Myth vs. Reality Preventing HIV Drug Resistance in Resource-Limited Settings

Transcription

1 Myth vs. Reality Preventing HIV Drug Resistance in Resource-Limited Settings Neil T Parkin HIV/AIDS Dept, ATC Unit World Health Organization Geneva, Switzerland

2 Overview Summary of public-health efforts to prevent and assess HIVDR in RLS A few big issues and common misconceptions Research gaps

3 This presentation is not: A comprehensive (or fair) review of all published studies A poster review session! A complete summary of all public-health approaches to drug resistance A representation of the consensus view at WHO

4 Irony Hundreds of people get the Swine Flu and everybody wants to wear a mask. Millions of people have AIDS and no one wants to wear a condom.

5 Adults and children estimated to be living with HIV, 2007 North America 1.2 million [ million] Caribbean [ ] Latin America 1.7 million [ million] Western & Central Europe [ million] Middle East & North Africa [ ] Sub-Saharan Africa 22.0 million [ million] Eastern Europe & Central Asia 1.5 million [ million] East Asia [ million] South & South-East Asia 4.2 million [ million] Oceania [ ] Total: 33 million (30 36 million) July 2008 e 5

6 Number of people receiving ARV therapy in lowand middle-income countries Towards Universal Access Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

7 Median price (USD) of first-line ARV regimens in low-income countries, % 12% 14% 9% Towards Universal Access Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

8 Median price (USD) of second-line ARV regimens in low-income countries, AZT/3TC/EFV AZT/3TC/NVP d4t/3tc/efv d4t/3tc/nvp Towards Universal Access Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

9 HIV Drug Resistance is Inevitable HIV DR is an inevitable consequence of ART, influenced by: Removal of barriers to access to care Availability/continuity of drug supply Ability of regimens to suppress replication completely Adherence and tolerability of regimens "Genetic barrier" to resistance Relative fitness of resistant variant(s) Pharmacokinetics (IQ) Therefore, efforts to prevent HIVDR should be focused on these factors

10 HIV DR Testing in Resource Rich Settings ^ Prevalence of HIVDR at baseline Resistance developing on therapy Utility Will of standard resistance 1 st line testing before regimens initiating be effective? therapy Prevalence Resistance and testing patterns before of resistance switching therapy in population (SOC) Individualization Determination of of standard 1 line 1st line regimen regimen Individualization Determination of of standard 2 line and 2nd subsequent line regimens regimens 24+ ~6 drugs from 36 classes

11 5 Myths (?) About HIV DR in RLS Nobody is monitoring the potential resistance problem in RLS Rapid scale-up of ART in RLS will create a dramatic drug resistance problem Lack of intensive virological monitoring will lead to highly-resistant viruses and reduced efficacy of 2 nd line therapy Single dose NVP for PMTCT will jeopardize future maternal treatment response We don't know how to interpret genotypes in non-b subtypes

12 Myth #1: Nobody is monitoring the potential resistance problem in RLS

13 Elements of a National HIVDR Prevention and Assessment Strategy A. Development of a national HIVDR Working Group, five year plan and budget B. Regular assessment of HIVDR "early warning" indicators (EWI) from all antiretroviral treatment (ART) sites (or representative sites) C. Surveys to monitor HIVDR prevention and associated factors in sentinel ART sites D. HIVDR transmission threshold surveys in geographic areas where ART has been widespread for > 3 years E. HIVDR database development F. Designation of an in-country or regional WHO-accredited HIVDR genotyping laboratory G. HIVDR prevention activities review and support H. Preparation of annual HIVDR report and recommendations; use of data for ART and prevention planning Bennett, Bertagnolio, Sutherland and Gilks, Antiviral Therapy 13 Suppl 2:1 13, 2008

14 WHO HIVDR Global Assessment Overview Transmission of DR HIV to uninfected individuals Emergence of HIVDR in treated patients ART site factors associated with HIVDR Prevention Threshold Surveys (Surveillance) Sentinel ART Site Monitoring Surveys* Early Warning Indicators Genotyping Laboratory Genotyping, VL Laboratory Non-Laboratory Data collection DR HIV prevalence < or 5%, 15% To which drugs? HIVDR Prevention at 12 months; prevalence and patterns of DR; associated factors Areas to directly target for improvement PUBLIC HEALTH ACTION Database, analysis *Surveys to monitor HIV DR prevention and associated factors in sentinel ARV treatment sites

15 HIVDR Early Warning Indicators (EWI) Proportion lost to follow-up during the first 12 months of ART Prescribing practices Drug supply continuity Site-level ART Program Function Patient retention on first-line ART On-time ARV drug pick up Viral load months ART appointmentkeeping Pill count/ adherence

16 HIVDR EWI Site-Based Report Example Site Months with no ARV drug stockouts Target: 12 % appropriate Initial ART regimen prescriptions Target: 100% % starting first line ART lost to follow up at 12 months Target: < 20% % on ART keeping all clinical appointments on time Target: > 80% % on ART picking up all ART drugs on time Target: 90% /94 (100%) 4/96 (4%) 182/209 (87%) 184/192 (96%) /81 (100%) 9/74 (12%) 342/402 (85%) 176/220 (80%) /40 (78%) 12/37 (32%) 122/244 (50%) 144/206 (70%) /104 (100%) 10/99 (10%) 891/993 (90%) 483/508 (95%) /112(100%) 13/105 (12%) 262/305 (85%) 184/202 (91%) /101 (97%) 2/90 (2%) 416/442 (95%) 254/359 (71%) /98 (100%) 9/88 (10%) 602/683 (88%) 369/402 (95%) /203 (100%) 43 /195 (22%) 292/356 (82%) 254/284 (86%) /305 (99.7%) 117/260 (45%) 753/1506 (50%) 829/1202 (69%) /94 (100%) 12/90 (13%) 271/305 (89%) 269/290 (93%) /33(100%) 4/31 (13%) 147/180 (82%) 143/159 (90%) /34 (76%) 7/35 (20%) 148/224 (66%) 129/182 (71%) /73(100%) 9/69 (16%) 178/203 (87% ) 146/154 (95%)

17 Implementation of the WHO HIVDR Strategy June 2009 Countries implementing or planning a national HIVDR strategy Implementation of at least 1 component of the HIVDR strategy in 41 countries HIVDR transmission surveys completed in 11 countries EWI piloted in 23 countries HIVDR training workshops: Africa (3), Asia, Caribbean 22 accredited HIVDR Genotyping labs HIVDR laboratory training package Annual external Quality Assurance (supported by NIH, through the VQA) Countries with a national HIVDR working group implementing > 1 assessment element as of 2/2009 Countries setting up a working group and planning to implement > 1 assessment element in 2009

18 GLOBAL REGIONAL NATIONAL Structure of the WHO HIVDR Laboratory Network HIV ResNet Lab WG HIVResNet Lab WG Advisory group WHO Specialized Labs (SDRL) Regional HIV DR Lab (RDRL) National HIV DR Lab (NDRL) National Plan for the collection, handling, storage and shipment of specimens

19 WHO HIVDR Laboratory Network (May 2009)

20 HIVDR Laboratory Training Workshop Dakar, Senegal May 2009

21 Biregional Workshop on Prevention and Surveillance of HIV DR Bangkok, Thailand May 2009

22 Definitions of Transmitted HIV DR Notably absent: PR: L33F, M36I, H69K, L89V RT: V90I, A98G, V106I, V108I, E138A

23 Transmitted HIV DR: Cautions Minimize the risk that previously treated individuals are included in surveillance studies Caution: definition of recent infection based on BED Transmitted resistance should be estimated separately for specific drug classes rather than reporting an overall prevalence of transmitted resistance, which will multiply the effect of infrequent polymorphisms The occurrence of mutations associated with a drug or drug class seldom or never used in a country or region should not be considered as strong evidence for DR HIV transmission.

24 PASER network Research centers The Netherlands UMCU (Utrecht) AMC-CPCD (Amsterdam) Kenya ICRH (Mombasa) Uganda JCRC (Kampala) UVRI/MRC (Entebbe) South Africa Wits-MMH (Joburg) Wits-CHRU (Joburg) Reference laboratories Uganda JCRC (Kampala) UVRI (Entebbe) South Africa Wits-MMH (Joburg) Nigeria LUTH (Lagos) Clinical sites Uganda JCRC-TREAT sites (Mbale, Kampala, Fort Portal) Kenya CPGH (Mombasa) Mater (Nairobi) Zambia Lusaka Trust (Lusaka) KARA Clinic (Lusaka) Coptic Hospital (Lusaka) Zimbabwe Newlands Clinic (Harare) South Africa Muelmed Hospital (Pretoria) RTC Themba Lethu (Joburg) RTC Acts Clinic (White River)

25 TREAT Asia Adult Network India: YRG Care, Chennai Institute of Infectious Diseases, Pune South Korea: Yonsei University, Seoul Japan: Int l Medical Center of Japan, Tokyo People's Republic of China: Beijing Ditan Hosp, Beijing Queen Elizabeth Hosp, Hong Kong Taiwan: National Yang-Ming University, Taipei Thailand: HIV-NAT/ Thai Red Cross, Bangkok Ramathibodi Hosp, Bangkok Chiang Mai University, Chiang Mai Chiang Rai Regional Hospital, Chiang Rai Siriraj Hospital, Bangkok Philippines: Research Institute for Tropical Medicine, Manila Cambodia: NCHADS, Phnom Penh Malaysia: Sungai Buloh Hosp, Kuala Lumpur University of Malaya, Kuala Lumpur Singapore: Tan Tock Seng Hospital, Singapore Indonesia: Udayana University, Bali Hospital Cipto Mangunkusumo, Jakarta Papua New Guinea: Port Moresby General Hospital

26 PEPFAR Worldwide Activities HIVDR Surveillance in Botswana, Cote d'ivoire, Ethiopia, Kenya, Mozambique, Nigeria, Rwanda, South Africa, Tanzania, Uganda, Vietnam, Zambia

27 Brazil South Africa Zambia Argentina Cameroon Cote d'ivoire Kenya Nigeria number of abstracts 45 Abstracts Presented at this Conference plus 1 abstract each related to Angola, Burkina Faso, China, DRC, India, Israel, Malawi, Mali, Mexico, Mozambique, Peru, Thailand, Uganda

28 Myth #1: Nobody is monitoring the potential resistance problem in RLS

29 Myth #2: Rapid scale-up of ART in RLS will create a dramatic drug resistance problem

30 "Widespread, unregulated access to antiretroviral drugs in sub-saharan Africa could lead to the rapid emergence of resistant viral strains, spelling doom for the individual, curtailing future treatment options, and leading to transmission of resistant virus." Preventing antiretroviral anarchy in sub-saharan Africa AD Harries, DS Nyangulu, NJ Hargreaves, O Kaluwa and FM Salaniponi The Lancet : "If compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in multidrug-resistant HIV mutants whose further spread will only exacerbate the epidemic." Prospects for the Future Robert C. Gallo and Luc Montagnier Science :

31 HIVDR Transmission Threshold Surveys Country Year Setting 1 GT Subtypes Resistance Ethiopia 2005 ANC 39 C, AG <5% India 2007 VCT 47 C <5% Malawi 2006 ANC 54 2 C <5% South Africa 2002 ANC 65 C <5% South Africa 2004 ANC 48 C <5% 3 Swaziland 2006 ANC 61 C, B <5% 4 Tanzania 2005 ANC 50 2 A, C, D <5% Thailand 2005 BD, VCT 50 AE, B <5% Uganda 2006 ANC 46 A, D, C <5% Vietnam 2006 VCT 49 AE, CRF15 <5% 5 1 ANC: antenatal clinic BD: Blood donors VCT: Voluntary counseling & testing center 2 DBS 3 2 with NRTI mtns 4 2 with PI mtns 5 1 with NRTI+NNRTI mtns

32 Possible Reasons for Low Prevalence of Transmitted DR HIV Treatment coverage still low Especially >3 years ago Models suggest need widespread treatment for 10 years HAART from the START Little history of mono- or dual therapy Potent NNRTI-based regimens When PIs used, boosted with RTV Adherence Social factors pressure high adherence rates Regimens more tolerant to missed doses than unboosted PI-based HAART

33 Antiretroviral therapy coverage in the 15 countries accounting for 75% of the 3 million people receiving treatment in low- and middle-income countries in 2007 Towards Universal Access Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

34 " the potential short term gains from reducing individual morbidity and mortality may be far outweighed by the potential for the long term spread of drug resistance if the experience of adherence to treatment for tuberculosis is repeated This risks the rapid development and transmission of drug resistance." "In Africa, a higher proportion of patients are likely to fall into the category of potential poor adherers unless resource intensive adherence programmes are available" Antiretroviral therapy in Africa Warren Stevens, Steve Kaye, Tumani Corrah BMJ 2004;328:280 2

35 Meta-Analysis of Barriers to Adherence in Africa and North America Systematic review of adherence rates 28,689 patients in 228 studies North America Brazil, Uganda, Cote d Ivoire, South Africa, Malawi, Botswana, Costa Rica, Romania Resource-Rich Country Summary 54.7% (95% CI: ) Resource-Poor Country Summary 77.1% (95% CI: 67.3%-85.6) Mills and Bangsberg JAMA 296: (2006)

36 Percent of patients with resistance-conferring mutations Resistance Risk by Adherence and Regimen Class 6 5 NNRTI PI boosted PI < 75% 75-95% > 95% Adherence Maggiolo et al HIV Clin Trials, 8(5): (2007)

37 Myth #2: Rapid scale-up of ART in RLS will create a big drug resistance problem

38 Myth #3: Lack of intensive virological monitoring will lead to highly-resistant viruses and reduced 2 nd line efficacy

39 Resistance Patterns in Treated Patients NNRTI (NVP or EFV) + 2 NRTI (3TC + d4t or ZDV) >80% M184V and 1 or more NNRTI RAM (K103N, V106M, Y181C, G190A/S) Roughly 20-40% TAMs Low % K65R and/or Q151M PI/r (LPV) + 2 NRTI (3TC + d4t or ZDV) >80% M184V Roughly 20-40% TAMs Low % with PI RAMs

40 Characteristics of 101 Patients that Initiated Second-Line ART in Malawi d4t/3tc/nvp failures based on clinical/immunological criteria, confirmed by HIV-RNA >400 Hosseinipour et al. AIDS 23(9):

41 Drug Resistance after Failure of 1st Line (d4t/3tc/nvp) and Clinical Monitoring 1000 Fold Change in IC ZDV ABC ddi 3TC d4t TDF EFV NVP Hosseinipour et al. AIDS 23(9):

42 Resistance South Africa 1 Thailand 2 Cameroon Cameroon 12 month 3 24 month 3 Malawi 4 None 16% 5% 68% 21% 5% M184V 64% 89% 29% 71% 81% Any TAMS 32% 37% 6% 18% 56% 3 TAMS 13% 13% 3% 8% 25% K65R or K70E 3% 6% 0% 0% 23% Q151M 1% 8% 0% 0% 19% Subtype C AE AG, D AG, D C 1. Marconi CID 2008; VL every 6 mths 2. Sungkanuparhph CID 2007; VL rebound 2-6 mths 3. Kouanfack CID 2009; clinical/immunological failure; cross-sectional data 4. Hosseinipour AIDS 2009; clinical/immunological failure 42

43 HIV RNA and CD4 Response to 2 nd Line (ZDV/3TC/TDF/LPV/r) Hosseinipour et al. Abstract 605 CROI 2009

44 Myth #3: Lack of intensive virological monitoring will lead to highly-resistant viruses and reduced 2 nd line efficacy *but preliminary

45 5 Myths (?) About HIV DR in RLS Nobody is monitoring the potential resistance problem in RLS Rapid Scale-up of ART in RLS will create a dramatic drug resistance problem Lack of intensive virological monitoring will lead to highly-resistant viruses and reduced 2 nd line efficacy Single Dose NVP for PMTCT will Jeopardize Future Maternal Treatment Response Subtype B-based genotype data is not good enough to interpret genotypes in non-b subtypes

46 Research Gaps Dried Blood Spots for DR testing Stability at "room temperature" and high humidity Contribution of DNA Sensitivity and VL comparability Alternative ambient temperature storage and shipping DPS Sample Tanker Lower cost genotyping assays Point mutation assays? Subtype-independent amplification

47 +/- of Using DBS for HIVDR Genotyping Feature Plasma DBS Requires venipuncture Yes No Requires centrifugation Yes No Stable at "room temperature" No Yes Biohazard for shipping purposes Yes No Dry ice required for shipping Yes No Routinely used for genotyping Yes No Possible contribution from DNA No Yes Volume range 1-5 ml ml

48 The Art of Compromise "Le mieux est l'ennemi du bien." Voltaire's Dictionnaire Philosophique (1764) "The man who insists on seeing with perfect clearness before he decides, never decides." Henri-Frédéric Amiel (1856)

49 Acknowledgments WHO HIV DR Team Diane Bennett Silvia Bertagnolio Don Sutherland (emeritus) Michael Jordan HIV ResNet including the Specialized DR Laboratories and many of you Bob Shafer David Bangsberg Mina Hosseinipour PharmAccess, TreatAsia, CDC Bill & Melinda Gates Foundation, Spanish Govt.

50 ATC Team (December 2008)

51 THANK YOU!