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Disclosures

Disclosures. PC served as advisor for: Avexa Gilead J & J - Tibotec Merck/Schering Plough ViiV (GSK & Pfizer). VL Monitoring in RLS. Recommended in Western countries guidelines Lots of papers addressing the cost-efficacy issue Mainly based on modeling

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Disclosures

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  1. Disclosures PC served as advisor for: • Avexa • Gilead • J & J - Tibotec • Merck/Schering Plough • ViiV (GSK & Pfizer)

  2. VL Monitoring in RLS • Recommended in Western countries guidelines • Lots of papers addressing the cost-efficacy issue • Mainly based on modeling • Even some of those acknowledging advantages of VL testing question “the equity” vs. HAART expansion

  3. RCT study: VL vs CD4 vs clinical monitoring in patients on HAART: in Uganda, 2003-7 Per protocol analysis excluding first 90 days of ART, VL CD4 Clinical VL or CD4 was superior to clinical monitoring alone p= 0.004 p= 0.034 Mermin J et al. BMJ 2011;343:d6792 doi: 10.1136/bmj.d6792

  4. WHO-defined clinical and immunologic criteria are poor predictors of virologic failure • Adults in India with >6 months standard 1st line ART enrolled • Clinical or immunologic failure • CD4 decline to pre-ART • CD4 decrease by 50% of peak on-ART value • Development of new AIDS defining illness • Referred for assessment and VL testing Rewari BB et al JAIDS 2010

  5. 2nd line ART recommended Initiated after 3 Adherence counselling sessions Rewari BB et al JAIDS 2010

  6. WHO-defined clinical and immunologic criteria are poor predictors of virologic failure • Positive predictive value of WHO criteria to determine virologic failure only 71% (95%CI 63-79%) • 24% of patients with clinical/immunologic failure had virologic suppression • Targeted VL testing to evaluate treatment failure can prevent unnecessary switch Rewari BB et al JAIDS 2010

  7. CD4 predicts virologic failure in about half the cases • Nigeria, baseline CD4 then every 6 months • Assessed performance of CD4 criteria to predict virologic failure in patients after 6/12 cART(PEPFAR) • Immunologic failure: WHO criteria • Virologic failure: 2 consecutive VL>1000 • n = 9690 patients, n = 1225 “CD4 failure” • Sensitivity of CD4 to predict virologic failure 58% • Specificity 75% • PPV 39% Ramizza HE Clin Infect Dis 2011 53:1283

  8. Why measure HIV viral load? • an independent measure of HIV progression • the best lab test for monitoring response to cART • Should decrease by 1 log within a month & to undetectable within 3-6 months of starting Rx • Virologic failure, due to poor adherence or absorption, or drug resistance, cannot be predicted accurately by clinical or CD4 criteria • Standard practice in well-resourced countries Reynolds SJ et al., AIDS 2009, 23:697; Kantor R et al., CID 2009; 49;454; Bisson GP et al., AIDS 2006, 20:1613

  9. 138 patients genotyped at treatment failure (WHO criteria) “Overall > 50% have multiple treatment-limiting mutations” Kantor R: Kumarasamy N: 3TC resistance: 80.5% vs 40.3% (p<0・001); at least one TAM: 27.8% and 12.1%, “Lack of viral monitoring associated with resistance in the vast majority of those with viral failure after the 1st year of HAART”. N: 149 patients, 58% misclassified. “Immunological monitoring would lead to a premature switch to 2nd line regimens” Kantor R: Kantor R:

  10. NNRTI mutations +/-184V containing virus • + additional mutations • TAM containing virus 56% • TDF mutations 23% • TDF +TAMs 7% • Q151MComplex 19% • Q151 + TDF 16%

  11. Changing patterns of NRTI and PI resistance mutations between 2006 and 2011 in >1,200 ART-experienced South African patients: association with the introduction of tenofovir (TDF) and abacavir (ABC) and with the cumulative effects of LPV/r therapyG. van Zyl1, M. Claassen2, S. Engelbrecht1, T. de Oliveira3, W. Preiser1, N. Wood4, S. Travers4, R. Shafer51National Health Laboratory Service & Stellenbosch University, Pathology (Medical Virology), Cape Town, South Africa, 2National Health Laboratory Service (NHLS), Pathology (Medical Virology), Cape Town, South Africa, 3Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Mtubatuba, South Africa, 4South African National Bioinformatics Institute (SANBI), University of Western Cape, Cape Town, South Africa, 5Stanford University Medical Center, Division of Infectious Diseases, Center for AIDS Research, Stanford, United States

  12. Monitoring in the era of TasP

  13. Can wemove forward in a cost-effectivemanner?

  14. Strategies to monitor VL to detect HAART Failure Ruxrunthgram K

  15. Reduced VL monitoring (RVLM) model WHO : VL at failure DHHS : 15 VL tests in 5 yrs Median time for the development of firstthymidine-analog mutation (TAM) was 594 days RVLM : 4 tests in 5 yrs DHHS 2012: VL: Yr 1=5-6 tests, Yr2 = 4, after Yr2: 2. Total 5 yrs = >15 tests RVLM: Yr1 = 2, Yr2 =1, Yr3-4 =0, Yr 5 =1 Total 5 yrs = 4 tests WHO: VL only at immunologic failure Total 5 yrs = 1 test Bryant et al. J Int Assoc Physicians AIDS Care (Chic). 2012 May 2. [Epub ahead of print]

  16. 6.0 5.0 Log VL Plasma 4.0 3.0 2.0 Log VL DBS log plasma VL – log DBS VL 4.0 5.0 6.0 2.0 3.0 Averages SENSITIVITY: 92.2% SPECIFICITY: 100% POSITIVE PREDICTIVE VALUE: 100% NEGATIVE PREDICTIVE VALUE: 88.6% DBS BlandAltman´sAnalysis

  17. Levels of laboratory infrastructure in RCCs Tier 3 City hospitals, reference labs, PCR, flow Tier 2 Mid level hospital some specialized equipment Tier 1 Basic hospital minimal equipment, 1 technician Outreach clinics no hospital, no laboratory, no trained technicians point of care rapid test

  18. Low cost VL and EID Technology Pipeline* SAMBA VL & EID GenExpert VL Cavidi ExaVir 3 North Western VL Alere PIMA Liat ……. 2007 2012 - 2013 * Dates not fixed; information from UNITAID and some companies. Slide by S. Crowe

  19. Cavidi Exavir 3 • Cavidi ExaVir3® is suitable for VL monitoring, especially when lab facilities are basic & resources are constrained • Sensitivity and specificity well established in published studies* • General agreement in published studies that it is satisfactory for clinical use • Currently being used in Botswana, Kenya, Uganda, Zambia, Zimbabwe, Tanzania, Ghana, Vietnam, Fiji, PNG and India * Greengrass V et al, J Clin Micro 2010

  20. TAG 2012 Pipeline Report www.piplelinereport.org

  21. Equity, a moral dilemma?

  22. Equity, a moral dilemma? • US bailouts (2009) : 350 trillions * • European bailouts: 440 billion Euros**, and counting • Spent & Approved war-spending: • About $1 trillion of US taxpayers' funds spent • or approved for spending** * Feb 11, 2009 ** June 14,2012 *** Jan 31, 2012 GFTaM requirements: 20 billion

  23. Strategic use of viral load: Expected benefits • Improve outcomes • Protect 1st and 2nd -line regimens by avoiding unnecessary switches • Delay initiation of 2nd line ART • Resolve discordant cases of clinical and/or immunological failure • Improve and monitor adherence • Reduce resistance risk • Reduce MTCT identifying viral failures UNITAID Expert Consensus, 2009

  24. Monitoring HIV Antiretroviral Therapy in Resource-Limited Settings: Time to Avoid Costly Outcomes “Viral load testing needs to be introduced with the same sense of urgency and commitment as the world approached ART access. To do less is to abandon ART to an early collapse” Editorial by Sawe and McIntyre; CID 2009:49

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