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The 7th Conference on Retroviruses and Opportunistic Infections
Session 36
Antiviral Therapy: Resistance and Reservoirs

Coverage provided by Brian Coppedge

January 31, 2000


It has been reported at past conferences by several different presenters, that as many as 50% of the people who start antiretroviral therapy experience resistance to their initial therapy. The questions that still looms in the mind of many people living with HIV and their providers, is how best to develop a treatment strategy once resistance is detected.

Several different questions are raised when considering how to choose new therapies after resistance. Is there a way to determine the drugs from which someone is likely to benefit before they start new drugs? Some people believe that we may already have tests available that could supply this information. The tests, referred to as "resistance tests," are of two distinct types -- genotypic or phenotypic. Genotype tests look at an individual's virus to determine "mutations" and to record where on the virus's genetic code these mutations occur. If mutations occur in the same place as mutations that are associated with resistance to a particular drug, then the virus is determined to be "resistant" to that specific drug. Phenotypic tests use an individual's virus to grow a new virus in test tubes and then record how much of a particular drug is required to suppress the virus's ability to reproduce. Based on this information, the test reports to which drugs an individual's virus is most likely not to respond. There is currently disagreement among providers about how useful these tests are when developing "salvage" therapies.

Slide 233: Measuring the Replicative Fitness of Recombinant HIV-1 Vectors Expressing Protease and Reverse Transcriptase Derived from Patient Viruses

To paraphrase Thomas Jefferson "all viruses are not created equal," or least they don't all end up being equal. There has been some discussion at past conferences about the possibility that once a virus mutates to avoid the effects of anti-HIV drugs that the new virus might not be as "fit" to reproduce as the original "wild type" virus. In this paper, a diagnostic company from South San Francisco, ViroLogic, presented data on a new assay they are developing the test the "fitness" of resistant virus. While the information presented was provocative it needs further study to determine how effective it will be in assisting providers in the management of anti-HIV therapies.

Slide 234: Reduced Susceptibility to NRTI Is Associated with NNRTI Hypersensitivity in Virus from HIV-1-Infected Patients

The presentation continues with the theme that not all things about resistant viruses are bad. Again researchers from ViroLogic were responsible for reporting data on how some resistant viruses may respond to new therapies. In this study, they discussed the results of phenotypic tests conducted on people who were part of a study looking at the impact of structured therapy interruption (taking people off successful therapy until a viral load increase is detected and then starting therapy again) and people who were part of a database from previous studies.

The presenter observed that many of the people on the study who were resistant to one or more of the nucleoside analog reverse transcriptase inhibitors (NRTI) were "hypersensitive" to drugs from the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of drugs. Based on this observation, the researchers looked at a database of people who had similar NRTI resistance to see if they were also hypersensitive to the NNRTIs.

They determined that when you compared people with resistance to the NRTIs to those without this resistance, the people with resistance exhibited hypersensitivity to NNRTIs, while those without resistance did not. While the presenter was quick to point out that the study could not determine the clinical significance of this information, it does seem to suggest that some people may respond better to a salvage regimen that includes a NNRTI if they have a virus that is resistant to NRTIs.

Slide 237: Phenotypic Resistance Testing Significantly Improves Response to Therapy (Tx): A Randomized Trial (VIRA 3001)

So you want to have a phenotypic resistance test run, but your provider says, "Well, there really isn't any good information showing that those tests will supply us with any useful information," maybe this study will help you with your argument.

Dr. Calvin Cohen presented a preliminary analysis of a study that asked providers to choose a therapy for people who had developed resistance to their first therapy, which included a protease inhibitor. The study participants where separated into similar groups -- with the first group's providers given the results of a phenotypic resistance test and the second group not having a phenotypic test performed.

The providers using the phenotypic test placed people on at least three active drugs 77% of the time. The providers who did not have phenotypic test, placed people on at least three active drugs 68% of the time. There was also a difference in how large of a median decline in viral load participants in each arm of this study experienced. The people who were not given a phenotypic test had a median viral load drop of .75 log. The people who received a phenotypic test had a median drop of 1.27 log.

It is important to note that this study did not provide the study doctors with "expert interpretation" of the phenotypic test, they simply provided them with the results and allowed them to reach their own conclusions. While this study does not guarantee people will have better results with "salvage therapy" if they use phenotypic testing, it does suggest that providers might benefit from the additional information provided by this type of resistance test.


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