|
|  |
|
Therapeutic Decision Making Based on Antiretroviral Drug Resistance Testing: Are We There Yet?
|
written by Brian Conway, M.D.
published on HIVresistanceWeb: April 1, 1999
Last summer, the International AIDS Society (IAS)-USA expanded the scope of its annual reports to include a review of antiretroviral drug resistance testing in adults with HIV infection [1]. In the section on the use of resistance testing when changing therapy, it was pointed out that the cause of the loss of efficacy of a given regimen is often multifactorial. It was also stated that the main trigger for a change in therapy should be an increase in plasma viral load. Furthermore, it was felt that in the absence of obvious clinical factors, such as a lack of adherence to a particular agent, resistance testing may serve as a useful guide for the selection of a new regimen when current therapy fails. Over the past 6 months, data have been generated to show us how this might work in clinical practice.
The VIRADAPT study was conducted in Europe [2], and its results are summarized in Dr. Jonathan Schapiro's article: Improving HIV Therapy with Drug Resistance Genotyping: The VIRADAPT Study. It addressed a very common problem in HIV medicine today, namely, what to do when a patient with extensive drug experience (with both NRTIs and PIs) presents with a plasma viral load above 100,000 copies/mL and the choice of salvage therapy is not clear-cut. Based on the study results, it appears that genotypic resistance test results do influence the selection of drugs used in second-line and salvage therapy, and that these treatment decisions differ significantly from those based solely on current standard of care practices (defined in this study as the treating physician's clinical judgement as guided by the U.S. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents). More importantly, it appears that this difference is beneficial, leading to greater reductions in plasma viral load over a period of 6 months. However, it should be pointed out that, even with the insight provided by resistance test results, less than one third of the study population achieved a reduction in plasma viral load to below 200 copies/mL.
At the recent conference on Retroviruses and Opportunistic Infections in Chicago, the results of the CPCRA's Genotypic Antiretroviral Resistance Testing (GART) study were presented (see Dr. Michelle Roland's article: The Impact of Genotypic Antiretroviral Resistance Testing (GART) in Patients Failing Antiretroviral Therapy) [3]. Similar in design and size to the VIRADAPT protocol, it showed that the results of resistance tests influenced the choice of subsequent antiretroviral therapy and led to more favorable virologic responses (-1.17 log10 copies/mL for GART patients vs. -0.62 log10 copies/mL for non-GART patients over 4-8 weeks). This was largely due to the increased usage of agents expected to be active against the particular viral isolates of individual patients in the GART group. Once again, however, maximal virologic benefit—i.e., undetectable plasma HIV RNA levels (<500 copies/mL, bDNA)—occurred in only one half of GART patients at 8 weeks, and only one third of GART patients (in limited follow-up) at 12 weeks.
Taken together, the results of the VIRADAPT and GART studies are quite encouraging. They support the widely held belief that "resistance matters". As in the management of bacterial and fungal infections, it would appear that the ability to identify individual susceptibility patterns may help us make smarter therapeutic decisions for our patients. But, as in other infectious diseases, we must not consider resistance testing as a remedy or safety net for treatment failures. The selection and successful upkeep of the initial antiretroviral regimen is crucial. The consequences of treatment failure are too high. Even with the insight provided by resistance test results, salvage therapy is maximally effective only half the time, at best. In an ideal situation, we should be doing our best to avoid the need for resistance testing, rather than relying on it to help us solve a problem that may well have been avoided.
In addition to the obvious issue of reimbursement by third party payers for the cost of resistance testing, other considerations must accompany its introduction into clinical practice. First, compliance must always be properly addressed, as poor adherence to therapy will doom even the best agent or regimen. We must develop a systematic approach to the assessment and measurement of compliance, as well as strategies to enhance it on an ongoing basis. Second, drug levels may well become more relevant as we use multiple agents simultaneously (as many as 9 drugs!!!), many of which are metabolized by the same hepatic enzyme system. Unpredictable interactions may occur, reducing the blood levels of one or more agents to subtherapeutic levels. At the very least, we should consider the monitoring of pre-drug (trough) levels in the case of regimens containing three or more drugs cleared by the cytochrome P450 system, especially in the case of drugs for which population-based pharmacokinetic data are not yet available.
It is quite heartening to see the incremental progress in knowledge that is improving the field of antiretroviral therapy from one year to the next. The "proof of concept" embodied in the results of the VIRADAPT and GART studies represent just such a step. Of course resistance testing is not the final answer to all our woes, but, when used in context, it may play an essential role in making HIV infection a chronic, manageable condition.
Related HIVresistanceWeb Articles:
Improving HIV Therapy with Drug Resistance Genotyping: The VIRADAPT Study.
(Jonathan Schapiro, February/March 1999)
The Impact of Genotypic Antiretroviral Resistance Testing (GART) in Patients Failing Antiretroviral Therapy.
(Michelle Roland, March/April 1999)
References
|
- Antiretroviral Drug Resistance Testing in Adults With HIV Infection: Implications for Clinical Management.
Hirsch MS, Conway B, Richman D, Brun-Vézinet F, Clotet B, D'Aquila R , et al. J Amer Med Assoc. 1998;279:1984-1991.
- Improving HIV therapy with drug resistance genotyping - The VIRADAPT Study.
J. Durant, P. Clevenbergh, P. Halfon, P. Delguidice, S. Porsin, P. Simonet, N. Montagne, E. Dohin, P. Dellamonica. 4th International Congress on Drug Therapy in HIV Infection. 8-12 November 1998, Glasgow, Scotland.
- A pilot study of the short-term effects of antiretroviral management based on plasma genotypic antiretroviral resistance testing (GART) in patients failing antiretroviral therapy.
Baxter JD, Mayers DL, Wentworth DN, Neaton JD, Merigan TC and the and the CPCRA 046 Study Team. 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract LB8.
|
|
(click titles to read abstracts)
|
|
back to the top of this page
|
|
|
