ICAAC: Treatment breaks riskier if NNRTIs involved

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Individuals who interrupt highly active antiretroviral therapy (HAART) that contains a non-nucleoside reverse transcriptase inhibitor (NNRTI), or resume HAART with an NNRTI, are more likely to have resistance than patients who were taking a protease inhibitor before taking a treatment break, according to a study presented to the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington.

Investigators wished to see if there were differences between the performance of protease inhibitor-based and NNRTI-based HAART regimens after a structured treatment interruption. It is well known that protease inhibitors have a higher genetic barrier to resistance than NNRTIs and the pharmacology of NNRTIs can mean that suboptimal levels of the drug remain in the body for several weeks after treatment discontinuation, encouraging the development of resistance.

The medical records of 45 patients who took a structured treatment interruption in 2002 were retrospectively analysed. Prior to taking a break from HAART, all the patients had a viral load below 50 copies/ml and a CD4 cell count above 350 cells/mm3. In total, 33 patients were taking an NNRTI-based regimen prior to their treatment break and twelve patients were taking a protease inhibitor-based regimen.

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. 

treatment interruption

Taking a planned break from HIV treatment, sometimes known as a ‘drugs holiday’. As this has been shown to lead to worse outcomes, treatment interruptions are not recommended. 

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). 

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

treatment failure

Inability of a medical therapy to achieve the desired results. 

Three months after starting the treatment break, and then three months after reinitiating HAART, investigators conducted phenotypic resistance tests.

In total, eleven patients restarted HAART with a protease inhibitor-based regimen. Three months after reinitiating treatment all these individuals had a viral load below 50 copies/ml.

Of the 34 patients who restarted HAART with an NNRTI, only 44% (15 of 34 individuals), achieved a viral load of below 50 copies/ml three months after reinitiating treatment. This was significantly inferior to the response of patients taking protease inhibitors (p

Genotypic resistance test results off-treatment were available for 13 of the patients failing their reinitiated NNRTI regimen. Eleven out of 13 had drug resistance mutations to nucleoside analogues, but only one had an NNRTI-associated mutation (K103N).

These mutations appeared to have developed during the treatment break, as only one patient had recognised resistance mutations during treatment prior to the structured treatment interruption.

Amongst the patients who experienced failure of an NNRTI-containing regimen after resuming treatment, all had acquired NNRTI resistance mutations, suggesting the presence of minority populations of NNRTI-resistant virus prior to the resumption of treatment.

The investigators also noted that 83% of individuals who switched from a protease inhibitor-based regimen to an NNRTI-based regimen after the three-month treatment break also had detectable virus. They believe that this may be due to the emergence of nucleoside analogue reverse transcriptase inhibitor (NRTI) resistance mutations during the treatment break, which the NNRTI regimen was then unable to contain, leading to treatment failure.

“Discontinuation of NNRTI-HAART is risky”, conclude the investigators. They recommend that if NNRTI based-treatment is going to be interrupted, then NRTIs should be continued for two weeks after the NNRTI is stopped. They also warn that treatment breaks entail further risks for treatment-experienced patients “as NNRTIs have a lower genetic-barrier, treatment-experienced patients off-therapy who resume NNRTI-HAART may fail due to the presence of NRTI mutations.”

References

Barriero P et al. Superior performance of protease inhibitors over non-nucleosides when HAART is resumed after treatment interruptions. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-576, 2004.