A warning on simplification strategies: not suitable for all
To overcome potential problems associated with long term protease inhibitor use, such as more complex dosing regimens (therefore more difficult adherence) and possible metabolic and body habitus changes, both patients and clinicians are finding the idea of switching to a simplified non-nucleoside (NNRTI), or even a triple NRTI regimen increasingly attractive.
Two presentations looked at the impact of treatment history and baseline genotypic resistance on virologic failure in groups of patients switching from PI-containing to NNRTI or NRTI regimens.
Prior Treatment with Mono or Dual NRTIs before HAART as Predictor of Virological Failure in Simplified Abacavir-Based Triple NRTI Regimens combined results from two studies, the Simplified Maintenance Trial (SMT) and CNA30017. In both studies, patients were randomised to continue their current PI-containing HAART regimen (continuation arm) or to switch to an abacavir-based triple NRTI regimen (simplification arm). The simplified arm in the SMT study used a triple nucleoside regimen of abacavir and Combivir’ (lamivudine plus zidovudine) and the CNA 30017 study used abacavir plus two pre-existing nucleosides.
In the SMT study 47% of patients (n=163) had used mono or dual nucleosides before the initiation of HAART. All had been on stable PI-containing HAART regimens with undetectable HIV-RNA (<400 copies/ml) for at least six months prior to randomisation. In the simplification arm patients (n=84) were <50 HIV/RNA copies/ml, negative for 215 zidovudine resistance mutation and had no prior virologic failure on both zidovudine or lamivudine. Patients with previous virologic failure were not excluded in the continuation arm (n=79).
In CNA30017, the study was designed to recruit patients (n=211) with no (or limited) prior mono or dual nucleoside therapy and no previous virological failure; all patients were using PI-containing HAART regimens before randomisation. Patients in the continuation arm (n=106) were undetectable (as measured by any licensed assay) since initiation of ART, with prior treatment switches only permitted due to intolerance. Patients in the simplification arm (n=105) were <50 copies/ml and had been using stable PI-containing triple HAART for a minimum of six months prior to switching.
In both studies the two treatment groups were similar at baseline. HIV-RNA was measured approximately every four weeks during the first six months and virological failure was defined as two consecutive results of HIV-RNA >400 copies/ml. In this presentation, data described virological failure that occurred after randomisation by week 48 in the SMT study and preliminary data at week 24 in the CNA30017 study.
In the SMT study 7/9 (78%) virological failures occurred in the simplified arm before week 20 and 4/9 before or at week 8, but in the continuation arm these occurred at later time points. In both arms, whatever the time to virological failure, multiple NRTI resistance mutations were detected in plasma virus but they were only partially detected in viral DNA isolated from baseline PBMCs. The investigators observed that, ‘The speed of initial rebound and the genotypic profile is not consistent with our understanding of viral dynamics and the known resistance profile of PI or abacavir-based HAART, suggesting that the resistance mutations detected at the time of virological failure were not de novo mutations but rather re-selection of archived mutations not detected at screening.’ All three rebounds in the continuation arm were associated with 1 to 3 PI resistance-associated mutations, including the D30N, G48V, 154V/I and V82A. All instances of virological failure, 9/12 (75%), in both arms of the SMT study occurred in patients who had used mono zidovudine or dual zidovudine/3TC therapy prior to the initiation of HAART.
In the CNA30017 study however, where patients were recruited with limited or no prior mono/dual nucleoside therapy, virological failure was associated with plasma virus with no resistance-associated mutation in the continuation arm or with the M184V/I only in the simplified arm. The M41L and T215Y were detected in one patient who had prior zidovudine monotherapy at time of failure. The investigators also noted that in this patient population, viral DNA species detected in baseline PBMCs are similar to the major plasma virus detected at the time of first virological rebound.
A separate simplification study entitled Mechanism of virological failure after substitution of a protease inhibitor by nevirapine in patients with controlled HIV-1 RNA, was also reported at this meeting. This was designed to study the emergence of viral resistance after switching from a stable PI-containing regimen to a simplified regimen containing nevirapine.
All patients in this study (n=38) had no history of prior NNRTI use and had been using PI-containing HAART for at least 6 months with undetectable HIV-RNA (<500 copies/ml) and CD4>200 cells/ml. Group 1 (n=22) had been antiretroviral naive prior to initiation of HAART and group 2 had used mono or dual nucleoside therapy prior to their HAART regimen. The only treatment change was a switch from the PI (68% of patients in group 1 and 62% in group 2 used indinavir with stavudine and lamivudine prior to switch), maintaining the previous nucleosides. Virological failure was defined as plasma HIV-RNA>500 copies/ml.
After switching to nevirapine, none of the patients in group 1 had developed virological failure after a median follow up of 54 weeks. In contrast, 8/16 (50%) of the group 2 patients experienced virological failure in a median time of 20 weeks. The rebound was associated with the appearance of HIV variants with NNRTI-resistance (as shown in table 3). Zidovudine mutations were also present in 7/8 patients related to prior use of mono and dual therapy.
Findings from both reports show that previous treatment with mono and/or dual nucleoside analogue treatment before the start of HAART is an important determinant for virological failure overall, when switching to NNRTI-containing or, much hyped for it’s simplicity ‘triple nuke’ regimens. Archived nucleoside resistance mutations selected before HAART are likely to facilitate resistance to nucleosides (and NNRTIs) in the setting of a less potent regimen. Screening at baseline may not always detect archived resistance and the efficacy of simplified treatment may be dependent on a patient’s treatment history and careful assessment of previous virological failure.
These data provide a clear warning against simplification for anyone with a prior history of treatment with mono or dual nucleoside analogues. Caution might also be suggested for anyone with a history of partially suppressive therapy whatever the combination.
Simplification would seem to be best applied only to those starting PI containing HAART when completely antiretroviral treatment na•ve who had a rapid and complete virological response to treatment. Transmission of drug resistant HIV prior to treatment would also be expected to sabotage later simplification attempts.
- L Perrin,M. Opravil et al. Prior Treatment with Mono or Dual NRTIs before HAART as Predictor of Virological Failure in Simplified Abacavir-Based Triple NRTI Regimens: Results from the Simplified Maintenance Trial (SMT), and CNA30017, CNA30017 Study Team. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 4th International Workshop on HIV Drug 12-16 June 2000, Sitges, Spain. Abstract 120.
- B Masquelier, HJ Fleury et al. Mechanism of virological failure after substitution of a protease inhibitor by nevirapine in patienys with controlled HIV-1 RNA. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 4th International Workshop on HIV Drug 12-16 June 2000, Sitges, Spain. Abstract 119.