Professor Anna Maria Geretti

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2 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Professor Anna Maria Geretti Institute of Infection & Global Health, University of Liverpool 1-4 April 2014, Arena and Convention Centre Liverpool

3 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Professor Anna Maria Geretti Institute of Infection & Global Health, University of Liverpool COMPETING INTEREST OF FINANCIAL VALUE > 1,000: Speaker Name Prof Anna Maria Geretti Statement In the last 12 months has acted in a Consultancy capacity for Gilead, GSK/ViiV, Janssen, MSD, Roche, and Tobira, and as a speaker at company-sponsored events for GSK/ViiV, Janssen, MSD, and Qiagen. Over the last three years her department has received grants for research from GSK/ViiV, Janssen, and MSD. Date April April 2014, Arena and Convention Centre Liverpool

4 Management of Sustained Low Level Viraemia

5 Q1: Which is your preferred definition of virological failure? 1. Confirmed HIV RNA detection 2. Confirmed viral load >50 cps/ml 3. Confirmed viral load >125 cps/ml 4. Confirmed viral load >200 cps/ml 5. Confirmed viral load >400 cps/ml 6. Confirmed viral load >1000 cps/ml

6 Defining virological failure EACS 2014: Confirmed >50 cps 6 months after ART initiation or modification DHHS 2013: Inability to achieve or maintain <200 cps IAS-USA 2012: Sustained elevation cps should prompt evaluation of factors leading to failure and consideration of changing ART BHIVA 2013: Failure to achieve <50 cps 6 months after starting ART, or confirmed rebound >400 cps after suppression <50 cps WHO 2013: Confirmed >1000 cps after 6 months of ART

7 Defining sustained low-level viraemia (sllv) VL *Cut-off for sllv: 50 cps 125 cps 200 cps % 400 cps 1000 cps Blip Bump sllv* Cut-off *sllv= repeatedly detectable LLV over a sustained period of time

8 HIV-1 RNA cps Residual HIV-1 RNA detection during ART Subjects on 1 st -line NNRTI-based ART with VL consistently <50 cps Tested by single copy HIV-1 RNA assay n = Years of ART HIV-1 RNA detection not associated with age, sex, race, risk group, duration of HIV diagnosis, nadir & current CD4 count, pre-art VL, NNRTI used, NNRTI concentration HIV-1 RNA Years of ART Total P cps/ml 0-4 (n=31) 5-7 (n=33) 8-15 (n=40) (n=104) Median (range) 3 (1, 35) 3 (1, 10) 3 (1, 11) 3 (1, 35) Geretti et al. International Workshop on HIV & Hepatitis Viruses Drug Resistance 2013

9 HIV-1 RNA kinetics after starting ART VL Phase 1 (days) Median months to cut-off (95%CI) 1 <50 cps 4.1 (3.3, 5.1) <40 cps 4.4 (3.7, 5.4) % <10 cps 6.2 (5.4, 7.2) Phase 2 (weeks) Cut-off Phase 3 (months) Doyle et al. Clin Inf Dis 2012

10 HIV-1 RNA kinetics after starting ART VL Phase 1 (days) % Cut-off Phase 3 (months) Phase 2 (weeks) Sanctuary sites Latently infected cell

11 HIV-1 RNA kinetics after starting ART VL Phase 1 (days) % Phase 2 (weeks) Cut-off Phase 3 (months)

12 Persistent HIV-1 replication associated with lower ARV concentrations in lymphatic tissues ARV concentrations measured in plasma + mononuclear cells from peripheral blood, lymph nodes (LN), ileum & rectum (n=12) Median % difference between PBMC and lymphoid tissue from all samples obtained during 6 months of ART Expected concentrations in plasma and PBMC Lower concentrations in lymphatic tissue, particularly LN Reduced viral decay in lymphatic tissue Fletcher et al. PNAS 2014

13 sllv by routine assays: Why do we worry? Reflects ongoing virus replication Predicts VL rebound with a dose-dependent effect Potential for viral genetic evolution Emergence of drug resistance Immune activation and inflammation May signal suboptimal control in certain compartments

14 Q2: Which is your preferred initial strategy in sllv? 1. Ignore it hoping it will go away 2. Change ART to include a PI/r 3. Intensify ART with a new agent 4. Repeat the viral load with a different assay 5. Request a resistance test 6. Request a resistance test & drug levels

15 What happens to patients with sllv? Patients with 12 months of ART who achieved <1000 cps sllv for 6 months, strata , , cps Versant bdna v3 (99-10) and Abbott Real-Time (since 2010) Virologic Failure sllv predicts VL >1000 cps after 1 yr (Cox model) Persistence Duration, HIV Load Univariate Multivariate a 6 mo HR (95% CI) P Value Adjusted HR (95% CI) P Value <50 RNA copies/ml 1.00 (reference) 1.00 (reference) RNA copies/ml 2.61 ( ) < ( ) < RNA copies/ml 2.92 ( ) < ( ) < RNA copies/ml 5.57 ( ) < ( ) <.001 Adjusted 9 mo for age, sex, race, sexual orientation, IDU, monthly income, type <50 of RNA employment, copies/mldate of HIV diagnosis, 1.00 (reference) baseline CD4 count, ART use 1.00 (reference) RNA copies/ml 3.35 ( ) < ( ) <.001 Laprise et al. Clin Infect Dis RNA copies/ml 3.73 ( ) < ( ).001

16 % with rebound What happens to patients with LLV? Rebound >50 and >400 cps over 1 year according to LLV stratum (n= 1247) % Rebound >50 cps/ml Rebound >400 cps/ml Same findings in separate study using Abbott RealTime % 11.3% 3.8% 4% 1.2% cps cps TND* T0 VL cps/ml T0 RNA+ T0 RNA- Same findings with Roche TaqMan v1 3 & v2 4 *TND = Target not detected (approx. <10 cps) Doyle et al. Clin Inf Dis 2012; 2. Calcagno et al. EACS 2013; Henrich et al. PlosOne 2012; 4. Álvarez et al. J Clin Microbiol 2013

17 Factors associated with LLV by routine assays Patients more likely to show LLV Lower adherence 1 Younger age 1 Gender/risk group other than white MSM 1 Higher pre-art viral load 1 Shorter duration of ART 1 Lower CD4 count 1 On PI/r-based ART (PI monotherapy > PI/r+2NRTIs) 1-5 HCV positive 2 Higher cellular HIV DNA load 4,5 1.Doyle et al. Clin Infect Dis 2012; 2. Arribas et al. HIV Med 2012; 3. Paton et al. CROI 2014; 4. Lambert-Niclot et al. PlosOne 2012; 5. Geretti et al. HCT 2013

18 HIV-1 RNA detection below 50 cps during randomised 1 st -line ART STUDIES 102 and 103 (TDF/FTC + EVG/c, EFV or ATV/r) HIV-1 RNA ~10-49 cps at wk 144 <200 cps <400cps CD4 <200 (n=187) 43% HIV-1 RNA detected <50 cps CD4 >200 (n=1221) 37% Adherence <95% 52% Adherence >95% 32% BL VL >100K HIV-1 (n=525) RNA Target Not Detected 46% BL VL <100K (n=883) 30% % cps at week 144 TND* wks 48 to 144 (9 visits) ATV/r (n=355) EVG/c (n=353) EFV (n=352) EVG/c (n=348) % TND wk % 15% 17% 17% *TND = Target not detected (approx. <10 cps) White et al. CROI 2014

19 Detection of LLV varies according to the assay <50 cps >50 cps Amplicor 1.5 RealTime TaqMan v2 Amplicor NA 6%-23% RealTime NA - 13% TaqMan v2 5% 7% - ~125 cps by TaqMan v2 = 50 cps by Amplicor v1.5 1 Assays that capture RNA and DNA during extraction are vulnerable to variations in sample collection and handling (e.g., PTT vs. EDTA tubes, delays in plasma separation) 2 1. The International Viral Load Assay Collaboration. JCM 2014; 2. Adachi et al. IAS 2013

20 Management strategies for sllv -1 Management options remain anecdotal Doing nothing is probably not best practice Review: Adherence, tolerability, life style, personal/social issues Expected potency of the regimen Potential for drug interactions Potential for worse control in key compartments Reasonable to perform drug resistance testing Reasonable to check drug levels in selected cases Consider technical issues of viral load testing

21 Management strategies for sllv-2 Management options remain anecdotal Doing nothing is probably not best practice At a minimum adjust the frequency of follow-up to capture rebound at higher levels In selected cases, a short trial of intensification may be considered Consider a change of ART to a PI/r to limit build up of resistance Change of PI/r (if already on PI/r) a reasonable option

22 False facts are highly injurious to the progress of science, for they often endure long; but false views, if supported by some evidence, do little harm, for every one takes a salutary pleasure in proving their falseness. Charles Darwin Thank you

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