Changes in cellular HIV DNA levels during the MONET trial: 144 Weeks of darunavir/ritonavir monotherapy versus DRV/r + 2NRTIs

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1 Changes in cellular HIV DNA levels during the MONET trial: 144 Weeks of darunavir/ritonavir monotherapy versus DRV/r + 2NRTIs Anna Maria Geretti, Jose R Arribas, Johan Vingerhoets, Geraldine Foster, Sabine Kinloch, Andrew Hill, Yvon van Delft, Christiane Moecklinghoff 10 th European Meeting on HIV & Hepatitis Treatment Strategies & Antiviral Drug Resistance March 2012, Barcelona, Spain [abstract O-06]

2 Background In virologically suppressed patients, switching to DRV/r monotherapy can maintain HIV RNA suppression with no treatment-emergent drug resistance. Effects of PI monotherapy on HIV DNA levels are unknown.

3 MONET Trial Design Inclusion: Taking 2 NRTI + either NNRTI or boosted PI at screening (stratified) HIV RNA <50 copies/ml for at least 6 months, no prior use of darunavir (DRV) No history of virological failure DRV/r 800/100 mg OD + 2 NRTI (re-optimised at baseline) n = 129 Follow-up phase 96 weeks 256 subjects DRV/r 800/100 mg OD n = 127 BL, 4, 12, 24, 36, 48 weeks Follow-up phase 96 weeks 96 wks Primary Endpoint: failure at week 48 (TLOVR). Per Protocol, Switch = Failure 2 consecutive HIV RNA > 50 copies/ml (Roche Amplicor HIV-1 Monitor assay 1.5) Discontinuation of study drugs. Stopping DRV/r Stopping NRTIs in the control arm (switches in NRTIs were permitted at any time).

4 Methods HIV RNA was tested at each patient visit, using the Roche Amplicor HIV-1 Monitor assay 1.5, at a single central laboratory Levels of Interleukin-6 (IL-6) and hs-c Reactive Protein (hs-crp) were measured at Week 144. HIV DNA was also tested from available stored PBMC samples, at baseline, Week 48, Week 96 and Week 144 using a real-time PCR assay (lower limit of quantification = 6 copies/10 6 PBMC) Changes in HIV DNA over time were compared between the treatment arms using all available data (on treatment analysis). HIV DNA levels were correlated with CD4 nadir, HIV RNA elevations and the inflammatory markers IL-6 and hs-crp

5 Baseline Characteristics (ITT) Baseline characteristics DRV/r +2NRTI (n=129) DRV/r (n=127) Age, years (median, range) Male (%) Caucasian (%) 44 (24-72) 83% 90% 43 (25-67) 78% 92% Disease characteristics CD4 count (mean, cells/µl) CD4 <350 cells/µl (%) Duration of prior ARVs, years (mean, sd) Use of PI at screening (%) Use of NNRTI at screening (%) On their first NRTI combination PI naïve Hep B Surface Antigen, positive, n (%) Hep C Antibody, positive, n (%) % 6.5 (4.09) 57% 36% 47% 28% 0 15 (12%) % 7.4 (4.13) 54% 42% 35% 23% 0 23 (18%)

6 HIV RNA <50 copies/ml at Week 144, TLOVR, Switch=failure Per Protocol analysis (PP) Intent to Treat analysis (ITT) 100% 90% 80% 70% HIV RNA <50 by Week 144 (%) 60% 50% 40% 30% 77.7% 72.1% 75.2% 69.3% 20% 10% 0% DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT) n=121 n=122 n=129 n=127

7 HIV RNA by study visit (observed data only patients still on randomised treatment) 100% Percentage of patients with HIV RNA: DRV/r + 2 NRTIs >1000 copies/ml copies/ml copies/ml <50 copies/ml 100% DRV/r 80% 80% 60% 60% 40% 40% 20% 20% 0% 0% SCR SCR Time on treatment - weeks Time on treatment - weeks

8 HIV DNA: changes over time by treatment arm Mean and Median Log 10 HIV DNA versus time, by treatment group (patients with paired baseline and on-treatment data) DRV/r DRV/r+2NRTIs Time Weeks Mean Log 10 HIV DNA Mean Log 10 HIV DNA n ±SE Median n ±SE Median Baseline ± ± WK ± ± WK ± ± WK ± ± Mean and Median change from baseline in Log 10 HIV DNA, by treatment group (patients with paired baseline and on-treatment data) DRV/r DRV/r+2NRTIs Time weeks Mean Log 10 HIV DNA Mean Log 10 HIV DNA n ±SE Median n ±SE Median WK ± ± WK ± ± WK ± ±

9 HIV DNA: correlation with CD4 nadir (p=0.03) Log 10 HIV DNA by CD4 nadir HIV DNA - combined treatment arms Nadir CD4 count N Mean Log 10 HIV DNA ±SE Median < 200 cells/ul ± >= 200 cells/ul ± p=0.03 CD4 nadir >100 cells/µl was an inclusion criterion for the MONET trial. Patients needed to have CD4 counts at least 200 cells/µl at the screening visit.

10 HIV DNA: correlation with elevations in HIV RNA Log 10 HIV DNA for patients with HIV RNA elevations >50 copies/ml during the trial, versus no elevations HIV RNA category At least one HIV RNA >=50 No HIV RNA above 50 p<0.05 DRV/r DRV/r+2NRTIs N Mean Log 10 HIV DNA ±SE Median n Mean Log 10 HIV DNA ±SE Median ± ± ± ± In both treatment arms, HIV DNA levels were higher for patients with at least one elevation In HIV RNA >= 50 copies/ml, compared to patients with HIV RNA consistently below 50 copies/ml At individual patient visits, mean HIV DNA was: 2.48 log 10 copies for samples with HIV RNA <5 copies/ml 2.72 log 10 copies for samples with HIV RNA 5-50 copies/ml 2.82 log 10 copies for samples with HIV RNA >50 copies/ml

11 IL-6 or hs-crp above pre-defined limits at Week 144 Treatment arm Marker DRV/r + 2NRTIs DRV/r mono IL-6 >3 pg/ml 20/65 (31%) 15/64 (23%) CRP > 5 mg/l 8/80 (10%) 9/75 (12%) There was no significant correlation between HIV DNA levels at Week 144 and levels of the inflammatory markers hs-crp or Interleukin-6 (p=n.s.).

12 Conclusions In the Monet trial, HIV DNA levels remained stable during 144 weeks of either DRV/r monotherapy or DRV/r + 2NRTIs. Higher HIV DNA levels were seen in patients with nadir CD4 counts below 200 cells/µl and/or detectable plasma HIV RNA. There was no difference in levels of IL-6 or hs-crp between the arms at Week 144. Levels of these inflammatory markers did not correlate with HIV DNA levels. We only have information on a subset of patients at Week 144. This was a post-hoc analysis of available stored samples.

13 Thanks to the patients, investigators and study coordinators who participated in the MONET trial Recruitment by country Switzerland 0.8% UK 8.2% Austria 6.3% Belgium 9.4% Spain 18.8% Denmark 10.9% Russia 4.3% Portugal 5.5% Germany 10.9% Poland 11.3% Italy 6.3% Hungary Israel 4.3% 3.1% Display GEN 67