Antiretroviral Therapy: When and What to Start Joe Eron, MD University of North Carolina at Chapel Hill School of Medicine
Learning Objectives As a results of participating in this activity participants will be better able to apply recommendations for when to start HIV therapy to their patients with newly diagnosed HIV infection As a results of participating in this activity participants will be better able to successfully prescribe initial antiretroviral therapy for most uncomplicated HIV infected patient in their care who are initiating ART Off-Label Disclosure During this presentation I intend to discuss either non-approved or investigational use of dolutegravir.
When to Start
When to Start Therapy: Drug toxicity Preservation of limited Rx options Risk of resistance development Delayed ART
When to Start Therapy: Balance Now Favors Earlier ART Drug toxicity Preservation of limited Rx options Risk of resistance (and transmission of resistant virus) potency, durability, simplicity, safety of current regimens emergence of resistance toxicity with earlier therapy subsequent treatment options Risk of uncontrolled viremia transmission Near normal survival if CD4 > 500 Delayed ART Early ART Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf.
When to Start: DHHS Guidelines 2/13/2013 ART recommended for all HIV+ individuals. Strength of recommendation varies based on CD4 count: CD4 350 Clinical Condition and/or CD4 Count CD4 350-500 CD4 >500 Pregnancy History of AIDS-defining illness HIV-associated nephropathy HBV coinfection Risk of sexual transmission -heterosexual -other risk groups Acute and Early Infection US DHHS Guidelines, January 2011. Recommendations AI AII BIII AI AI AII AII AI AIII BII
Association Between Current CD4 Cell Count and Non-AIDS Complications Study Non-AIDS Malignancies Renal Disease/Death CVD Events/Death Liver Disease/ Death FIRST Yes Yes Trend No D:A:D Yes Yes Trend Yes CASCADE Yes NA Yes Yes SMART Trend Trend Trend Yes Phillips A, et al. 15 th CROI; 2008; Boston. Abstract 8.
CD4 Cell Count (cells/mm 3 ) ATHENA: Suboptimal CD4 Gains Common Among Patients who Initiate ART Late 1000 Baseline CD4 Count 900 800 700 600 500 400 300 200 100 0 0 48 96 144 192 240 288 366 Week >500 (n=389) 350 500 (n=694) 200 350 (n=1,513) 50 200 (n=1,773) <50 (n=930) ~50% of those with CD4 nadir <200 fail to reach 500 after 7 years VL suppression. Gras L, et al. JAIDS. 2007;45:183 192.
Association of CD4 nadir with clinical outcomes Low CD4 nadir associated with Increased rates of HIV-associated neurocognitive disorders [1] Arterial stiffness contributing to CV risk [2] Coronary heart disease [3] Increased risk of fracture [4] Malignancies [5,6] 1. Ellis R, et al. AIDS. 2011;25:1747-51 2. Ho JE, Scherzer R, Hecht FM, et al. AIDS. 2012 [Epub ahead of print] and CROI 2012 3. Klein D, et al. CROI 2011. Abstract 810. 4. Young B, et al. Clin Infect Dis. 2011 Apr 15;52(8):1061-8. 5. Abraham A, et al. CROI 2012. Abstract 133 6. Worm S, et al. CROI 2012. Abstract 130
CD4, viral load, and risk of non- Hodgkin lymphoma CNICS Cohort: N= 10,406 VL 50-500 on ART tripled risk of NHL (vs. <50) Risk decreased by 40% for every 100 cell increase in current CD4 count Further reduction of NHL incidence will depend on early detection of HIV infection, prompt initiation of ART at higher CD4 cell counts and maximal sustained HIV suppression Achenbach C, et al. Abstract 131. 19 th CROI, Seattle, 2012
NA-ACCORD: Early vs. Deferred ART Risk of Death With Deferral of ART a CD4 Count Relative Risk (95% CI) P Value 351-500 1.69 (1.26-2.26) <0.001 >500 1.94 (1.37-2.79) <0.001 Study controlled for factors that could affect decision to defer ART Adjustment for sex, age, and CD4 counts at baseline VL response similar in early vs. deferred arms Results similar when IDUs excluded Limitations: observational study with potential for unmeasured confounding a Without inclusion of VL data. Kitahata MM, et al. N Engl J Med. 2009;360:1815-1826.
HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4 count of infected partner: 350-550 (N = 1763 couples) Immediate ART Initiate ART at CD4 350-550 (n = 886 couples) Delayed ART Initiate ART at CD4 250* (n = 877 couples) *Based on 2 consecutive values 250 cells/mm 3. Primary efficacy endpoint: virologically linked HIV transmission Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death Couples received intensive counseling on risk reduction and use of condoms DSMB recommended release of results as soon as possible following 4/28/11 review; follow-up continues but all HIV+ partners offered ART after release of results. Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med 2011
HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 Delayed Arm: 27 P <.001 Immediate Arm: 1 Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to suppression of VL Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med 2011
Efficacy of HIV Prevention Strategies From Randomized Clinical Trials FemPrep - TDF/FTC as pre-exposure in high risk women no effect (Van Damme et al N Engl J Med. 2012 Aug 2;367(5):411-22 VOICE comparing TDF microbicide gel, TDF PrEP or TDF/FTC PrEP to placebo in high risk women in Africa no effect. Marrazzo et al CROI 2013 Abdool Karim SS, et al. Lancet 2011; Jul 17.
Tanser F, et al Science. 2013 Feb 22;339(6122):966-71
Each percentage point increase in ART coverage among all HIV + adults in a community associated with 1.7% decline in the hazard of HIV acquisition (P <.001) faced by an HIV adult living in the same community Tanser F, et al. Science. 2013 Feb 22;339(6122):966-71
How are we doing?
Patients Starting ART at Higher CD4+ Cell Counts Overall, but Disparities Remain CD4+ cell count at start of ART (cells/mm 3 ), 2009 [1] 246 307 Low income Middle income High income 225 262 118 252 137 234 140 185 145-176 89 200 150 286 In San Francisco study, overall trends of starting ART at higher CD4+ counts, but pts initiating ART at CD4+ counts > 350 cells/mm 3 significantly more likely to be white, older, MSM, nonpoor, and diagnosed by private provider [2] 1. Mugglin C, et al. CROI 2012. Abstract 100. 2. Truong HH, et al. CROI 2012. Abstract 139.
Life Expectancy at Age 20, Yrs NA-ACCORD: Increasing Life Expectancy in North American HIV+ Pts on HAART Analysis of 23,730 HIV+ pts in NA-ACCORD, on ART, with recent active data available Estimated life expectancy at age 20 yrs increased in later periods 100 80 60 40 20 0 34.4 36.9 43.1 47.1 1996-9 2000-2 2003-5 Hogg R, et al. CROI 2012. Abstract 137. 2006-7 Life Expectancy at 20 Yrs of Age, 1996-2007, Yrs Sex NA- ACCORD US Life Expectancy Data After Age 20 Male 41.3 55.3 Female 42.7 60.4 Race Black 41.0 54.7 White 50.0 59.0 Hispanic 52.6 61.4 Transmission category Heterosexual 47.7 NR IDU 28.1 NR MSM 51.6 NR
Life Expectancy by Population Population Life Expectancy Glasgow (low income areas) 54 Australian indigenous 59 India 61 Philippines 65 Lithuania 66 U.S. 75 U.K. 76 Australia (average) 77 Glasgow (high income areas) 82 Perry. U.S. Social Determinants of Health and Health Inequalities Lancet 2002
HIV Rx Cascade : Aspiration Meets Reality 80% 850,000 HIV+ Americans (72%) lack viral control 77% 66% 89% 77% Multiplies to 28% CDC. MMWR Morb Mortal Wkly Rep. 2011;60:1618-1623.
Urgency of ART Predicted nonadherence Reluctance to start High CD4 Low viral load Slow CD4 decline Low CD4 High VL Rapid CD4 decline Opportunistic diseases Pregnancy HIVAN HBV coinfection Risk of transmission High-risk behavior Willingness to start
What to Start Many Choices to Consider
Case Study: RM, a 25-year-old College Student Newly Diagnosed With HIV CD4+ cell count: 275 cells/mm³ HIV-1 RNA: 215,000 c/ml Genotype: WT virus All baseline safety labs are normal PMHx negative He wants to start ART but insists on a once-daily regimen As he is a full-time student He is concerned about his ability to concentrate He doesn t eat regular meals He frequently buys over the counter omeprazole
Which Regimen Would You Recommend? 1. TDF/FTC/EFV fixeddose combination (FDC) 2. TDF/FTC + ATV/RTV 3. TDF/FTC + DRV/RTV 4. TDF/FTC + RAL (QD) 5. TDF/FTC/rilpivirine FDC 6. TDF/FTC/ELV/cobi FDC 7. Something else
DHHS Guidelines, February 2013 Preferred Regimens Preferred regimens: Optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use (Arranged in order of duration of clinical experience of third agent) NNRTI based Boosted PI based INSTI based EFV + TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC RAL + TDF/FTC An alternative to EFV should be considered in women considering pregnancy Atazanavir should be avoided in patient on > 20 mg omeprazole daily (or equivalent TDF should be used with caution in patients with renal insufficiency DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. Feb 2013.
DHHS Guidelines, March 2012: Alternative Regimens Effective and tolerable but have potential disadvantages compared with preferred regimens. May be the preferred regimen for some patients. NNRTI based Boosted PI based INSTI based EFV + (ABC or ZDV) + 3TC RPV/TDF/FTC RPV + ABC/3TC ATV/RTV + ABC/3TC DRV/RTV + ABC/3TC FPV/RTV (QD or BID) + ABC/3TC or TDF/FTC LPV/RTV (QD or BID) + ABC/3TC or TDF/FTC RAL + ABC/3TC ELV/COBI/TDF/FTC ABC should not be used in HLA B5701 positive patients and with caution in patients with VL > 100,000 c/ml or cardiovascular disease RPV is not recommended in patients with VL > 100,000 c/ml and is contraindicated with PPI ELV/COBI/TDF/FTC should not be started in patients with est. CrCl < 70 ml/min DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. Feb 2013.
Choosing the Initial Regimen: How to Choose the Anchor Agent? Is there transmitted drug resistance? What side effects will be tolerated? Is there a reason to use a boosted PI? Fixed-dose combination? Once vs. twice daily? Are there other considerations? eg, drug-drug interactions, comorbidity Cost, co-payments, access
Comparisons of Agents Used in First-Line Trials Anchor Drug Anchor Drug Result Efavirenz Lopinavir/RTV (96 wks) Superior 1 Efavirenz Atazanavir/RTV (96 wks) Tied 2 Efavirenz Raltegravir (5 years double blind) Tied (Superior) 3 Efavirenz Rilpivirine (96 wks) Tied 4 Efavirenz Maraviroc (48 wks) Superior 5 Efavirenz Elvitegravir/cobicistat (96 wks) Tied 6 Atazanavir/RTV Elvitegravir/cobicistat (48 wks) Tied 7 Lopinavir/RTV Atazanavir/RTV (96 wks) Tied 8 Lopinavir/RTV Darunavir/RTV (192 wks) Tied (Superior) 9 1 Riddler et al N Engl J Med. 2008 May 15;358(20):2095-106; 2 Daar et al Ann Intern Med. 2011 Apr 5;154(7):445-56; Rockstroh et al J Acquir Immune Defic Syndr. 2013; 4 Cohen et al AIDS. 2012 Dec 3; 5 Cooper et al J Infect Dis. 2010 Mar 15;201(6):803-13; 6 Zolopa et al J Acquir Immune Defic Syndr. 2013 Feb 7 7 Rockstroh et al J Acquir Immune Defic Syndr. 2013 Jan 18; 8 Molina et al J Acquir Immune Defic Syndr. 2010 Mar;53(3):323-32 9 Orkin et al HIV Med. 2013 Jan;14(1):49-59
HIV-1 RNA < 50 c/ml, % ECHO/THRIVE: RPV + TDF/FTC vs EFV + TDF/FTC 96-Wk Efficacy 100 80 60 84% 82% 78% 78% 40 20 RPV 25 mg QD (n = 686) EFV 600 mg QD (n = 682) 0 0 2 4 8 12 16 24 32 40 48 60 72 84 96 Wks Cohen C, et al. IAS 2011. Abstract TULBPE032. Cohen C, et al. Lancet. 2011; 378: 229-237. Molina J-M, et al. Lancet. 2011;378:238-246
ECHO and THRIVE (Combined Data) All RPV (n = 686) EFV (n = 682) Difference (95% CI) VL < 50 c/ml (ITT-TLOVR) 84 82 2.0 (-2.0 to 6.0) VF 9 5 DC AE/Death 2 7 DC Other 5 6 > 100K to 500 K RPV (n = 249) EFV (n = 270) VL < 50 c/ml (ITT-TLOVR) 80 83-3.1 (-9.8 to 3.7) VF 13 5 DC AE/Death 2 9 DC Other 6 4 > 500,000 c/ml RPV (n = 69) EFV (n = 82) VL < 50 c/ml (ITT-TLOVR) 70 76-6.0 (-20.4 to 8.3) VF 22 11 DC AE/Death 4 7 DC Other 4 6 Cohen C, et al. J Acquir Immune Defic Syndr. 2012 Feb 16. [Epub ahead of print]
Percent of Patients with HIV RNA Levels <50 Copies/mL RAL plus TDF/FTC vs. EFV plus TDF/FTC Proportion of Patients Achieving HIV RNA <50 copies/ml Over Time Non-Completer = Failure Approach 100 80 60 86 82 81 79 75 69 76 67 71% 61% 40 +9.5 (1.7, 17.3) 20 0 0 12 24 48 72 96 120 144 168 192 216 240 Weeks Number of Contributing Patients Raltegravir 400 mg bid. Efavirenz 600 mg qhs. 281 278 279 280 281 281 277 280 281 281 277 279 282 282 282 281 282 282 281 281 282 282 282 279 Rockstroh et al AIDS 2012 Poster #LBPE19
RAL once vs twice daily with TDF/FTC in treatment naïve patients Eron et al Lancet ID 2011
Elvitegravir/Cobicistat/TDF/FTC vs EFV/TDF/FTC in Treatment-Naive Patients Multicenter, randomized, double-blinded, active-controlled phase III study Stratified by baseline HIV-1 RNA > or 100,000 copies/ml Wk 48 primary analysis Planned follow-up to Wk 192 HIV-infected treatment-naive patients with HIV-1 RNA 5000 copies/ml, any CD4+ cell count, CL CR 70 ml/min (N = 700) Elvitegravir/Cobicistat/TDF/FTC QD + EFV/TDF/FTC placebo QD (n = 348) EFV/TDF/FTC QD + Elvitegravir/Cobicistat/TDF/FTC placebo QD (n = 352) Sax P, et al. CROI 2012. Abstract 101.
HIV-1 RNA < 50 c/ml (%) EVG/COBI Non-inferior to EFV at 96 weeks both in a FDC with TDF/FTC Efficacy of EVG/COBI maintained within noninferiority margin (-12%) through Wk 96 Consistent across subgroups: BL HIV-1 RNA, CD4+ count, age, sex, race CD4+ count increase at Wk 96: +295 (EVG/COBI) vs +273 (EFV) 100 80 Difference: 3.6% (95% CI: -1.6 to 8.8) 88 84 Difference: 2.7% (95% CI: -2.9 to 8.3) 84 82 EVG/COBI/TDF/FTC (n = 348) EFV/TDF/FTC (n = 352) 60 40 20 0 Wk 48 Wk 96 Zolopa et al; J Acquir Immune Defic Syndr. 2013 Feb 7
Safety Outcomes With ELV/COBI vs EFV Safety Outcomes at Wk 48 ELV/COBI EFV P Nausea, % 21 14 <.05 CNS Events Abnormal dreams, % Dizziness, % Insomnia, % 15 7 9 27 24 14 <.01 <.01 <.05 Rash, % 6 12.009 Discontinuation for AE, % 4 5 NS Increase in lipids, mg/dl TC LDL-c HDL-c TGs 10 10 5 7 19 17 8 7 <.01.001.001 NS Increase in serum Cr, mg/dl 0.14.01 <.001 Sax P, Lancet. 2012 Jun 30;379(9835):2439-48
Elvitegravir/Cobicistat/TDF/FTC vs ATV/RTV + TDF/FTC in Tx-Naive Patients Multicenter, randomized, double-blinded, active-controlled phase III study Stratified by baseline HIV-1 RNA > or 100,000 copies/ml Wk 48 primary analysis Planned follow-up to Wk 192 HIV-infected treatment-naive patients, HIV-1 RNA 5000 copies/ml, any CD4+ cell count, CL CR 70 ml/min (N = 708) Elvitegravir/Cobicistat/TDF/FTC QD + ATV/RTV + FTC/TDF placebo QD (n = 353) ATV/RTV + TDF/FTC QD + Elvitegravir/Cobicistat/TDF/FTC placebo QD (n = 355) DeJesus E, et al. CROI 2012. Abstract 627.
HIV-1 RNA < 50 c/ml (%) EVG/COBI Regimen Noninferior to ATV/RTV Regimen at Wk 96 (with TDF/FTC) Efficacy of EVG/COBI maintained within noninferiority margin (-12%) through Wk 96 Consistent across subgroups: BL HIV-1 RNA, CD4+, adherence, age, sex, race CD4+ count increase at Wk 96: +256 (EVG/COBI) vs +261 (ATV/RTV) 100 80 60 40 Difference: 2.7% (95% CI: -2.1 to 7.5) Difference: 1.1% (95% CI: -4.5 to 6.7) EVG/COBI/TDF/FTC 90 87 (n = 353) 83 82 ATV/RTV + TDF/FTC (n = 355) 20 0 Wk 48 Wk 96 Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013.
Safety of ELV/COBI vs ATV/RTV at Wk 48 Hyperbilirubinemia more common in ATV/RTV group 58% vs 1% Greater increase in serum Cr in ELV/COBI group 0.12 vs 0.08 mg/dl (P <.001) Greater increase in TGs in ATV/RTV group 23 vs 8 mg/dl (P =.006) Similar rates of grade 3/4 adverse events between groups 13% in ELV/COBI vs 14% in ATV/RTV Low rate of discontinuation related to study drug 4% in ELV/COBI vs 5% in ATV/RTV No primary resistance mutations emerged with ATV/r DeJesus E, et al. Lancet. 2012 Jun 30;379(9835):2429-38
Change from BL in Serum Creatinine (mg/dl) (IQR) Median Change from Baseline in Serum Creatinine 0.35 0.30 Sax et al Lancet. 2012 Jun 30;379(9835):2439-48 0.25 0.20 0.15 0.10 0.05 0.00-0.05-0.10 BL 2 4 8 12 16 24 32 40 48 Week Quad (n=): 348 341 345 345 337 335 328 323 320 320 EFV/FTC/TDF (n=): 352 340 340 336 327 323 317 313 309 307 Median change at Week 48: 0.14 mg/dl vs. 0.01 mg/dl (Quad vs. EFV/FTC/TDF group, p<0.001)
Which NRTI Backbone? NRTIs PROs CONs TDF/FTC Best backbone with EFV Preferred for HBV coinfection 1 Renal toxicity long term Possible increased risk with PIs Bone density 3 ABC/3TC Lack of renal toxicity Less data with raltegravir Need for HLA B*5701 screening to avoid ABC HSR 2 Inferior to TDF/FTC with VL > 100,000 4 Inferior with low CD4 5 Increased risk of MI? ACTG 5202 safety/tolerability data 1 DHHS guidelines 2013; 2 Mallal et al N Engl J Med. 2008 Feb 7;358(6):568-79; 3 McComsey et al J Infect Dis. 2011 Jun 15;203(12):1791-801 4 Sax et al N Engl J Med. 2009 Dec 3;361(23):2230-40; 5 Grant P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 535 and expert opinion
Probability of Remaining Free of Virologic Failure A5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count (Week 192) Slide #47 ABC/3TC TDF/FTC n=98 35 VF n=78 23 VF n=80 n=153 19 VF 10 VF n=39 6 VF n=273 28 VF n=23 5 VF n=184 29 VF n=80 6 VF n=83 17 VF n=70 9 VF n=158 19 VF n=55 8 VF n=289 29 VF n=20 2 VF n=173 24 VF CD4 (cells/mm 3 ) Baseline lower CD4 or higher VL associated with Increased risk of VF with ABC/3TC Grant P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 535.
Abacavir and MI Risk: Recent published studies Reference Study Design Increased risk? Choi, AIDS 2011, VA Observational Yes Bedimo, CID 2011, VA Observational No Durand, J AIDS 2011, Montreal Observational Yes Ribaudo, CID 2011, ACTG Cohort from RCTs No Cruciani, AIDS 2011 Met-analysis No How difficult it is to find a consensus can be exemplifiedby the fact that even identical data sources (Veterans Health Administration) analyzed by different investigators can lead to conflicting results Georg Behrens, AIDS 2011;2043-2045. Courtesy of Paul Sax
FDA Meta-analysis of Risk of MI in Abacavir Trials Conflicting evidence from previous datasets regarding possible association of ABC use with increase in MI risk Current analysis: 26 controlled trials in which ABC use was randomized; source data obtained for analysis No significant relationship between ABC use and risk of MI Academic Center Trials Mantel-Haenszel Risk Difference, % (95% CI) -0.53 0.31 1.16 MI Frequency (Events/Subjects) ABC No ABC 6/702 4/863 NIH (ACTG) Trials -0.45 0.03 0.51 12/1985 9/1610 Manufacturer Trials -0.43-0.11 0.21 6/2341 9/2367 All Trials -0.26 0.008 0.27 24/5028 22/4840-0.8-0.6-0.4-0.2 0 0.2 0.4 0.6 0.8 1.0 1.2 Ding X, et al. CROI 2011. Abstract 808. 1.4
Tenofovir and Renal Risk TDF nephrotoxicity: Glomerular: decreased kidney function Tubular: Fanconi s syndrome, phosphate wasting, osteomalacia Low risk, especially with initial therapy or when combined with EFV Boosted PIs increase tenofovir levels and may increase nephrotoxicity, though incidence has been low in trials of first-line therapy Tubular toxicity not detected by creatinine alone. Look for glycosuria, proteinuria, phosphate wasting
TDF and Kidney Outcomes in VA Cohort 10,841 HIV-infected pts from VA who started ART,1997 to 2007 Parameter. Events, n HR (95% CI) P Value Cumulative exposure to TDF/ yr Proteinuria Rapid decline CKD 3400 3078 553 1.34 (1.25-1.45) 1.11 (1.03-1.18) 1.33 (1.18-1.51) <.0001.0033 <.0001 Ever exposure to TDF Proteinuria Rapid decline CKD 3400 3078 553 1.68 (1.52-1.85) 1.36 (1.23-1.50) 1.71 (1.38-2.12) <.0001 <.0001 <.0001 Pre-existing renal risk factors did not worsen effects of TDF In those who d/c d TDF, kidney events did not decrease during F/U Other ART drugs showed weak or no association with kidney events Sherzer R, et al. AIDS 2012;26:867-875.
HR for Fracture, HAART Era Cumulative Use of TDF and/or Boosted PIs And Risk of Osteoporotic Fractures Retrospective analysis of 56,660 HIV+ male Veterans enrolled from 1988-2009 Osteoporotic fractures assessed from ICD-9 codes Cumulative use of TDF and/or PI/r associated with higher risk in ART era, after controlling for risk factors Highest risk with concomitant use Cumulative use of LPV/r also associated with higher fracture risk PI association limited to LPV/r Cumulative use of ABC, thymidine analogs, NNRTIs not associated with higher risk Bedimo R, et al. AIDS. 2012. 1.3 1.2 1.1 1.0 0.9 Limitations TDF Univariate analysis Controlled for effects of CKD, age, race, smoking, DM, BMI, and HCV. Controlled for covariates in Model 1 plus concomitant exposure to ARVs. Retrospective cohort study BMD data not available PI/r Fractures not verified to be osteoporotic
Which NRTI Backbone? TDF/FTC Kidney disease HLA B*5701 negative, low CV risk ABC/3TC
Which NRTI Backbone? HLA B*5701 positive, (high CV risk?) TDF/FTC Kidney disease NRTI-sparing regimen? ABC/3TC
None of the DHHS Regimens (preferred, alternative, acceptable) Are NRTI Sparing
NRTI-Sparing Regimens Study Regimen Efficacy/ Resistance Lipids Renal Bone Bilirubin A5142 [1-3] LPV/RTV + EFV - PROGRESS [4] LPV/RTV + RAL - - CCTG589 [5] LPV/RTV + RAL - - - - SPARTAN [6] ATV + RAL - - A4001078 [7] ATV/RTV + MVC Neutral - - - ACTG 5262 [8] DRV/RTV + RAL Inferior TBD TBD TBD TBD RADAR [9] DRV/RTV + RAL 1. Riddler S, et al. New Engl J Med. 2008;358:2095-2106. 2. Huang J, et al. IAC 2010. Abs WEAB0304. 3. Goicoechea M, et al. IAC 2010. Abstract WEAB0304. 4. Reynes J, et al. HIV Clin Trials. 2011;12:255-267. 5. Goicoechea M, et al. IAC 2010. Abstract THPE0068. 6. Kozal MJ, et al. IAC 2010. Abstract THLBB204. 7. Portsmouth S, et al. IAS 2011. Abstract TUAB103. 8. Taiwo B, et al. AIDS. 2011;25:2113-2122. 9. Bedimo R, et al. IAS 2011. Abstract MOPE214.
Single tablet regimens PROS TDF/FTC/EFV PK forgiving of missed doses CNS side effects Teratogenicity CONS Resistance with interruption Rash More lipid effects than others TDF/FTC/RPV Better tolerated than EFV Less effective at high VL? Less forgiving of non-adherence TDF/FTC/ EVG/COBI Non-inferior to TDF/FTC/ EFV Better tolerated than EFV More resistance with failure, including ETR cross-resistance Food requirement No PPI, caution with H2 blockers COBI drug interactions COBI effect on egfr
Why use multiple tablet regimens? Expert opinion Boosted PI + 2 NRTIs: Lack of resistance with failure. Ideal for patients with unreliable adherence. Preferred in pregnancy RAL + 2 NRTIs: Superior to EFV at 4 & 5 years. Few drug interactions. Ideal for patients needing HCV therapy ABC/3TC + 3 rd agent: Patients with kidney disease
Choice of ART: Special populations and scenarios Expert opinion Pregnancy or likelihood of pregnancy Avoid EFV (1 st trimester) No data on newer agents (RPV, EVG/COBI) NRTIs: AZT/3TC, TDF/FTC PIs: LPV/r, ATV/r HCV coinfection RAL: can be used with telaprevir, boceprevir ATV: can be used with telaprevir EFV: requires higher dose telaprevir HBV coinfection TDF/FTC-based regimen if possible
Choice of ART: Special populations and scenarios Expert opinion Chronic kidney disease Avoid TDF (and ATV, LPV/r?) Pre-existing osteoporosis/osteopenia Avoid TDF Need for urgent ART without resistance data (primary HIV, acute OI) Boosted PI-based regimen Transmitted resistance Depends on mutations PI-based regimen preferred for NRTI resistance
Percent (%) Prevalence of Transmitted HIV Drug Resistance in US, 2006-2009 Genotypic analysis of samples from newly diagnosed patients in CDC National HIV Surveillance System (N = 12,688) 20 16 12 15.6 All cases with sequences Cases classified as recent infections Cases classified as long-standing infections 8 4 7.8 6.8 4.1 0 1 or more 1-class 2-class 3-class NNRTI NRTI PI Transmitted Drug Resistance Mutations (TDRMs) Ocfemia MCB, et al. CROI 2012. Abstract 730.
ART: New formulations 3 single-tablet regimens now available; 2 more in development: Dolutegravir/ABC/3TC DRV/COBI/TAF/FTC Other new formulations planned: DRV 800 mg tab ATV/COBI DRV/COBI EVG/COBI GS7340/FTC
Slide #63 Treatment Goals and Challenges Treatment Naïve Patient Virtually all patients should be considered for therapy The regimen should be tailored to the patient Consider: HIV disease characteristic (CD4, VL, resistance) Co-morbid illness: HBV, HCV, CKD, DM, mental illness Adherence factors, living conditions, disclosure Risk of side effects: age, sex, lipids, tolerability DRUG-DRUG interactions Simpler is usually better Careful follow-up and adherence monitoring.