The World Health Organization (WHO) welcomes the latest effort by Drs. Raffaele Vardavas and Sally Blower to model scenarios for the transmission of HIV drug resistance (HIVDR).[1] Vardavas and Blower suggest that transmitted HIVDR in Botswana is unlikely to exceed the WHO's threshold of 5% by 2009 even if the rate of acquired resistance is high, provided resistant strains are half as fit as wild-type strains. The threshold survey method, one element of the WHO-recommended strategy for HIVDR prevention and assessment, was developed to take into account priorities for ART scale-up[2] and scenarios modelling HIVDR transmission, including previous exercises by Blower and colleagues.[3,4] We agree that it is unlikely that transmitted HIVDR will reach levels of >5% quickly in resource-restricted countries where antiretroviral treatment (ART) is being scaled up: for this very reason, we believe that extensive surveillance methods are not initially indicated. WHO recommends countries use the minimum-resource method of 50-70 specimens to assess transmitted resistance in geographic areas (and, where appropriate, in subpopulations) in which ART is widely available, to categorize at the population level transmitted HIVDR overall, and to individual drugs and drug classes, as < 5%, 5-15%, or > 15%. Until surveys indicate that transmitted resistance is >5%, other elements of the WHO-recommended national strategy to assess and minimize HIVDR emergence and transmission will be emphasized.

Vardavas and Blower suggest that that the threshold be lowered to 3%, which would require far larger sample sizes. Few individuals are diagnosed with HIV in developing countries until they are symptomatic (that is, until HIV has progressed usually over several years), so that specimens from recently infected persons are difficult to obtain for surveillance of transmission. Our method was developed partly based on the numbers of eligible specimens obtainable from HIV serosurveys in the geographic areas within developing countries where transmitted HIVDR is likely to be seen first. Use of remnant HIV serosurvey specimens minimizes costs and takes advantage of the representative sampling methods already in place. Given competing priorities during ART scale up, we do not believe that the logistical difficulties and expense of collecting larger numbers of specimens are justified. Although it would be of interest to know when transmitted HIVDR reaches 3%, this level would not trigger any additional public health action -- indeed, the sole recommendation of Vardavas and Blower after a 3% threshold is reached is to repeat the survey using a 5% threshold. Because scarce laboratory and human resources are required for higher-priority elements of ART scale-up, WHO therefore continues to recommend the 5% threshold.

Should the more alarming scenario described by Vardavas and Blower occur, in which transmission could reach 15% in Botswana by 2009 if drug resistant strains as fit as wild-type evolve, the WHO method will detect transmission before that time; and critically additional measures to assess and minimize transmission should have been put in place. It is important to point out that the other elements of the WHO HIVDR strategy should also be implemented before or at the same time as threshold surveys to assess transmitted HIVDR. These include monitoring in each country to assess prescribing practices, barriers to continuity of treatment, continuity of drug supplies, losses to follow up, and adherence, in order to take action at the ART programme level if conditions conducive to the emergence of resistance are seen. Sentinel surveys to monitor the emergence of HIVDR during ART and associated ART programme factors, which include baseline HIVDR assessments in cohorts of 100 patients before initiation of ART at representative treatment sites and an evaluation of viral load and resistance at 12 months or at switch to second-line, will provide additional data on which public health actions can be based.

We believe that the standardized data collection methods will also provide better data for modelling the emergence and transmission of HIVDR than are currently available. More information on all elements of the WHO HIVDR strategy, including threshold survey results from four countries, will be available in an upcoming supplement to the journal Antiviral Therapy.

References

1. Vardavas R, Blower S. The Emergence of HIV Transmitted Resistance in Botswana: When Will the WHO Detection Threshold BeExceeded?. PLoS ONE 2007; 2:e152. doi:10.137/journal.pone.0000152-
2. Gilks CF, Crowley S, Ekpini R et al. The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings. Lancet 2006; 368:505-510.
3. Blower S, Ma L, Farmer P, Koenig S. Predicting the Impact of Antiretrovirals in Resource-Poor Settings: preventing HIV Infections whilst Controlling Drug Resistance. Current Drug Targets - Infectious Disorders 2003; 3:345-353.
4. Blower S, Brodine E, Kahn J, McFarland W. The antiretroviral rollout and drug-resistant HIV in Africa: insights from empirical data and theoretical models. AIDS 2005; 19:1-14.