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Adding More NRTIs to Salvage May Lower Chance of Response
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
Indiscriminately adding nucleotide/nucleosides (NRTIs) to salvage regimens--even if the NRTIs have little apparent activity against a patient's virus--tended to lower the chance of 24-week virologic response in a 116-person Montreal study [1]. As in earlier salvage studies, more active antiretrovirals in a regimen independently improved chances of virologic response.
Brian Trottier (Clinique Medicale l'Actuel) and coworkers analyzed the impact of active and inactive drugs on 24-week virologic response to rescue regimens because they wondered if adding more NRTIs helps chances of success. Piling on NRTIs has become routine practice in some clinics because even agents classified as inactive may have some residual activity, or because the mutant virus they evoke may have diminished replication capacity or may be more sensitive to other NRTIs. But more NRTIs inevitably raise cost and the risk of toxicity and drug interactions.
The Montreal clinicians retrospectively analyzed response rates in people with triple-class antiretroviral experience who met the following criteria: (1) at least one genotypic resistance test, (2) resistance to at least one antiretroviral class documented by genotyping, and (3) starting a rescue regimen containing etravirine, maraviroc, and/or raltegravir, plus other antiretrovirals chosen by the clinician. The Clinique l'Actuel team considered an antiretroviral active if all genotypes for that person failed to show mutations conferring resistance to that drug.
The 116 study participants had taken antiretrovirals for a median of 13 years and had a median viral load of 8000 copies. While 29 people (25%) had a viral load under 50 copies when they started their rescue regimen, 14 (12%) had 50 to 999 copies, 15 (13%) had 1000 to 9999 copies, 35 (31%) had 10,000 to 99,999 copies, and 21 (18%) had 100,000 copies or more. Median lowest-ever (nadir) CD4 count in the group stood at 120 (interquartile range [IQR] 50 to 200), median time since HIV diagnosis was 17 years (IQR 14 to 20), and median age was 47 years (IQR 44 to 53). Twenty-two people (17%) had tried antiretrovirals from three classes, 46 (40%) from four, 39 (34%) from five, and 11 (9%) from all six current classes.
Sixty-four people (55%) started etravirine, 63 (54%) raltegravir, and 17 (15%) maraviroc. Twenty-eight people (24%) started two of these drugs (always including raltegravir), but no one started all three. Nine people (8%) had no NRTIs in their new regimen, 18 (16%) had 1, 79 (68%) had 2, and 10 (9%) had 10.
While 30 people (26%) began a 3-drug regimen, 57 (49%) began 4 drugs and 29 (25%) began 5 or more. But genotyping data indicated that only 20% of the study group started 3 active antiretrovirals, while 53% started 2 active drugs, and 27% started 0 or 1 active drug. Although 106 people included 1 or more NRTIs in the new regimen, only 12% started 1 active NRTI and the remaining 88% started no active NRTIs.
As in previous salvage studies, more active antiretrovirals in the regimen enhanced prospects of virologic response. While 55% with fewer than 2 active drugs had a viral load under 50 copies 6 months after starting the rescue regimen, 79% with 2 active drugs and everyone with 3 active drugs had an undetectable load at that point (P = 0.002). But the number of prescribed drugs did not correlate with virologic response. And virologic response correlated inversely with the number of NRTIs prescribed. Everyone taking a regimen with no NRTIs had a sub-50-copy load at 6 months, compared with 89% taking 1 NRTI, 76% taking 2, and 40% taking 3 (P = 0.009).
In a multivariate analysis that factored in age, gender, injecting drug use, and number of prescribed antiretrovirals, number of NRTIs prescribed did not emerge as an independent predictor of response at 6 months. More active antiretrovirals (in any class) raised chances of a 6-month response 2.6 times (95% confidence interval 1.1 to 6.5), while a higher viral load before salvage lowered chances of response 60%. Gender, injecting drug use, and age did not independently predict response in this analysis.
Trottier and colleagues believe their findings suggest that "non-active NRTIs (or any other nonactive antiretrovirals) should not be part of effective salvage regimens." Nevertheless, they think clinicians may still have reasons to put nonactive NRTIs in a rescue regimen, including "protecting the brain (or other organs) if these drugs have demonstrated activity and good penetration in that reservoir" and increasing the sensitivity of HIV to other NRTIs in the regimen.
Reference
1. Trottier B, Thomas R, Nguyen VK, et al. Should inactive nucleoside/tide reverse transcriptase inhibitors (NRTIs) still be used in salvage regimens, with new classes/generations of antiretrovirals in three-class-experienced, multi-drug resistant patients? 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUPDB205.
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