February 27, 2002
This plenary talk by Dr. Collier was a review of the clinical aspects of HIV drug resistance. Dr. Collier began by reviewing a recent prevalence study that had been presented by Dr. Doug Richman at ICAAC in Chicago last December.
In Richman's study of over 1000 patients in care between 1996 and 1998, all of whom had a phenotypic resistance test performed, over 70 percent had evidence of resistance to at least one HIV drug. Factors that correlated with the presence of drug resistance included: currently on antiretroviral therapy, advanced HIV status, CD4 nadir (lowest CD4 achieved), access to care, and care in smaller medical practices. Dr. Collier then reviewed the many factors that contribute to clinical HIV drug resistance. These factors include: sub-inhibitory drug concentrations that may be related to underlying host genetics, drug-drug interactions, potency of interactions and dosing schedules. All of these factors may lead to persistent viral replication in the presence of drugs, ultimately leading to drug resistance.
Viral factors that may contribute to the development of resistance include: different strains within a patient that have different susceptibilities to an HIV medication or strains that may replicate at differing rates. Successful therapy, as measured by a durable virologic response, has now been found to be directly correlated with the level of adherence to HIV medications. Variation in the complexity of regimens can lead to differing levels of adherence and development of resistance.
Dr. Collier briefly reviewed the types of resistance tests, including genotypic, phenotypic and virtual phenotypic testing. Each of these tests have different advantages and disadvantages, but, their use, in general, have been found to result in a modest reduction in viral load that is greater when compared to a standard of care not using resistance testing.
One of the major roles of resistance testing may then be to exclude certain drug choices when designing a new regimen. Dr. Collier further described predictors of treatment failure. Variables that have now been found to correlate with treatment failure of a new regimen include: a high baseline viral load, no new class of drugs, low adherence, and lower drug exposure.
Dr. Collier then described strategies that might be used to counter drug resistance in people who have limited (i.e., one- or two-drug) or multi-drug resistance. These strategies might include either modifying or switching medications, pharmacokinetic enhancement (i.e., using low dose ritonavir to boost other protease inhibitor drug levels), intensification (adding more drugs), or, in the case of multi-drug resistance -- treatment interruptions.
The use of mega-HAART (greater than five drugs) in highly drug resistant patients assumes that not all HIV virus is resistant and has resulted in 30-40 percent of patients achieving a viral load of less than 400 at 6-12 months. Predictors of successful mega-HAART regimens include those patients with lower viral loads, higher CD4 counts, and who are NNRTI naive. Due to frequent toxicities, complexity of regimens and costs, this may not be a viable strategy.
Dr. Collier touched briefly on the topic of therapeutic drug monitoring (TDM). Two studies have yielded conflicting results as to the clinical utility of this strategy. Several investigators have introduced the concept of an inhibitory quotient (IQ) that takes into account the plasma concentration of an HIV drug and the inhibitory concentration required to inhibit the patient's strain of virus. It remains to be seen whether an IQ will be a useful tool in clinical practice. Dr. Collier finished her presentation by describing several new agents in the NNRTI and PI classes of HIV medications that appear to have good activity against virus resistant to currently available HIV medications. These drugs, currently in clinical trials, show good promise to be highly active in patients who have failed currently available regimens.
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