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Uses of Data from the WHO HIV Drug Resistance Strategy: Monitoring of HIVDR emerging in treated groups in sentinel ART clinics. HIV Drug Resistance Team World Health Organization. Goal. - PowerPoint PPT Presentation
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Uses of Data from the WHO HIV DrugResistance Strategy:
1. Monitoring of HIVDR emerging in treated groups in sentinel ART clinics
HIV Drug Resistance TeamWorld Health Organization
GoalGoal
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
ObjectivesObjectives
Estimate the proportion of the ART site population achieving HIVDR prevention as measured by viral load suppression, 12 months after starting first-line ART
Genotype specimens to identify specific HIVDR mutations and mutation patterns in patient groups not achieving prevention of HIVDR.
Collect and analyze data on ART programme factors potentially associated with the prevention (or non-prevention) of HIVDR
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 treatmentMonitoring of HIVDR emerging in treatment Cohorts beginning ART at sentinel sites followed for 12 months Blood draw for viral load and genotyping at baseline, and at
regimen switch or 12 months (may extend to 24/36 months) Outcome measures: viral suppression (prevention of HIVDR
emergence) and genotype– HIVDR mutations evaluated if viral load is detectable
Potentially associated factors (adherence, drug supply, subtype, previous antiretorivral (ARV) drugs, ART regimen) evaluated
Evidence-based recommendations, and lessons learned for other ART programs, to be disseminated by the HIVDR working group
Monitoring: Inclusion and Exclusion CriteriaMonitoring: 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 Potentially-associated ART clinic factors (independent variables: minimum dataset)(independent variables: minimum dataset)
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
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 PointsProspective Cohort: Definition of Time Points
TIME 1 (Baseline): Time of commencement of first-line ART 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 endpointOutcomes at 12 months or earlier endpoint
Undetectable viral load at Time2 Ξ Prevention of HIVDR*
Classification of outcomes in those lacking evidence of HIVDR prevention:
Detectable viral load + "resistant" genotype at Time2 Ξ HIVDR Detectable viral load + "susceptible" genotype at Time2 Ξ potential
HIVDR Lost to follow-up, Stop Ξ potential HIVDR 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 SizeHIVDR Monitoring Sample Size
“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
The first consecutive eligible N individuals presenting for ART on and after the start date are selected for sentinel HIVDR monitoring
Point estimate is used to classify the proportion of viral suppression (ΞHIVDR prevention) as being above or below 70%
Time1
ART 1Time2
Transfer out*Transfer out*Death*
LTFU
Detectable viral load
Suppressed viral load
Detectable HIVDR mutations
Time2
Switch
Blood Draw for genotyping
Blood Draw for genotyping + viral load
HIVDR muts not seen
Resistance
Potential resistance
Prevention of resistance
Outcomes
12 MonthsIf still on 1st line
stop
Omitted from numerator anddenominator
Data SourcesData Sources 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 1st-line regimen, substitution, stop, switch of regimen)
– Pharmacy records Additional data collected for HIVDR monitoring
– Genotyping: residual blood specimen: Time1 (Baseline) and Time2 (12 months or regimen switch) + viral load at Time2
– If needed, minimal supplemental questions at Time1 + Time2 =========================
**previous ARV and pill counts abstracted if available
Key HIVDRKey HIVDR Monitoring resultsMonitoring results1. % 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 patterns3. Assess association between levels of HIVDR prevention
and HIVDR mutation patterns with:a) previous ART b) drug pick-up regularityc) appointment keepingd) adherencee) baseline mutations
4. For analysis of more than one site's data, also assess association with:
a) HIV-1 subtypesb) Drug supply continuityc) Prescribing practices
Public Health Implications of results: Public Health Implications of results: HIVDR preventionHIVDR 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: Public Health Implications of results: HIVDR mutation patternsHIVDR mutation patterns
Recommendations for action depend upon mutations seen and their distribution + patterns. Examples of action include:
If specific mutations are associated with PMTCT or other previous ART, consider (on a population basis) alternate regimens for individuals with specific histories
If specific mutations are associated with particular prescribing practices, consider training or other measures to standardize prescribing
Depending on the patterns, consider implications for standard first and second-line regimens currently in use
If indicated, develop research strategies to study questions in depth
Multi-site and multi-country analysesMulti-site and multi-country analyses Multi-site and multi-country analyses may be possible
To evaluate the association between independent variables and viral suppression/resistance patterns
Monitoring results may generate hypotheses to be tested by supplemental research projects
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 resultsSummary of uses for results 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
Inform policy decisions at national and global levels on effectiveness of first line regimens and composition of second-line regimens
Reinforce programme practices and ART programme monitoring recommended as part of overall WHO treatment strategy
Key HIVDR Monitoring ResultsKey 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 Summary of current WHO language on uses of resultson uses of results
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
Inform policy decisions at national and global levels on effectiveness of first line regimens and composition of second-line regimens
Reinforce programme practices and ART programme monitoring recommended as part of overall WHO treatment strategy
Examples: HIVDR suppression Examples: HIVDR suppression 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
Low % HIVDR suppression, no particular associations– Data suggests possible association but sample too small– Data suggests no particular associations
High % HIVDR suppression – "good" indicators (> 80% adherence, drug pick-up, etc.)– despite high % previous ARV use– despite high % poor reported adherence
Examples: HIVDR patternsExamples: HIVDR patterns
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) High % of resistance to specific drug or drug class with
no clear associations Low % HIVDR suppression but very few isolates with any
resistance mutations
Recommendations (general)Recommendations (general)
Will probably always include the word "consider" Should specify additional data needed for the
considerations
Which groups or experts should review the data with national HIVDR working groups to make recommendations?
To which groups should recommendations be made?
National RecommendationsNational Recommendations 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?
Which scenarios would prompt a definite recommendation in one of these categories?
Regional/global recommendationsRegional/global recommendations 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?
Which scenarios would prompt a definite recommendation in one of these categories?