRTI cumulative resistance; • Cost effectiveness

  43. Messou E, JAIDS 2010 Half of patients withdetectable viral loadat 12 months have no resistance mutations Interest of early viral load (M4-M6) Interventions to reinforceadherence, maintain first line

  44. Case for routine use of viral load • Best tool to assessadherence • Maintain first line therapy • Earlierswitch to second line limit NRTI and NNRTI cumulative resistance; Keiser et al, AIDS 2011 • Costeffectiveness

  45. Case for routine use of viral load • Best tool to assess adherence • Maintain first line therapy • Earlier switch to second line  limit NRTI and NNRTI cumulative resistance; • Cost effectiveness

  46. 1 HIV RNA Tests Cost 87 USD 2 HIV RNA Tests Cost 25 USD Source: Kimmel AD,JAIDS 2010

  47. Challenges for use of viral load in RLS • Affordability (once again… costs…) : • Advocacy (same as before with ARV drugs) • Generics tests • Availability in rural settings: • Point of care • Dried Blood Spot • Power (electricity) • Maintenance Rouet F and Rouzioux C, Expert Rev Mol Diagn 2007 Calmy A, AIDS 2008

  48. Main changes in WHO 2010 Guidelines 1)Start earlier : CD4 < 350/mm3 or WHO stage 3,4 2) First line: «3) Include viral load in routine monitoring 4) Second line

  49. Challenges for second line • Costs • Time to switch to second line in patients failing 1st line • Effective NRTI backbone • Place of drugs already ordered or used (ABC/ddI) • Fixed Drug Combination or co-blister • Availability of ritonavir heat stable capsule • Use in TB co-infected patients • Forecasting (Renaud-Thery F, AIDS Res and Treatment 2011)

  50. ARV cost per patient per year Sources: WHO/UNAIDS/UNICEF, Clinton Foundation Health Access Iinitiative, MSF

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