Analysis of neurocognitive function and CNS endpoints in the PROTEA trial: darunavir/ritonavir with or without nucleoside analogues

Abstract

IntroductionDuring treatment with protease inhibitor monotherapy, the number of antiretrovirals with therapeutic concentrations in the cerebrospinal fluid (CSF) is lower, compared to standard triple therapy. However, the clinical consequences are unclear.MethodsA total of 273 patients with HIV RNA <50 copies/mL for over 24 weeks on current antiretrovirals randomized to darunavir/ritonavir (DRV/r) 800/100 mg once-daily, either as monotherapy (n=137) or with 2NRTIs (n=136). Neurocognitive function was evaluated in all patients by the Hopkins Verbal Learning Tests, the Colour Trail Tests and the Grooved Pegboard Test at screening, baseline and at Week 48. A global neurocognitive score (NPZ-5) was derived by averaging the standardized results of the five domains. In a central nervous system (CNS) sub-study (n=70), HIV RNA levels in the CNS were evaluated at baseline and Week 48. Clinical adverse events related to the CNS were collected at each visit.ResultsPatients were 83% male and 88% White, with median age 43 years. There were more patients with nadir CD4 count below 200 cells/µL in the DRV/r monotherapy arm (41/137, 30%) than the triple therapy arm (30/136, 22%). At Week 48, there was no difference between the treatment arms for the five combined domains of the neurocognitive score. At Week 48, the percentage of patients with an abnormal neurocognitive score among the five domains was 12.2% for DRV/r monotherapy and 14.9% for triple therapy. However, one patient on DRV/r monotherapy with a CD4 nadir of 17 cells/µL was hospitalized with HIV encephalomyelitis at Week 24, with HIV RNA 2500 copies/mL in the CSF and 125 copies/mL in the plasma. Symptoms resolved after intensification with high dose zidovudine. A second patient on DRV/r monotherapy with CD4 nadir of 166 cells/µL had a rise in HIV RNA in CSF from <40 copies/mL at baseline to 654 copies/mL at Week 48, with concurrent plasma HIV RNA of 77 copies/mL.ConclusionsIn this study for patients with HIV RNA <50 copies/mL at baseline, there was no difference in neurocognitive function between the treatment arms. However two patients on PI monotherapy with CD4 nadir <200 cells/µL developed viraemia in both CSF and plasma, with one symptomatic case. DRV/r monotherapy should be used with caution in patients with nadir CD4 counts below 200 cells/µL.

Effect of Monotherapy with Darunavir/Ritonavir on Viral Load in Seminal Fluid, and Quality Parameters of Semen in HIV-1-Positive Patients

“…These findings of a very low percentage of positive viral load with mDRV/r in seminal fluid lead us to believe that this type of therapy is as safe as ART, with respect to levels of viral load seminal fluid. In the central nervous system, similarly good results have been reported for mDRV/r [ 25 , 35 , 36 ]. Monotherapy with protease inhibitors has been shown to produce results to comparable with those of ART in other body compartments, such as lymphatic tissue [ 37 ].…”

Efficacy of protease inhibitor monotherapy vs. triple therapy: meta‐analysis of data from 2303 patients in 13 randomized trials

“…Of the 13 studies, three, PROTEA, MONOI and MOST, included data on HIV‐1 RNA in the CSF (Table ) . Of these, two conducted a prospective evaluation either of all patients (MOST) or of patients in a pre‐selected substudy (PROTEA); in the MONOI study, lumbar punctures were carried out on two symptomatic patients.…”

“…Neurocognitive testing was undertaken in the PROTEA, DREAM, MOST and PIVOT studies to detect changes in neurocognitive function longitudinally . In the PROTEA and PIVOT studies, an overall score for neurocognitive function was determined based on the individual scores from five separate domains.…”

Cerebrospinal Fluid Viral Escape and Acute Encephalitis in a Patient on Boosted Protease Inhibitor Monotherapy

“…A recent randomized clinical trial and two observational studies showed that PI monotherapy was not associated with poorer neurocognitive performance compared to triple therapy [10,11] and that neurocognitive end points did not differ between the strategies [12]. A nadir CD4 + T-cell count <200 cells/ml has been identified as a risk factor for PI monotherapy failure in some studies [7,13].…”