Impact’of’An,retroviral’ TreatmentContainingTenofovir ... presentations/R… ·...

Impact of An,retroviral Treatment Containing Tenofovir

Difumarate on Telomere Length A9ri,on in a Prospec,ve Cohort of Aviremic HIV-‐Infected

Par,cipants Rocio Montejano1 , Natalia Stella-‐Ascariz1 , Susana Monge1 , Jose I Bernardino1 ,

Ignacio Pérez-‐Valero1 , Laura Pintado2 , Marisa Montes1 , Jesus Mingorance1, Rosario Perona2, Jose R Arribas1

(1) Hospital Universitario La Paz-‐IdiPAZ, Madrid, Spain, (2) Ins,tuto de Inves,gaciones Biomédicas CSIC/UAM, IdiPAZ, Madrid, Spain

Disclosures

•  Payment for lectures: Janssen

► It is unknown if telomere a6ri7on contributes to accelerated/accentuated aging in HIV infected pa7ents.

► Two in vitro studies showed that TFV inhibits human telomerase in ac7vated PBMCs at therapeu7c concentra7ons while ABC inhibits telomerase at high concentra7ons. 3TC and FTC inhibited telomerase in one study but not in the other

Background

J Infect Dis. 2013; 207(7):1157–65. J Acquir Immune Defic Syndr. 2017 Jan 1;74(1):91-‐94.

0.5μM: ↓ 29%-‐34% 3μM: ↓ 12% 10μM: ↓ 14%

The effect of NRTIs on telomerase activity (activated PBMC)

J Acquir Immune Defic Syndr 2017; 74:91–94.

► Only one prior longitudinal study (MONET) has evaluated the impact of different ART regimens (darunavir/r monotherapy vs. darunavir/r + 2 NRTIs) on telomere length (TL) changes in virologically suppressed pa7ents.

•  The study found no differences ader two years of follow-‐up

Background

PLoS ONE 2014; 9:e109718.

Hypothesis and Objectives ► Con7nuous exposure to TDF has a nega7ve impact on blood TL changes. OBJECTIVES ► To elucidate the impact of TDF on whole blood TL changes in a prospec7ve cohort of aviremic HIV-‐infected par7cipants. ► To evaluate other factors associated with TL changes.

Participants ► Prospec7ve cohort of HIV-‐1 infected par7cipants

–  Inclusion criteria: plasma HIV RNA <50 copies/mL and stable ART for ≥12 mo. prior to enrollment.

–  Exclusion criteria: chemotherapy/biologic treatments, acute infec7on, alcoholism, pregnancy.

Current exposure to TDF 67 pa7ents

Never exposed to TDF 105 pa7ents

Baseline 2 years follow-‐up

Eligible par7cipants

TL Measurement (whole blood)

► Monochrome quan7ta7ve mul7plex PCR assay.

– TL expressed as the ra7o 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 varia7on > 0.1 were retested.

Nucleic Acids Res 2009; 37:e21–e21.

Statistical analysis –  Linear regression adjus7ng for baseline TL. Mul7variate analysis for

es7ma7ve model and predic7ve models for TL change (follow-‐up minus baseline)

–  All models were adjusted by baseline TL

–  Inten7on to treat (ITT): all par7cipants analyzed, ignoring TDF changes

–  Per protocol (PP): only pa7ents who remained on their ini7al TDF group

Current exposure to TDF (67 pa7ents)

Never exposed to TDF (105 pa7ents)


ITT

Current exposure to TDF (51 pa7ents)

Never exposed to TDF (103 pa7ents) PP


Non-‐TDF group TDF group p-‐value

N 105 67

Age, (yr) * 49.7 ± 9.8 49.4 ± 7.5 NS

Sex (Female), n(%) 26 (24.8) 20 (29.9) NS

Father’s age at birth, (yr) * 32.5 ± 7.0 32.8 ± 5.5 NS

Ethnicity, Caucasian, n(%) 96 (91.4) 64 (95.5) NS

Tobacco, Ac7ve, n(%) 50 (47.6) 36 (53.7) NS

Alcohol, Ac7ve, n(%) 36 (34.3) 40 (59.7) 0.002

HIV transmission Route, Sexual n(%) 70 (66.7) 45 (67.2) NS

Time with HIV infec,on (yr) * 16.3 ± 6.4 18.1 ± 6.0 0.067

Time VL<50 cop/ml (yr) * 6.6 ± 2.88 7.16 ± 1.9 NS

NRTI at baseline, n(%) 77 (73.3) 67 (100.0) <0.001

ABC, n(%) 71 (67.2) -‐ -‐

Nucs-‐sparing regimen, n(%) 28 (26.7) -‐ -‐

CD4 count (cells/ml)* 846.1 (364.9) 743.5 (342.8) 0.069 *Mean ± Standard deviation

Baseline characteristics

Non-‐TDF

N=105

TDF

N=67 p-‐value

Baseline Mean TL by T/S ra7o (SD) 1.30 (0.32) 1.21 (0.28) NS

Follow-‐up Mean TL by T/S ra7o (SD) 1.35 (0.28) 1.24 (0.24) 0.009

TL Change (Follow-‐up minus baseline) 0.050

(-‐0.001 to 0.101) 0.028

(-‐0.028 to 0.085) NS

Mean annual change (corrected for varying intervals between baseline and follow-‐up).*

0.025 (-‐0.001 to 0.051)

0.013 (-‐0.015 to 0.041)

NS

* Mean (95% CI)

Telomere length change (ITT)

* Effect measured in 10-‐2 units of length.

Change in length adjusted by baseline length. a In the inten7on-‐to-‐treat analysis adjusted by ac7ve alcohol consump7on

Effect of TDF on TL changes after two years

Inten,on-‐to-‐treat (N=172)

Mean Difference (95% CI) p-‐value

TDF vs. Non-‐TDF Crude -‐3.19 (-‐6.48 to 0.10) 0.058

Adjusteda -‐3.91 (-‐7.29 to -‐0.53) 0.024

Inten,on-‐to-‐treat (N=172) Per-‐protocol (N=154)

Mean Difference (95% CI) p-‐value Mean Difference

(95% CI) p-‐value

TDF vs. Non-‐TDF Crude -‐3.19 (-‐6.48 to 0.10) 0.058 -‐3.62 (-‐7.33 to 0.10) 0.056

Adjusteda -‐3.91 (-‐7.29 to -‐0.53) 0.024 -‐4.88 (-‐8.59 to -‐1.17) 0.010


Change in length adjusted by baseline length. a In the inten7on-‐to-‐treat analysis adjusted by ac7ve alcohol consump7on, the per-‐protocol analysis is addi7onally adjusted by change in fibrinogen during follow-‐up;

Effect of TDF on TL changes after two years


Change in length adjusted by baseline length. b Both inten7on-‐to-‐treat and per-‐protocol analyses adjusted by 7me since HIV infec7on

Effect of NRTIs on TL changes after two years

Inten,on-‐to-‐treat (N=172)

Mean Difference (95% CI) p-‐value

NRTIs vs. No NRTIs Crude -‐5.27 (-‐9.62 to -‐0.92) 0.018

Adjustedb -‐6.06 (-‐10.40 to -‐1.72) 0.006


Change in length adjusted by baseline length b Both inten7on-‐to-‐treat and per-‐protocol analyses adjusted by 7me since HIV infec7on



(95% CI) p-‐value

NRTIs vs. No NRTIs Crude -‐5.27 (-‐9.62 to -‐0.92) 0.018 -‐4.84 (-‐9.67 to -‐0.02) 0.049

Adjustedb -‐6.06 (-‐10.40 to -‐1.72) 0.006 -‐5.64 (-‐10.43 to -‐0.85) 0.021

Effect of NRTIs on TL changes after two years


Change in length adjusted by baseline length c Inten7on-‐to-‐treat adjusted by age, 7me since HIV infec7on, ac7ve alcohol and tobacco consump7on, per-‐protocol analysis addi7onally adjusted by change in fibrinogen during follow-‐up and sta7ns intake

Es,ma,ve model for the effect of treatment with TDF and NRTI



(95% CI) p-‐value

TDF in those taking NRTI

Crude -‐1.99 (-‐5.19 to 1.21) 0.221 -‐2.34 (-‐5.91 to 1.23) 0.196

Adjustedc -‐2.49 (-‐5.83 to 0.85) 0.143 -‐2.06 (-‐5.73 to 1.68) 0.281

Effect of TDF on TL changes after two years (only in those on NRTIS)

Predictive model Independent predictors of annual change in telomere length

Mean Difference

(95% CI) p-‐value

Sex Female 4.06 (0.53 to 7.58) 0.024

Time since HIV infec,on (per 5 years) -‐1.67 (-‐2.93 to -‐0.42) 0.009

Baseline NRTI Yes -‐6.16 (-‐10.45 to -‐1.87) 0.005

Conclusions ► This is the first prospec7ve cohort evalua7ng longitudinal TL changes in aviremic HIV infected par7cipants ► NRTIs exposure, male gender and dura7on of known HIV infec7on were associated with lower TL gain ► TDF exposure did not impact on TL independently of NRTI exposure.

HIV Unit at La Paz Hospital Pa,ents & Study Team

PI13/01467 and PI14/01495 from Fondo de Inves,gaciones Sanitarias (supported by FEDER funds) Natalia Stella is supported by a predoctoral fellowship from Fondo de Inves,gaciones Sanitarias

Aknowledgments

THANK YOU

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