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The WHO HIV Drug Resistance Strategy


The WHO HIV Drug Resistance Strategy. Prevention, Surveillance and Monitoring ... The World Health Organization has brought together WHO HIVResNet, a global group ... – PowerPoint PPT presentation

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Title: The WHO HIV Drug Resistance Strategy

  • The WHO HIV Drug Resistance Strategy
  • Prevention, Surveillance and Monitoring
  • The "Essential Package"

Presented by Dr Donald Sutherland Prepared
with the assistance of Dr Diane Bennett and Dr
Silvia Bertagnolio HIV Drug Resistance
Program HIV Department World Health Organization
HIV drug resistance (HIVDR)
  • The ability of HIV to enter human cells and
    multiplyin the presence of antiretroviral drugs


Daily production of HIV mutations in an untreated
HIV-infected person
  • Up to 10 billion new viruses are produced daily 1
  • 10 million viruses per day will have one new
    "error" (mutation) 1
  • 100 million new cells are infected/day
  • Under drug selection pressures, complete
    replacement of wild-type (WT) virus
    bydrug-resistant virus can occur in 14-28 days4

1Coffin. Science 1995267483. 2Mansky. J
Virol 1995695087. 3Perelson. Science
19962711582. 4Wei. Nature 1995373117.
  • Some degree of HIV drug resistance (HIVDR) is
  • Lifelong treatment, no cure
  • high rate of mutation
  • Minimizing HIVDR reducing the rate of
    emergence and spread of HIVDR and limiting its
    public health consequences.
  • Principles
  • appropriate drug prescribing and usage
  • fostering adherence
  • preventing HIV transmission
  • appropriate action based on monitoring and

1. WHO HIVDR Strategy Context
  • WHO is approaching Universal ARV Access by
    developing an "essential package" for ART
    scale-up and HIV prevention, including an
    "essential HIVDR package"
  • Support and implementation of the essential
    package is provided by WHO, mobilizing its
    international partners, including WHO HIVResNet,
    an international advisory network of clinicians,
    virologists, and epidemiologists with
    HIVDR-related expertise

Country HIVDR Committees
HIVDR monitoring surveillance
The World Health Organization has brought
together WHO HIVResNet, a global group of
experts, laboratories, and organizations to
develop methods for and support or HIV drug
resistance (HIVDR) prevention, surveillance, and
monitoring as antiretroviral treatment (ART) is
rolled out worldwide.
Steering Committee
WHO Secretariat
Each working group (WG) is co-chaired by 1
developing country expert 1 industrialized
country expert
(US, Canada, Latin America, Africa, Asia, the
Middle East, Europe, Australia)
Information Exchange HIVDR research studies,
clinical trials worldwide support networking and
public health uses of HIVDR data
Epidemiology, Statistics Protocols, training,
analytic tools
Technical Committee
Global Laboratory Network Criteria, Protocols,
Training, QA
HIVDR database development and support
Clinical Program Support HIVDR monitoring at
sentinel sites
What are the determinants of HIV Drug Resistance
  • Primary HIV Drug Resistance
  • the HIVDR that results from becoming infected
    with a virus that is already resistant
  • Secondary HIV Drug Resistance
  • the HIVDR that occurs during ART treatment
  • Program factors
  • Patient factors
  • Viral factors

What are the determinants of HIV Drug Resistance
  • Primary the HIVDR that results from becoming
    infected with a virus that is already resistant
  • In this case it is a double case of unsuccessful
  • Prevention of HIVDR during treatment
  • Prevention of ongoing HIV transmission from an
    HIVDR infected person

What are the determinants of HIV Drug Resistance
that occurs within treatment programs?
  • Program factors may be assessed by measures of
    ART 'adherence rates', drug supply records,
    virologic suppressions rates, of patients
    retained in treatment programs
  • Direct costs
  • for medical care,
  • laboratory tests,
  • medications including ART, OI treatment/
    prophylaxis or drug dependence treatments
  • Drug treatment policy.
  • Standard 3 drug regimen vs ad hoc,
  • "treatment failure" -when to switch to second
  • Drug Supply
  • Any interruption of any first line drug

What are the determinants of HIV Drug Resistance
that occurs within treatment programs? (2)
  • Patient factors usually lead to low 'adherence
  • -unprepared, not well informed, may need
    treatment partner
  • -drug toxicities reduce adherence
  • -poor absorption of drug - formulation,
    toxicity, concurrent illness
  • -poverty
  • -stigmatized in family and community
  • -ART drug sharing
  • -other illnesses may interfere with ART drug
    taking, such as TB, Malaria, Hepatitis, mental
    illness, opiate dependency
  • -super-infection with second strain -possible
    but likely rare

What are the determinants of HIV Drug Resistance
that occurs within treatment programs? (3)
  • Viral factors
  • Some new evidence to suggest that different viral
    subtypes evolved different degrees of drug
    resistant to first line regimens and thus may
    respond differently to ART regimens over time and
    affect choices of second line drug policies.
    (Kantor et al 2005)
  • - However currently most experts feel that it
    is very unlikely there will be any effective
    differences in development of drug resistance
    depending on subtype.
  • Some mutations while leading to increased
    likelihood of resistance are also associated with
    lower replication capacity and so may not lead to
    viral rebound

General Relationship between Adherence to ART and
Probability of resistance emerging 0

0 Adherence
AFROland HIV Drug Resistance (HIVDR) Country Plan
2006/7Two key Questions
  • Is HIV Drug Resistance occurring during the ART
    scale up in AFROland?
  • 2. Is HIV Drug Resistance 'spreading like
    wildfire' in AFROland?
  • The following is a proposal for AFROland to
    assess the situation and make recommendations to
    the National ART and HIV Prevention program

Background Information
  • Country population 1.1 Million (2004)
  • Estimated Number of PLWHAs 210,000 -230,000
  • Estimated Number of persons eligible for ART
    42,000 (2006)
  • Number of persons currently on ART 15,000
  • Number of persons who will be on ART by end 2006
  • Number of persons who will be on ART by end 2007
  • Major in-country and international partners
  • Before National ART Program started (end 2003),
    HIV drugs were available mainly in Capital of
  • ART scale-up has been in past 2 years expanding
    to all regions (urban and rural), moving now to
    public health units and clinic level

Information needed for the HIVDR Country Plan
  • Institutions and individuals with
    expertise/interest in HIV surveillance, ART
    issues, virology, and HIVDR
  • Proposed HIVDR working group composition
  • HIVDR Key activities proposed for AFROland 2006

HIVDR Strategy
  • Development of a National HIVDR Working Group and
    the detailed National HIVDR Strategy
  • Identify and agree on HIVDR Early Warning
    Indicators (EWI)
  • Surveillance of transmitted HIVDR using the
    threshold survey method
  • Monitoring of HIVDR arising in populations
    starting and continuing ART.
  • Designation of one or more genotyping
  • Database development for HIVDR surveillance and
  • Harmonization of work with other groups and
  • Budget development and acquisition of needed
  • Writing of the Annual HIVDR Report and

HIVDR Key activities proposed for AFROland
2006details in following slides and attached
  • HIVDR W/G formed (done) and HIVDR plan
  • HIVDR Prevention (already part of ART scale up
  • National first/second line drug supply, all ART
    according to guidelines, National ART number for
    all on ART, adherence measures in place
  • HIVDR early warning indicators from all ART sites
  • can be done from EPIINFO system
  • HIVDR Transmission Threshold Survey (TS)
  • Can be done with available data and specimens
    from current round of HIV Surveillance with WHO
    assistance for testing
  • HIVDR Annual situation report
  • Can be prepared from available data and TS
  • HIVDR Monitoring of ART program at sentinel sites
  • Can be planned for 2007
  • All aspects can be put into TAP or GFATM next
    round proposal (with WHO assistance)

HIVDR Early Warning Indicators (EWI)
  • AFROland has ART information system (EPIINFO)
    that collects information on
  • Prescribing practices
  • lost to follow-up
  • of persons starting first-line ART who are
    still taking first-line ART one year later
  • Simple adherence measures (not currently in
  • Appointment keeping (not yet in EPIINFO)
  • is in Appt register at site need to be
    incorporated in EPIINFO
  • Drug supply continuity -central data (yes), ART
    sites specific data- on cards
  • Drug quality
  • CMS buys from WHO pre-qualified manufacturer
  • CMS does drug storage/dispensing facility quality
    assurance visits

HIVDR Assessment using HIVDR Early Warning
Indicators from all ART sites and HIVDR sentinel
Monitoring in Malawi
Example HIVDR EWI at ART sites (2006, mock)
EWI 2 prescription practices (first-line
regimen,1st Q 2006)
EWI 3 1st line continuation (Jan 2005 cohort
Plan for collection of HIVDR EWI
  • Plan for collection of indicators
  • Indicators 1-3 immediate collection
  • Indicator 4 collection after amendment of the
    EpiInfo database (end of 2006)
  • Indicator 5 after amendment of EpiInfo or
    cross-link with new Pharmacy database (2007)
  • Targets for indicators
  • EWI 1 no stock-outs in last 6 months
  • EWI 2 no presciptions out of guidelines
  • EWI 3 80 on first-line ART at 12 months
  • EWI 4 80 On first-line and kept all
  • EWI 5 90 pick-up all drugs

HIVDR Assessment using HIVDR Early Warning
Indicators from all ART sites and HIVDR sentinel
Monitoring in Malawi
Is HIV Drug Resistance occurring in AFROland
during the ART scale up?
  • AFROland HIV Drug Resistance (HIVDR) Country Plan

HIVDR Monitoring in AFROland ART program using
sentinel sites
  • AFROland plans to develop HIVDR Monitoring
    activity for implementation in 2007
  • There are sites with capacity that are recruiting
    new patients at sufficient rate to set up a
    monitoring cohort.
  • -4 ART sites possible "Big city", "major
    District", "St Somebody" and "active NGO"
  • The clinical records are probably sufficient and
    specimens can be collected for timely transport
    to national lab for viral load and storage
  • Proposed persons responsible for developing this
    HIVDR Monitoring nationally/ locally
  • Dr "Clinical" P.I. Ms "Hard Work"
  • Each site has co-PI such as Dr. "Locale 1" , Dr.
    "Locale 2" etc.

Is HIV Drug Resistance 'spreading like
wildfire' in AFROland?
  • AFROland HIV Drug Resistance (HIVDR) Country Plan

Surveillance of transmitted HIVDR looking for
HIVDR in recently infected population using a
threshold survey (TS)
  • Do you have a geographic area with sufficient
    specimens available for a Threshold Survey to be
    done in 2006 2007? i.e. a Geographic area where
    HIVDR is most likely to be seen first capital
  • Who would take responsibility for design and
  • Potential site types ANC Sites
  • Available routinely-collected data
  • Available routinely-collected specimens plasma
  • Numbers of eligible specimens 60
  • Result will tell if HIVDR spread in recent times

HIVDR threshold survey for surveillance of
transmitted HIVDR
  • Requires 47 or fewer specimens from recently
    infected persons sequentially diagnosed in a
    geographic area
  • Utilizes sequential HIV diagnostic specimens from
    HIV serosurveys in antenatal clinics, voluntary
    counselling and testing centres, or other HIV
    diagnostic settings
  • Inclusion
  • Ideal All persons recently infected with HIV
  • Practical Newly diagnosed persons likely to have
    been recently infected
  • Allows area-specific classification of
    transmitted HIVDR to individual drugs and drug
    classes as 15 for specific
    geographic areas
  • HIVDR prevalence classifications trigger specific
    recommendations for action by the HIVDR working

Writing of the Annual HIVDR report as part of
the national Annual Report on HIV/AIDS country
level (UNGASS or MDG reports) and recommendations
  • Any statement/publication regarding HIVDR in
    AFROland must be reviewed and approved by W/G
  • Key activity of National HIVDR Working Group
  • Used to report on
  • HIVDR situation
  • contributing factors
  • recommendations for ART and HIV prevention
    program adjustments and plans for implementation
    of recommendations
  • Surveillance and monitoring planning for the
    following year
  • Can contribute to Africa region annual report
  • Dr. "X" and Mr. "Y" responsible for report writing

Genotyping Laboratory Selection
  • List the annual number of specimens likely to
    require HIVDR genotyping for surveillance and
    monitoring only during the piloting of HIVDR
    surveillance and monitoring.
  • 2006
  • surveillance 60
  • 2007
  • Surveillance 60
  • Monitoring 100 -400
  • List HIVDR genotyping labs within the country
    that might be designated by the government as
    surveillance and monitoring HIVDR genotyping
  • None
  • List international HIVDR genotyping labs that
    might be designated by the government as
    surveillance and monitoring HIVDR genotyping
  • - WHO Accredited Member of AFRO HIVDR Lab

G. A designated HIVDR testing laboratory
  • One or more genotyping laboratories meeting WHO
    criteria will be selected by the Ministry of
    Health for HIVDR surveillance and monitoring
  • Two options
  • Local laboratory meeting WHO HIVResNet criteria
  • Regional laboratory from the WHO HIVResNet
  • Technical assistance and training can be provided
    by the WHO HIVResNet network to support
    in-country laboratory development to achieve
    network designation
  • Assessment visits and genotyping of quality
    assurance panels regularly assure continued
    standardization of results globally

  • WHO/HIVResNet has developed a set of criteria for
    WHO "accreditation" as an HIVDR testing lab to
    support national HIVDR surveillance and
    monitoring. These include
  • Sufficient experience in HIVDR genotyping
  • Necessary amplification and sequencing equipment
    and appropriately trained staff
  • Participation in WHO HIVResNet-approved
    internationally recognized HIVDR QA/QC program
  • Etc.
  • If no national laboratory meets the criteria,
    genotyping can be performed can be done at a
    WHO/HIVResNet regional lab
  • Training and support for capacity-building is
    also available

(No Transcript)
AFROland HIVDR Database development and
  • AFROland has opted to use the WHO/HIVResNet HIVDR
  • MOH (M and E unit) would be responsible for
    keeping this database, data input, report
    production from database etc.
  • AFROland is willing to participate in an AFRO
    regional HIVDR database as part of the WHO
    Global HIVDR Database
  • WHO/AFRO can provide HIVDR database and training

National HIVDR Data Flow and Processing
HIVDR Transmission Surveillance
HIVDR Monitoring of ART Programs
Eligible recently infected individuals
Eligible new ART patients
National Genotyping Laboratory
Viral Load Lab
  • HIVDR transmission surveillance
  • Monitoring of ART-related HIVDR Genotyping results

HIVDR Country Report
Relevant ART Program, treatment, prevention
indicators HIVDR research studies
Regional/Global HIVDR Data Flow and Processing
HIVDR Country Report
National Genotyping Laboratory
Regional/Global HIVDR Databases
Regional Global Reports
Laboratory Data
Demographic, Clinical Data
Results and analysis
Queries and cleaned data
Budgeting and use of other Resources
  • Resources (human, financial, institutional,
    other) currently available from MOH and WHO and
    partners to support the national HIVDR strategy
  • HIV Surveillance round data and specimens
  • Viral load testing at national Reference Lab
  • National HIVDR W/G participation
  • budget preparation for the HIVDR work
  • HIVDR Protocol development and HIVDR report
  • Use of EPI-INFO database personnel and data (EWI)
  • Additional resources may be required for
  • piloting
  • other HIVDR work to take place in the next one to
    two years under the national plan
  • expansion of the strategy
  • Additional Laboratory activities
  • Identify and list specific Technical assistance
    required for development and implementation of a
    comprehensive national HIVDR Surveillance and
  • Need to identify donors who might be interested
    to assist TAP, USG, GFATM, UN, Italian Gov ,
    others etc.?

Example Mock Budget HIV Drug Resistance
Surveillance and Monitoring
Year 1 1. Surveillance of HIVDR Transmission
Total est. 25,000 per site if done within HIV
surveillance round includes specimen shipping
and genotyping costs) 2. Monitoring of HIVDR in
ART Total est. 50,000 setting up first
protocol and site then 100,000 per sentinel
site (including VL 250 X 25? Plus genotyping
150 X 300, shipping ? Etc.) 3. Technical
Assistance (Total 55,000 e.g. visiting
consultants) 5. Development of National HIVDR
Database (Total 20,000) Dedicated computer,
Software provided by WHO, Training
Example Mock Budget HIV Drug Resistance
Surveillance and Monitoring
Year 2 Scenario 1 If NO or little evidence of
HIVDR transmission (i.e. Transmission Surveillance (25,000) 2.Monitoring
HIVDR (Continue site 1 cohort- 75,000, Add
second site 100,000) 3. Repeat Technical
Assistance, HR, and National HIVDR Database as
above Scenario 2 If evidence of HIVDR
transmission (5) or emergence on ART 1. Add 1
Surveillance sites (2 total sites1 from Year 11
additional sites) (50,000) 2. Monitoring and
other items same as Scenario 1 Year 3,4,5 (need
to be planned for)
Technical Assistance that might be requested from
AFRO, CDC, WHO HQ, and other organizations
  • Working group development (TOR)
  • National strategy development
  • Collection and analysis of HIVDR "early warning
  • Protocol development and planning
  • Surveillance of transmitted HIVDR (TS),
  • Monitoring of HIVDR in ART sentinel sites
  • Standard operating procedures for specimen
    collection, processing, and shipment
  • Database development and training
  • Preparation of budgets and requests for funds

  • Threshold surveys have begun in 9 countries
    funded and planned in 8 additional countries
  • Monitoring beginning in one country planned in 3
    additional countries
  • Technical assistance requested for planning in
    many more countries
  • Preliminary lab assessments performed in 4
  • Our in-country strategy focuses on the national
    strategy supported by the Ministry of Health
  • Partnerships required to extend data collection
    to the private sector in each country
  • National HIVDR working group should incorporate
    clinicians, epidemiologists, laboratorians from
    public sector, private sector, academia
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