GESIDA 2018 ANTIRETROVIRAL TREATMENT MAINTENANCE STRATEGIES AND BLOOD TELOMERE LENGTH CHANGE

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1 ANTIRETROVIRAL TREATMENT MAINTENANCE STRATEGIES AND BLOOD TELOMERE LENGTH CHANGE Rocío Montejano 1, Natalia Stella-Ascariz 1, Susana Monge 1, Jose I Bernardino 1, Ignacio Perez-Valero 1, Marisa Montes 1, Luz Martin-Carbonero 1, Juan Gonzalez-García 1, Javier Rodriguez-Centeno 1, Berta Rodes 1, Belén Alejos 2, Rosa De Miguel 1, Andres Esteban-Cantos 1, Rosario Perona 3, Jose R Arribas 1 (1) Hospital Universitario La Paz-IdiPAZ, Madrid, Spain, (2) Instituto Salud Carlos III, Madrid, (3) Instituto de Investigaciones Biomedicas Alberto Sols, Madrid

2 Telomerase is a ribonucleoprotein that extends telomeres (TTAGGG) N Engl J Med Apr 27;342(17): Telomerase RNA is complementary to telomere repeat sequence Serves as template for addition of new DNA repeat sequences to telomere Additional rounds of telomere elongation occur after telomeres translocate to newlysynthesized end

3 Background Compared to HIV negative controls, HIV-infected individuals have shorter blood telomere length (TL) 1,2 After HIV seroconversion a rapid and substantial decrease in blood TL 3,4. Multiple mechanisms can contribute to TL attrition during HIV infection: inhibition of telomerase by HIV proteins such as HIV-Tat 5 chronic antigenic stimulation leading to a immunosenescence status characterized by a preponderance of well-differentiated T cells with shorter telomeres 6 direct inhibition of telomerase caused by nucleos(t)ide reverse transcriptase inhibitors [N(t)RTI] 7,8 1.Clin Infect Dis 2014;58(9): PLoS ONE 2015;10(4):e J Acquir Immune Defic Syndr 2017;76(1):e29 e32. 4.Aging (Albany NY) 2017; 9: Mol Immunol 2013; 54: Immunol 2012; 24: J Infect Dis. 2013; 207(7): J Acquir Immune Defic Syndr Jan 1;74(1):91-94.

4 A 0.5μM: 29%-34% J Acquir Immune Defic Syndr Jan 1;74(1): G 3μM: 12% 10μM: 14%

5 Hypothesis and Objectives Continuous exposure to TDF has a negative impact on blood TL changes. OBJECTIVES To elucidate the impact of TDF on TL changes in whole blood in a prospective cohort of aviremic HIV-infected participants. To evaluate other factors associated with TL changes.

6 Participants Prospective cohort of HIV-1 infected participants Inclusion criteria: plasma HIV RNA <50 copies/ml and stable ART for 12 mo. prior to enrollment. Exclusion criteria: chemotherapy/biologic treatments, acute infection, alcoholism, pregnancy. Eligible participants Never exposed to TDF 105 patients Current exposure to TDF 67 patients Baseline 2 years follow-up

7 TL Measurement (whole blood) Monochrome quantitative multiplex PCR assay. TL expressed as the ratio of telomeric product (T) / single copy gene product (S). Baseline and follow-up samples were analyzed in the same run. All samples were run in triplicate. Those with a coefficient of variation > 0.1 were retested. Nucleic Acids Res 2009; 37:e21 e21.

8 Statistical analysis Linear regression adjusting for baseline TL. Multivariate analysis for estimative model and predictive models for TL change (follow-up minus baseline) All models were adjusted by baseline TL Intention to continue treatment (ITCT): all participants analyzed, ignoring TDF changes ITCT Never exposed to TDF (105 patients) Current exposure to TDF (67 patients) Baseline As treated (AT): only patients who remained on their initial TDF group AT Never exposed to TDF (103 patients) Current exposure to TDF (51 patients) 2 years follow-up Baseline 2 years follow-up

9 ART characteristics Non-TDF group N(t)RTI TDF group N(t)RTI NRTI sparing N N(t)RTI at baseline, n (%) 75 (71.4) 67 (100) 142 (100) 75 (100) 5 (17.0) ABC/3TC 69 (92.0) - 69 (48.5) 69 (92.0) - TDF/FTC 64 (95.5) 64 (45.1) - - AZT/3TC 3 (4.0) - 3 (2.1) 3 (4.0) - TDF + 3TC - 2 (2.99) 2 (1.4) - 3TC (17.0) ABC/3TC/AZT 1 (1.33) - 1 (0.7) 1 (1.3) - ABC 1 (1.33) - 1 (0.7) 1 (1.3) - 3TC + ddi 1 (1.33) - 1 (0.7) 1 (1.3) - 3TC + d4t + TDF - 1 (1.49) 1 (0.7) - - N(t)RTI Sparing regimen, n(%) 30 (28.5) (100) Protease inhibitor monotherapy 22 (73.3) (73.3) Protease inhibitor + 3TC 3 (10.0) (10.0) Lopinavir/ritonavir + Etravirine 1 (3.3) (3.3) Lopinavir/ritonavir + Raltegravir 1 (3.3) (3.3) Etravirine + Raltegravir 1 (3.3) (3.3) 3TC + Etravirine + Raltegravir 1 (3.3) (3.3) 3TC+ Atazanavir + Raltegravir 1 (3.3) (3.3)

10 Participants characteristics Non-TDF group TDF group p-value N(t)RTI NRTI N(t)RTI sparing N Age (yrs) * 49.7 ± ± 7.5 NS 49.5 ± ± ± 9.8 Sex (Female), n(%) 26 (24.8) 20 (29.9) NS 38 (26.8) 18 (24.0) 8 (26.7) Father s age at birth (yrs) * 32.5 ± ± 5.5 NS 32.4 ± ± ± 5.9 Ethnicity, Caucasian, n(%) 96 (91.4) 64 (95.5) NS 131 (92.3) 67 (89.3) 29 (96.7) Current Tobacco consumption, n (%) 50 (47.6) 36 (53.7) NS 67 (47.2) 31 (41.3) 19 (63.3) Current Alcohol consumption, n (%) 36 (34.3) 40 (59.7) (43.7) 22 (29.3) 14 (46.7) HIV transmission Route, Sexual n(%) 70 (66.7) 45 (67.2) NS 98 (69.0) 53 (70.7) 17 (56.7) Previous AIDS stage, n(%) 59 (56.2) 37 (55.2) NS 77 (54.2) 40 (53.3) 19 (63.3) Time since HIV diagnosis (yrs) * 16.3± ± 6.0 NS 16.6 ± ± ±5.4 Time with viral load <50 cop/ml (yrs)* 6.7 ± ±1.9 NS 6.7 ± ± ± 3.3 HIV RNA < 50 copies/ml follow-up n (%) 104 (100) 67 (100) (100) 75 (100) 29 (100) CD4 cell count baseline, (cells/ml)* 846 ± ± 340 NS 806 ± ± ± 401 CD4 cell count follow up, (cells/ml) * 824 ± ± 313 NS 816 ± ± ± 319 CD4 cell change, (cells/ml)* -13 ± ± 164 NS 14 ± ± ± 225 *Mean ± Standard deviation

11 Blood telomere length at baseline and after 2 years of follow-up, by regimen. (Intention to continue treatment analysis) p= p= p= p= p< p= p< p= n=67 n=142 n=75 n=105 N=30 n=172 TL change (95% CI, ) (P =.030)

12 Mean difference in blood telomere length changes (adjusted by baseline telomere length) after two years. Less TL gain

13 Predictive model Independent predictors of annual change in telomere length Multivariate association between different independent factors and annual change in TL Mean Difference (95% CI) p-value Sex Female (0.007 to 0.077) Time since HIV infection (per 5 years) ( to ) Baseline N(t)RTI Yes ( to ) 0.001

14 Conclusions This is the first prospective cohort evaluating longitudinal TL changes in aviremic HIV infected participants Mean blood TL increased after two years regardless of the ART strategy After two years, N(t)RTI sparing ART, compared to TDF and/or ABC containing ART, had greater gains in blood TL suggesting enhanced recovery from immunosenescence N(t)RTIs exposure, male gender and duration of known HIV infection were associated with lower TL gain J Infect Dis Oct 5;218(10):

15 Additional data on telomeres and ART PO-01 Determinants of Telomere Length in antiretroviral treatment naïve HIV-Positive participants enrolled in NEAT 001/ANRS 143 PO-02 Blood telomere length changes after DRV/R + either RAL or TDF/FTC as first line ART 07/11/18 Sesión Poster Orales 15:00

16 Aknowledgments Patients, Study Team & HIV unit members