The WHO HIV Drug Resistance Strategy

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• 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
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HIV drug resistance (HIVDR)

• The ability of HIV to enter human cells and
  multiplyin the presence of antiretroviral drugs

3


4
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.
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Background

• Some degree of HIV drug resistance (HIVDR) is
  inevitable
• 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
  surveillance

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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

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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
HIVResNet
Each working group (WG) is co-chaired by 1
developing country expert 1 industrialized
country expert
WG
(US, Canada, Latin America, Africa, Asia, the
Middle East, Europe, Australia)
WG
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
WG
WG
Global Laboratory Network Criteria, Protocols,
Training, QA
HIVDR database development and support
WG
Clinical Program Support HIVDR monitoring at
sentinel sites
EVALUATING THE EMERGENCE AND TRANSMISSION OF HIV
DRUG RESISTANCE
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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

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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
• Prevention of HIVDR during treatment
• Prevention of ongoing HIV transmission from an
  HIVDR infected person

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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
  line
• Drug Supply
• Any interruption of any first line drug

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What are the determinants of HIV Drug Resistance
that occurs within treatment programs? (2)

• Patient factors usually lead to low 'adherence
  rates'
• -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

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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

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General Relationship between Adherence to ART and
Resistance
Probability of resistance emerging 0
0.5

0 Adherence
100
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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

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Background Information

• Country population 1.1 Million (2004)
• Estimated Number of PLWHAs 210,000 -230,000
  (2005)
• 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
  19,000
• Number of persons who will be on ART by end 2007
  28,000
• Major in-country and international partners
• TAP, GFATM, OPEC CDC/USG etc.
• Before National ART Program started (end 2003),
  HIV drugs were available mainly in Capital of
  AFROland
• 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

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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

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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
  laboratories
• Database development for HIVDR surveillance and
  monitoring
• Harmonization of work with other groups and
  institutions
• Budget development and acquisition of needed
  resources
• Writing of the Annual HIVDR Report and
  recommendations

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HIVDR Key activities proposed for AFROland
2006details in following slides and attached
protocols

• HIVDR W/G formed (done) and HIVDR plan
  (developed)
• HIVDR Prevention (already part of ART scale up
  plans)
• 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)

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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
  EPIINFO)
• 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

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HIVDR Assessment using HIVDR Early Warning
Indicators from all ART sites and HIVDR sentinel
Monitoring in Malawi
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Example HIVDR EWI at ART sites (2006, mock)
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EWI 2 prescription practices (first-line
regimen,1st Q 2006)
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EWI 3 1st line continuation (Jan 2005 cohort
PuHo1)
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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
  appointments
• EWI 5 90 pick-up all drugs

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

• AFROland HIV Drug Resistance (HIVDR) Country Plan
  2006/7

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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.

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Is HIV Drug Resistance 'spreading like
wildfire' in AFROland?

• AFROland HIV Drug Resistance (HIVDR) Country Plan
  2006/7

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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
  city?
• Who would take responsibility for design and
  implementation?
• 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
  is

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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
  group

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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

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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
  labs.
• None
• List international HIVDR genotyping labs that
  might be designated by the government as
  surveillance and monitoring HIVDR genotyping
  labs.
• - WHO Accredited Member of AFRO HIVDR Lab
  network

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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
  network
• 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

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HOW SHOULD GENOTYPING LABORATORIES BE SELECTED TO
SUPPORT SURVEILLANCE AND MONITORING?

• 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

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(No Transcript)
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AFROland HIVDR Database development and
management

• AFROland has opted to use the WHO/HIVResNet HIVDR
  Database.
• 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

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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

• National HIVDR DATABASE
• HIVDR transmission surveillance
• Monitoring of ART-related HIVDR Genotyping results

HIVDR Country Report
Relevant ART Program, treatment, prevention
indicators HIVDR research studies
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Regional/Global HIVDR Data Flow and Processing
National HIVDR DATABASE
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
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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
  preparation
• 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
  monitoring
• Need to identify donors who might be interested
  to assist TAP, USG, GFATM, UN, Italian Gov ,
  others etc.?

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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
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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)
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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
  indicators"
• 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

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Work!

• 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
  countries
• 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