Changes in prevalence of mutations associated with HIV treatment failure

The results from a longitudinal study of the relative frequency of various types of HIV mutations associated with the use of antiretroviral therapy (ART) were presented today at a meeting of leading AIDS researchers. The study showed that the prevalence of most key mutations associated with antiretroviral resistance have changed significantly from 1999-2002.

Specifically, the results showed that the prevalence of thymidine analog mutations (TAMs) and other key mutations associated with HIV drug resistance has decreased significantly as reported in the LabCorp Database in recent years, while mutations such as K65R and Y115F are on the rise.

“Although further studies are needed to determine the reasons behind these findings, the increased use of three drug regimens, the introduction of new drugs and/or drug combinations and changes in the submission of patient samples for genotyping may all be factors affecting the changing patterns of HIV mutations in this large sample,” said Doug Manion, M.D., vice president of Clinical Development, GSK.

The results come from a longitudinal study of the relative frequency of all primary mutations and many combinations of mutations associated with ART from January 1, 1999, through July 1, 2002. The study involved nearly 38,000 genotypic tests performed between 1999 and mid-2002 to identify mutations associated with HIV resistance to antiretroviral drugs, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

Trends in the use of specific antiretroviral therapies in the United States during the same time period also were presented by the researchers.

Study investigators noted that the databases used are not linked, and the results show independent trends, not a direct correlation between drug usage and mutation incidence. However, the data show that the changes in prescribing patterns of antiretroviral therapy and in the mutations associated with specific drugs or drug combinations follow expected parallel trends. Further studies are warranted to directly show the relationship between mutations, antiretroviral therapy choices and clinical practices.

The following trends were seen in mutations associated with resistance to the three classes of drugs included in the study:

Wild-Type

• Wild-type samples increased from 29 percent to 37 percent.

NRTIs

• The greatest proportional increases were for K65R (from 0.64 percent to 1.69 percent) and for Y115F (0.59 percent to 1.42 percent).
• TAMS decreased steadily, including: T215Y (32 percent to 23 percent); D67N, K70R and 219E/Q (13 percent to 8 percent); and M41L, L210W and T215Y (17 percent to 11 percent).
• L74V also decreased (9.77 percent to 7.85 percent).
• No significant changes were seen in M184V (44 percent to 42 percent), T69SXX (0.81 percent to 0.73 percent) or Q151M (1.79 percent to 1.39 percent).

NNRTIs

• Y181C decreased from 19 percent to 12 percent.
• K103N was stable (29 percent to 30 percent).

Protease Inhibitors

• All PI-associated mutations decreased with the exception of a small increase in I50V.
• The most pronounced decreases were seen for M461/L, V82A, 184V and L90M.

“Resistance to antiretroviral therapy is a major factor that limits the effectiveness of drug therapy. As specific drugs increase or decrease in usage, the prevalence of mutations associated with those drugs should also rise or fall, although many other factors may alter the rate of mutant selection,” said Manion.

Resistance Data May Help Predict Best Options

In a related study, resistance data were used to evaluate the median phenotype for 30 mutational patterns associated with resistance to NRTIs. Although further study is needed to determine utility in clinical practice, study investigators believe the technique may be useful to minimize the potential for the rapid selection of mutations resistant to multiple NRTIs arising from specific drug combinations, and guide the selection of treatment options after virologic failure.

“For example, patterns involving 65R and/or 74V in conjunction with M184V are associated with resistance to multiple NRTIs, and require substantially fewer mutations than TAM patterns associated with resistance to multiple NRTIs. TAMs individually and in many combinations do not increase phenotypic resistance to the NRTIs as much as some individual NRTI-associated mutations,” said Manion.

In the study, a major database was searched for paired genotypes and phenotypes, and 10,478 unique pairs were studied based on clinically determined phenotypic “breakpoints” associated with resistance to the various drugs in the NRTI class.

GlaxoSmithKline is one of the world’s leading research-based pharmaceutical and healthcare companies and an industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV.

AT A GLANCE

The prevalence of most key mutations associated with antiretroviral resistance have changed significantly from 1999-2002.

The largest increase was seen in the K65R and Y115F mutations, while thymidine analog mutations (TAMs) and most mutations associated with protease inhibitors have decreased steadily.

Resistance data from mutational patterns associated with specific drug combinations may be useful in predicting potential treatment failure or choosing future treatment options.

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