WHO Maps HIV Drug Resistance

28 February 2007 (Last Updated February 28th, 2007 18:30)

HIV/AIDS continues to be the scourge of developing countries, but the World Health Organisation aims to change this. Zeenat Patel, Diane E Bennett, Silvia Bertagnolio and Donald Sutherland report on the organisation’s global effort to assess and prevent the emergence of HIV drug resistance.

In the last 25 years, the HIV/AIDS epidemic has taken an enormous toll, infecting approximately 65 million individuals around the world. According to WHO/UNAIDS, some 4.3 million people were newly infected with HIV in 2006 alone, an increase of about 400,000 since 2004. Nearly 25 million women, men and children have already died as a result of the epidemic. About 95% of people with HIV/AIDS live in developing countries, nearly two-thirds of them in sub-Saharan Africa.

In 2003, WHO launched its Three by Five initiative, which aimed to have three million people in low-income countries on antiretrovirals by 2005. By June 2006, approximately 1.6 million people had begun a WHO-recommended first-line antiretroviral drug treatment, up 400% from the 400,000 in 2003. More recently, at the September 2005 World Summit, global leaders committed to a massive scaling up of HIV prevention, treatment and care with the aim of universal access to treatment by 2010 for all who need it.

"By June 2006, approximately 1.6 million people had begun a WHO-recommended first-line antiretroviral drug treatment."

WHO, the UN agency responsible for health, promotes a public health approach to antiretroviral treatment (ART) in resource-limited settings, which focuses on the health needs of a population or the collective health status of people rather than individuals. The western model of specialist physician management and advanced laboratory monitoring is not feasible in resource-limited settings.

The key tenets of this approach are the standardisation and simplification of regimens to support efficient implementation, decentralised service delivery, equity, and patient and community participation. Experience and data have now shown that this approach is safe, effective and life saving.

DRUG RESISTANCE

Although it is universally recognised that combined ART has dramatically reduced HIV-related mortality, one major concern over the rapid scaling up of ART is the emergence and transmission of HIV drug resistant strains at the population level. This could lead to the failure of basic ART programmes as well as strategies to prevent HIV transmission through pre-exposure prophylaxis or the use of topical microbicides.

While the current reported low levels of HIV drug resistance (HIVDR) in resource-limited countries is reassuring, WHO recommends that each country be vigilant in measuring drug resistance transmission and the emergence of drug resistance within their treatment programmes, and increase programme support and make changes in the recommended regimens as necessary.

Countries should make use of clinical, immunological (CD4 monitoring), if available, and virological monitoring (viral load testing) for patient management. Until access to more basic monitoring tools becomes widely available, WHO does not recommend individual HIVDR testing for ART adjustment.

GLOBAL DRUG RESISTANCE STRATEGY

WHO in partnership with HIVResNet, a global advisory network of HIVDR experts, has developed a minimum-resource package for the prevention and assessment of HIVDR at a population level. Prevention and treatment strategies can help limit unnecessary HIVDR emergence on a population basis.

One approach to minimising the emergence of resistance is to create simplified and standardised national guidelines for ART provision that deliver highly effective first-line regimens. Good ART programming, with decentralised ART delivery and uninterrupted antiretroviral supplies, is crucial. A second way to minimise resistance is to administer regimens in ways that ensure patient adherence: fewer pills, simple dosing schedules, and adequate support for treatment adherence within the healthcare setting and in communities.

As a key component of the HIVDR strategy, WHO supports focus countries in setting up national HIVDR working groups. Among the main tasks of the national HIVDR working groups is the collection and analysis of the early warning indicators (EWIs) associated with preventable HIVDR, carrying out surveys assessing emerging HIVDR during treatment and measuring the transmission of HIVDR by testing recently infected populations.

Additional components of the strategy include the designation of WHO-accredited laboratories to perform quality-assured genotyping for the surveys, and the maintenance of a national, regional and central database containing HIV strain data, collected through surveillance and monitoring, to support the selection of optimal ART regimens on a population basis.

WHO also recommends that national HIVDR working groups take advantage of information being collected routinely for ART programme monitoring to watch for factors associated with preventable HIVDR emergence. WHO recommends that countries begin by evaluating which of the EWIs can be captured from current ART medical records systems or ART cards and collect those EWIs that are readily available and most useful.

HIVDR MONITORING

The purpose of monitoring HIVDR emerging in populations starting and continuing treatment is to assess the effectiveness of ART programmes in minimising the emergence of HIVDR in the first year of antiretroviral treatment and to assess the impact of programme factors associated with HIVDR. WHO recommends that sentinel ART sites be selected to represent the main clinic types in the country. The monitoring of HIVDR emerging in treated populations is designed to be incorporated into the routine functioning of ART sites.

Where drug resistance emerges, the data collected under the national and global WHO HIVDR strategy will inform the guidelines on appropriate population-based first- and second-line regimens, indications for time-of-regimen switch on a population basis, and specific actions to improve outcomes at sentinel clinics and other ART sites.

TRANSMITTED HIVDR SURVEILLANCE

Transmitted drug resistance occurs when an individual infected with an HIV-resistant virus, transmits the resistant virus to another individual. WHO has developed a minimum resource threshold survey to determine whether the proportion of HIV transmissions that are caused by drug-resistant strains in a population of newly infected and untreated persons exceeds a threshold.

Early in ART programme expansion, representative sampling to categorise a country-wide prevalence of transmitted HIVDR in resource-limited countries is neither feasible nor desirable. The risk for HIVDR transmission is likely to vary widely in different areas of a resource-limited country, and the resources required to obtain a large representative sample from all areas of the country would be prohibitive. In countries where transmitted HIVDR risk may vary for different sub-groups, separate sub-group specific surveys should be carried out.

Specific public health measures are recommended based on the prevalence category for resistance to drugs and drug classes. If prevalence is classified as less than 5% for all relevant drugs, the survey can be repeated in two years. If prevalence is higher, additional surveys or more intensive surveillance, as well as specific public health measures, may be required.

Results of the threshold surveys will be used to inform policy on ART regimens, and post- and pre-exposure prophylaxis, including prevention of mother-to-child transmission and the use of topical microbicides.

HIVDR LABORATORY NETWORK

To ensure accurate and standardised measurement of the rate of resistance in individual countries, WHO has formed a global HIVDR laboratory network to provide quality-assured genotyping of specimens collected for HIV drug resistance surveillance and monitoring. With the backing of their health ministries, laboratories may apply for membership in the WHO global HIVDR laboratory network to be accredited as a national, regional or specialised genotyping laboratory.

"This is the first global, coordinated effort to evaluate the emergence and transmission of HIV drug resistance."

WHO generally recommends that HIVDR working groups in resource-limited countries make use of a regional laboratory for the genotyping of surveillance and monitoring specimens. If capacity exists, the national government may nominate one or more in-country national genotyping laboratories to be assessed for accreditation within WHO’s global HIVDR laboratory network. These laboratories must meet specified criteria and undergo an on-site assessment before accreditation.

Training and technical support can be provided by WHO or HIVResNet partners to national laboratories that fulfil a number of specifications but fail to meet all requirements.

DRUG RESISTANCE DATABASE

National and global HIVDR surveillance and monitoring requires a simple shareware database application that can be used to collect data and report results at the country level and transfer a subset of data to the regional and central levels. Shareware for this purpose is provided at a country level by WHO in collaboration with the Centers for Disease Control and Prevention (CDC).

The application includes demographic and clinical variables required for HIVDR surveillance and monitoring, as well as a linked module that takes in, cleans and interprets nucleotide sequences. The nucleotide sequence module allows countries to collect sequences in addition to those collected in the routine surveillance and monitoring system, so that more complex analyses, of the associations between HIV-1 subtypes, ARV regimens and resistance mutations, for example, can be performed.

At the regional level, the software also automatically performs quality checks for sequence data, complementing the laboratory quality assurance system. The application can produce automated reports for countries and export the more complex datasets required to produce population-based HIVDR estimates and link them to ART programme practices and risk factors. The application is currently being tested in Africa and Asia.

VITAL ROLE

WHO’s Global Strategy for Prevention and Assessment of HIVDR will play a vital role in ensuring the success of ART scale-up as we work towards the goal of universal access to treatment for all those who need it by 2010. As of December 2006, 25 countries have requested technical assistance from WHO to implement the HIVDR strategy, and a number of these countries have formed national HIVDR working groups and planned or implemented HIVDR surveillance and monitoring protocols.

This is the first global, coordinated effort to evaluate the emergence and transmission of HIV drug resistance. As well as providing information on drug resistance patterns for an evidence-based approach to ART regimen planning in countries, the information provided through the strategy will allow evidence-based recommendations to be made by international bodies making ART policy decisions.

Data from the global HIVDR surveillance and monitoring database will inform planning for prevention strategies, including pre- and post-exposure prophylaxis and the use of microbicides.