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HIV Drug Therapy: Darunavir/Ritonavir Protease Inhibitor Monotherapy Less Effective than 3-Drug ART


Monotherapy with ritonavir-boosted darunavir (Prezista) results in a lower rate of viral suppression after 48 weeks when compared to darunavir/ritonavir plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), but may be just as effective as 3-drug therapy in people with nadir (lowest-ever) CD4 cell counts above 200 cells/mm3, according to a 48-week analysis of the PROTEA study presented last week at the HIV Drug Therapy Glasgow conference.

Monotherapy with a boosted protease inhibitor has been proposed as a form of maintenance therapy for people who have achieved viral load suppression, as a means of reducing toxicity and cost while preserving future treatment options in the event of virological rebound.

Monotherapy with a ritonavir-boosted protease inhibitor has been evaluated in numerous studies of lopinavir/ritonavir (Kaletra), atazanavir/ritonavir (boosted Reyataz), and darunavir/ritonavir. A meta-analysis and review of 10 studies of protease inhibitor monotherapy found a lower rate of viral suppression (76% vs 82%) but no increased risk of drug resistance in the monotherapy arm in these studies (Arribas, abstract P256).

The largest study of boosted protease inhibitor monotherapy, PIVOT, conducted in the U.K. by the Medical Research Council, randomized 587 people to continue a 3-drug regimen containing either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI), or to switch to a boosted protease inhibitor chosen by patient and clinician. In that study, 79% of the participants in the monotherapy arm took darunavir/ritonavir. After 5 years of follow-up, 32% of participants in the monotherapy arm had to return to taking a 3-drug regimen in order to re-suppress viral load. But despite the higher rate of viral rebound in the monotherapy arm, the study found no significant difference in the rate at which participants lost future treatment options as a consequence of developing drug resistance. Since loss of future drug options was the primary endpoint in the PIVOT study, the strategy of boosted PI monotherapy was found to be non-inferior. However, in the 3-drug arm only 3.2% of participants experienced viral rebound (Paton, CROI 2014, abstract 550LB).

A health economic analysis of PIVOT, presented at the Glasgow meeting by Simon Walker of York University, showed that protease inhibitor monotherapy was cost-effective compared to 3-drug therapy and cost-saving (Oddershede, abstract O217).

PROTEA study of Darunavir/Ritonavir

The PROTEA study randomized 273 people on stable antiretroviral therapy (ART) with suppressed viral load to either darunavir/ritonavir monotherapy or darunavir/ritonavir plus 2 NRTIs. The study population had been taking antiretroviral therapy for an average of just over 5 years and had a median CD4 cell count of 593 cells/mm3 in the monotherapy arm and 623 cells/mm3 in the triple therapy arm. 29.9% of participants in the monotherapy group and 22.1% of the triple therapy arm had had a lowest-ever CD4 count prior to treatment below 200 cells/mm3.

The primary efficacy endpoint of the study was the proportion of participants with viral load below 50 copies/mL at week 48, with patients who had switched from their initially assigned regimen for any reason counted as virological failures. 86.1% of participants in the darunavir monotherapy arm and 94.9% in the triple therapy arm had viral load below 50 copies/mL by this intent-to-treat analysis. Although this difference did not meet the criterion for inferiority, the efficacy of darunavir/ritonavir monotherapy was described as lower by Andrea Antinori of the National Institute of Infectious Diseases in Rome, when presenting the results (abstract O423A).

A post-hoc analysis (not part of the original study design) found no difference in efficacy between the 2 arms among 202 participants with lowest-ever CD4 cell counts above 200 cells/mm3 (94.8% vs 94.3%), but a substantial difference in efficacy among 71 participants with a lowest-ever CD4 cell count below 200 cells/mm3 (65.9% vs 96.7%), favoring triple therapy.

Darunavir/ritonavir monotherapy was associated with a slightly higher rate of treatment-emergent adverse events. Due to lower penetration of protease inhibitors into the cerebrospinal fluid (CSF), 40 participants underwent CSF sampling at baseline and week 48 in order to evaluate viral load in CSF (abstract O423B).

A single person in the darunavir monotherapy arm had detectable HIV in CSF (654 copies/mL) and in plasma (77 copies/mL) at week 48. One person in the darunavir monotherapy arm, not enrolled in the CSF sub-study, developed HIV encephalomyelitis at week 24 with a CSF viral load of 2500 copies/mL and plasma viral load of 500 copies/mL. Viral load was re-suppressed and symptoms resolved after 2 NRTIs were added.



J Arribas, PM Girard, N Paton, et al. Efficacy of PI monotherapy versus triple therapy for 1964 patients in 10 randomised trials. HIV Drug Therapy 2014. Glasgow, November 2-6, 2014. Abstract P256.

L Oddershede, S Walker, N Paton, L et al. Cost-effectiveness analysis of protease inhibitor monotherapy vs ongoing triple therapy in the long-term management of HIV patients. HIV Drug Therapy 2014. Glasgow, November 2-6, 2014. Abstract O217.

A Antinori, J Arribas, J Fehr, et al. Week 48 efficacy analysis of the PROTEA trial: darunavir/ritonavir monotherapy versus darunavir/ritonavir with two nucleoside analogues, for patients with HIV-1 RNA below 50 copies/mL at baseline. HIV Drug Therapy 2014. Glasgow, November 2-6, 2014. Abstract O423A.

A Clarke, V Johanssen, J Gerstoft, et al. Analysis of neurocognitive function and CNS endpoints in the PROTEA trial: darunavir/ritonavir with or without nucleoside analogues. HIV Drug Therapy 2014. Glasgow, November 2-6, 2014. Abstract O423B.