Inappropriate claim of ‘failure of ritonavir-boosted lopinavir monotherapy in HIV’ in the Monotherapy Switzerland/Thailand (MOST) trial
Paton, Nicholas Ia; Meynard, Jean-Lucb; Pulido, Federicoc; Arenas-Pinto, Alejandroa; Girard, Pierre-Marieb; Arribas, Josed
aMedical Research Council Clinical Trials Unit, London, UK
bService des Maladies Infectieuses, Hopital Saint-Antoine, Faculte' de Medecine Pierre et Marie Curie, Paris, France
cUnidad HIV, Hospital 12 de Octubre, Universidad Complutense de Madrid, Spain
dServicio de Medicina Interna, Hospital La Paz, Universidad Autonoma de Madrid, Madrid, Spain.
Received 6 November, 2010
Accepted 14 November, 2010
Correspondence to Nicholas I. Paton, MD, FRCP, MRC Clinical Trials Unit, 222 Euston Road, London, NW1 2DA, UK. Tel: +44 20 7670 4700; e-mail: email@example.com
A number of randomized controlled trials, each enrolling several hundred patients, have demonstrated that the strategy of protease inhibitor monotherapy with reintroduction of nucleoside reverse transcriptase inhibitors (NRTIs) as needed – when started in patients who have achieved sustained virological suppression – is noninferior to conventional triple therapy for up to 96 weeks of follow-up [1–4]. Thus, the finding of Monotherapy Switzerland/Thailand (MOST) (a trial of a similar strategy performed in 60 patients followed for a median of 48 weeks) that a high proportion (six of 29) of patients in the protease inhibitor monotherapy arm developed detectable viral load appears to be an anomaly . The results may in part be explained by tolerability issues – three of the patients with rebound started ritonavir-boosted lopinavir (LPV/r) for the first time (two switched from an efavirenz-based regimen, and one from an atazanavir-based regimen). The relatively small size of the trial compared with the others that have contrary findings, and the fact that plasma viral load was not the primary end point, should lead to caution in interpreting the findings. Furthermore, it is hard to regard this as clinically meaningful treatment failure, given that all six patients were able to resuppress viral load following reintroduction of NRTIs – as has been consistently shown in other studies. In view of these factors, the claim in the title that the study is ‘demonstrating failure of LPV/r monotherapy in HIV’ is inappropriately negative.
The trial was designed to test the hypothesis that the rate of central nervous system (CNS) compartment failure (defined as increase of cerebrospinal fluid (CSF) viral load of greater than 1 log10 copies/ml above baseline in patients who had undetectable viral load in plasma) was noninferior in the protease inhibitor monotherapy group. The authors identified just one patient in the protease inhibitor monotherapy arm who met these failure criteria, and a further three patients who had low-level detectable viral load in CSF. None of these patients had any evidence of an associated inflammatory reaction (CSF white cell count was not raised) or any associated neuropsychiatric symptoms. Drug levels are not presented, so it is not possible to relate this to viral replication. A similar picture (undetectable viral load in plasma, detectable viral load in CSF, no CSF inflammatory reaction) was seen in three patients taking triple therapy when measured at baseline, demonstrating that this picture is not unique for protease inhibitor monotherapy. If there were evidence of occult viral replication and associated CNS pathology ongoing in patients whilst they had full viral load suppression in plasma, and if this occurred at a higher rate on protease inhibitor monotherapy, this would indeed be of concern. However, this is not the case and in contrast to the alarm implied by the authors, we, therefore, find the CSF findings to be quite reassuring. The authors also place undue weight on the finding of detectable viral load in CSF in patients who have detectable viral load in plasma in the protease inhibitor monotherapy arm. However, this is an expected finding in any patient with viral load rebound in plasma (not just on protease inhibitor monotherapy). This is again of limited concern, given that such patients will be identified on routine plasma viral load monitoring and can have viral load suppression reinstated in both blood and CNS compartments by simple reintroduction of NRTIs. We do not follow the authors' logic that there is a need to consider routine lumbar puncture as part of the management of such patients prior to instituting appropriate antiretroviral therapy management. The authors also highlight the fact that four of six patients with viral load rebound in plasma on protease inhibitor monotherapy reported neurological symptoms. This high proportion of patients with CNS symptoms after viral load rebound on protease inhibitor monotherapy has not been reported in the previous trials of monotherapy, and we, therefore, wonder whether more specific questioning in these patients could have contributed to this finding. Again it is reassuring to note that the symptoms resolved completely after treatment switch.
The potential advantages of protease inhibitor monotherapy are substantial, and therefore we need to be careful before dismissing this as a therapeutic option. The findings of the MOST trial do not diminish the case, formed on the basis of a number of larger trials with longer duration of follow-up, that protease inhibitor monotherapy represents a viable therapeutic option for the majority of patients. Although not substantiated by the findings of the MOST trial, the issue of efficacy of protease inhibitor monotherapy in the CNS compartment does remain a legitimate but theoretical concern, and the Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial (NCT01230580), a long-term clinical trial of protease inhibitor monotherapy with longitudinal neurocognitive assessments will provide the best assessment of whether this is a clinically meaningful issue.
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© 2011 Lippincott Williams & Wilkins, Inc.
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