Cambiano, V

Castro, H

Chadwick, D

Dunn, D

Geretti, AM

Phillips, A

Smit, E

English

UCL Discovery

All eligible patients (n=1,636) Patients with a resistance test after TI (while off-ART) Yes (n=208) No (n=1,428) p Male, n (%) 1,137 (69%) 136 (65%) 1,001 (70%) 0.1678 Ethnicity*, n (%) White 885 (54%) 113 (56%) 772 (55%) 0.4005 Black 595 (36%) 71 (35%) 524 (38%) Other 115 (7%) 19 (9%) 96 (7%) Mode of infection**, n (%) MSM 732 (45%) 115 (57%) 617 (47%) 0.0089 HT 683 (42%) 80 (40%) 603 (46%) Other 97 (6%) 6 (3%) 91 (7%) Age, med (IQR) 38 (33-45) 35 (30-40) 38 (33-45) <.0001 Calendar year of TI, med (IQR) Apr04 (Feb02; Dec06) Jan03 (Sep01; Sep04) Sep04 (Mar02; Apr07) <.0001 VL at TI <50 copies/ml, n (%) 1,421 (87%) 172 (83%) 1,249 (87%) 0.0600 Maximum VL on ART, med (IQR) 251 (50-2,703) 406 (60-20,536) 230 (50-1,974) 0.0033 Months with VL<200 copies/ml, med (IQR) 12 (4-30) 6 (2-21) 12 (4-32) <.0001 Resistance test pre-ART, n (%) (if done, no NNRTI mutations were detected) 384 (23%) 51 (25%) 333 (23%) 0.7029 Years ART initiation - TI, med (IQR) 1.70 (0.63-3.62) 1.05 (0.40-2.71) 1.77 (0.68-3.69) <.0001 Most recent CD4 count (cells/μl) at TI, med (IQR) 415 (271-586) 456 (305-640) 408 (270-576) 0.0102 CD4+ nadir count (cells/μl), med (IQR) 295 (140-466) 379 (230-513) 280 (135-453) <.0001 NNRTI at TI, n (%) NVP 779 (48%) 127 (61%) 652 (46%) <.0001 EFV 864 (53%) 81 (39%) 783 (55%) <.0001 Other 5 (0%) 1 (0%) 4 (0%) 0.6243 NRTI at TI, n (%)  AZT 778 (48%) 132 (48%) 646 (45%) <.0001 DdC 2 (0%) 1 (0%) 1 (0%) 0.2382 DdI 176 (11%) 20 (7%) 156 (11%) 0.5692 D4t 229 (14%) 33 (12%) 196 (14%) 0.4060 3TC 1,179 (72%) 177 (64%) 1,002 (70%) <.0001 ABC 253 (15%) 34 (12%) 219 (15%) 0.7066 TDF 369 (23%) 21 (8%) 348 (24%) <.0001 FTC 240 (15%) 8 (3%) 232 (16%) <.0001 • Among the 208 individuals with a resistance test performed after stopping suppressive NNRTI-based ART (see characteristics in table 1), 12% (n=25, 95% CI: 8%-17%) had ≥1 NNRTI resistance mutation detected at the first resistance test following ART treatment interruption.  • In those with at least 1 NNRTI resistance mutation detected the median time between TI and the resistance test was 12 months (IQR: 3-20 months). • The distribution of NNRTI resistance mutations, when detected after ART interruption is illustrated in Figure 2. K103N was the most prevalent mutation. There was no occurrence of K101H/P, V106M, Y181/V, Y188C/H or G190S.   • To our knowledge this is the largest study to evaluate the detection of NNRTI resistance in the rebound viremia that follows interruption of a suppressive NNRTI-based regimen.  • It confirms that resistance is a relatively common phenomenon, occurring in 12% of patients tested. • These estimates support the concept that interruption of EFV or NVP based ART carries a significant risk to the patient and informs models that incorporate HIV drug resistance emergence and transmission. Detection of NNRTI resistance mutations after interrupting NNRTI-based regimens Valentina Cambiano1, Hannah Castro2, David Chadwick3, Erasmus Smit4, Anna Maria Geretti5, David Dunn2, Andrew Phillips1  on behalf of UK HIV Drug Resistance Database & UK CHIC study.   1. UCL, London, UK; 2. MRC CTU at UCL, London, UK; 3. South Tees Hospital NHS Foundation Trust, Middlesbrough, UK; 4. Birmingham Heartlands and Solihull NHS Trust, Birmingham, UK; 5. University of Liverpool, Liverpool, UK;  BACKGROUND   There is evidence that NNRTI mutants emerge after interruption of suppressive NNRTI-based ART, due to the long half-life of NNRTIs.  This has implications for both loss of treatment options for people undergoing ART interruption and potential transmission of drug resistance.  The aim of this study was to quantify the extent to which NNRTI mutations can be detected in the rebound viremia following interruption of suppressive NNRTI-based ART. METHODS   The study population comprised patients from the UK HIV Drug Resistance Database and from the UK Collaborative HIV Cohort study (UK CHIC).  Figure 1 illustrates  the  eligibility criteria and the size of the population eligible for the analysis. Virologic failure is defined as a VL>200 copies/ml, after at least 6 months on a certain regimen. Resistance Only resistance tests conducted after treatment interruption (TI) while off ART were considered.  NNRTI resistance was defined as at least one major NNRTI  mutation according to the IAS-USA list (2008).   Statistical analysis • Firstly, it was assessed whether there were significant differences, for the covariates listed below, between those who had a resistance test performed during the TI and those who did not. Chi-square test for categorical variable and Kruskal Wallis test for continuous variables were used. Crude and adjusted relative risks (RR) of having a resistance test performed after TI were calculated using a modified Poisson regression approach. • Covariates considered include: demographic variables, calendar year of TI, whether the viral load (VL) was below 50 copies/ml at TI, length of virologic suppression, whether a resistance test was conducted pre-ART, time from ART initiation to TI, CD4 count at TI and CD4 count nadir, type of antiretroviral drug at TI and type and number of antiretroviral drugs experienced before TI (not shown).  • For the main analysis, the same approach was used to identify predictors of having NNRTI resistance detected in the rebound viremia after TI. • Additional covariates considered include time from TI to resistance test, CD4 count at resistance test off-ART and subtype   RESULTS   Predictors of resistance test availability  Acknowledgements: UK CHIC and UK HDRD were funded by the Medical Research Council, UK (Grant numbers G0000199, G0600337 and G0900274). This work was supported by the UK Medical Research Council (grant G0900274) and the European Community’s 7th framework programme (FP7/2007-2013) under the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; project 223131). The views expressed in this poster are those of the researchers and not necessarily those of the MRC. UK Collaborative Group on HIV Drug Resistance Steering Committee: Celia Aitken, David Asboe, Anton Pozniak, Patricia Cane, Hannah Castro, David Dunn (Co-PI), Esther Fearnhill, Kholoud Porter, David Chadwick, Duncan Churchill, Duncan Clark, Simon Collins, Valerie Delpech, Sam Douthwaite, Anna Maria Geretti, Antony Hale, Stéphane Hué, Steve Kaye, Paul Kellam, Linda Lazarus, Andrew Leigh-Brown, Tamyo Mbisa, Nicola Mackie, Chloe Orkin, Eleni Nastouli, Deenan Pillay (Co-PI), Andrew Phillips, Caroline Sabin, Erasmus Smit, Kate Templeton, Peter Tilston, Daniel Webster, Ian Williams, Hongyi Zhang, Mark Zuckerman.   UK CHIC Steering Committee: Jonathan Ainsworth, Jane Anderson, Abdel Babiker, David Chadwick, Valerie Delpech, David Dunn, Martin Fisher, Brian Gazzard, Richard Gilson, Mark Gompels, Phillip Hay, Teresa Hill, Margaret Johnson, Stephen Kegg, Clifford Leen, Mark Nelson, Chloe Orkin, Adrian Palfreeman, Andrew Phillips, Deenan Pillay, Frank Post, Caroline Sabin (PI), Memory Sachikonye, Achim Schwenk, John Walsh. Figure 1.Overview of patients eligible for the analysis   • Of 1,636 eligible patients, 13% (n=208) had a resistance test performed after stopping suppressive NNRTI-based ART. Table 1 illustrates the characteristics of the people who did and did not have a resistance test after treatment interruption. • The covariates significantly associated with the presence of a resistance test after TI (mode of infection, age, calendar year of TI, maximum VL achieved, length of time with VL<200 copies/ml, years from ART initiation to TI, most recent CD4 count at  TI, CD4 nadir, being on NVP, EFV, AZT, 3TC, TDF, FTC) were considered in a multivariate model. • Independent predictors of having a resistance test were: − older calendar year of TI (range 1997-2008, aRR per 1 more recent calendar year = 0.89; 95% confidence interval [CI]: 0.85-0.93; p<0.0001)  − higher maximum VL on ART pre-TI  (aRR per 1 log increase=1.14; 95% CI: 1.04-1.26; p=0.0042) − younger age (aRR per 1 year older = 0.96; 95%CI: 0.94-0.97; p<0.0001) − higher CD4 count nadir (aRR per 100 cells/µl increase=1.08; 95%CI: 1.04-1.12; p<0.0001) − being on 3TC at ART interruption (aRR = 1.99; 95%CI: 1.39-2.87; p<0.0001).  CONCLUSIONS MSM: men having sex with men; HT: heterosexual; med: median; IQR: interquartile range; *n=2440; **n=2351; ***n=2181 Table 1. Baseline characteristics  Detection of NNRTI resistance mutations  Detection of NNRTI resistance mutations  Figure 2. NNRTI resistance mutations detected after NNRTI interruption • The only independent predictor of NNRTI resistance being detected (in a multivariate model including CD4 cell count at TI, CD4 nadir and NVP at TI) was CD4 nadir (aRR for 100 cells/µl increase in CD4 nadir = 0.67; 95% CI: 0.53-0.85; p=0.001).  Sensitivity analysis  1. Patients who stopped their ART regimen while having a VL ≤ 50 copies/ml (n=1,421, 87%) with a resistance test after TI (172/1421, 12%)  • 12% (20; 95%CI: 7-17%) had NNRTI resistance 2. People who had a resistance test performed within 2 months since TI (n=55/208, 26%).  • 7% (4; 95% CI: 3-19%) had NNRTI resistance 3. People who had a resistance test performed within 6 months since TI (n=94/208, 45%).  • 9% (8; 95% CI: 4-17%) had NNRTI resistance 4.  Simultaneous TI, with resistance test (n=188): • 12% (23; 95% CI: 7-17%) had NNRTI resistance  5. Staggered TI, with resistance test (n=20): • 10% (2; 95% CI: 1-32%) had NNRTI resistance Eligible for analysis:  1,636 patients who at TI:  • had no evidence of NNRTI resistance  • had VL<200 copies/ml at TI • did not experience virologic failure 2,439 patients • interrupted NNRTI-based ART  • had viral load data available 28 had NNRTI resistance mutations pre-TI 338 failed NNRTI pre-TI 437 had a VL>200 copies/ml at TI 16,472 patients in UK CHIC had been exposed to NNRTI 287 no virologic data before TI 13,746 did not interrupt ART 

Detection of NNRTI resistance mutations after interrupting NNRTI-based regimens

https://discovery.ucl.ac.uk/10085822/1/CROI2014_593_Cambiano_Detection%20of%20NNRTI%20resistance%20mutations%20after%20interrupting%20NNRTI-based%20regimens.pdf

Detection of NNRTI resistance mutations after interrupting NNRTI-based regimens

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