Big falls in prevalence of protease inhibitor and triple-class resistance

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The prevalence of HIV resistance to protease inhibitors fell sharply between 2003 and 2010, according to a study presented to the 51st ICAAC meeting in Chicago.

Investigators from Monogram Biosciences analysed the profile of almost 70,000 stored blood samples with resistance to at least one antiretroviral drug. Over the seven years of the study, the percentage of samples with resistance to a protease inhibitor fell by half.

A marked fall was also observed in the proportion of samples with resistance to drugs in the three main antiretroviral classes.

Glossary

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. 

integrase

HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase (see ‘integrase’). Blocking integrase prevents HIV from replicating.

trend

In everyday language, a general movement upwards or downwards (e.g. every year there are more HIV infections). When discussing statistics, a trend often describes an apparent difference between results that is not statistically significant. 

HIV can develop resistance to the drugs used in antiretroviral therapy.

Early generations of anti-HIV drugs had a low genetic barrier to resistance, and demanded extremely high levels of patient adherence. This was especially the case with unboosted protease inhibitors, some of which needed to be taken two or three times daily and also had complicated food and drink restrictions.

However, since 2000 there have been significant improvements in HIV care, including the almost universal adoption of ritonavir-boosting of protease inhibitors. These drugs have a powerful anti-HIV effect. Even if they fail to suppress viral load, this rarely involves the emergence of drug-resistant virus.

Improved drugs in the nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) classes have been introduced, and completely new classes of antiretrovirals such as entry and integrase inhibitors have been developed. This means that an undetectable viral load is now the aim of HIV therapy, regardless of a patient’s treatment history or resistance profile.

Resistance tests are an integral component of HIV care and are used to guide the choice of suitable antiretroviral agents. Investigators from Monogram Biosciences wished to see if the prevalence of virus resistant to any protease inhibitor, NRTI, or NNRTI had changed in recent years. They also wished to establish trends in the prevalence of single, dual and triple class resistance.

A total of 68,587 samples submitted to their laboratories between 2003 and 2010 for resistance testing were analysed.

In 2003, a total of 52% of samples had detectable resistance to a protease inhibitor. However, this had fallen to 26% by 2010 (p < 0.05).

“A strong trend of decreasing prevalence of protease inhibitor resistance was observed in the…database between 2003 and 2010,” comment the investigators.

Prevalence of NRTI resistance also fell from 77% to 70% (p < 0.05), and there was also a fall in the proportion of samples with evidence of resistance to NNRTIs (70% to 61%; p < 0.05).

Moreover, there was also a significant decline in the proportion of blood samples with triple-class resistance. Prevalence fell from 29% in 2003 to 11% in 2010 (p < 0.05). The prevalence of dual-class resistance also fell, from 40% to 35%. These falls were accompanied by an increase in the proportion of samples with resistance to one class of drug (31% to 54%; p < 0.05).

The resistance profile of samples with dual-class resistance was examined in more detail.

In 2003, resistance to NRTIs and NNRTIs was detected in 54% of samples; 37% exhibited resistance to protease inhibitors and NRTIs; and 9% showed evidence of resistance to protease inhibitors and NNRTIs.

By 2010, however, dual-class resistance profiles had changed significantly. Resistance to NRTIs and NNRTIs was evident in 70% of samples; protease inhibitor and NRTI resistance in 24%; and protease inhibitor and NNRTI resistance in 7%.

The investigators believe their results “may have important implications for ARV [antiretroviral] selection, clinical trial design and drug development.”

References

Paquet AC et al. Significant reductions in the prevalence of protease inhibitor and 3-class resistance: recent trends in a large HIV-1 protease/reverse transcriptase database. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract H2-800, Chicago, 2011. (Click here for the abstract.)

This article is also available in Spanish.

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