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Nucleoside Resistance Risk Higher With NNRTI Than With Boosted PI

Author: Mark Mascolini

29 November 2012

Loss of nucleoside reverse transcriptase inhibitor (NRTI) activity was significantly greater among people combining two NRTIs with a nonnucleoside reverse transcriptase inhibitor (NNRTI) as first-line therapy than among those taking two NRTIs plus a ritonavir-boosted protease inhibitor (PI), according to results of a Swiss HIV Cohort Study (SHCS) analysis.

Resistance risk was lower with a boosted PI regimen than with an NNRTI combination within 3 months of virologic failure, 3 to 6 months after failure, and more than 6 months after failure. The findings have especially important implications for resource-poor settings where viral load monitoring may be infrequent and resistance testing is even less common.

Resistance mutations accumulate when an antiretroviral regimen fails. If a person continues taking a failing regimen, mutations continue to accumulate and may greatly limit options for subsequent effective regimens. In most low-income countries, the preferred first-line regimen contains an NNRTI plus two NRTIs. But the impact of continued treatment with a failing NNRTI or PI regimen remains incompletely understood.

To address these issues, SHCS investigators analyzed resistance development in patients taking a failing standard first-line NNRTI or boosted-PI combination. They defined virologic failure as a viral load at or above 50 copies/mL after a previous load below 50 copies/mL, or failure to reach a viral load below 50 copies/mL within 180 days of starting treatment.

The researchers examined viral sequences collected from these people to determine which resistance mutations emerged up to and beyond 6 months of continued treatment with a failed regimen. They used a standard method to determine loss of NRTI, NNRTI, and PI activity within 3 months of failure, 3 to 6 months after failure, and more than 6 months after failure.

The analysis included 99 genotypic resistance tests of virus from people treated with a ritonavir-boosted PI plus two NRTIs and 129 resistance tests of virus from people treated with an NNRTI plus two NRTIs. The risk of losing activity of one or more NRTIs was lower among people taking a boosted-PI regimen than among those taking an NNRTI regimen in every period analyzed:

Lost NRTI activity with boosted PI vs NNRTI:
• Within 3 months of failure: 8.8% vs 38.2% (P = 0.009)
• 3 to 6 months after failure: 7.1% vs 46.9% (P < 0.001)
• More than 6 months after failure: 18.9% vs 60.9% (P < 0.001)

In the same three periods, percentages of patients who lost PI activity were significantly lower than percentages who lost NNRTI activity (all P < 0.001):

Lost PI vs NNRTI activity:
• Within 3 months of failure: 2.9% vs 41.2%
• 3 to 6 months after failure: 3.6% vs 49.0%
• More than 6 months after failure: 5.4% vs 63.0%

Compared with people taking a ritonavir-boosted PI, those taking an NNRTI had more than a 13 times higher chance of accumulating NRTI resistance mutations within 6 months of starting treatment (adjusted odds ratio 13.3, 95% confidence interval 4.1 to 42.8, P < 0.001).

Although these findings are important for anyone taking a failing antiretroviral regimen, the SHCS team notes that they are particularly relevant in resource-poor regions where viral load monitoring is infrequent or entirely absent. Continuing a failing regimen holds greater risk in low-resource regions, which typically have fewer options for subsequent regimens.

Source: Alexandra U. Scherrer, Jürg Böni, Sabine Yerly, Thomas Klimkait, Vincent Aubert, Hansjakob Furrer, Alexandra Calmy, Matthias Cavassini, Luigia Elzi, Pietro L. Vernazza, Enos Bernasconi, Bruno Ledergerber, Huldrych F. Günthard, the Swiss HIV Cohort Study (SHCS). Long-lasting protection of activity of nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) by boosted PI containing regimens. PLoS One. 2012; 7: e50307.

Complete article provided by PLoS One, an open-access journal