Low-Level Viremia in HIV Arevir Meeting 03.05.2012 Thomas Berg, - PowerPoint PPT Presentation

Low-Level Viremia in HIV Arevir Meeting 03.05.2012 Thomas Berg, Martin Obermeier Berlin

Low Level Viremia – What is it? Low – level viraemia on HAART: significance and management, Doyle T, Geretti AM, Curr Opin Infect Dis, 2012, 25:17- 25.

Low Level Viremia (LLV)? Currently no standardized definition Ranges between 1 cop/ml and 500 cop/ml Sometimes distinction between “blip” (once detected viral load in a certain range) and LLV (repeated detected viral load)

Patient 16483 background data Sex : male Age : 46 years old Time of first dagnosis : 1988 HIV subtype : B Way of transmission : MSM BMI : 21,8 Kg/m², 78 Kg, 189 cm comorbidities : phlebothrombosis right lower limb 200606 no Hepatits B/C coinfection, no Lues

Patient 16483 background data Presented himself 2005, previous physician stopped practising his profession May 2005: Treatment : AZT + 3TC + IDV 3x400 unboosted Laboratory values: CD4 : 625 /µl CD4 % : 32 VL : 390 cop./ml

Patient 16483 Date treatment 1995 AZT mono 1996 - beginning 1997 AZT + 3TC 1997 - 2005 AZT + 3TC + IDV 3x 400 unboosted patient does not want to change treatment

Patient 16483 date treatment 1997 - 2005 AZT + 3TC + IDV 3x 400 unboosted 2005 – 2008 CBV + IDV 3x400 unboosted

Patient 16483 VL and CD4 1000 700 VL CD4 600 500 100 HIV-VL cop./ml 400 CD4/µl 300 10 200 100 1 0 F A F A F A F A F e u e u e u e u e b g b g b g b g b 0 0 0 0 0 0 0 0 0 5 5 6 6 7 7 8 8 9 Is the low level replication relevant?

Genotypic drug resistance testing 16483 Date RT- Gene Protease- Gene 11 / 05 not possible 08 / 06 not possible 12 / 07 not possible 11 / 08 VL 410 cop./ml M41L,E44D,D67N, L10F, M184V,L210W,T215Y K20T,V32I,M46I,I47V, A71T, L89V,L90M Coreceptor usage: CXCR4 (geno2pheno FPR 1.7), HIV-Subtyp: B HIV-Subtyp: A HLA B 5701 negative

Genotyp drug resistance 16483

Genotyp drug resistance 16483 Interpretation: NNRTI possible, PI: I.choice TPV, II.choice DRV, HIV-Subtyp: B HIV-Subtyp: A Coreceptor usage: CXCR4 (geno2pheno FPR 1.7), HLA B 5701 negative

Follow-up Patient 16483 Treatment was changed to : - Raltegravir 400 2x1 (Isentress) - Darunavir 300 2x2 (Prezista) - Etravirine 100 2x2 (Intelence) - Ritonavir 100 2x1 (Norvir)

Follow-up Patient 16483 1000 700 600 VL 500 CD4 100 HIV-VL cop./ml 400 CD4/µl 300 10 200 100 1 0 Aug 04 Feb 05 Aug 05 Feb 06 Aug 06 Feb 07 Aug 07 Feb 08 Aug 08 Feb 09 Aug 09 Feb 10 Aug 10 Feb 11 Aug 11 Feb 12 Aug 12

Patient 28971 background data sex : male age : 30 years old Time of diagnosis : 2007 HIV subtype : B Way of transmission : MSM Co-morbidities : none No Hepatitis B/C coinfection, no Lues

Patient 28971 background data Presented to physician 2010 October 2010: Current treatment : none Laboratory findings: CD4 : 68 /µl CD4 % : 8 VL : 506000 cop./ml Genotypic drug resistance result (november 2010): no resistance associated mutations Treatment (started november 2010): FTC/TDF/EFV

Follow-up Patient 28971 November 2010 1000000 350 FTC + TDF + EFV 300 100000 VL HIV-VL cop./ml 250 CD4 10000 CD4/µl 200 1000 August 2011 until end of 150 December 2011 + RAL 100 100 10 50 1 0 Aug 10 Aug 11 Aug 12 Feb 11 Feb 12

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial Gandhi RT et al. PLoS Med 2010; 7(8): e1000321. doi:10.1371/journal.pmed.1000321

Plama HIV-1 Detection Below 50 Copies/mL and Risk of Virologic Rebound in Patients Recieving Highly Active Antiretroviral Therapy Time to VL >400 cop/ml stratified by baseline viremia RNA 40-49 cps/ml <40 cps/ml (RNA detected) <40 cps/ml (RNA not detected) Doyle T et al, Clinical Infectious Diseases 2012;54(5):724-32

Inter-assay variability : 10fold measurement (undiluted) clinical sample with previous result <40 Kopien/ml (detected) Abbott Roche Abbott Roche RealTime TaqMan v.2 RealTime TaqMan v.2 copies/ml copies/ml log 10 log 10 (v.2) Tag 1 <40 (26) 110 1,59 2,04 Tag 2 62 155 1,79 2,19 Tag 3 57 33 1,76 1,52 Tag 4 <40 (29) 101 1,59 2,00 Tag 5 <40 (20) 57 1,59 1,76 Tag 6 <40 (16) 50 1,59 1,70 Tag 7 <40 (9) 59 1,59 1,77 Tag 8 83 70 1,92 1,85 Tag 9 <40 (39) 63 1,59 1,80 Tag 10 50 103 1,70 2,01 Mean ± SD 48 ± 15,8 60 ± 36,5 1,67 ± 0,12 2,17 ± 0,19 Median 39 66 1,59 1,82 VK 33% 61% 7% 11% Naeth G, Ehret R, Wiesmann F, Jates C, Berger A, Braun P and Knechten H; ICAAC, 2011; EACS, 2011

Inter-assay variability : 10fold measurement undiluted clinical samples sample 1 sample 1 sample 2 sample 2 RealTime TaqMan v.2 RealTime TaqMan v.2 copies/ml copies/ml copies/ml copies/ml Tag 1 90 110 80 110 Tag 2 91 244 75 127 Tag 3 95 161 102 241 Tag 4 161 56 113 214 Tag 5 101 174 85 58 Tag 6 86 105 66 177 Tag 7 68 241 137 112 Tag 8 101 157 78 125 Tag 9 105 188 <40 (29) 209 Tag 10 76 173 91 295 Mean ± SD 91,4 ± 25,1 160,9 ± 58,8 85,6 ± 28,8 166,8 ± 72,61 Median 93 167 83 152 VK 26% 37% 34% 44% Naeth G, Ehret R, Wiesmann F, Jates C, Berger A, Braun P and Knechten H; ICAAC, 2011; EACS, 2011

Retrospective study with 139 patients under HAART 69 patients with VLLV (<40 cop./ml „detectable“ versus 70 patients < 40 „undetectable“) Observation period 36 months Assessment of virological, immunological and clinical outcome Always undetectable Always <50 cop/ml No significant difference in „virological failure“ = repeatedly VL > 50 cop./ml or treatment change because of viremia (n=8/3, p=0.112) No significant difference in CD4 cell count No significant difference in treatment outcome = treatment change (n=30/34) or development of resistance (n=5/2) (n=„detectable“/“undetectable“) Widdrington, J., Payne, B., Medhi, M., Valappil, M. & Schmid, M. L. The significance of very low-level viraemia detected by sensitive viral load assays in HIV infected patients on HAART. J. Infect. 62 , 87–92 (2011).

Prevalence, predictors and outcome in patients with low level viral replication (LLVR) Spanish cohort (1999-2006), retrospective analysis of all patients with low VL (50-500 copies/ml) remaining on same HAART (655 of 2720) Virological failure was defined as VL >500 copies/ml (n=66, 9.1 %) Garcia-Gasco et al.; Journal of Antimicrobial Chemotherapie (2008) 61 , 699 - 704

Prevalence, predictors and outcome in patients with low level viral replication Garcia-Gasco et al.; Journal of Antimicrobial Chemotherapie (2008) 61 , 699 - 704

Height of viral rebound (51-500 copies/ml) and risk of virological failure 20 18 Virological failure (%) 16 14 12 10 Only risk factor for virological failure was a viral load >120 cop/ml !! 8 6 4 2 0 Plasma HIV-RNA 51-100 101-300 301-500 Number of patients 345 246 64 Garcia-Gasco et al.; Journal of Antimicrobial Chemotherapie (2008) 61 , 699 - 704

Low Level Viremia – what is the explanation? 3 10 ongoing (HIV-1 RNA copies/ml plasma) 400 replication 2 10 50 viral load 20 1 10 release from the 1 latent reservoir -1 10 time on ART L Shen und RF Siliciano, JACI, 2008

Mutations plotted against viral load

Resistance plotted against viral load (HIV-GRADE Interpretation) 90 80 70 60 50 keine resistenz 1 Klasse 40 2Klasse 30 3 Klassen 20 10 0 200-400 1000-10000 >100000 <200 400-1000 10000-100000 n= 35 47 115 440 706 596 Obermeier, Berg accepted at international HIV and Hepatitis workshop

Low Level Viremia What are the consequences ? Further studies are required to elucidate the desirable , clinical- relevant sensitivity of VL-monitoring in clinicle practice, and the optimal management of patients showing LLV The target level of VL suppression may need revision to a lower cutoff than 50 cop./ml but there is no evidence for general, assay-independent recommandations General recommandations include confirmation of LLV in a repeat sample…,a clinical review…and the assesment of drug resistance and plasma drug levels Most treated patients with long-term VL suppression show residual viraemia between 1 -10 cop./ml, but the source and clinical significance remain controversial, and there is limited evidence that HAART modifications have a appreciable impact Low – level viraemia on HAART: significance and management, Doyle T, Geretti AM, Curr Opin Infect Dis, 2012, 25:17- 25.

Low Level Viremia What are the consequences? (lab opinion) Do not overreact to viral loads betwen 1-50 cop/ml Higher costs due to repeated retesting But !! unnecessary treatment intensification with potential Acknowledgment toxicities Axel Baumgarten Treatment needs to be individualized !! Confusing patients and physicians Patrick Braun Patrick Ingiliz …….lab values are surrogate markers! Rolf Kaiser Between 50-200 cop/ml perform drug resistance testing Thomas Berg Above 200 cop/ml drug resistance testing and treatment change