Efficacy, Safety, and Adherence of TDF/3TC/EFV Once Daily in Virologic-suppressed HIV-infected Children following Switching from NNRTI-based Regimens

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1 O_05 Efficacy, Safety, and Adherence of TDF/3TC/EFV Once Daily in Virologic-suppressed HIV-infected Children following Switching from NNRTI-based Regimens Linda Aurpibul MD. 1, Thition Narkbunnam MD. 2, Virat Sirisanthana MD. 1, Orasri Wittawatmongkol MD. 2, Wanatpreeya Phongsamart MD. 2, Tavitiya Sudjaritruk MD. 3, Tim R Cressey PhD. 4,5,6, Kulkanya Chokephaibulkit MD. 2 1 Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand, 2 Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, 3 Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, 4 Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand, 5 Harvard School of Public Health, Boston, MA, 6 Institut de Recherche pour le Développement (IRD), Marseille, France The study was supported by Government Pharmaceutical Organization, Thailand

2 Background Simplifying ART regimen is desirable in HIV-infected children and adolescents. In resource-limited setting, the combination of tenofovir, lamivudine plus efavirenz is the most affordable first line once-daily regimen. The study objectives were to determine the efficacy, safety, and adherence of this regimen in children.

3 A 48-week prospective, single arm, open label, multi-center study Study participants : 1.HIV-infected children 2.Aged between 3-18 years 3.Receiving a NNRTI-based regimen without TDF 4. HIV RNA level < 400 copies/ml 5. Weighing 15 kg Control group: Age, sex, and CD4 matched HIVinfected children on ART without TDF Switched to TDF/3TC/EFV once daily regimen Continued unchanged ARV treatment Assessments at 24-week interval CD4 Renal function (egfr, FECa, FEP) HIV RNA level Bone mineral density (DXA) Adherence & QOL assessment Clinical events

4 Materials and Methods At entry, the ART regimen was changed to a once daily TDF/3TC/EFV. Weight band(kg) Total daily dose (mg) Tenofovir (Oval-shaped scored tablet 300 mg) 15-< /2 22-< /4 > PENTA2009; recommended dose 8 mg/kg (for age < 8years) or 210mg/m 2 (for age >8years), acceptable range % is within 7-10 mg/kg or mg/m 2

5 Results Characteristics of study participants (n=80) Total Study Control p-value Characteristics group group (n=80) (n=40) (n= 40) Age, years (SD) 11.5(3.5) 11.7(3.5) 11.4(3.5) Male gender (%) 35(44) 18(45) 17(43) Body surface area, m 2 (SD) 1.13(0.26) 1.13(0.26) 1.13(0.26) CD4 lymphocyte count prior to ART initiation, cells/mm3 (SD) 617(798) 453(493) 785(1000) HAART regimen prior to study enrollment nevirapine-based 44(55) 23(58) 21(52) efavirenz-based 25(31) 17(42) 8(20) PI-based a 11(14) 0(0) 11(28) Mean duration on HAART prior to study enrollment, years (SD) 7.0(3.0) 6.7(2.6) 7.4(3.3) CD4 lymphocyte count at the time of study entry, cells/mm 3 (SD) 911(462) 857(425) 947(516) Number with HIV RNA level <400 copies/ml at study entry b 78(98) 40(100) 38(95) a Ten received lopinavir/ritonavir, one received darunvir/ritonavir B There were 2 participants in control group with HIV RNA level 403 and 635 copies/ml at entry

6 Results -Efficacy The mean TDF dose prescribed was 8.1 mg/kg (SD 1.0) or 210 mg/m 2 (SD 30) At week 48, thirty-nine of 40 children receiving TDF (97.5%) remained virologicsuppressed (HIV RNA level < 50 copies/ml). During the 48-week follow-up, 34 clinical events occurred in 23 children. None were classified as a serious adverse event or related to the study drugs.

7 Results-Renal safety There was a downward trend of egfr for study participants in both groups. No significant difference in change of egfr from baseline when compared between the study and control groups ( vs , p=0.82). None developed significant impaired glomerular function The fractional excretion of calcium and phosphate were slightly increased with time, but not clinically or statistically significant. No case with proteinuria, glucosuria. acidosis, hypokalemia or hyperuricemia.

8 Results-Bone safety There was a significant decrease in mean (SD) BMDZ among the group of children receiving TDF from 0.01(1.31) at baseline to -0.68(2.07) at week 24, and remained stable thereafter. Study group (children on TDF) At entry 1 children had BMDZ < -2.0 Three experienced low BMDZ at wk 24, two of 3 persisted to wk 48. One developed low BMDZ at wk 48. All except 1 of 5 had normal vitamin D level. Control group (children on other ART regimens) At entry 1 children had BMDZ < and persisted up to wk 48 At wk 24, two experienced low BMDZ, one persisted to wk 48 and another drop out after switching to second-line TDF-including regimen due to virologic failure. One developed low BMDZ at wk 48.

9 Results-Adherence and QOL All had > 95% treatment adherence.

10 Discussion (1) Low BMD has been reported in 24-32% of HIVinfected children on ART. 1,2 Similar to our finding, a decrease BMD in the first weeks on TDF was previously reported. 3,4 A 60-month follow-up study from the US reported no significant decrease in BMD among perinatally HIV-infected children and adolescents receiving TDF. 5 1 Puthanakit et al. JAIDS 2012;61: Schtscherbyna et al. Int J Infect Dis. 2012;16:e872-e Gafni et al. Pediatrics. 2006;118:e711-e Hazra et al. Pediatrics. 2005;116:e846-e Viganò et al. Clin Drug Investig. 2011;31:

11 Discussion (2) Previous observational cohort studies demonstrated the effect of TDF on renal function (either tubular or glomerular, or both) in pediatric populations. 1-5 Our prospective with control group study reported no change in glomerular function and no definite change in tubular function. BUT, there is a trend in decreasing tubular resorption of calcium and phosphorus. 1 Pontrelli et al. BMC Infect Dis 2012;12:18. 2 Soler-Palacín et al. AIDS 2011;25: Viganò et al. Clin Drug Investig 2011;31: Della Negra et al. Pediatr Infect Dis J 2012 ;31: Purswani et al. Pediatr Infect Dis J 2012 Dec 17. [Epub ahead of print]

12 Conclusions Switching to TDF/3TC/EFV in HIV-infected children was safe, effective, and favorable. This simplified regimen may improve adherence as well as quality of life. However, monitoring of BMD and renal function is important. Further study in larger sample size with extended follow-up period is required to determine long term adverse events associated with TDF use, as well as to identify markers for early detection of renal impairment.