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  11th Workshop on Adverse Drug Reactions
and Co-morbidities in HIV
Philadelphia, USA, October 2009
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Neuropsychiatric adverse events in the MONET trial: darunavir/ritonavir with and without nucleoside analogues for patients with HIV RNA <50 copies/mL at screening
  Reported by Jules Levin
11th Workshop on Adverse Drug Reactions and Co-morbidities in HIV, Philadelphia, USA, October 2009
Giovanni di Perri, Ospedale Amedeo di Savoia, Torino, Italy, Gerd Fatkenheuer, Universitat Koln, Germany, Andrew Hill, Pharmacology Research Laboratories, University of Liverpool, UK, Yvon van Delft, Janssen-Cilag EMEA, Tilburg, The Netherlands, Christiane Moecklinghoff, Janssen-Cilag EMEA, Neuss, Germany
In the MONET study, drug-related neuropsychiatric adverse events were infrequent for darunavir/ritonavir, either used as monotherapy or with nucleoside analogues
Most reported adverse events were Grade 1 (mild) and not drug related.
By the FAHI questionnaire, patients reported no loss in concentration or memory over 48 weeks. However, this study is limited in size and duration: the results need to be confirmed in longer-term follow up.
The MONET trial recruited 256 patients who were receiving HAART at baseline and had HIV RNA <50 copies/mL for over 24 weeks beforehand. Patients switched to DRV/r 800/100 mg once daily, either as monotherapy or with two nucleoside analogues. After 48 weeks of treatment, the percentage of patients with HIV RNA suppression below 50 copies/mL in the monotherapy arm was 86.2%, versus 87.8% in the triple therapy arm, showing non-inferior efficacy (Arribas 2009).
Two studies have shown that darunavir has good penetration in the Cerebrospinal Fluid (Yilmaz 2009, Letendre 2009) but the clinical implications of this level of penetration are unknown.
At each study visit, data on clinical adverse events were collected and all neuropsychological adverse events were analysedseparately. Study physicians graded all adverse events by severity as either Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or Grade 4 (life-threatening), using the Division of AIDS 2007 classification system.
Study subjects also self-scored an assessment of clarity of thinking, concentration and memory, using part of the Functional Assessment of HIV Infection (FAHI) Quality of Life questionnaire at weeks 0, 24 and 48 (Cella 1996). Patients were asked about three measures of cognitive functioning: "my thinking is clear", "I have trouble concentrating" and "I have trouble remembering things".
For each question, patients gave a score of either 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit) and 4 (very much). The mean scores were compared between treatment arms at each timepoint using t-tests. The total score from the three questions was also compared between the treatment arms.


Of 256 subjects in the MONET study, 81% were male and 91% Caucasian, the median age was 43 years, and the median baseline CD4 count was 575 cells/uL. A summary of baseline characteristics is shown in Table 1.


Nervous system or psychiatric adverse events
After 48 weeks of therapy, clinician-reported Grade 1-4 psychiatric adverse events (all cause) were seen in 9% of patients in each treatment arm, while adverse events of the nervous system were seen in 16% of patients in each arm. Details of the individual adverse events are shown in Tables 2 and 3. The majority of these events were Grade 1 (mild) in severity and not judged to be related to study medication.
The most frequently reported nervous system adverse event was headache, while the most frequently reported psychiatric adverse event was depression. Of the 33 patients with Grade 1-4 neuropsychiatric adverse events in the DRV/r monotherapy arm, two patients reported as Grade 2-4 drug related headache. Of the 32 patients with Grade 1-4 neuropsychiatric adverse events in the triple therapy arm, three patients reported Grade 2-4 drug related events (headache, migraine and cervical radiculitis). One patient in the monotherapy arm discontinued randomised treatment for a Grade 3 headache.



FAHI questionnaire results
In the DRV/r monotherapy arm, the overall mean FAHI score for, cognitive functioning was 8.9 (SD 2.4) at baseline and 9.0 (SD 2.6) at Week 48. In the triple therapy arm, the mean score was 8.8 (SD 2.6) at baseline and 8.9 (SD 2.8) at Week 48. Changes in scores over 48 weeks are shown in Figures 1-4. There were no significant differences between the treatment arms for any of the scores, at either Week 24 or Week 48.





DAIDS 2007. Division of AIDS table for grading the severity of adult and paediatric adverse events.
http://rcc.tech.res.com/DAIDS%20RCC%20Forms/TB_ToxicityTables_DAIDS_AE_GradingTable_FinalDec2004.pdf (accessed March 2007)
Arribas J et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/mL. AIDS 2009, in press. Cella D et al (1996). Development and validation of the Functional Assessment of Human
Immunodeficiency Virus Infection (FAHI) quality of life instrument. Quality of Life Research 1996, 5, 450-463.
Yilmaz A et al. Darunavir concentrations in cerebrospinal fluid and blood in HIV-1 infected adults. AIDS Res Hum Retro 2009, 25: 1-5
Letendre et al, Darunavir concentrations in CSF exceed the median inhibitory concentration. ICAAC, 2009 (poster 45)