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HIV drug resistance status report

Countries that received technical assistance visits between August 2007 and December 2008 included Brazil, Burkina Faso, Cameroon, El Salvador, Ghana, Haiti, Honduras, India, Indonesia, Kenya, Malawi, Mali, Namibia, Papua New Guinea, Rwanda, Russia, Senegal, Trinidad and Tobago, Ukraine, and Vietnam. This brings to a total of 34 countries to which technical assistance has been provided since project start, some of which are funded through our Gates grant and some of which are funded from other sources.

Centrally driven project activities to augment all aspects of the project include national workgroup coordination, consensus meetings, evaluation and updating of HIVDR guidelines, standards, and policies related to implementation, scale-up, and operations.

Terms of Reference for national HIVDR working groups, and HIVDR strategy were developed in the following 11 WHO focus countries - Burkina Faso, Cambodia, Ghana, India, Indonesia, Namibia, Rwanda, Senegal, Ukraine, Zambia, and Zimbabwe. This adds to the 11 countries from 2007.

Regional trainings took place in two subregions within Africa: the Western Africa subregion and the Southern and Eastern Africa subregion. Included in the trainings were countries that are being supported from other sources to develop the WHO-recommended strategy. Eastern European training supported by WHO European Region took place in Russia (September 2008) and in Zagreb, Croatia (November 2008), and included Ukraine and Russia, and other countries (Belarus, Croatia, Latvia, Georgia, Moldova, Slovenia, and Sudan); which are being supported by other means to implement the WHO-recommended HIVDR strategy.

Guidance for development of national HIVDR working groups, surveillance and monitoring survey implementation protocols, and other tools have been posted on the WHO website.

The WHO HIV Drug Resistance Strategy (ResNet) Steering Committee met for two days in November 2008 to review progress and provide recommendations to the HQ Team. Through the end of 2008, 26 countries (Figure 1) in five WHO regions received technical assistance from WHO and its HIVResNet partners to develop and implement national HIVDR plans. All of these countries implemented one or more elements of their national HIVDR strategies.

HIVDR threshold surveys

HIVDR threshold surveys were implemented in Burkina Faso, Ghana, India, Indonesia, Uganda, Ukraine, South Africa, Zambia and Zimbabwe in 2008 bringing to a total of 22 countries that have implemented surveys. With technical support from WHO and financial support from other organizations, some of these countries are expanding implementation to additional geographic areas in 2009. WHO's threshold survey methodology has also been adopted in additional countries where training has been provided in regional workshops but where WHO is not providing financial support.

Eight countries have reported results from surveillance of transmitted HIVDR in geographic areas where ART was first used within the country (Table 1) at international conferences or in peer-reviewed journals. Data obtained from the HIVDR transmission surveys is providing information on the extent and patterns of drug resistance in newly acquired HIV infections. Thus far, recommendations to continue the use of current ART regimens have been made based on the surveys from 2007 and 2008, all of which report < 5% transmitted resistance to all drugs and drug classes in geographic areas where ART is widely available. The WHO mutations list for HIVDR transmission surveys was published in Antiviral Therapy and is also available on the Stanford website and used by several institutions in addition to WHO.

HIVDR monitoring surveys

Training of country coordinators, identification of suitable sentinel ART sites, and development and submission of country protocols for HIVDR monitoring surveys at sentinel ART sites has occurred in Burkina Faso, Ghana, Haiti, Kenya, Mozambique, Rwanda, Senegal, Ukraine, Vietnam and Zimbabwe. These countries are successfully adopting and piloting WHO HIVDR monitoring protocols in one to four sentinel ART sites in preparation for routine implementation of a rolling three year cycle of three to ten sites annually.

HIVDR Early Warning Indicators (EWI)

As a supplement to these surveys WHO has developed ART site quality assurance tools: the HIVDR Early Warning Indicators (EWI). With the EWI, a larger number of representative ART sites are assessed than with the genotyping surveys. The EWI assess the extent to which sites are functioning optimally to prevent HIVDR. These indicators evaluate issues known to be associated with the emergence or prevention of HIVDR at the ART site level, including prescribing practices, losses to follow-up during the first year of ART the extent to which patients pick up their ARV drugs on time, and ARV drug shortages at the site level. EWI monitoring evaluates the key factors in ART sites without the expense of HIVDR testing, and results can be used to optimize both ART site and national ART program functioning. EWI are abstracted retroactively so that results are available for analysis more quickly than for the prospective surveys. WHO recommends monitoring six EWI (plus two optional EWI) to supplement results from HIVDR monitoring surveys at sentinel ART sites.

WHO provided training and technical assistance in nine new countries in 2008 for the planning and development of protocols for HIVDR monitoring surveys. These countries included Burkina Faso, Ghana, Haiti, Kenya, Rwanda, Senegal, Ukraine, Vietnam, Zimbabwe. In many of the countries protocols are still under ethics committee review but implementation of HIVDR monitoring surveys began in Burkina Faso, Mozambique, Nigeria, Swaziland, Uganda and Zambia in 2008. This adds to those countries in which this was achieved for the first year of the project namely Burundi, India, and Malawi thus bringing the total number of countries implementing monitoring surveys to nine since starting the project.

Only basic demographic data, pre-ART clinical data, baseline genotyping data and data on experience with ARVs before ART start are available for the surveys implemented so far. Data cleaning is currently taking place. None of the surveys including those which started in 2007, has reached endpoint, because patients are enrolled over three to six months in order to reach the optimum sample size and must be followed for up to 15 months.

For the EWI training, site selection, and review of medical records to evaluate feasibility of indicator collection took place in 15 countries: Burkina Faso, Burundi, Cambodia, Ethiopia, Ghana, Haiti, Indonesia, India, Malawi, Swaziland, Tanzania, Uganda, Vietnam, Zambia, and Zimbabwe. Monitoring of EWI were implemented in Burkina Faso, Ethiopia, Ghana, Haiti, Malawi, Mozambique, Swaziland, Zambia, and Zimbabwe. Malawi's results were published in Antiviral Therapy in May 2008 and reported at the International AIDS Conference in Mexico City, August 2008.

WHO Global HIV Drug Resistance Laboratory Network

The WHO Global HIV Drug Resistance Laboratory Network has been established and member laboratories have provided quality-assured results for HIV drug resistance surveys. At annual meetings with an independent panel of experts, findings of the assessment visits, laboratory performance, and accreditation status is reviewed in accordance with WHO requirements. Laboratory assessments were performed and technical assistance provided in 22 countries by WHO staff or consultants. As of February 2009, 21 labs have been accredited (Table 2). Additional assessment visits are planned for 2009. Figure 1 illustrates the location of accredited laboratories and the laboratories assessed or currently undergoing assessment. The procedures, the accreditation criteria and checklists used for genotyping laboratories assessment have been finalized and published on the WHO website. These have also been published in Antiviral Therapy in May 2008, together with a summary of the WHO HIV drug resistance laboratory strategy, by the HIVResNet laboratory advisory group. Other laboratory-related activities are summarized below:

• Laboratory training and capacity building. Training to laboratory technicians has been provided through the WHO team and their consultants directly during site visits. Laboratory sessions were also presented as part of regional workshops on HIV drug resistance training in Tanzania (Oct 2008) and Russia (September 2008). A twinning program, coordinated by WHO, links WHO accredited laboratories with strong capacity in HIVDR genotyping to labs with less capacity and experience. This method has been very useful to increase technology transfer and knowledge sharing between labs with different capacities.
  
  
• An HIVDR training package is under development in collaboration with one of the specialized drug resistance laboratories. A draft training package was completed in December 2008. The final version of the training package will be produced by June 2009, after piloting the material in two regional workshops during the first half of 2009 in Africa and Asia.
  
  
• External Quality Assurance. External QA of laboratory performance for genotyping from plasma is carried out using proficiency panels (PP) samples provided by the VQA programme of NIH. NIH has modified the VQA panel to accommodate WHO specifications. Two shipments of the PP were made in 2008 and sent to a total of 33 labs. Reports have been produced - including recommendations and next steps – for each of the labs individually. PP results from 2007-2008 were presented in a poster at the Conference on Retroviruses and Opportunistic Infections in Montreal in February, 2009.
  
  
• Dried blood spots (DBS) testing. Expert meetings to discuss feasibility and development of proficiency panels using DBS were held in Chicago in November 2008, and Madrid in December 2008. A specific plan to develop a proficiency panel using DBS has been developed and will be finalized in Q1 2009; DBS proficiency panels will be distributed by NIH to the network labs in Q3 2009 . The network is currently reviewing evidence on use of DBS for genotyping in treated populations with low viral load and planning operational research on DBS-related issues.
  
  
• Key operational research questions have been identified that are important for the network and implementation of the HIVDR strategy at country level including:
• Stability of HIV in DBS over time and at different temperature conditions. A study has been designed with the collaboration of an accredited laboratory in Uganda and a specialized laboratory who are committed to the WHO ResNet research agenda.
• Viral load correlation in DBS vs plasma and equivalence in specimens with VL < 10,000 copies/ml.
  
  
• Network laboratories use different methods for DBS genotyping, that differ in performance and cost. The WHO ResNet laboratory group has developed standard criteria to validate in-house methods for DBS genotyping. A validation panel has been produced by two specialized laboratories and will be shipped to 15 network laboratories to validate their extraction and sequencing method using DBS by Q2 2009.

Figure 1. Map showing countries implementing at least one aspect of the Global HIVDR Strategy and locations of HIVDR testing laboratories accredited or undergoing assessment

Table 1: Surveys of transmitted HIV drug resistance

Table 2: WHO Accredited HIVDR laboratories (as of February 2009)

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