Tenofovir: resistance profile of non-responders becomes clearer

Keith Alcorn
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This article is more than 23 years old.

The new antiretroviral drug tenofovir (Viread) launched last month in Europe, is currently licensed for all patients who have experienced failure of at least one treatment regimen. Determining which patients will benefit from tenofovir has been somewhat hindered by a lack of information about precisely which reverse transcriptase mutations are associated with a poor response.

At last week’s Ninth Annual Retroviruses Conference, Gilead scientists presented further analysis from study 907, a 48 weeks study in which tenofovir was added to a failing treatment regimen, and study 902, a dose ranging study of tenofovir.

Patients in the 907 study had an average of 5.4 years of prior antiretroviral treatment, and of the 274 patients assigned to the genotypic resistance sub-study, 24% in the placebo group and 16% in the tenofovir group had nucleoside analogue-associated mutations at baseline.

Glossary

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

sensitivity

When using a diagnostic test, the probability that a person who does have a medical condition will receive the correct test result (i.e. positive). 

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

dose-ranging trial

A clinical trial where two or more doses of a drug are compared to see which works best and is least harmful, usually done at an early stage of drug development.

As has been reported previously, a high degree of nucleoside analogue mutations blunted response to tenofovir in this study, but it was not clear which mutations were most strongly associated with reduced sensitivity to tenofovir.

This study found that mutations at codons 67, 70, 215 or 219 did not compromise response to tenofovir. Only those at codons 41L or L210W were associated with a reduced response.

The M41L mutation is relatively uncommon in people with extensive nucleoside analogue experience because it is a mutation that tends to arise early after the failure of AZT, and it fades once the T215Y mutation is selected. T215Y is not associated with tenofovir resistance.

Phenotypic susceptibility data were also presented to help in the definition of likely non-responders , since genotypic tests may not always pick up every mutation. A reduction in susceptibility of 3.8-fold or more was associated with non-response in this study.

References

Margot NA et al. Final 48-Week genotypic and phenotypic analyses of study 907: Tenofovir DF (TDF) added to stable background regimens. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 414, 2002.

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