HIV Drug Resistance Training

1. HIV Drug Resistance Training Module 1: Introduction to HIV Drug Resistance

2. Topics • Impact of HIV Drug Resistance • Factors that Influence Development of Drug Resistance • How to Minimize Drug Resistance • How to Respond to Detection of Drug Resistance • Drug Resistance Assays

3. Objectives • Understand importance of measuring drug resistance for large-scale treatment programs. • Identify factors that influence drug resistance. • Understand the methods available for the measuring HIV drug resistance. • Identify strategies for minimizing development of drug resistance. • Identify strategies for responding to detection of moderate to high levels of drug resistant HIV.

4. impact of drug resistance Why is it important to measure drug resistance? How does it impact the success of large-scale treatment programs?

5. What is Antiviral Drug Resistance? • Drugs no longer block virus replication • Cause: • Mutations in the viral genome • One or more: • Specific for an antiviral drug OR • Affecting related drugs (cross-resistance) • How much resistance? Which drugs? • Depends on type and number of mutations

6. Adults and Children Estimated to be Living with HIV, 2007 Eastern Europe & Central Asia 1.5 million [1.1 – 1.9 million] Western & Central Europe 730 000 [580 000 – 1.0 million] North America 1.2 million [760 000 – 2.0 million] East Asia 740 000 [480 000 – 1.1 million] Middle East&North Africa 380 000 [280 000 – 510 000] Caribbean 230 000 [210 000 – 270 000] South & South-East Asia 4.2 million [3.5 – 5.3 million] Sub-Saharan Africa 22.0 million [20.5 – 23.6 million] Latin America 1.7 million [1.5 – 2.1 million] Oceania 74 000 [66 000 – 93 000] Total: 33 million (30 – 36 million)

7. Number of People Receiving ARV Therapy In Low- and Middle-income Countries 2002-2007 Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

8. Median Price (USD) of First-line ARV Regimens in Low-income Countries, 2004-2007 51% 12% 14% 9% Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

9. AZT/3TC/EFV AZT/3TC/NVP d4T/3TC/EFV d4T/3TC/NVP Median Price (USD) of second-line ARV regimens in Low-income Countries, 2004-2007 Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

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

11. Prevalence of HIVDR at baseline Resistance developing on therapy Utility of resistance testing before initiating therapy Resistance testing before switching therapy (SOC) Individualization of 1st line regimen Individualization of 2nd line and subsequent regimens 24+ drugs from 6 classes HIV DR Testing in Resource Rich Settings

12. Prevalence of HIVDR at baseline Prevalence of HIVDR at baseline Resistance developing on therapy Resistance developing on therapy Utility of resistance testing before initiating therapy Will standard 1st line regimens be effective? Resistance testing before switching therapy (SOC) Prevalence and patterns of resistance in population Individualization of 1st line regimen Determination of standard 1st line regimen Individualization of 2nd line and subsequent regimens Determination of standard 2nd line regimens 24+ drugs from 6 classes HIV DR Testing in Resource Limited Settings ~6 drugs from 3 classes

13. Need for Population-based Therapies

14. Need to Maintain Effectiveness

15. Drug Resistance and HIV HIV… • evolves rapidly within human body • has a high replication rate • has a high mutation rate  • Resistant strains can emerge within days if drug pressure is not sufficient to suppress replication. • Resistant strains persist indefinitely and can re-emerge if same drugs are stopped and restarted (even if they are not detected by standard resistance assays).

16. Review • Why is it important to measure drug resistance? • How does it impact the success of large-scale treatment programs?

17. factors that influence development of drug resistance What regimens influence drug resistance? What patient factors influence drug resistance? What public health approaches influence drug resistance?

18. In Which Conditions is DR More Likely? • Treatment with <3 drugs • Inappropriate selection of drugs • Adding one drug to a failing regimen • Interruption of treatment (even for a few days) • Prolonging a failing regimen

19. In Which Conditions is DR Less Likely?Medication Factors • All patients treated with 3 or more drugs • Use of appropriate drug regimens • Can reliably suppress HIV replication to levels of <50 copies/ml • Use of fixed-dose combinations to support adherence

20. In Which Conditions is DR Less Likely?Systems Factors • Limited number of regimens • Trained personnel, low turnover • Supervision and monitoring • Adequate lab services • Drug supply and delivery systems

21. In Which Conditions is DR Less Likely?Patient Factors • Adherence to treatment regimen • Avoiding interruption of treatment, even if only a few days • Regular follow-up (going to clinic) • Staying on uninterrupted first-line ART as long as possible CONTINUITY!

22. Programmatic Factors Affecting Patient Compliance • Cost of treatment to patient • Distance patient must travel to get treatment • Supply interruptions • Availability of second-line regimens for patients whose first-line regimens fail • Timing of use of second-line regimens

23. Discussion • What regimens influence drug resistance? • What patient factors influence drug resistance? • What public health approaches influence drug resistance?

24. Reflection • What regimens do we use in our country? • What systematic and programmatic challenges do we face?

25. how to minimize drug resistance What can countries do to minimize or suppress drug resistance?

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

27. Transmission of DR HIV to uninfected individuals Emergence of HIVDR in treated patients ART site factors associated with minimizing HIVDR 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 Relationship of Different Assessment Factors *Surveys to monitor HIV DR prevention and associated factors in sentinel ARV treatment sites

28. General WHO Strategies (1 of 2) • Strengthen existing programmes that minimize HIVDR • Form national HIV drug resistance working group • Monitor Early Warning Indicators • Survey to monitor HIVDR prevention and associated factors in sentinel ART sites • Watch for transmitted HIVDR in recently infected individuals

29. General Strategies (2 of 2) • Designate one or more genotyping labs for HIVDR surveillance and monitoring • Maintain a national database to hold the HIV sequences collected through surveillance, monitoring, and research projects • Produce an annual report summarizing results from all the above

30. Strengthen Existing Programmes That Minimize HIVDR • Support for adherence and follow-up • Removal of barriers to ART access • Drug supply continuity at the individual, ART site, and national levels

31. Form National HIV Drug Resistance Working Group • Develop HIVDR prevention, surveillance and monitoring plan • Make evidence-based recommendations for HIVDR prevention • Includes epidemiologists, clinicians, researchers, and laboratorians • Collect indicators and implement surveys • Develop evaluation strategies

32. Monitor Early Warning Indicators • Routine collection of medical and pharmacy records • Monitor for factors associated with HIVDR prevention or emergence • Extent to which prescribing practices meet national and international guidelines • % of patients still on first-line; % lost to follow-up • % patients with timely medication pick up and clinical follow-up • Drug supply continuity at site • Adherence and viral load, if feasible

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

34. HIVDR EWI Site-Based Report Example

35. For More Information • See Bennett, Bertagnolio, Sutherland and Gilks (2008). The World Health Organization’s global strategy for prevention and assessment of HIV drug resistance. Antiviral Therapy 13 Suppl 2:1-13.

36. Implementation of the WHO HIVDR Strategy – June 2009 • 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)

37. Other • Designate one or more genotyping labs for HIVDR surveillance and monitoring • The WHO offers accreditation, support, and training through the WHO Global HIVDR laboratory network • Maintain a national database to hold the HIV sequences collected through surveillance, monitoring, and research projects • Produce an annual report summarizing results from all the above

38. Discussion • What can countries do to minimize drug resistance?

39. Reflection • What are our highest-priority “next steps” for minimizing drug resistance?

40. how to respond to detection of drug resistance What can be done if widespread drug resistance is found?

41. Response to Detection of Transmitted Drug Resistance • If the prevalence of transmitted resistance to important drugs or drug classes is 5-15% or > 15%, surveys should be repeated in the original areas annually and extended to additional areas • Consider changing standard 1st line regimen • Monitor Early Warning Indicators for clues about what can be improved at a programmatic level

42. Response to Results from Monitoring Surveys If the patterns of resistance indicate reduced susceptibility to 2nd line drugs, surveys should be repeated in the original areas annually and extended to additional areas. Consider changing standard 2nd line regimen. Monitor Early Warning Indicators for clues about what can be improved at a programmatic level.

43. hiv drug resistance assays What are the different types of resistance assays? What are the advantages and limitations of these assays? What results can we expect from these tests? What if the results from one type of test are inconsistent with results from another?

44. Clinical Use of Resistance Data Resistance tests are most accurate in assessing resistance to current regimen Absence of resistance to previously used drug does not rule out reservoirs of resistant virus that might emerge after re-initiation of that drug If resistance to given drug has ever been detected, that drug should probably not be used again, even if current test results suggest viral susceptibility

45. Conditions for Drug Resistance Testing:Individual Patient Management When to use: When there are treatment options To indicate drug exposure While patient is on therapy or before starting for the 1st time What to consider: Treatment history, other reasons for therapy failure Lab-to-lab variability of results and interpretations Requires expert advice for optimal use Only test single agents, not combinations

46. Conditions for Drug Resistance Testing: Public Health Applications When to use: When making decisions for national treatment guidelines 1st line regimens (based on results of surveillance for transmitted drug resistant HIV) 2nd line regimens (based on patterns of resistance in treated patients) To monitor program effectiveness minimizing HIVDR What to consider: Early Warning Indicators, programme and site factors Treatment history, other reasons for therapy failure Lab-to-lab variability of results and interpretations

47. Limitations of Resistance Testing: Only possible in case of a detectable viral load Lack of consistent quality control (see ENVA) Current assays do not pick up “minority species;” information is given on predominant strain Assays have mostly been studied in “late” failures; what is their value in early failures? Susceptibility is not equal to activity (clinical efficacy) Clinical validation: more data necessary

48. Reflection What benefits do I hope to see through DR testing in our country? What are my concerns right now about this type of testing?

49. Types of Resistance Assays Genotypic Testing: Prediction of phenotype based on sequence Phenotypic Testing: Measure of susceptibility to specific drugs Recombinant Assays: RT/PCR portion of patient virus and transfer into a vector Several different versions commercialized, automated and regulated PBMC Assay: Culture virus from patient Largely replaced by recombinant assays due to difficulties in reproducibility and throughput

50. Genotype Assays: Generic Procedure RT-PCR PR-RT DNA Sequencing Protein Sequence Selection Resistance Mutations Interpretation Prediction of Drug Susceptibility Patient virus