1. Monitoring ART in Resource Limited Settings Elly T Katabira, FRCP Department of Medicine Makerere University Medical School 2 nd Global Experts Summit: Leading by Example in Public Health Approach to ART. Vancouver, Canada, 13 Feb 2009

2. The ART response Success story of WHO 3 by 5 campain  Over 2M on ART  Scaling up access to ART continues with unprecidented enthusiasm, supported by GFATM, PEPFAR and others  Short term gaols being achieved Emphasis is on putting patients on treatment Morbidity and mortality down Longterm goals needs to be addressed now Monitoring for drug failure, resistence & adherence

3. ARV therapy coverage in low and middle income countries, Dec 2003 Geographical RegionNumber of people receiving ARV therapy Estimated need Coverage Sub-Saharan Africa100,0004,400,0002% Latin America and the Caribbean210,000250,00084% East, South and South-East Asia60,000900,0007% Europe and Central Asia15,000 80,00019% North Africa and the Middle East1,00075,0005% Total (All WHO regions)400,0005,900,0007%

4. ARV therapy coverage in low and middle income countries, Dec 2005 Geographical RegionNumber of people receiving ARV therapy Estimated need Coverage (low estimate – high estimate) Sub-Saharan Africa810,000(730,000 –890,000)4,700,00017% Latin America and the Caribbean315,000(295,000 –335,000)465,00068% East, South and South-East Asia180,000(150,000 –210,000)1,100,00016% Europe and Central Asia21,000 (22,000 – 22,000)160,00013% North Africa and the Middle East4,000(3,000 –5,000)75,0005% Total1,330,000 (1.2 –1.46 million)6.5 million15%

5. Common monitoring practices in Resource Limited Settings At the time of ART initiation:  Pre- and post-test counseling  ART related counseling  Baseline screening FBC, LFTs, RFTs, etc. CD4 cell counts Rarely VL evaluation (in research centers)

6. Common monitoring practices in Resource Limited Settings During follow-up  Regular counseling Adherence Behavior change  Clinical evaluation looking for: ART complications New or worsening OIs  Lab evaluation CD4 cell counts – 0-2x a year if no problems LFTs, etc. – only in big sites

10. Short comings of common ART monitoring strategies Quality of clinical monitoring depends on:  Quality/experience of monitoring health staff  Health seeking behavior of patients Patient interactions with other providers & relatives/friends Lab services inadequate and expensive  Lab costs/access are prohibitive at smaller units Adherence adversely affected by poor health systems  Frequent stock outs, etc.

11. What happens elsewhere HIV care (including ART monitoring) is individualized in the North  Expensive screening services E.g. Resistance testing at ART initiation Frequent vs non-frequent lab tests – CD4 & VL In spite of these advances:  Primary resistance is on the increase  Need for multiple, complicated, expensive regimens on the increase A road RLS should avoid at all costs

12. CDC Survey: Drug-Resistant HIV Among Newly Diagnosed Patients Prevalence of Drug Resistance, % 1998 [1] (n = 257) 1999 [1] (n = 239) 2000 [1] (n = 299) 2003- 2004 [2] (n = 633) 2003- 2006 [3] (n = 3130) Any drug5.58.810.714.510.4 NRTI5.17.17.77.13.6 NNRTI0.42.11.78.46.9 PI00.83.02.82.4 ≥ 2 drug classes01.3 3.11.9 1. Bennett D, et al. CROI 2002. Abstract 372. 2. Bennett D, et al. CROI 2005. Abstract 674. 3. Wheeler W, et al. CROI 2007. Abstract 648.

13. Increasing prevalence of NNRTI-associated drug-resistance mutations in patients with acute, early HIV in San Francisco Prevalence of Drug-Resistance Mutations 2003 (n = 58) 2004 (n = 54) 2005 (n = 43) 2006 (n = 29) 2007 (n = 40) Any resistance10%11%19%17%28% NRTI7%6%12%7%15% NNRTI2%6%9%10%8% PI9%4%0%7%8% Jain V et al. UCSF San Francisco – CROI 2009 Abstract 673

14. When to Use Resistance Testing 1. Hirsch MS, et al. Clin Infect Dis. 2008;47:266-285. 2. DHHS guidelines. Available at: http://www.aidsinfo.nih.gov. Accessed January 12, 2009. 3. EACS Guidelines Version 3. Available at: http://www.eacs.eu/guide/index.htm. Accessed October 24, 2008. *Test source patient especially if treated with antiretroviral drugs. IAS-USA [1] DHHS [2] European [3] Primary/acuteRecommend Postexposure prophylaxis -- Recommend* Chronic, tx naiveRecommend FailureRecommend PregnancyRecommend Pediatric--Recommend

15. PREDICT-1: HLA-B*5701 Allele Screening to Reduce ABC-HSR 6-week observation period Screen for HLA-B*5701 (n = 980) No Screening Control ABC regimen + standard monitoring for HSR (n = 976) HLA-B*5701–positive subjects excluded from ABC treatment HLA-B*5701–negative subjects* treated with ABC + standard monitoring for HSR HIV-infected abacavir-naive patients (N = 1956) *Physicians not informed of screening status. Incidence of ABC HSRScreened for HLA-B*5701, % (n/N) Not Screened, % (n/N) OR (95% CI) P Value Clinically suspected3.4 (27/803)7.8 (66/847)0.40 (0.25-0.62)<.001 Skin patch test positive0 (0/802)2.7 (23/842)0.03 (0-0.18)<.001 Mallal S, et al. N Engl J Med. 2008;358:568-579.

16. Possible solutions WHO guidelines – based on expert opinions  Probably not sensitive or specific enough Intensified & improved clinical monitoring  But poorly reflects Virologic failure More frequent CD4 (immunological monitoring)  But also poorly reflects Virologic failure VL monitoring, though superior over CD4, no significant benefit to CD4 monitoring

17. Performance of WHO immunologic failure criteria at various viral load thresholds SensitivitySpecificityPPVNPV Viral load > 10,000 copies /mL 23% (18/80)90% (946/1053) 14% (18/125) 94% (946/1008) Viral load > 10,000 copies /mL 28% (10/36)90% (982/1097) 8% (10/125) 97% (982/1008) Viral load > 400 copies /mL 23% (26/112) 90% (922/1021) 21% (26/125) 91% (922/1008) They propose periodic viral load measurements as a better alternative Reynolds S et al. Rakai, Uganda – CROI 2009 Abstract 144

18. HIV-related symptoms or signs predicting treatment failure Prurigo Unexplained persistent diarrhea Unexplained persistent fever Unexplained weight loss Unexplained polynueritis Unexplained cognitive impairment Loss of individual milestones in children Growth retardation in children Colebunders et al. The Lancet Vol 6 2006

19. Proposed steps to assess virological treatment failure Colebunders et al – The Lancet vol 6 2006  Obtain an ART treatment history Including monotherapy for PMTCT  Assess quality of HAART regimen and concomitant medication  Assess adherence to treatment Need good and experienced counselors  Assess clinical symptom development and lab test results VL testing in selected patients

20. Some suggested monitoring strategies Selected VL for problem cases  Need guidelines for selection criteria OR for effectiveness of such guidelines Refine clinical monitoring with enhanced supervision – The Senegal model Use CD4 count gain to triage for VL  VL if CD4 gain <50 cells/µl in 6 months – particularly if had low BL CD4 count Bisson G et al. AIDS 2006, 20:1613-1619

21. Conclusions All patients on ART should have a VL at least once a year Clinical monitoring, adherence profile and CD4 testing should be used to prioritize VL needs Operation research should be done to refine the criteria as who should have a VL when resources are limited