Resistance Testing: What's New
When it comes to HIV resistance testing, there are still many unanswered questions. Should resistance testing be performed before initiating antiretroviral therapy? How useful is resistance testing when determining a salvage regimen? Are there new methods of resistance testing in development? Data presented at the recent 7th Conference on Retroviruses and Opportunistic Infections (CROI) addressed these issues, but there is more work to be done before conclusions can be drawn.
Let's review. What is drug resistance, and how is it measured with resistance testing? Antiretroviral drugs work by inhibiting HIV's ability to replicate and infect new cells. Drug resistance results from small changes, called mutations, in HIV's genetic material. These mutations occur frequently in HIV replication, as the virus reproduces at an exceptionally fast rate (1 to 10 billion new copies per day) too quickly to copy its genetic material very accurately. Multiple mutations lead to changes in the genes that code for enzymes, the proteins that regulate HIV production, including the reverse transcriptase enzyme and the protease enzyme. Antiretroviral medications work by blocking the action of these enzymes, but multiple mutations result in strains of HIV which are not affected by the presence of antiretroviral drugs, allowing HIV to replicate, usually resulting in an increase in viral load.
Two resistance tests are currently available, both with advantages and disadvantages. Genotypic testing identifies specific mutations in the genetic structure of HIV. Since specific mutations are usually associated with one or more antiviral drugs, the test can help determine which antiviral drugs may not be effective. Advantages of genotypic testing are that it is readily available, relatively rapid, and easy to perform. A disadvantage of genotypic testing is that it is expensive (about $300-500 per test), and is not currently covered by Medicaid or ADAP programs in New York State. In addition, genotypic testing does not identify mutations in minority species of the virus, species that can multiply rapidly and become dominant. Finally, the test can only be performed on individuals with a viral load greater than 1,000 copies/mL.
Phenotypic testing measures the concentration of a drug required to inhibit HIV replication in a test tube by an amount such as 50% or 95%. The defined amount is called IC (inhibitory concentration) 50 or IC95. Interestingly, this is the method used by researchers to determine whether a drug might be effective against HIV before starting a human clinical trial. Unlike genotypic tests, phenotypic resistance testing generally does not require a high viral load. Disadvantages of phenotypic testing are that it is extremely labor intensive and can take several weeks to perform. Phenotypic testing is very expensive, generally $800 and up per test (again, not covered by NYS Medicaid or ADAP).
So what's the latest news on resistance testing and its benefits in clinical care? Prior to CROI, at the 3rd International Workshop on HIV Drug Resistance and Treatment Strategies held in June 1999, Clevenbergh and colleagues presented 12-month follow-up data from the Viradapt study, in which over 100 patients who were failing a protease inhibitor combination regimen started a salvage treatment regimen. The new regimen was assigned based on either treatment history or on resistance mutations as determined by genotypic testing. After six months of treatment, about 32% of patients in the genotypic group had a viral load less than 200 copies, as compared to 14% of the patients in the treatment history group. The members of the treatment history group were offered genotypic testing, and almost 70% elected to have the testing performed. After 12 months, about 26% of these patients had a viral load less than 200 copies. Of the group who started the study with genotypic-guided therapy, about 28% still had a viral load less than 200.
On the whole, news from CROI supported the Viradapt data. A study by Melnick and colleagues examined the usefulness of phenotypic testing in determining effective salvage regimens for individuals failing a protease inhibitor combination regimen. In this short (16-week) study, 115 subjects were assigned to a salvage regimen based on phenotypic test results or treatment history. The subjects were heavily treatment experienced, but all were naive to NNRTIs (Sustiva®, Viramune®, and Rescriptor®). The results showed that individuals in the phenotypic test group had a greater viral load decrease after four weeks of treatment, but did not sustain a decrease after 16 weeks of treatment. At the time of the study (1997-98), there were fewer drugs available on the market, limiting treatment options.
A study of phenotypic testing by Cohen and colleagues performed in a similar patient population showed more favorable results.
We've examined some of the data from individuals failing treatment regimens, but what about individuals who have never taken antiretroviral treatment? In an interesting study out of Montreal, Canada, Routy and colleagues studied resistance mutations in patients with early HIV infection. Both genotypic and phenotypic testing were performed on samples from 87 recently infected patients. Mutations in both the non-nucleoside reverse transcriptase and protease gene were found in 5% of patients, mutations in the nucleoside reverse transcriptase and protease were found in 7% of patients, and mutations in all three were found in 2% of patients. Two patients in the study were determined to be resistant to all available drugs except ddI and d4T because of their multiple mutations. These findings may indicate that resistance testing is necessary to determine the most effective initial treatment regimen.
While we still don't have clear answers to all of the questions about resistance testing, researchers are gaining information that may ultimately move resistance testing from the realm of clinical trials to a component of standard care for HIV. The potential utility of resistance testing in HIV management must be balanced against its expense, and only further study can lead us to definitive answers.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.