TDF containing ART: Efficacy and Safety. Dr Lloyd B. Mulenga Adult Infectious Diseases Centre University Teaching Hospital Lusaka, Zambia

TDF containing ART: Efficacy and Safety Dr Lloyd B. Mulenga Adult Infectious Diseases Centre University Teaching Hospital Lusaka, Zambia 1

Indications Treatment of HIV-1 in combination with other antiretroviral agents in adults paediatric population from age 2 years Treatment of chronic Hepatitis B 2

Currently available co-formulated TDF-based antiretroviral agents Tenofovir + Emtricitabine (TRUVADA) Tenofovir + Lamivudine Tenofovir + Emtricitabine + Efavirenz (ATRIPLA) Tenofovir + Lamivudine + Efavirenz Tenofovir + Emtricitabine + Rilpivirine (COMPLERA) Tenofovir + Emtricitabine + Elvitegravir + Cobicistat (QUAD PILL = STRILBID) 3

Currently available co-formulated antiretroviral agents and regimens Agent Regimen D4T/3TC Dual NRTI D4T/3TC/NVP NNRTI + dual NRTI ZDV/3TC Dual NRTI ZDV/3TC/ABC Triple NRTI LPV/RTV Boosted PI ATV/RTV Boosted PI DTG/ABC/3TC INSTI + dual NNRTI ABC/3TC Dual NRTI TDF/XTC Dual NRTI TDF/XTC/EFV NNRTI + dual NRTI TDF/FTC/RPV NNRTI + dual NRTI TDF/FTC/EVG/COBI Dual NRTI + INSTI + booster 4

Treatment Guidelines Which regimen to start with? 5

IAS-USA Guidelines: July 2012 Recommended Regimens NNRTI based Boosted PI based INSTI based Alternative Regimens NNRTI based EFV + (TDF/FTC or ABC/3TC) ATV/RTV + (TDF/FTC or ABC/3TC) DRV/RTV + TDF/FTC RAL + TDF/FTC NVP + (TDF/FTC or ABC/3TC) RPV + (TDF/FTC or ABC/3TC) Boosted PI based INSTI based DRV/RTV + ABC/3TC LPV/RTV + (TDF/FTC or ABC/3TC) RAL + ABC/3TC EVG/COBI/TDF/FTC IAS-USA Practice Guidelines. Antiretorviral Treatment of Adult HIV Infection; 2012 July. https://www.iasusa.org/content/antiretroviral-treatment-adult-hiv-infection-0 6

DHHS Guidelines: 2014 update Recommended Regimens NNRTI based Boosted PI based INSTI based EFV/TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC DTG + TDF/FTC Alternative Regimens Boosted PI based INSTI based LPV/RTV + (TDF/FTC or ABC/3TC) DRV/RTV + ABC/3TC RAL + ABC/3TC DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents; 2014 May. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. 7

EACS Guidelines: 2013 update Recommended Regimens NNRTI based EFV + (TDF/FTC or ABC/3TC) RPV + (TDF/FTC or ABC/3TC) Boosted PI based INSTI based Alternative Regimens NNRTI based Boosted PI based ATV/RTV + (TDF/FTC or ABC/3TC) DRV/RTV + (TDF/FTC or ABC/3TC) RAL + (TDF/FTC or ABC/3TC) NVP + (TDF/FTC or ABC/3TC) LPV/RTV + (TDF/FTC or ABC/3TC) INSTI based EVG/COBI/TDF/FTC EACS Guidelines Version 7.0; 2013 October. http://www.eacsociety.org/portals/0/guidelines_online_131014.pdf 8

WHO Guidelines: 2013 Update Recommended Regimens NNRTI based EFV + (TDF/FTC or AZT/3TC) Alternative Regimens NNRTI based NVP + (TDF/FTC or AZT/3TC) 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. WHO; 2013 June. 9

Reduced pill burden with TDF-based combinations 10

HIV Lifecycle and Existing Drug Targets Fusion/Entry inhibitor Fusion Reverse transcription Uncoating Budding Viral DNA 3 -processing RT inhibitors TDF Assembly Pre-Integration Complex Protease inhibitors Viral proteins Nucleus Integration (strand transfer) Integrase inhibitors Transcription Protein chains Translation Viral RNA Human Genomic DNA Viral DNA RNA 11

Mechanism of action: TDF Acyclic nucleoside phosphonate diester analog of adenosine monophosphate Requires initial diester hydrolysis for conversion to tenofovir subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain terminator inhibits HIV-1 and HBV RT by competing with the natural substrate deoxyadenosine 5 -triphosphate and, after incorporation into DNA, by DNA chain termination 12

Clinical efficacy of TDF-based regimens 13

GS 903: d4t/3tc vs TDF + 3TC, each with EFV Double-blind, active-controlled multicentre trial 600 ARV-naive patients Mean age 36 years (range 18 64) 74% male, 64% Caucasian and 20% Black Mean baseline CD4 279 cells/mm 3 (range 3 956) Median baseline plasma HIV-1 RNA 77,600 c/ml (range 417 5,130,000) Gallant JE et al. JAMA. 2004;292:191-201. 14

GS 903: d4t/3tc vs TDF + 3TC, each with EFV At week 144: Plasma HIV-1 RNA <400 c/ml similar in both arms 62% in the TDF and 58% in the d4t arm achieved and maintained confirmed HIV-1 RNA <50 c/ml Mean increase from baseline CD4 of 263 cells/mm 3 in the TDF arm and 283 cells/mm 3 in the d4t arm Gallant JE et al. JAMA. 2004;292:191-201. 15

GS 934: ZDV/3TC vs TDF + FTC, each with EFV A randomized, open-label, active-controlled multicentre trial 511 ARV-naive patients From Weeks 96 144 patients received a fixed-dose combination of FTC/TDF in place of FTC + TDF Mean age 38 years (range 18 80) 86% male, 59% Caucasian and 23% Black Mean baseline CD4 245 cells/mm3 (range 2 1,191) Median baseline HIV-1 RNA 5.01 log 10 c/ml (range 3.56 6.54) Arribas JR et al. J Acquir Immune Defic Syndr. 2008;47:74-8. 16

GS 934: ZDV/3TC vs TDF + FTC each with EFV Stratification by CD4+ cell count (<200 vs 200 cells/mm 3 ) Week 144 Treatment-naive patients with HIV-1 RNA >10,000 c/ml and no CD4 cell count restrictions (N = 517 initially randomized) TDF 300 mg/day + FTC 200 mg/day + EFV 600 mg/day (n = 227*) ZDV/3TC 300/150 mg twice daily + EFV 600 mg/day (n = 229*) *Patients with baseline NNRTI mutations and those who did not consent to continue after Weeks 48 and 96 excluded from Week 144 analysis. Arribas JR et al. J Acquir Immune Defic Syndr. 2008;47:74-8. 17

GS 934: Virologic and immunologic outcomes (Week 144, TLOVR) Patients (%) TDF + FTC ZDV/3TC P = 0.09 100 312 P = 0.004 80 271 P = 0.08 71 64 60 58 56 40 20 350 300 250 200 150 100 50 Mean Change From BL (cells/mm 3 ) 0 <400 c/ml <50 c/ml CD4+ Cell Count 0 Arribas JR et al. J Acquir Immune Defic Syndr. 2008;47:74-8. 18

GS 934: Resistance development through Week 144 TDF + FTC (n = 244) ZDV/3TC (n = 243) Patients genotyped, n (%) 19 (8) 29 (12) Wild type, n 6 7 Any resistance, n EFV resistance mutations, n M184V/I, n TAMs, n K65R, n *P = 0.02 No emergence of K65R over 3 years 13 13 2 0 0 22 21 10* 2 0 1. p=0.037 Arribas JR et al. J Acquir Immune Defic Syndr. 2008;47:74-8. 19

Safety of TDF-based regimens 24

Renal events in patients receiving TDF Complications data from large clinical trials generally reassuring re: safety of TDF Measures of Renal Function GS 903 (Week 144 data) 1 Δ CrCl, ml/min* Δ GFR, ml/min/1.73m 2 TDF + 3TC + EFV +2-2 d4t + 3TC + EFV +7 +9 GS 934 (Week 48 data) 2 TDF + FTC + EFV -1 < -1 ZDV/3TC + EFV +6 < -1 *CrCl calculated by Cockcroft-Gault formula; GFR calculated by Modification of Diet in Renal Disease formula. 1. Gallant JE et al. JAMA. 2004;292:191-201; 2. Gallant J et al. N Engl J Med. 2006;354:251-60. 25

TDF and renal events in CDC Cohort Longitudinal study of CDC Adult/Adolescent Spectrum of HIV Disease Cohort (N = 11,362) Inclusion: GFR 90 ml/min by MDRD calculation Renal insufficiency, if present, determined by calculated GFR and ranked as mild (GFR 60 89 ml/min), moderate (GFR 30 59 ml/min), or severe (GFR <30 ml/min) Persons taking TDF more likely to have renal insufficiency than those not taking TDF (odds ratio, 1.6; 95% CI 1.5 1.8) in separate multivariate analyses, TDF associated with mild or moderate impairment, not severe Caveat: Observational cohort, not randomized study TDF-recipients may have had more advanced/progressive disease or more exposure to nephrotoxins than those on other NRTIs Heffelfinger J et al. CROI 2006. Abstract #779. 26

Low rate of renal events in TDF clinical dataset Retrospective analysis of TDF Expanded Access Programme and postmarketing data after 4 years of TDF availability Serious Renal Adverse Events in EAP and Postmarketing Databases Event EAP N = 10343/3700 PY Postmarketing 455,392 PY % Cases/100,000 PY Reporting Rate/100,000 PY Renal failure 0.3 865 24.2 Fanconi/tubular disorder/ hypophosphataemia/glycosuria <0.1 270 22.4 Elevated serum creatinine, BUN <0.1 189 5.1 Risk factors for serious renal adverse events included sepsis or serious infection, history of renal disease, late-stage HIV, concomitant nephrotoxic medications, and hypertension Nelson M et al. CROI 2006. Abstract #781. 27

Cooper RD et al. Clin Infect Dis. 2010;51:496-505. 24

Renal safety of TDF: Systematic review and meta-analysis 17 studies included Median sample size was 517 participants There was significantly greater loss of kidney function among the TDF recipients, compared with control subjects (mean difference in calculated CrCl, 3.92 ml/min; 95% CI, 2.13 5.70 ml/min) a greater risk of acute renal failure (risk difference, 0.7%; 95% CI, 0.2 1.2) no evidence that TDF-use led to increased risk of severe proteinuria, hypophosphataemia, or fractures Cooper RD et al. Clin Infect Dis. 2010;51:496-505. 25

Zambian Experience 26

First-line TDF introduced: July 2007 Benefits Proven efficacy Once-daily dosing Favourable toxicity profile Favourable resistance profile Cost Greater expense for drugs TDF/FTC/EFV = $430/yr d4t/3tc/nvp = $96/yr Renal monitoring 27

Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 28

Methods Data extracted from our nationwide Electronic Medical Record System (SmartCare) First line regimen: 2 NRTIs + 1 NNRTI Included treatment-naive patients starting ART from Jul 2007 to Jan 2009 excluded patients with Hb <10 g/dl and CrCl <90 ml/min at baseline Exposure category based on initial drug regimen prescribed Outcome Measures single-drug substitution overall mortality changes in CrCl at 6 and 12 months Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 29

Prescriptions over time 1000 800 Tenofovir Stavudine Zidovudine 600 400 200 0 July 2007 Jan 2008 July 2008 Jan 2009 Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 30

Comparison of groups Baseline Characteristics TDF ZDV d4t Median age (years) 35 34 33 Male 49% 37% 29% WHO stage III/IV 63% 47% 50% CD4 cells/mm 3 149 171 176 Hemoglobin (g/dl) 11.8 12.0 11.0 CrCl (ml/min) 98 112 106 BMI (kg/m 2 ) 20.1 21.1 20.9 Median follow-up (days) 208 306 275 All comparisons had P-value <0.01 Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 31

Comparison of groups Baseline Characteristics TDF ZDV d4t Median age (years) 35 34 33 Male 49% 37% 29% WHO stage III/IV 63% 47% 50% CD4 cells/mm 3 149 171 176 Hemoglobin (g/dl) 11.8 12.0 11.0 CrCl (ml/min) 98 112 106 BMI (kg/m 2 ) 20.1 21.1 20.9 Median follow-up (days) 208 306 275 All comparisons had P-value <0.01 Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 32

Single-drug substitution ZDV: 27.0 per 100 p-y (95%CI = 24.6 29.5) d4t: 21.5 per 100 p-y (95%CI = 18.4 24.8) TDF: 9.0 per 100 p-y (95%CI = 8.1 10.0) Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 33

Overall mortality TDF: 7.8 per 100 p-y (95%CI = 7.0 8.7) d4t: 5.8 per 100 p-y (95%CI = 4.3 7.4) ZDV: 4.4 per 100 p-y (95%CI = 3.6 5.4) Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 34

Adjusted hazard for mortality based on initial regimen 90 days AHR (95% CI) >90 days AHR (95% CI) Overall AHR (95% CI) TDF Ref Ref Ref ZDV 0.80 (0.57 1.13) 0.67 (0.40 1.12) 0.81 (0.62 1.06) d4t 0.97 (0.63 1.50) 1.18 (0.66 2.11) 1.03 (0.74 1.43) AHR, adjusted hazard ratio. All analyses adjusted for age, sex, CD4 count, WHO stage, BMI, hemoglobin, tuberculosis co-infection, and renal function. Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 35

Creatinine clearance at Months 6 and 12 0,06 60 0,05 50 Patients with CrCl <50 ml/min (%) 0,04 40 0,03 30 0,02 20 0,01 10 0 TDF-6m TDF-12m ZDV-6m ZDV-12m d4t-6m d4t-12m Chi BH et al. J Acquir Immune Defic Syndr. 2010;54:63-70. 36

Conclusions TDF better tolerated than d4t or ZDV ZDV may be associated with improved survival Drop in CrCl to <50 ml/min is uncommon and similar across all groups Long-term data required to fully validate this policy choice for Zambia 37

Mulenga L et al. Clin Infect Dis. 2014;58:1473-80. 38

Objectives To assess changes in renal function and allcause mortality in patients starting TDF- or non TDF-containing ART To determine the proportion of patients in both treatment groups developing incident episodes of renal impairment during ART Mulenga L et al. Clin Infect Dis. 2014;58:1473-80. 39

Methods Patients aged 16 years who started ART from 2007 onward in Lusaka, Zambia all with documented serum creatinine and weight at baseline using the CKD-Epidemiology (CKD-EPI) formula repeat analyses used the Cockroft-Gault and the Modification of Diet and Renal Disease (MDRD) equations Renal impairment was categorized by egfr as: mild (60 89 ml/min) moderate (30 59 ml/min) or severe (<30 ml/min) Mulenga L et al. Clin Infect Dis. 2014;58:1473-80. 40

Statistical analyses Differences in egfr during the first year of ART were analyzed with linear mixed-effect models Odds of developing moderate or severe renal impairment were calculated with logistic regression Mortality was assessed using a proportional hazard models including loss to follow-up as a competing risk Mulenga L et al. Clin Infect Dis. 2014;58:1473-80. 41

Proportion of patients with no or mild renal impairment at baseline developing moderate or severe renal impairment on ART Mulenga L et al. Clin Infect Dis. 2014;58:1473-80. 42

Comparison of renal outcomes and mortality between patients starting ART with and without TDF (ref: patients not on TDF) Mulenga L et al. Clin Infect Dis. 2014;58:1473-80. 43

Crude change in renal function during ART, by baseline renal function and treatment group No renal impairment Mild renal impairment GFR CKD-EPI change -40-20 0 20 40 GFR CKD-EPI change -40-20 0 20 40 Without TDF With TDF Without TDF With TDF 6 months 1 year Moderate renal impairment Without TDF With TDF Without TDF With TDF 6 months 1 year Severe renal impairment GFR CKD-EPI change -40-20 0 20 40 GFR CKD-EPI change -40-20 0 20 40 Without TDF With TDF Without TDF With TDF 6 months 1 year Without TDF With TDF Without TDF With TDF 6 months 1 year Mulenga L et al. Clin Infect Dis. 2014;58:1473-80. 44

Conclusions Among patients with moderate or severe renal impairment at ART initiation changes in renal function over time and mortality appeared similar, irrespective of ART regimen Among individuals with normal or mild renal impairment at baseline TDF-use was associated with increased risk of severe renal failure within the first 12 months of ART initiation overall occurrence of this outcome was rare Due to easier dosing, better tolerability and co-formulation with XTC and EFV, use of TDF should be encouraged in adolescents, pregnant women, TB patients, and generally adults without contraindications Mulenga L et al. Clin Infect Dis. 2014;58:1473-80. 45