The impact of weak health systems on the development of resistance

1. The impact of weak health systems on the development of resistance John Idoko MD, National Agency for the Control AIDS, Abuja, Nigeria

2. ARV Therapy in theDeveloping World • Successes • 4 million people on ARV Therapy in developing world • Patients are adhering better than in the West • Nurses now starting patients on treatment and monitoring them (some countries) • Death rates are beginning to fall • But Challenges exist…… • New infections outpace numbers starting ARVs 2.5 to 1 • High death rates with CD4 <200 cells and TB • Late initiation of ART with outmoded drugs • Weak health systems and chronic shortage of health care workers

3. Factors Relevant for Long-term Success of First-line HAART

4. Key questions in management of HIV • What is the optimal time for initiating ART? • What should be the initial drug regimen? • What are the optimal indications for changing therapy? Is it clinical, CD4 or viral load? • What should therapy be changed to?

5. What Evidence Supports Earlier Therapy? • As CD4 count declines and viral load increases, mortality increases • MACS • Delaying therapy in the face of acute infectious complications is harmful • ACTG 5164 • Starting ART at CD4 counts between 200 and 350 yeilded substantially better outcomes than deferring treatment till counts drop below 200 • CIPRA HT 001 • Patients who interrupt therapy have higher mortality • SMART

6. ART CC: Supports Initiating ART at CD4 Threshold of 350 cells/mm3 • Analysis of 15 cohorts from US and Europe (ART Cohort Collaboration) N = 24,444 4.0 2.0 HR for AIDS or Death* 1.0 0.5 *Adjusted for lead-time and unobserved events. 0 500 400 300 100 200 CD4 Threshold (cells/mm3) Sterne J, et al. CROI 2009. Abstract 72LB. Graphic reproduced with permission for educational use only.

7. Updated IAS-USA Guidelines: When to Start *Non-AIDS risk factors include HIV-associated nephropathy, hepatitis C, hepatitis B Hammer SM, et al. JAMA. 2008;300:555-570.

8. WHO Guidelines in Adults (2006) WHO, 2006

9. Recommended Initial Regimens for Antiretroviral-Naive Patients, 2008 *Except during first trimester of pregnancy or in women with high pregnancy potential. †Contraindicated if HLA-B*5701 positive. Recent data suggest ABC should be used with caution in patients with a high cardiovascular risk or HIV-1 RNA > 100,000 c/mL. 1. DHHS Guidelines. Available at: http://AIDSinfo.nih.gov. 2. Hammer SM, et al. JAMA. 2008;300:555-570.

10. WHO Guidelines (2006):

11. Clinical Monitoring Inaccurately Predicts Virologic Failure • Virologic analysis of 910 pts in Haitiwith failure by WHO criteria[1] • 48% of patients with WHO stage III/IV clinical symptoms had undetectable viral loads • 90% of patients with 50% decrease in CD4+ cell count had detectable HIV-1 RNA • 88% of viremic patients had resistance mutations • 33% of patients had ≥ 2 TAMs • Ugandan study also found lack of correlation between clinical or immunologic failures and VF[2] 1. Charles M, et al. IAC 2008. Abstract MOPDC105. 2. Besenero A, et al. IAC 2007. Abstract WEAB102.

12. High Rate of Resistance in Patients Failing First-line Regimens in Malawi • 94 patients who failed on first-line d4T/3TC/NVP (or ZDV, EFV substituted for toxicity) analyzed for resistance. Switch to 2nd line ART only on clinical or CD4 decline. 100 93 81 80 60 56 Patients (%) 40 23 19 17 16 20 7 5 0 M184V + NNRTI mutations only Pan-NRTI (Q151 + TDF mutns or 69 insertion) M184V/I NRTI Mutations TAM(s) containing virus TDF mutations (K65R or K70E) TDF + TAM(s) Q151M complex WT + NNRTI mutations ± 184V Hosseinipour M, et al. IAC 2008. Abstract TUAB0105.

13. Accumulation of resistance on a failed regimen K65R V75I F77L Y115F F116Y Q151M -- NNRTIs K65R V75I F77L F116Y Q151M -- NNRTIs K65R Q151M -- NNRTIs CRF02 d4T-3TC-NVP AZT-TDF-LPV/r Kanki, 2007

14. Drug resistance in d4t or AZT based first line regimens • “Options for 2nd line ART regimens whose initial regimen of d4T+3TC+NVP fails” • 92-95% of mulit-drug resistance to all NRTIs (89% M184V) • TAMs (37%), K65R (6%), Q151M (8%) • (Sungkanuparph et al, CID 2007:44-447)

15. HIV drug resistance in a rapid scale-up ART program in Nigeria and the impact of HIV-1 subtype • 338 patients failing 1st line regimen d4T/AZT/TDF + FTC/3TC + NVP/EFV • Major NRTI and NNRTI mutations but ≥25% minor mutations – I13V, K201, M36I and H69K – more common in s/type G and CFRO2 than B. V82I in G and G16E in CRFO2 > s/type B • K65R present in 37/338 (10.9%); 13 (3.8%) had no TDF • No patient in 6 mth ART group had ≥ 3 etravirine RAMs (0% vs 24%, p<0.005) • A score ≥ 4 by Schema M or ≥ 2.5 by Schema T was less frequent with 6mths ART (20%vs 53.5%, p<0.005) and (20% vs 60.0%, p<0.00%) • Kanki et al, 2009

16. Maternal Treatment Failures Due to NVP Drug Resistance < 6 Months since Exposure/Birth > 6 Months since Exposure/Birth NVP NVP NVP No NVP No NVP No NVP No NVP Lockman et al, 2007 13-23

17. What needs to done........ • We need to address the Weak Health System • ART without adequate monitoring • The continuing use of d4T • The use of sdNVP in PMTCT • We need to abolish the two tier system of standards – “Gold standard and resource limited”

18. What needs to done........ • We need to address the “Weak Money System” - Governments & Donors • Only then can we ensure efforts that will strengthen system against dev ART resistance • Expanding universal access for testing, so HIV can be diagnosed early • Earlier treatment • Use of potent and less toxic drugs with high resistance barrier • Provision of wider access to monitoring tools

19. P. Kanki R. Murphy J-L Sankalé A. Dieng-Sarr S. Meloni B. Chaplin S. Calves H. Rawizza B. Taiwo K. Scarsi K. Hurt E. Ekong P. Okonkwo T. Jolayemi S. Ochigbo B. Aluko J. Samuels P. Akande O. Odutolu T. Oyebode O. Agbaji S. Sagay S. Yohanna P. Agaba F. Kakjing G. Imade H. Sule R. Ojoh M. Muazu S. Oguche E. Ejeliogwu L. Apena R. Makai E. Digin