FTC therapy reduces risk of important resistance mutation

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The important M184V resistance mutation is less likely to emerge if a patient is receiving an HIV treatment combination that includes FTC and tenofovir rather than a combination that contains 3TC, an international team of investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

The study also showed that treatment with a boosted protease inhibitor was protective against the emergence of the M184V mutation and that the combination of FTC and tenofovir had a high genetic barrier to resistance.

The investigators believe that the study’s “overall findings highlight the importance to identify those drug combinations that can minimize drug resistance to HAART [highly active antiretroviral therapy]. Understanding the point is crucial to maximize the opportunity for successful and subsequent therapies after viral rebound not only in western countries but also in resource-limited settings.”

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

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). 

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. 

prognosis

The prospect of survival and/or recovery from a disease as anticipated from the usual course of that disease or indicated by the characteristics of the patient.

Thanks to antiretroviral therapy, many patients with HIV now have a near normal prognosis. However, the emergence of drug resistance can mean that the potential benefits of treatment are reduced. Understanding the factors that can reduce the risk of resistance is therefore important.

Recent research suggests that the risk of resistance is reduced if a patient is taking a ritonavir-boosted protease inhibitor. In addition, treatment with FTC (emtricitabine, Emtriva, also in the combination pills Truvada and Atripla) appears to be less likely to result in resistance than therapy with 3TC (lamivudine, Epivir, also in the combination pills Combivir and Trizivir).

An international team of investigators wished to gain a better understanding of the risk of the M184V resistance mutation in patients taking failing antiretroviral therapy containing FTC and tenofovir compared to combinations containing 3TC and tenofovir, or 3TC with another nucleoside reverse transcriptase inhibitor (NRTI).

A total of 352 patients were included in the study. Of these, 42 were taking FTC and tenofovir, 40  were treated with 3TC plus tenofovir, and 270 with 3TC and another NRTI. None had received these drugs as part of an earlier HIV treatment combination. All the patients had experienced virologic failure (two consecutive viral load measurements above 50 copies/ml) and their characteristics were broadly comparable.

There was a significantly lower prevalence of the M184V mutation in patients taking FTC and tenofovir than in those taking either 3TC and tenofovir or 3TC and another drug (14% vs. 40% vs. 56%, p = 0.01 and p < 0.001).

Subsequent statistical analysis showed that treatment with FTC reduced the risk the M184V mutation by 68% (OR = 0.32; 95% CI, 0.10-0.99, p = 0.04).

Compared to therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI), treatment with a ritonavir-boosted protease inhibitor was also associated with a lower risk of the M184V mutation (OR = 0.019; 95% CI, 0.10-0.37, p < 0.01). Treatment with tenofovir also reduced this risk (p = 0.05).

Separate test tube analysis showed that HIV infected cell cultures were significantly more likely to be free of the virus when exposed to FTC and tenofovir than after exposure to 3TC and tenofovir (p < 0.0005).

In addition, laboratory analysis suggested that FTC and tenofovir had a higher genetic barrier to resistance.

“This study shows that the use of FTC significantly correlates with a decreased probability of M184V emergence at HAART failure compared with the use of 3TC”, comment the investigators. They add, “the lower prevalence of M184V can be explained by the higher potency of FTC than 3TC”.

References

Svicher V et al. Different evolution of genotypic resistance profiles to emtricitabine versus lamivudine in tenofovir-containing regimens. J Acquir Immune Defic Syndr, advance online publication, August 24, 2010. (Link to abstract and full text article).