Low-level Viremia below 50 cps/mL in treated HIV-infected patients predicts viral load rebound above 400 cps/mL independently of adherence levels P Vitiello † , T Doyle † , C Smith † , V Cambiano † , A Owen*, A Philips † , AM Geretti † , † University College London *University of Liverpool
Introduction Treatment guidelines recommend plasma HIV-1 RNA suppression <50 cps/ml as the optimal outcome of HAART 1,2 However, using sensitive detection methods, plasma HIV-1 RNA can be detected in up to 80% of treated patients with VL <50 copies/ml 3,4 Mean level of residual viraemia approx 3-10 cps/ml 3,4 , comprised by invariant clones from unclear source 5,6 1. Gazzard et al 2008. 2. Thompson et al 2010 3. Maldarelli et al 2007 4. Palmer et al 2008 5. Bailey et al 2006 6. Brennan et al 2009
Clinical significance of low level viraemia (LLV) LLV originates from virus reactivation and is then suppressed Residual viremia is unresponsive to short-term intensification with EFV, ATZ/RTV, LPV/RTV, T20 or raltegravir 7,8 Or LLV represents ongoing replication Suppression of LLV after abacavir intensification 9 Progressive increase in LLV prior to rebound 10 2-LTR circles increase in raltegravir intensification studies 11 7. Dinoso et al, 2009 8.Archin et al, 2010 9. Havlir et al, 2003 10.Wilkin et al, 2009 11. Buzon et al, 2010
Sensitive VL monitoring Abbott RealTime PCR currently in use for routine monitoring in our department Assay quantifies between 40-49 copies/ml Reports qualitative RNA detection below 40 copies/ml with decreasing sensitivity at lower viral loads VL <50 cps/ml not reported to treating clinician
Aims To investigate the virologic outcomes of treated patients showing a VL <50 copies/ml at an arbitrarily selected time point according to the actual level of viraemia below 50 cps/ml To characterise the resistance profile of patients who experienced virological failure subsequent to experiencing LLV <50 cps/ml
Methods Patients selected with one of the following measurements: 40-49 copies/ml RNA detected <40 copies/ml (RNA + ) RNA not detected (RNA - ) Patients were selected that had at least 12 months of follow-up after this time point (T0) Demographic and clinical data were obtained from the clinic database for RFH treated patients Adherence was estimated at T0 based upon the proportion of days covered by a valid prescription in the 6 months prior to T0
Methods-statistical analysis The characteristics of the three groups were compared at T0 Virologic failure identified according to 2 definitions 1) Two consecutive VLs >50 copies/ml (or a single VL>50 copies/ml if this was the last available). 2) Equivalent definition using >400 cps/ml Difference in time to virologic rebound assessed Factors associated with rebound identified using Cox Proportional Hazards model (adjusted for all available variables)
Results- Patient characteristics at T0 VL T0 40-49 RNA + RNA - P Number 240 507 500 Whole population Yrs of VL <50 cps/mL Median (IQR) 0.2 (0.0, 0.6) 1.3 (0.4, 2.8) 2.8 (1.2, 4.5) <0.0001 pre-T0 Month of follow-up post- Median (range) 14 (1, 33) 14 (2, 21) 14 (4, 17) 0.69 T0 Number 164 352 375 RFH patients alone Yrs of VL <50 cps/mL Median (IQR) 0.2 (0.0, 1.0) 1.9 (0.5, 3.2) 3.2 (1.9, 4.7) <0.0001 pre-T0 Pre-HAART VL, log 10 Median (IQR) 5.3 (4.7, 5.8) 5.1 (4.6, 5.6) 5.0 (4.5, 5.6) 0.04 cps/mL Yrs of HAART Median (IQR) 2.9 (1.1, 7.9) 5.8 (2.4, 9.8) 6.9 (4.1, 10.1) <0.0001 CD4 count, cells/mm 3 Median (IQR) 405 (268, 559) 564 (413, 725) 581 (419, 794) <0.0001 Age, yrs Median (IQR) 40 (34, 44) 43 (38, 48) 43 (38, 48) <0.0001 Gender, n (%) Male 112 (68.3) 267 (75.9) 284 (75.7) 0.14 Ethnicity, n (%) White 79 (48.2) 233 (66.2) 253 (67.5) 0.0006 Black 67 (40.9) 95 (27.0) 98 (26.1) Other 18 (11.0) 24 (6.8) 24 (6.4)
Patient characteristics at T0 VL T0 40-49 RNA + RNA - P Risk group, n (%) MSM 75 (45.7) 212 (60.2) 219 (58.4) 0.0001 Hetero 86 (52.4) 116 (33.0) 131 (34.9) Other 3 (1.8) 24 (6.8) 25 (6.7) HAART regimen, n (%) NRTI+NNRTI 26 (15.9) 95 (27.0) 147 (39.2) <0.0001 NRTI+PI/r 114 (69.5) 196 (55.7) 165 (44.0) NRTI+PI 1 (0.6) 10 (2.8) 6 (1.6) NRTI only 3 (1.8) 16 (4.6) 11 (2.9) Other c 20 (12.2) 35 (9.9) 46 (12.3) Line of HAART, n (%) 1 st 72 (43.9) 164 (46.6) 191 (50.9) 0.14 ≥ 2 nd 51 (31.1) 87 (24.7) 78 (20.8) Unknown 41 (25.0) 101 (28.7) 106 (28.3) Adherence Unavailable 42 (25.6) 38 (10.8) 20 (5.3) <0.0001 (% refilled ≤ 60% 27 (16.5) 47 (13.4) 40 (10.7) prescriptions) >60 to ≤ 80 20 (12.2) 46 (13.0) 41 (10.9) >80 to ≤ 95 35 (21.3) 76 (21.6) 95 (25.3) >95 to ≤ 99.9 11 (6.7) 53 (15.1) 63 (16.8) 100 29 (17.7) 92 (26.1) 116 (30.9)
Time to virological failure (confirmed >50 cps/ml) ― 40-49 Confirmed VL >50 cps/ml ― RNA+ ― RNA- Time since T0 (months) P<0.0001 Log rank test
Time to virological failure (confirmed >400 cps/ml) ― 40-49 ― RNA+ Confirmed VL>400 cps/ml ― RNA- Time since T0 (months) P<0.0001 Log rank test
Factors associated with confirmed VL rebound >400 cps/ml Univariable results Multivariable results Whole population HR 95% CI P HR 95% CI P VL group 40-49 8.64 4.30, 17.35 <0.0001 6.91 2.90, <0.0001 T0 16.47 RNA + 3.01 1.48, 6.15 2.88 1.24, 6.69 RNA - 1.00 - 1.00 - Length VL <50 cps/mL Per yr longer 0.67 0.56, 0.80 <0.0001 0.82 0.69, 0.02 pre-T0 0.97
Univariable results Multivariable results HR 95% CI P HR 95% CI RFH patients alone P VL group 40-49 13.92 5.39, <0.0001 10.71 3.30, <0.0001 T0 35.94 34.81 RNA + 4.16 1.56, 3.78 1.23, 11.10 11.59 RNA - 1.00 - 1.00 - Length VL <50 cps/ml pre-T0 Per yr longer 0.70 0.58, 0.84 <0.0001 0.88 0.72, 1.06 0.15 Pre-HAART VL Per log 10 higher 0.79 0.59, 1.06 0.74 0.52, 1.05 0.13 0.10 Time since starting HAART Per yr longer 0.95 0.89, 1.01 1.14 1.02, 1.27 0.10 0.03 CD4 count Per 100 cells 0.88 0.79, 0.99 1.00 0.87, 1.15 0.02 0.97 higher Age Per 10 yrs older 0.72 0.52, 1.00 1.07 0.71, 1.62 0.05 0.74 Gender Male 0.69 0.39, 1.21 1.49 0.65, 3.38 0.21 0.35 Female 1.00 - 1.00 - - Ethnicity White 1.00 - 1.00 - 0.002 0.17 Black 2.73 1.57, 4.77 2.40 0.91, 6.36 Other 1.90 0.72, 5.00 1.85 0.59, 5.83 Risk group MSM 1.00 - 1.00 - 0.03 0.63 Hetero 2.07 1.19, 3.61 1.36 0.48, 3.85 Other 1.86 0.64, 5.41 2.07 0.50, 8.60 HAART NNRTI-based 0.32 0.14, 0.71 0.46 0.17, 1.23 0.007 0.23 Other 0.80 0.39, 1.66 0.99 0.40, 2.46 PI-based 1.00 - 1.00 - Adherence Unavailable 1.32 0.65, 2.68 0.99 0.39, 2.47 0.009 0.99 <=95% 1.00 - 1.00 - >95% 0.43 0.22, 0.83 0.96 0.45, 2.07
Efavirenz plasma concentration at T0 P=0.48 At T0 plasma EFV concentrations were measured by HPLC in stored plasma from 187 patients. Median values were 1666, 1339 and 1593 ng/ml in the T0 VL 40-49, RNA+ and RNA- respectively
Resistance analysis 80 patients experienced virologic rebound >400 copies/ml. 63 resistance test results were obtained The median (IQR) interval between the first VL measurement >400 copies/ml and the resistance test was 5.5 weeks (2, 8.5). The proportion of tests showing ≥ 1 major RAM was 12/35 (34.3%), 9/21 (42.9%) and 2/7 (28.6%) in patients with T0 VL 40- 49 copies/ml, RNA + , and RNA - respectively (p=0.75) Amongst those who developed ≥ 1 major RAM, the breakdown by drug class was NRTIs 18/23 (78.3%), NNRTIs 10/23 (43.5%), and PIs 5/23 (21.7%). Overall 17/23 (73.9%) patients with resistance had ≥ 1 RAM affecting drugs taken at the time of rebound .
Conclusions VL levels of 40-49 cps/ml and to a lesser extent RNA detection <40 cps/ml at an arbitrary time point during HAART strongly and independently predicted VL rebound >50 and >400 cps/ml at 12 months This suggests that the optimum goal of HAART may need to be reviewed HIV-1 RNA detection below 50 cps/mL during HAART varied with the levels of adherence, but there appeared to be no relation with EFV plasma levels among EFV-treated patients. There was no significant difference in RAMs present at subsequent virological rebound across the three groups using population sequencing.
Ackowledgements Department of Virology Anna Maria Geretti Tomas Doyle Department of Bioepidemiology and Statistics Colette Smith Valentina Cambiano Andrew Phillips
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