Pharmacologic Monitoring for Adherence and the role of a Clinical Pharmacology Laboratory

Transcription

1 Pharmacologic Monitoring for Adherence and the role of a Clinical Pharmacology Laboratory Adherence to HIV Prevention and Treatment: Key Populations in Zimbabwe and sub-saharan Africa Tinashe Mudzviti University of Zimbabwe - International Pharmacology Specialty Laboratory (UZ-IPSL) School of Pharmacy, University of Zimbabwe Newlands Clinic

2 Potential Conflicts and Financial Disclosures Potential Conflicts I have NO actual or potential conflicts to declare in relation to this programme and presentation Consulting: None to disclose Grant/Research support MWV Aardex Letten Foundation, Norway Fogarty International Center - D43TW NIH - Center for AIDS Research - P30 AI078498

3 Recap! >95% adherence to achieve viral suppression Self Report Pill Count Medication Event Monitoring System (MEMS cap)

4 Terribly exciting

5 Leading Case - Brian 23 year old male TDF/3TC + LPV/rtv since 29 Mar 2010 ATV/rtv since 1 Mar 2013 Happy lad!

6 Adherence assessed by pill count

7 Pill Count Data (ATV/rtv)

8 Lab Data Date Viral Load Count CD4 count 22 Aug Aug , Jan , Jul Dec ,731 93

9 Comparison of MEMS vs pill count

10 How do we monitor using pharmacologic measures of adherence? Measuring drug in a biomatrix (plasma, PBMCs, dried blood spots (DBS), hair, urine) to assess drug-taking and exposure Assess both behavior (adherence) and biology (pharmacokinetics) Has proven essential in PrEP Cannot measure HIV viral loads in HIV-negatives May be good for other prevention strategies employing meds TB infection monitoring (latent or active); 1,2 BP monitoring 1 Gerona IJTLD 2016; 2 Gandhi PLOS ONE 2016.

11 Untimed plasma measures used most commonly, but short-term; what are other novel measures of assessing adherence pharmacologically?

12 Plasma measures proved critical to the interpretation of various PrEP trials Efficacy of TDF/FTC in iprex rose from 44% to an estimated 92% (CI 40, 99%) among those with detectable drug levels (plasma or PBMC) Efficacy 93% (CI 60, 99%) Partners PrEP with TFV plasma levels c/w daily dosing Adherence Measure VOICE FEM-PrEP Self-report 91% 95% Returned pill counts 92% 88% Plasma TFV detection 29% 24% Grant et al. NEJM 2010; Marrazzo et al. NEJM 2015; Van Damme et al. NEJM 2012; Baeten et al. NEJM 2012; Donnell et al. JAIDS 2014

13 Untimed plasma samples to measure adherence have several limitations although they really have been the gold standard in PrEP trials Concentrations (ng/ml) Time (Hours) Blaschke T. Ann Rev Pharm Toxicol 2012 Super-therapeutic (toxicity) Super-therapeutic levels (toxicity) Periodic Sub-therapeutic loss of effectiveness; (loss of virologic emergence control; emergence of drug resistant of drug HIV resistant HIV Short window of exposure (same with urine, saliva) Can vary significantly dayto-day (intraindividual variability) so what is typical level? Interpretation relies on patient report of last dose taken Subject to white coat adherence

14 White coat effect with short-term measures BID QD Adherence 1-3 days prior gives plasma levels close to steady state Study used MEMS caps monitoring & TDM to assess adherence Improved compliance immediately prior to visits, leading to enhanced drug levels (79% of pts with <95% adherence took meds days 3, 2 and 1 before visit) Podsadecki TJ. HIV Clin Trials. 2008; 9(4):238

15 Drug levels in PBMC and DBS Drug levels (TFV-DP/ FTC-TP) in PBMC associated with protective efficacy in iprex Processing, isolating, counting costly, challenging Due to this, not used much anymore TFV-DP/ FTC-TP in dried blood spots (DBS) mainly red blood cells- provides longer-term exposure (half-life 17 days) Associated with protective efficacy in iprex OLE and PrEP Demo and incorporated into multiple PrEP settings around the world Must be standardized to hemoglobin counts, biohazard, cold chain Only good for meds processed intracellularly Increasingly important measure for PrEP adherence Anderson P. Sci. Trans. Med 2012; Castillo-Mancilla JR. ARHR 2013; Grant Lancet ID 2014; Liu A. JAMA Int Med 2015; Koss CID 2018; Gandhi AIDS 2017; Gandhi JID 2015; Anderson P AAC 2018

16 : Dapivirine vaginal ring (IPM-027, MTN-020/ASPIRE) Silicone ring containing 25 mg dapivirine (DPV) given every 4 weeks Novel methods of assessing adherence in these trials residual DPV levels in used rings (short-term plasma levels not as useful) Baeten J. NEJM 2016; Nel A. NEJM 2016; Brown E. IAS 2016

17 Bringing hair analysis to U. Zim International Pharmacology Specialty Laboratory

18 Use In HIV Pharmacotherapy discussed in previous talk

19 Local active protocols with hair sample collection Protocol Sponsor Investigators Neonatal hair measurements to evaluate in-utero tenofovir exposure Utility of antiretroviral levels in hair to quantify exposure and adherence (ADHAIR study) to protease inhibitors in Zimbabwean adolescents on antiretroviral therapy. NIH CFAR supplement Letten Foundation T. Mudzviti (UZ) C.C. Maponga (UZ-IPSL) L. Stranix-Chibanda (UZCHS-CTRC) GD. Morse (U Buffalo) S. Dewhurst (U. Rochester) T. Mudzviti (UZ) C.C. Maponga (UZ-IPSL) L. Stranix-Chibanda (UZCHS-CTRC) G.D. Morse (U Buffalo) R. Luethy (Newlands Clinic) B. Stray-Pedersen (U Oslo)

20 Acknowledgements UZ-IPSL Newlands Clinic Team School of Pharmacy, UZ UZCHS-CTRC University at Buffalo University of Rochester