Experts discuss findings on drug resistance
Experts discuss findings on drug resistance
Resistance testing linked with better outcomes
[Editor’s note: AIDS Alert asked John Mellors, MD, professor of medicine and chief of infectious diseases at the University of Pittsburgh, and Sharon Kemp, director of HIV Research for Virco UK in Cambridge, United Kingdom, to discuss a study presented in June at the 5th International Workshop on HIV Resistance and Treatment Strategies in Scottsdale, AZ. The study found that a change at position 318 in the genetic code of HIV can make the virus highly resistant to treatment with non-nucleoside reverse transcriptase inhibitors (NNRTIs).1 Mellors also is on the organizing committee of the annual International Workshop on HIV Drug Resistance. Mellors’ and Kemp’s discussion of the study is presented here in a question-and-answer format.]
AIDS Alert: Please explain the significance of the recent findings that a change in position 318 in the genetic code of HIV can make the virus highly resistant to treatment with NNRTIs. For example, how prevalent might this mutation be?
Kemp: Although this mutation is relatively uncommon, our analyses suggest that it is more than seven times more common than the "signature" delavirdine mutation 236L. Furthermore, it occurs at a similar frequency as some of the other well-established mutations known to cause NNRTI resistance. This mutation can render HIV-1 highly resistant to delavirdine on its own and can combine with other mutations to make the virus highly resistant to efavirenz. Its effect on nevirapine resistance is not clear, although it does not appear to confer nevirapine resistance by itself.
AIDS Alert: How is the Tibotec-Virco drug resistance test able to detect this mutation when other resistance tests do not?
Kemp: The Virco resistance tests are designed to capture and analyze a longer and more complete portion of the HIV genetic code than other tests, covering the whole of the protease gene and reverse transcriptase out to position [codon] 400. Most other assays stop between positions 200 and 300, and some miss out certain sections. The reason they stop here is that technically this is easier, and other providers do not necessarily appreciate the significance of capturing sequence information beyond codon 300.
AIDS Alert: As increasing numbers of studies are being published about HIV mutations and drug resistance, what do we now know about the disease that we didn’t know several years ago?
Mellors: In general terms, we know that HIV drug resistance is increasingly common and is being transmitted in more and more cases. Recent studies suggest 15% to 20% of new infections in the United States and Europe may involve transmission of resistance virus. Even if the viral load is very low or even below the limit of detection, viral replication may continue at a low rate and resistance can develop.
The genetic basis of resistance is extremely complex. There are approximately 250 different mutations involved. These combine in complex ways. For example, neural network analyses suggest that 28 mutations may be involved in lopinavir resistance and at least 26 to d4T. A mutation at 184 causes resistance to 3TC but counteracts the effect of AZT mutations. A mutation at codon 333, which also can only be detected if RT is sequenced to this codon, counteracts the effect of the 184V mutation and can enable the development of resistance to both 3TC and AZT.
Because of these facts, genotypic resistance testing requires sophisticated analysis, and the rules-based interpretation methods can differ significantly in their analysis of the same genetic sequences.
Data have accumulated demonstrating the clinical utility of resistance testing in managing antiretroviral therapy in HIV-infected patients. Treatment decisions made using the results of resistance testing yield virologic responses superior to those obtained when decisions are made without the benefit of resistance testing.
AIDS Alert: At which points in HIV treatment should a clinician recommend resistance testing, and how can this additional cost be justified?
Mellors: This is a matter for the clinician and patient to decide. It is generally accepted that resistance testing should be considered whenever treatment is started or changed. (Editor’s note: See table summarizing the recent joint recommendations of the International AIDS Society panel of HIV drug resistance testing and the EuroGuidelines Group, below.)
Recommendations for Resistance Testing from the IAS and EuroGuidelines | ||
Clinical Characteristics | IAS Recommendations | EuroGuidelines Recommendations |
Treatment-Naive
Patients Primary Infection |
Consider testing | Recommend testing |
|
||
Established HIV Infection | Consider testing | Consider testing |
|
||
Treatment Failure | Recommend testing | Recommend testing |
|
||
Pregnancy | Recommend testing | Recommend testing |
|
||
Postexposure Prophylaxis | Clinical characteristic not included in recommendations | Recommend testing |
|
||
Pediatrics | Clinical characteristic not included in recommendations | Recommend testing in children born to mothers with detectable viremia while on treatment |
Source: International AIDS Society, San Francisco; the EuroGuidelines Group. |
AIDS Alert: How can investigators continue to improve and update resistance tests to keep up with the virus’s evolution?
Mellors: Firstly by studying the resistance profiles of new drugs as an early part of the drug development process; secondly by applying sophisticated techniques such as neural networks, an AI technique, and recursive partitioning to unravel the genetic causation of drug resistance, thereby adding to our understanding of the relationships between complex genotypes and phenotype. Such understanding will help to improve a critical part of a genotypic resistance test, i.e., its interpretation.
AIDS Alert: What is being done to convince state AIDS Drug Assistance Programs [ADAPs] and other payers to add drug resistance testing to their formularies, and how commonly is this test being reimbursed by state ADAPs, Medicaid, and other payers?
Kemp: Virco Lab, our U.S. subsidiary, is actively working to achieve an adequate level of reimbursement and utilization guidelines for resistance testing by state Medicaid programs and state and local Ryan White programs.
This effort is under the direction of the Virco Professional Affairs Group, which brings together the assistance of national and local medical HIV opinion leaders and advocacy groups. The effort concentrates on providing the latest developments in resistance testing technology, clinical application, and medical economic outcome information.
Over the past 18 months or so, American Medical Association CPT codes have been issued for genotype, phenotype, and virtual phenotype. Reimbursement and the necessary procedures for reimbursement have been established and are in place or are in the process of approval in the majority of states for genotype, phenotype, and virtual phenotype. This progress is due, at least in part, to the efforts of the Virco Lab Professional Affairs Group.
Reference
1. Kemp SD, Salim M, Stammers DK, et al. A mutation in HIV-1 RT at codon 318 (Y--F) confers high level NNRTI resistance in clinical samples. Abstract presented at the 5th International Workshop on HIV Resistance and Treatment Strategies. Scottsdale, AZ; June 6, 2001.
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