Journal of Antimicrobial Chemotherapy published April, 2010
Modelling response to HIV therapy without a genotype: an argument for viral load monitoring in resource-limited settings
Revell AD1*, Wang D1, Harrigan R2, Hamers RL3, Wensing AMJ4 DeWolf F5, Nelson M6, Geretti A-M7, Larder BA1
1 The HIV Resistance Response Database Initiative (RDI), London, UK
2 The BC Centre for Excellence in HIV/AIDS, Vancouver, Canada
3 PharmAccess Foundation, Academic Medical Center, The Netherlands
4 University Medical Center, Utrecht, The Netherlands
5 Netherlands HIV Monitoring Foundation, Amsterdam, The Netherlands
6 Chelsea and Westminster Hospital, London, UK
7 Royal Free Hospital, London, UK
In the absence of widespread access to individualized laboratory monitoring, which forms an integral part of HIV patient management in resource-rich settings, the roll-out of highly active antiretroviral therapy (HAART) in resource-limited settings has adopted a public health approach based on standard HAART protocols and clinical/ immunological definitions of therapy failure. The cost-effectiveness of HIV-1 viral load monitoring at the individual level in such settings has been debated, and questions remain over the long-term and populationlevel impact of managing HAART without it. Computational models that accurately predict virological response to HAART using baseline data including CD4 count, viral load and genotypic resistance profile, as developed by the Resistance Database Initiative, have significant potential as an aid to treatment selection and optimization. Recently developed models have shown good predictive performance without the need for genotypic data, with viral load emerging as by far the most important variable. This finding provides further, indirect support for the use of viral load monitoring for the long-term optimization of HAART in resource-limited settings.
The first decade of the new millennium has seen the roll-out of highly active antiretroviral therapy (HAART) to communities in resource-limited settings hardest hit by the HIV-1 epidemic. The WHO reports that >4 million people in low and middle income countries were receiving HAART by the end of 2008, an increase of more than a million over 2007.1 While this falls far short of the 10 million that could benefit, a 10-fold increase in access over 5 years is a major achievement. This dramatic expansion of treatment in resource-limited settings brings with it enormous challenges for the future, not least of which is the need to monitor patients and modify their treatment regimens as required to sustain viral suppression and prevent clinical deterioration.
Experience in the developed world has demonstrated that HAART does not eradicate HIV and, over time, mutant variants that are drug resistant to one or more components are often selected. A timely change to the regimen is then required in order to reassert viral suppression. This principle lies at the heart of a clinical management template that includes regular viral load monitoring to detect increased viral replication as early as possible, followed by a resistance test to identify specific viral resistance mutations, interpretation to indicate which drugs may be affected and a change of regimen to drugs to which the mutant virus is presumed susceptible.2,3 Treatment changes are routinely achieved within a few weeks of the detection of resistant virus, minimizing the risk of progression, accumulation of resistance mutations and the risk of onward transmission of resistant virus.
This approach has been suitable in settings that have access to regular viral load evaluations, genotyping and the choice of ~25 drugs, but it is a very different picture in resource-limited settings. Here, cost and logistical constraints mean that viral loads and genotypes are usually unavailable, treatment changes are triggered clinically or immunologically, and typically there are only ~10 drugs available, organized into strict public health protocols with no scope or basis for individualization. This pared-down clinical strategy, with late switching of failing regimens, increases the risk of significant complex patterns of resistance at the individual and population levels.4,5 This compromises the potential for subsequent antiretroviral treatment success and ultimately increases the chances of disease progression.
There is, therefore, a major debate in progress regarding the relative importance of laboratory monitoring in resource-limited settings. The recent Development of Antiretroviral Therapy in Africa (DART) study, whilst finding a significant survival advantage among patients with CD4 and other laboratory monitoring compared with those monitored clinically, concluded that the added benefit was not cost-effective in the short term.6,7 The study did not include viral load monitoring, which is not included in the WHO guidelines for antiretroviral treatment, and there is a lack of robust evidence of its cost-effectiveness in such settings.8 However, the studies of laboratory monitoring that do exist examine the short- to medium-term outcomes for the individual but not, for example, the potential long-term impact of late and inadequately guided treatment changes on resistance, subsequent treatment outcomes and the spread of resistance among the wider population. On current evidence, the jury is out on the potential cost-effectiveness of viral load monitoring in resource-limited settings.
The HIV Resistance Response Database Initiative (RDI) is a notfor- profit research organization established in 2002 to collect data from clinical practice to train computational models to predict virological response to HAART. The aim is to make these models freely available over the Internet as an experimental tool to help optimize HAART. Over several years, data from 57000 patients have been collected, and considerable progress has been made in terms of developing and refining modelling methodologies. Artificial neural networks and random forest (RF) models have been developed that make predictions of virological response following a change to the antiretroviral regimen that correlate well with the actual viral load changes observed.9 Studies also showed that the models were most accurate in their predictions for patients from ‘familiar’ settings, i.e. those settings from where the data used to train the models were obtained.10
Recent models have been developed that predict the probability of the viral load going below 50 copies/mL with an accuracy of ~80%.11 The models use ~80 variables, including the viral load, CD4 count, treatment history and genotype, from immediately before the treatment change to make their predictions. The premise on which this work was based was to improve the ability to predict response to therapy over the use of a genotype with current interpretation methods. The models have consistently proved more accurate predictors of response than genotypic sensitivity scores from common rules-based interpretation systems.11-13
With the roll-out of HAART in resource-limited countries, it is especially critical that the best use is made of the limited treatment options available. However, doing so without the use of genotyping presents a major challenge. This raised the question of whether computational modelling could play a role.
As an initial attempt to address this question, we took data from >3000 treatment change episodes (TCEs) from clinics in North America, Europe, Japan and Australia that had recently been used to train a single RF model. This model predicted virological response among 100 independent test cases with an accuracy of 82%, using 82 baseline variables (including genotype). We removed the genotype data (53 of the 82 variables) from this dataset and repeated the study. The new model was able to predict virological responses for the same test set with an accuracy that, at 78%, was only slightly diminished.13 While genotyping plays an important role in optimizing therapy, it appears that use of other data, including treatment history information, in the modelling can partially compensate for its absence.
Encouraged by this, we set out to develop models that were more relevant to clinical practice in a resource-limited context As we did not have sufficient data from such settings, we selected TCEs that involved drugs in common use in these countries. Two RF models were trained using >8000 TCEs without the use of genotypes, one with comprehensive and one with simplified treatment history information. Both models predicted virological response for 400 independent test cases with an accuracy of ~82%. The models were able to identify alternative regimens (involving the same restricted range of drugs) that they predicted would have reduced viral load to below 50 copies/mL in almost half of the cases of actual treatment failure.11 They identified regimens that were predicted to be more effective than those that failed in almost all cases.11 A secondary analysis of the input variables used for these models revealed that the baseline viral load was by far the most important variable (considerably more so than CD4 counts, for example) for the models in making these predictions.
These studies suggest that with viral load monitoring in place, computational models could play an important future role in optimizing antiretroviral therapy in resource-limited settings. Even in the absence of resistance testing, this approach could potentially maximize virological suppression, minimize failure, preserve treatment options and reduce the spread of resistance at the population level.
Viral load monitoring has long been established and empirically supported as key to the effective management of HIV in richer countries. Our findings indicate that it is also likely to be the single most important laboratory monitoring tool for effective long-term treatment strategies in less wealthy settings and, after initial screening, where resources are limited, viral load monitoring could be considered a priority over CD4 determination.
Encouraged by our results, the RDI aims to develop free webbased systems using computational models to support treatment optimization in resource-limited settings.
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This research was supported by the National Institute of Allergy and Infectious Diseases.
1 WHO, UNAIDS, UNICEF. Towards Universal Access: Scaling Up Priority HIV/AIDS Interventions in the Health Sector: Progress Report 2009. Geneva: WHO, 2008.
2 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (2 December 2009, date last accessed).
3 Gazzard BG on behalf of the BHIVA Treatment Guidelines Writing Group. British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med 2008; 9: 563–608.
4 Gupta R, Hill A, Sawyer A et al. Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis. Lancet Infect Dis 2009; 9: 409–17.
5 Hosseinipour MC, van Oosterhout J, Weigel R et al. The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy. AIDS 2009; 23: 1127–34.
6 Mugyenyi P, Walker S, Hakin J et al. on behalf of the DART Trial team. Impact of routine laboratory monitoring over 5 years after ART initiation, the DART Trial final results. In: Abstracts of the Fifth IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, 2009. Abstract TuSS103, p. 101. International AIDS Society, Geneva, Switzerland.
7 Medina-Lara A, Kigozi J, Amurwon J et al. Cost effectiveness analysis of routine laboratory or clinically driven strategies for monitoring anti-retroviral therapy in Uganda and Zimbabwe (DART Trial). In: Abstracts of the Fifth IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, 2009. Abstract TuSS104, p. 101. International AIDS Society, Geneva, Switzerland.
8 WHO. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach, 2006 Revision. Geneva: WHO, 2006. http://www.who.int/hiv/pub/guidelines/artadultguidelines. pdf (2 December 2009, date last accessed).
9 Wang D, Larder B, Revell A et al. A comparison of three computational modelling methods for the prediction of virological response to combination HIV therapy. Artif Intell Med 2009; 47: 63–74.
10 Larder B, Wang D, Revell A et al. The development of artificial neural networks to predict virological response to combination HIV therapy. Antivir Ther 2007, 12: 15–24.
11 Revell AD, Wang D, Harrigan R et al. Computational models developed without a genotype for resource-poor countries predict response to HIV treatment with 82% accuracy. Antivir Ther 2009; 14 Suppl 1: A38.
12 Larder BA, Gerretti AM, Monno L et al. Neural networks are more accurate predictors of virologic response to antiretroviral therapy than rules-based genotype interpretation systems. In: Abstracts of the Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, CO, 2006. Abstract 653, p. 282. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.
13 Larder B,Wang D, Revell A et al. Computational models can accurately predict response to antiretroviral therapy without a genotype. In: Abstracts of the Forty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 2009. Abstract H-894. American Society
for Microbiology, Washington, DC, USA.