1 Uses of Data from the WHO HIV Drug Resistance Strategy: 1. Monitoring of HIVDR emerging in treated groups in sentinel ART clinics HIV Drug Resistance Team World Health Organization

Goal Monitor HIVDR emerging in cohorts starting ART at sentinel clinics, and associated ART program factors, in order to assist ART program planning and maintain effectiveness of first-line ART regimens Context: ART program evaluation of HIVDR prevention/emergence of HIVDR and associated ART program factors

Objectives l Estimate the proportion of the ART site population achieving HIVDR prevention as measured by viral load suppression, 12 months after starting first-line ART l Genotype specimens to identify specific HIVDR mutations and mutation patterns in patient groups not achieving prevention of HIVDR. l Collect and analyze data on ART programme factors potentially associated with the prevention (or non- prevention) of HIVDR l Use results to plan for further programme evaluation if necessary, to support optimal ART programme functioning at sentinel sites, to apply lessons learned to other programme sites, and to support planning and decision making to optimize ART effectiveness

Monitoring of HIVDR emerging in treatment l Cohorts beginning ART at sentinel sites followed for 12 months l Blood draw for viral load and genotyping at baseline, and at regimen switch or 12 months (may extend to 24/36 months) l Outcome measures: viral suppression (prevention of HIVDR emergence) and genotype –HIVDR mutations evaluated if viral load is detectable l Potentially associated factors (adherence, drug supply, subtype, previous antiretorivral (ARV) drugs, ART regimen) evaluated l Evidence-based recommendations, and lessons learned for other ART programs, to be disseminated by the HIVDR working group

Monitoring: Inclusion and Exclusion Criteria Inclusion Criteria: – Individuals initiating adult first-line ART at participating sentinel sites, regardless of age* Exclusion Criteria: – Individuals previously taking first-line ART at the sentinel monitoring site – Individuals transferring in from another ART delivery site on a first-line regimen * Paediatric monitoring protocol is also avialable

Potentially-associated ART clinic factors (independent variables: minimum dataset) l Individual Patient Factors* –Previous ARV exposure (PMCT, HIV mono or dual-therapy, partner's ARVs, informal sector ARVs) before first-line ART –Baseline HIVDR mutations –Drug pick-up % of expected –Adherence to first-line ART –ART clinic attendance % of expected –HIV-1 subtype l Aggregate Site Factors: –Drug supply continuity –Prescribing practices –Drug quality (if assessed as part of program monitoring) * Additional factors such as other clinical conditions, other medications may be collected if available

Prospective Cohort: Definition of Time Points l TIME 1 (Baseline): Time of commencement of first-line ART l TIME 2 (Endpoints): – Still on first line ART regimen at 12 months* – Switch: Change to second line regimen before 12 months – Stop: ART ends and patient continues in care at clinic for at least 30 days after ART ends, no resumption of first-line ART before 12 months from original ART start date (no prescription or no drug pick-up for two months before 12 months from original start date or report of no ARV drugs taken for 30 days before 12 months from original start date) – Loss to to follow-up: Break in appointment keeping and drug pick up; no return to clinic before 12 months – Death during first 12 months after start of first-line ART – Transfer out: Transferring care from the HIVDR monitoring site to another ART delivery site, still on first line ART *Patients experiencing a Substitution, that is, removal of one drug from a first line regimen and substituting another, are still considered to be on first line ART at 12 months if they do not reach another endpoint.

Outcomes at 12 months or earlier endpoint l Undetectable viral load at Time 2 Ξ Prevention of HIVDR* Classification of outcomes in those lacking evidence of HIVDR prevention: l Detectable viral load + "resistant" genotype at Time 2 Ξ HIVDR l Detectable viral load + "susceptible" genotype at Time 2 Ξ potential HIVDR l Lost to follow-up, Stop Ξ potential HIVDR l Transfer out, death Ξ not relevant, remove from numerator and denominator *Viral load suppression defines HIVDR prevention for the purposes of HIVDR sentinel monitoring

HIVDR Monitoring Sample Size l “ Effective” sample size of 96 (N = 96 + number of expected deaths + number of expected transfers out) guarantees a maximum width of a 95% CI +/- 10% regardless of the cumulative incidence of viral suppression l The first consecutive eligible N individuals presenting for ART on and after the start date are selected for sentinel HIVDR monitoring lPoint estimate is used to classify the proportion of viral suppression (ΞHIVDR prevention) as being above or below 70%

Time 1 ART 1 Time 2 Transfer out* Death* LTFU Detectable viral load Suppressed viral load D etectable HIVDR mutations Time 2 Switch Blood Draw for genotyping Blood Draw for genotyping + viral load HIVDR muts not seen Resistance Potential resistance Prevention of resistance Outcomes 12 Months If still on 1 st line stop Omitted from numerator and denominator

Data Sources l Capture of routine data: –HIV CARE/ART CARDS or medical records: previous ARV**, start date, prescriptions, drug pick-up, regularity of appointment keeping, pill counts**, endpoints (death, loss to follow-up, transfer out on 1 st -line regimen, substitution, stop, switch of regimen) –Pharmacy records l Additional data collected for HIVDR monitoring –Genotyping: residual blood specimen: Time 1 (Baseline) and Time 2 (12 months or regimen switch) + viral load at Time 2 –If needed, minimal supplemental questions at Time 1 + Time 2 ========================= **previous ARV and pill counts abstracted if available

Key HIVDR Monitoring results 1. % achieving HIVDR prevention after 12 months of ART (suggested target: >70% "HIVDR prevention") 2. Among those NOT achieving prevention: Description of HIVDR mutations and mutation patterns 3. Assess association between levels of HIVDR prevention and HIVDR mutation patterns with: a)previous ART b)drug pick-up regularity c)appointment keeping d)adherence e)baseline mutations 4. For analysis of more than one site's data, also assess association with: a)HIV-1 subtypes b)Drug supply continuity c)Prescribing practices

Public Health Implications of results: HIVDR prevention 1. >70% HIVDR prevention: – Evaluate for important lessons learned which can be qualitatively generalized to other sites – Encourage ongoing programme evaluation 2. < 70% HIVDR prevention : – May be associated with aggregate site factors, individual patient factors – both should be addressed by identifying elements of the ART programme which require increased support or change –HIVDR team should identify barriers to HIVDR prevention that affect other clinics Drug supply discontinuities Non-standard prescribing Previous ARV experience among those starting first-line ART Programmatic factors associated with lack of access or non- adherence, loss to follow-up –Evaluate program monitoring information or initiate program monitoring in other clinics –Address probable problems

Public Health Implications of results: HIVDR mutation patterns Recommendations for action depend upon mutations seen and their distribution + patterns. Examples of action include: l If specific mutations are associated with PMTCT or other previous ART, consider (on a population basis) alternate regimens for individuals with specific histories l If specific mutations are associated with particular prescribing practices, consider training or other measures to standardize prescribing l Depending on the patterns, consider implications for standard first and second-line regimens currently in use l If indicated, develop research strategies to study questions in depth

Multi-site and multi-country analyses l Multi-site and multi-country analyses may be possible  To evaluate the association between independent variables and viral suppression/resistance patterns l Monitoring results may generate hypotheses to be tested by supplemental research projects l Examples: association between HIVDR prevention or resistance patterns and –Previous PMTCT or previous “non-medical ARV” –Prescribing patterns –Interruptions in drug supply –Simple adherence measures (keeping appointments) –Interaction between HIV-1 subtypes + ARVS

Summary of uses for results l Will allow national HIVDR working group to identify and describe good ART practices or needed improvements in ART sites to limit HIVDR : –Program monitoring, prescribing practices, follow-up, support for adherence and ART access, assurance of uninterrupted drug supply l Inform policy decisions at national and global levels on effectiveness of first line regimens and composition of second-line regimens l Reinforce programme practices and ART programme monitoring recommended as part of overall WHO treatment strategy

Key HIVDR Monitoring Results Evaluate whether sentinel programs achieve >70% "HIVDR prevention" after 12 months of ART Among isolates with detectable virus: Describe HIVDR mutations and mutation patterns Assess association between levels of HIVDR prevention and mutation patterns with: –Previous ARV experience –Prescribing practices –Drug pick-up regularity –Appointment keeping –Continuity of drug supply –Pill count (if routinely performed at site) –Adherence scale question

Summary of current WHO language on uses of results l Will allow national HIVDR working group to identify and describe good ART practices or needed improvements in ART sites to limit HIVDR : –Program monitoring, prescribing practices, follow-up, support for adherence and ART access, assurance of uninterrupted drug supply l Inform policy decisions at national and global levels on effectiveness of first line regimens and composition of second-line regimens l Reinforce programme practices and ART programme monitoring recommended as part of overall WHO treatment strategy

Examples: HIVDR suppression l Low % HIVDR suppression associated with –poor drug supply continuity, or –previous ARV use, or –Poor appointment-keeping, or –Poor drug pick-up, or –Poor reported adherence, or –Specific subtype –Aberrant prescribing practices, or –Drug supply discontinuities l Low % HIVDR suppression, no particular associations –Data suggests possible association but sample too small –Data suggests no particular associations l High % HIVDR suppression –"good" indicators (> 80% adherence, drug pick-up, etc.) –despite high % previous ARV use –despite high % poor reported adherence

Examples: HIVDR patterns l Resistance to specific drug or drug class associated with: –Previous ARV –Specific HIV-1 subtype –Demographic variable (risk group, gender, ethnic group, residence area, clinician) l High % of resistance to specific drug or drug class with no clear associations l Low % HIVDR suppression but very few isolates with any resistance mutations

Recommendations (general) l Will probably always include the word "consider" l Should specify additional data needed for the considerations l Which groups or experts should review the data with national HIVDR working groups to make recommendations? l To which groups should recommendations be made?

National Recommendations l Recommendation categories within a country: –Research studies to answer a specific question –Enlargement of cohort size or number of sentinel sites to answer a specific question –Extension of the methodology to Year 2/3 –Consideration of changes to optimize ART program practices Training, support to staff, follow-up, clinic hours, financial or other support to increase access Additional methods to monitor individual patients and take specific actions for individuals based on results –Consideration of changes in standard first-line ART regimens for specific subgroups, all new patients in the clinic, all new patients in the area, all new patients in the country –Consideration of changes in the second line regimens for any of these –Consideration of additional monitoring of or changes in ART program practices –Others? l Which scenarios would prompt a definite recommendation in one of these categories?

Regional/global recommendations l Recommendation categories on the international level: –Research studies to answer a specific question –Enlargement of cohort size or number of sentinel sites in multiple countries to answer a specific question –General extension of the methodology to Year 2/3 –Consideration of multi-country support to optimize ART program practices Training, support to staff, follow-up, clinic hours, financial or other support to increase access Additional methods to monitor individual patients and take specific actions for individuals based on results –Consideration of changes in standard first-line ART regimens for specific subgroups, specific region(s), all resource-limited countries –Consideration of changes in the second line regimens for any of these –Consideration of additional monitoring of or changes in ART program practices –Others? l Which scenarios would prompt a definite recommendation in one of these categories?