Low-level Viremia below 50 cps/mL in treated HIV-infected patients - - PowerPoint PPT Presentation

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Dec 03, 2022 632 likes •818 views

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

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SLIDE 1

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

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SLIDE 2

Introduction

  • Treatment guidelines recommend plasma HIV-1 RNA

suppression <50 cps/ml as the optimal outcome of HAART1,2

  • However, using sensitive detection methods, plasma HIV-1

RNA can be detected in up to 80% of treated patients with VL <50 copies/ml3,4

  • Mean level of residual viraemia approx 3-10 cps/ml3,4,

comprised by invariant clones from unclear source5,6

  • 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

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SLIDE 3

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 raltegravir7,8 Or LLV represents ongoing replication

  • Suppression of LLV after abacavir intensification9
  • Progressive increase in LLV prior to rebound10
  • 2-LTR circles increase in raltegravir intensification studies11
  • 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

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SLIDE 4

Sensitive VL monitoring

  • Abbott RealTime PCR currently in use for routine monitoring in
  • ur 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
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SLIDE 5

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

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SLIDE 6

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

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SLIDE 7

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)

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SLIDE 8

Results- Patient characteristics at T0

T0

VL P 40-49 RNA+ RNA- Whole population Number 240 507 500 Yrs of VL <50 cps/mL pre-T0 Median (IQR) 0.2 (0.0, 0.6) 1.3 (0.4, 2.8) 2.8 (1.2, 4.5) <0.0001 Month of follow-up post- T0 Median (range) 14 (1, 33) 14 (2, 21) 14 (4, 17) 0.69 RFH patients alone Number 164 352 375 Yrs of VL <50 cps/mL pre-T0 Median (IQR) 0.2 (0.0, 1.0) 1.9 (0.5, 3.2) 3.2 (1.9, 4.7) <0.0001 Pre-HAART VL, log10 cps/mL Median (IQR) 5.3 (4.7, 5.8) 5.1 (4.6, 5.6) 5.0 (4.5, 5.6) 0.04 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/mm3 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)

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SLIDE 9

Patient characteristics at T0

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) Otherc 20 (12.2) 35 (9.9) 46 (12.3) Line of HAART, n (%) 1st 72 (43.9) 164 (46.6) 191 (50.9) 0.14 ≥2nd 51 (31.1) 87 (24.7) 78 (20.8) Unknown 41 (25.0) 101 (28.7) 106 (28.3) Adherence (% refilled prescriptions) Unavailable 42 (25.6) 38 (10.8) 20 (5.3) <0.0001 ≤60% 27 (16.5) 47 (13.4) 40 (10.7) >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)

T0

VL P 40-49 RNA+ RNA-

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SLIDE 10

Time to virological failure (confirmed >50 cps/ml)

Confirmed VL >50 cps/ml

Time since T0 (months)

― 40-49 ― RNA+ ― RNA-

P<0.0001 Log rank test

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SLIDE 11

Time to virological failure (confirmed >400 cps/ml)

Time since T0 (months)

Confirmed VL>400 cps/ml ― 40-49 ― RNA+ ― RNA-

P<0.0001 Log rank test

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SLIDE 12

Factors associated with confirmed VL rebound >400 cps/ml

Whole population Univariable results Multivariable results HR 95% CI P HR 95% CI P

T0

VL group 40-49 8.64 4.30, 17.35 <0.0001 6.91 2.90, 16.47 <0.0001 RNA+ 3.01 1.48, 6.15 2.88 1.24, 6.69 RNA- 1.00

  • 1.00 -

Length VL <50 cps/mL pre-T0 Per yr longer 0.67 0.56, 0.80 <0.0001 0.82 0.69, 0.97 0.02

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SLIDE 13

Univariable results Multivariable results RFH patients alone HR 95% CI P HR 95% CI P

T0

VL group 40-49 13.92 5.39, 35.94 <0.0001 10.71 3.30, 34.81 <0.0001 RNA+ 4.16 1.56, 11.10 3.78 1.23, 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 log10 higher 0.79 0.59, 1.06 0.13 0.74 0.52, 1.05 0.10 Time since starting HAART Per yr longer 0.95 0.89, 1.01 0.10 1.14 1.02, 1.27 0.03 CD4 count Per 100 cells higher 0.88 0.79, 0.99 0.02 1.00 0.87, 1.15 0.97 Age Per 10 yrs older 0.72 0.52, 1.00 0.05 1.07 0.71, 1.62 0.74 Gender Male 0.69 0.39, 1.21 0.21 1.49 0.65, 3.38 0.35 Female 1.00

  • 1.00
  • Ethnicity

White 1.00

  • 0.002

1.00

  • 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

  • 0.03

1.00

  • 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 0.007 0.46 0.17, 1.23 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 0.009 0.99 0.39, 2.47 0.99 <=95% 1.00

  • 1.00
  • >95%

0.43 0.22, 0.83 0.96 0.45, 2.07

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SLIDE 14

Efavirenz plasma concentration at T0

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 P=0.48

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SLIDE 15

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.

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SLIDE 16

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.

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SLIDE 17

Ackowledgements

Department of Virology

  • Anna Maria Geretti
  • Tomas Doyle

Department of Bioepidemiology and Statistics

  • Colette Smith
  • Valentina

Cambiano

  • Andrew Phillips