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Is There Any Clinical Benefit to Staying on a Failing Regimen?

The accumulation of drug resistance after the failure of an anti-HIV drug combination is slower in patients who had previously experienced only moderate// CD4 cell losses, according to a study of patients failing treatment at a network of European hospitals.

However, the study also found that on average, patients who remained on a failing regimen lost 1.25 active drugs from the choice still available to them for every six months on failing treatment, highlighting the need for prompt treatment switches wherever possible.

Participants in the study also showed minimal declines in their CD4 cell counts.

The results are published in the March 30th edition of the journal AIDS.

The development of drug resistance after treatment failure has led to the strong recommendation in various national treatment guidelines that treatment should be switched as soon as possible after virological failure is detected, and that resistance testing should be used in order to select the successor regimen.

However, not all patients are able to assemble a drug combination that will contain three fully active drugs, and researchers connected with the EuroSIDA cohort study wanted to assess how quickly people on failing drug regimens might accumulate further drug resistance mutations if they did not switch treatment.

They carried out a retrospective study using stored plasma samples from participants in the EuroSIDA cohort. Selected for study were patients who had been on a virologically failing regimen for at least six months, and thereafter, had two resistance tests during the period when viral load was below 400 copies/mL and who had also remained on an unchanged regimen containing at least three antiretrovirals.

Prior to their current failing regimen, on average, patients had previously used five other drugs and virologically failed one or more drug classes. Regimens being used included NRTIs, NNRTIs, single protease inhibitors and ritonavir-boosted protease inhibitors. 43% of patients were receiving two nucleoside analogues and a single protease inhibitor, while 39% were receiving a regimen containing drugs from all three classes.

One genotypic resistance test was used to define the baseline resistance pattern in 75 patients; two genotypic tests defined resistance in 23, and three tests defined resistance in the remaining 12 patients. Thymidine analogue mutations (TAMS) accounted for 75% of all DRGs and the mutation was primarily at the 184V codon. The evolution of resistance was then evaluated between the baseline test (t0) and a subsequent test a median of six months later (t1) (range 2-28 months).

From the time of the first genotypic test to the second, 77% of patients acquired one or more extra International AIDS Society (IAS)-defined drug resistance mutations, with an overall six month increase of 1.96 mutations. Using the Rega interpretation system, this meant an overall average loss of 1.25 active antiretroviral drugs per each six-month period that a patient remained on a failing regimen (this includes all ARVs available in January 2006). The authors note though that depending on the drug regimen followed and the extent of resistance, it cannot be assumed that the accumulation of mutations is limitless.

In this same time period, the mean CD4 cell count remained relatively stable at ~280 cells/mm3 with an estimated loss of 9.79 cells/mm3 while viral load rose by approximately 0.14 log10 copies/mL, resulting in a mean viral load of 3.87 log10 copies/mL.

The prevalence of resistance to the failing regimen at the time of the first resistance test was not predictive of the accumulation of drug resistance mutations when an adjusted analysis was performed. The main predictor of change in the number of IAS-defined mutations over time was an inverse association with CD4 cell count nadir. Those patients in the cohort with re latively higher CD4 cell count nadirs did not lose drug options to the same degree as did others in the study (0.34 drugs less per 100 cells/mm3). Additionally, patients on 3TC (lamivudine) showed a slower accumulation of nucleoside mutations and thymidine analogue mutations (TAMs).

According to the authors, this study suggests that each individual’s history of immune suppression can affect the accumulation of drug resistance mutations.

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