HAART Initiation/HIV Treatment for Antiretroviral-Naïve Patients. Ellen Kitchell, M.D.

Transcription

1 HAART Initiation/HIV Treatment for Antiretroviral-Naïve Patients Ellen Kitchell, M.D.

2 A Smorgasbord of Possibilities

3 Picking Out A Delicious Meal For Your Patient There are many fantastic options currently for patients with HIV that have few side effects and with minimal pill burden Certain factors influence your decisions in choosing a regimen for an individual patient (no one size fits all regimen) You are somewhat like a waiter to suggest a regimen that your patient will like to take

4 The Art of HAART

5 Goals of Therapy To come up with a regimen that a patient can take lifelong Durably suppress HIV viral load to <48 copies/ml Provide regimen that is compatible with patient s lifestyle, in order to ensure maximal adherence Minimize toxicity

6 A very good place to start Department of Health and Human Services Guidelines International AIDS Society-USA (IAS-USA) al-treatment-adult-hiv-infection-0

7 STARTING HAART: OPTIMAL TIMING

8 A Long Story Short All patients regardless of CD4 count should be offered antiretroviral therapy Very few exceptions 2 rationales: Individual medical benefit Prevention of transmission

9 START Trial Patients with CD4 count >500 cells/ul Randomized to either immediate initiation of therapy versus deferred until CD4 <350 cells/ul or clinician s judgment Evaluation of mortality, non-aids events, hospitalizations, bone mineral density, etc.

10 START 57% reduced risk of serious events or death with immediate ART 72% reduced risk of serious AIDS events with immediate ART AIDS-related events: any AIDS-defining illness as defined by CDC Serious non-aids defining events: CV disease, ESRD, death from liver disease, cancer

11 START Most of these endpoints occurred in pts with CD4+ cell counts > 500 cells/mm 3 Reduced risk of cancers, particularly in rates of Kaposi sarcoma and lymphoma No difference in rate of cardiovascular events between the arms, although study had to be stopped early INSIGHT START Group. N Engl J Med. 2015;373:

12 HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Linked Transmissions: 28 Delayed Arm: 27 Immediate Arm: 1 Single transmission in patient in immediate HAART arm believed to have occurred close to time therapy began and prior to suppression of genital tract HIV P <.001 Cohen MS, et al. N Engl J Med. 2011;365:

13 Update of HPTN 052 After results returned, ART offered to all pts in study No linked HIV transmissions observed when index participant stably suppressed on ART Risk reduction attributed to early ART was 93% HIV Infections Early Delayed All Linked 3 43 NEJM 2016; 375(9):

14 PARTNER Study 1166 serodifferent couples 40% MSM Inclusion criteria of having sexual contact without condoms at least some of the time HIV+ partner on ARVs, VL <200 copies/ml No documented cases of within-couple HIV transmission Rodger A. JAMA 2016; 316(2):

15 PARTNER MSM serodifferent couples from 14 European countries HIV+ partner was on suppressive ART Couples reported >77,000 episodes of condomless anal sex No transmission events during study period of 7 years Rodger A et al. Risk of HIV transmission through condomless sex in gay couples with suppressive ART: the PARTNER2 study expanded results in gay men. 22nd International AIDS Conference, Amsterdam, abstract WEAX0104LB, 2018.

16 Potential Benefits of Antiretroviral Therapy Initiation at High CD4 Counts Benefits: Prevention of AIDS events, even at high CD4 count Possible prevention of cancer, heart disease Possible prevention of neurocognitive decline Prevention of transmission

17 Potential Risks of Antiretroviral Therapy Initiation at High CD4 Counts Toxicities (including long-term toxicities, which may not be known) Development of resistance Adherence concerns Cost, in resource-limited settings

18 Guidelines for Timing of Antiretroviral Therapy 2018: DHHS and IAS-USA Antiretroviral therapy (ART) is recommended for all HIV-infected individuals, regardless of CD4 T lymphocyte cell count, to reduce the morbidity and mortality associated with HIV infection (AI). ART is also recommended for HIV-infected individuals to prevent HIV transmission (AI).

19 Guidelines for Antiretroviral Initiation: World Health Organization ART should be initiated in all adults living with HIV, regardless of WHO clinical stage and at any CD4 cell count

20 HAART IN THE TRENCHES: INITIATING IN THE SETTING OF OPPORTUNISTIC INFECTION

21 Previous Thoughts About ARV Initiation in Patients with Opportunistic Infections Concern for immune reconstitution syndrome (IRIS), which can cause clinical worsening when the patient s immune system starts to wake up Previously delayed ARVs for weeks to months to avoid this complication

22 ACTG 5164: Immediate versus Deferred Antiretroviral Therapy in the Setting of Opportunistic Infection Randomized patients with OIs to starting ART within 14 days versus deferring on average for 45 days AIDS progression/death in 14% of early HAART versus 24% in deferred arm (not statistically significant) However, fewer AIDS progression/deaths and longer time to AIDS progression/death

23 Caveats to ACTG 5164 Most patients included in study had Pneumocystis pneumonia, which has low risk of IRIS Other opportunistic infections more likely to cause life-threatening IRIS

24 HAART-Immediate Opportunistic Infections Symptomatic HIV infection Cryptosporidium/Microsporidium Kaposi s Sarcoma Lymphoma (especially PCNSL) PML HIV dementia

25 What are Opportunistic Infections with High Risk of IRIS to delay therapy? Cryptococcal meningitis Increased mortality with early ARV initiation in RCT comparing starting w/in 1-2 weeks versus waiting 5 weeks Recommended to delay 2-10 weeks Worse outcome if initial CSF WBC was <5, increased intracranial pressure

26 Other Opportunistic Infections Tuberculosis Recommendations to start therapy depend on baseline CD4 If <50 cells: start therapy w/in 2 weeks If >50, start w/in 8 weeks Caution regarding TB meningitis

27 CMV retinitis No specific recommendations, consider delay 1-2 weeks Toxoplasmosis No specific recommendations but I typically wait 2-3 weeks

28 WHAT TO START

29

30 Considering HAART Options 1. Will the regimen be expected to work against the patient s virus? Resistance testing results 2. Consider comorbidities, especially hepatitis B and C status 3. Baseline labs, including renal, hepatic function 4. Drug interaction issues and potential drug interactions 5. Potential side effects of the regimen: how will this affect the patient and adherence to medications 6. Lifestyle issues: ability to adhere to regimens, pill burden 7. For women, plans for pregnancy 8. Cost/insurance issues

31 Recommendations from Expert Panels DHHS, IAS, WHO Have preferred regimens selected on efficacy, tolerability Sometimes the preferred regimen for your patient is not one of these options

32 Recommended Regimens: DHHS Guidelines nucleos(t)ide reverse transcriptase inhibitors (NRTIs) + 3 rd active drug Integrase inhibitor (INSTI) = main dish Lamivudine OR emtricitabine = the fries Abacavir OR tenofovir = the drink? Have tried 2 drugs and 4+ medications, nothing seems to work as well for now, 3 is the magic number!

33 DHHS Guidelines: Preferred Raltegravir (ISENTRESS) With emtricitabine/tenofovir DF (TRUVADA) With emtricitabine/taf (DESCOVY)

34 Preferred Regimens: DHHS Elvitegravir With emtricitabine/tenofovir DF (co-formulated as STRIBILD) With emtricitabine /tenofovir AF (coformulated as GENVOYA)

35 Preferred Regimens: DHHS Dolutegravir (TIVICAY) With abacavir/lamivudine (EPZICOM or TRIUMEQ) With tenofovir DF/emtricitabine (TRUVADA) With tenofovir AF/emtricitabine (DESCOVY)

36 DHHS Guidelines: Preferred (New Update as of 3/2018) BIKTARVY: Bictegravir + emtricitabine + tenofovir alafenamide

37 Alternative Regimens for DHHS Considered effective and tolerable, but with potential disadvantages, limitations for use in certain populations or less supporting data from clinical trials Darunavir/cobi or darunavir/ritonavir + tenofovir/ftc or abacavir/lamivudine Boosted atazanavir + tenofovir DF or AF Efavirenz/emtricitabine/tenofovir DF or AF

38 Other Regimens If HIV RNA <100,000 copies/ml Boosted atazanavir + abacavir/lamivudine Efavirenz + abacavir/lamivudine Rilpivirine/tenofovir/emtricitabine (also need CD4 >200 cells/ul) Raltegravir + abacavir/lamivudine

39 IAS Recommendations 2018 Bictegravir/tenofovir alafenamide/emtricitabine Dolutegravir/abacavir/lamivudine Dolutegravir/tenofovir alafenamide/emtricitabine

40 WHO Recommendations Efavirenz + tenofovir + lamivudine (or emtricitabine) Alternative: dolutegravir + tenofovir + lamivudine

41 Comparison of Current International Guidelines for Treatment-Naive Pts Regimen DHHS IAS-USA WHO DTG/3TC/ABC* DTG + FTC/TDF or TAF EVG/COBI/FTC/TDF EVG/COBI/FTC/TAF RAL + FTC/TDF or TAF ATV/RTV + FTC/TDF DRV/RTV + FTC/TDF EFV/FTC/TDF RPV/FTC/TDF Recommended Alternative Not included *Only if HLA-B*5701 negative. Only if CrCl 70 ml/min. Only if CrCl 30 ml/min. Only if baseline HIV-1 RNA < 100,000 copies/ml and CD4+ cell count > 200 cells/mm 3.

42 THE MAIN DISH

43 Use of Efavirenz in Naïve Patients (SUSTIVA/ATRIPLA) Cheap(er) and a lot of side effects!

44 Efavirenz Is Efficaceous Up until recently, efavirenz was non-inferior or superior to other ARVs at suppressing HIV, regardless of baseline viral load or CD4 Key studies comparing efavirenz to other options: ACTG 5142 efavirenz superior to lopinavir/ritonavir (KALETRA) ACTG 5202: non-inferior to atazanavir/ritonavir ECHO/THRIVE: non-inferior to rilpivirine GS-US : non-inferior to elvitegravir

45 More Recent Efficacy Trials In studies of newer integrase-inhibitor regimens, some regimens have demonstrated superiority to efavirenz Primarily based on more discontinuations due to adverse effects in efavirenz arm

46 Adverse Effects of Efavirenz/Atripla Neuropsychiatric side effects are common: Strange/vivid dreams in ~50% Dizziness/feeling drunk Depression, unstable mania Increased suicidality noted Potential teratogen Some drug interactions (substrate of CYP3A4 and inducer of 3A4/2D6) Usually take at bedtime on empty stomach Low genetic barrier to resistance Includes tenofovir DF, no plans to co-formulate with other options

47 Rilpivirine: Alternative Therapy Very few side effects Not as potent Not for patients with heartburn

48 Alternative Therapy: Rilpivirine NNRTI medication set to compete with Atripla Co-formulated with emtricitabine/tenofovir DF (Complera) and FTC/TAF (Odefsey) Very well tolerated compared to Atripla However, more virologic failures, particularly in patients with low CD4 and high viral load (>100,000 copies/ml) ECHO/THRIVE. Lancet 2011; 378(9787):

49 Rilpivirine Usage Only approved for relatively well, adherent patients CD4 >200 cells/ul Viral load <100,000 copies/ml PPI lowers absorption Need to eat a high fat, large meal for absorption

50 Protease Inhibitor Based Regimens Durable, tough even in non-adherent patients Drug interactions Side effects

51 Protease Inhibitors Very potent class of medications Very low rates of baseline resistance Durable at suppressing virus High genetic barrier to resistance If patients fail a PI based regimen, rarely develop mutations, and if so, PI mutations are very rare (not true of integrase or NNRTI based regimens) Forgiving of non-adherence

52 Protease Inhibitors Recommended by many (including myself) to use in situation where genotype is not available yet

53 Adverse Effects of the Protease Inhibitor Class Gastrointestinal side effects (nausea/vomiting/diarrhea) Inhibit cytochrome P450 enzyme system Need to take with food Metabolic abnormalities Dyslipidemia Insulin resistance Lipodystrophy, weight gain Older Pis implicated in stroke, MI

54 Pill Burden with Protease Inhibitors Previously had greater pill burden with protease inhibitors which limited adherence Now with multiple co-formulated options with modern PIs: Evotaz (atazanavir/cobicistat) Prezcobix (darunavir/cobicistat) Symtuza (darunavir/cobicistat/tenofovir alafenamide/emtricitabine)

55 Efficacy Trials for Atazanavir (Reyataz) ACTG 5202 showed similar efficacy between efavirenz + atazanavir GS showed similar efficacy between elvitegravir + atazanavir ACTG 5257 showed similar virologic efficacy between atazanavir, darunavir and raltegravir However, more treatment discontinuations in atazanavir group

56 Unique Adverse Effects to Atazanavir Indirect hyperbilirubinemia Functional Gilbert s syndrome Expected and harmless to patient except for cosmetic appearance Scleral icterus, jaundice Some patients do not like the appearance Is NOT supposed to cause AST/ALT elevation Need for acidic gastric ph for absorption Nephrolithiasis (rare)

57 Efficacy Trials for Darunavir in Naïve Patients ARTEMIS showed superior efficacy to old PI, Kaletra ACTG 5257 showed similar virologic efficacy to raltegravir FLAMINGO study showed darunavir had lower rate of virologic suppression than dolutegravir Driven by drug discontinuation in darunavir group

58 Unique Adverse Effects to Darunavir Sulfonamide moiety Use in caution with patients with severe sulfa allergy; however most patients with h/o sulfa allergy tolerate darunavir well

59 Cobicistat Can be used as a booster for increasing drug levels of protease inhibitors and elvitegravir Co-formulated with multiple regimens Not recommended as preferred in DHHS because not as much clinical trial data

60 Protease Inhibitors in the Guidelines No longer recommended as first line in the DHHS and IAS guidelines Side effect burden Issues with drug interactions Is recommended for patients with concerns over adherence given their potency

61 Integrase-Inhibitor Based Regimens

62 Patients With HIV-1 RNA < 50 copies/ml (%) STARTMRK: Virologic and Immunologic Efficacy at Wk % 82% 81% 79% Study Week RAL EFV Significantly shorter time to virologic response with RAL vs EFV (P =.001)

63 Other Efficacy Studies for Raltegravir ACTG 5257 compared atazanavir, darunavir and raltegravir in combination with tenofovir/emtricitabine Similar virologic efficacy in all arms Fewer discontinuations in darunavir and raltegravir arms Ann Intern Med Oct 7; 161(7):

64 ACTG 5257 Virologic failure with drug resistance occurred infrequently More common in patients assigned to raltegravir arm Integrase inhibitor mutations found in all patients who developed virologic failure with drug resistance

65 Efficacy in Clinical Trials of Raltegravir SPRING-2 compared dolutegravir versus raltegravir in naïve patients Used background of abacavir/lamivudine or tenofovir/emtricitabine No difference in virologic response Lancet Infectious Diseases 13(11): P

66 Once-Daily Raltegravir: ONCEMRK Use of raltegravir 2 tablets of 600 mg dosage once daily compared with 400 mg twice daily In combination with emtricitabine/tenofovir DF Similar virologic suppression rates Similar side effect profile Cahn P. Lancet HIV. 2017

67 Adverse Effects of Raltegravir Very well tolerated Rarely causes CPK elevations, rhabdomyolysis, myositis Rare rashes Minimal drug interactions great for psych patients and herbal medication takers No food requirement but need to avoid divalent cations

68 Raltegravir Versus Other Options Benefits of using raltegravir Considered least metabolically toxic, both in terms of lipodystrophy and effect on triglycerides Lack of drug interactions Minimal side effects Quick virologic suppression and immunologic recovery Concerns about raltegravir Lower genetic barrier to resistance than PIs and second generation integrase inhibitors Greater number of pills

69 Why would you use elvitegravir (STRIBILD or GENVOYA)? Well-tolerated, low pill burden Renal issues Drug interactions Lower genetic barrier to resistance

70 Elvitegravir Elvitegravir/cobicistat was non-inferior to efavirenz containing regimen Did see resistance mutations developing in patients failing therapy in both arms of the study Journal of Acquired Immune Deficiency Syndromes. 2014;65(3):e

71 Safety of Elvitegravir/Cobicistat vs Efavirenz Elvitegravir very well-tolerated, main side effect was nausea, headaches Significantly greater increase in median serum creatinine from EVG/COBI group Thought to be related to cobicistat inhibition of creatinine secretion in distal tubule In Stribild (with tenofovir DF), limited use only in patients with creatinine clearance of >70 ml/min Genvoya (with tenofovir AF), can use down to CrCl 30 ml/min JAIDS 2013; 63(1):

72 Elvitegravir versus Atazanavir Elvitegravir/cobicistat non-inferior to atazanavir/ritonavir regimen In patients with confirmed virologic failure, resistance detected in 5/12 patients in elvitegravir arm; no resistance in atazanavir arm Not as tough as the PIs!

73 Pros and Cons of Elvitegravir Pros Low side effect profile Highly effective at viral suppression Low pill burden Cons Drug interactions Food requirements Expense Monitoring renal function Genetic barrier to resistance not as high as other meds

74 Why use dolutegravir (TIVICAY/TRIUMEQ)? Potent, low side effect burden Seems to have high genetic barrier to resistance Recent concerns about teratogenicity

75 Dolutegravir + Abacavir/Lamivudine versus Efavirenz/tenofovir/emtricitabine (SINGLE)

76 Dolutegravir Versus Efavirenz Dolutegravir was statistically superior at suppressing viral load at 48 and 96 weeks No integrase or NRTI mutations detected in patients on dolutegravir Dolutegravir had lower rate of CNS side effects and rash Fewer discontinuations due to AEs in dolutegravir group (10% in Atripla arm)

77 SPRING-2: Dolutegravir Noninferior to Raltegravir at 96 Wks (81% vs. 76%)

78 FLAMINGO Trial Open-label trial comparing dolutegravir to darunavir/ritonavir Could use abacavir/lamivudine or tenofovir/emtricitabine

79 FLAMINGO Results: Dolutegravir Superior to Darunavir in HIV <50 copies/ml (90% vs. 83%)

80 FLAMINGO Results Treatment success driven by higher discontinuation rates for darunavir patients (4% versus 2% in dolutegravir group) 2 patients in each group had virologic failure No treatment-emergent mutations detected Suggests that dolutegravir has high genetic barrier to resistance

81 Dolutegravir Insomnia and headache in 2% of patients Post-marketing notes concern for mood changes in some patients Decreased tubular secretion of creatinine, does not affect renal function Very few drug interactions (but still a few!) E.g. metformin, seizure medications, St. John s wort

82 Dolutegravir and Concerns About Teratogenicity Observational study of birth outcomes in pregnant women in Botswana Found 4/426 infants born with neural tube defects in women who were taking dolutegravir at the time of conception Also included 116 women who started on dolutegravir in 1 st trimester, no birth defects noted in this group No previous birth defects noted, including in United States Unclear whether dolutegravir is the only integrase inhibitor that can potentially do this Still awaiting additional data from this study

83 Dolutegravir Current Recommendations Per DHHS Recommend avoiding dolutegravir in women who: Desire pregnancy Not using effective contraception First trimester of pregnancy or possible pregnancy Check pregnancy testing prior to starting

84 Why use bictegravir (Biktarvy)? Potent, low side effect burden Seems to have high genetic barrier to resistance Newest antiretroviral

85 Bictegravir GS-US randomized patients to receive bictegravir/taf/ftc or dolutegravir/taf/ftc At week 48, 89% of patients in bictegravir arm and 93% of patients in dolutegravir arm had VL <50 GS-US randomized patients to Biktarvy versus Triumeq 92% of patients in bictegravir arm and 93% of patients in Triumeq were virally suppressed

86 Side Effects of Bictegravir (5%, mild) Nausea Diarrhea Headache Dizziness Insomnia

87 Regimen Advantages Disadvantages Efavirenz Rilpivirine Proteaseinhibitor based Raltegravir Elvitegravir Dolutegravir Bictegravir Cost Single-tablet regimen Long-term data available Single-tablet regimen Well-tolerated Most forgiving for non-adherent patients Safe to use in patients without genotype information Minimal adverse effects Very few drug-drug interactions Single tablet regimen Well-tolerated Single tablet regimen Few side effects High genetic barrier to resistance Single tablet regimen Low side effect profile High genetic barrier to resistance CNS side effects Teratogenicity Low genetic barrier to resistance Low genetic barrier to resistance Higher virologic failures in high viral loads Need for acid for absorption Metabolic side effects Drug interactions For atazanavir, jaundice and need for acid for absorption Higher pill burden Lower genetic barrier to resistance than protease inhibitors Renal effects Drug interactions Lower genetic barrier to resistance than protease inhibitors Mild renal effects Rare mood side effects Teratogenicity? New medication Few drug interactions

88 SIDE DISHES

89 The Fries of the Regimen: Lamivudine or Emtricitabine One of the earliest developed antiretrovirals Very safe, well-tolerated Emtricitabine very similar structure Use interchangeably Very similar resistance pattern (no reason to use both medications) Used in almost all regimens for HIV

90 Choosing Between the NRTIs: Abacavir versus Tenofovir

91 Abacavir Went Away then Returned to DHHS Previously had fallen off due to concerns about: Efficacy in comparison with tenofovir Possible cardiovascular toxicity Hypersensitivity reaction No activity against hepatitis B infection

92 ACTG 5202: Abacavir vs Tenofovir Study discontinued early In patients treated with atazanavir and efavirenz More virologic failure observed with abacavir in patients with HIV RNA >100,000 copies/ml versus in tenofovir.

93 HIV-1 RNA HEAT: Abacavir Noninferior to Tenofovir, even at high HIV viral loads ABC/3TC + LPV/RTV* (n = 343) TDF/FTC + LPV/RTV* (n = 345) < 50 copies/ml (%) [1] M = F MD = F VF (%) [2] ,000 copies/ml 250,000 - < 500,000 copies/ml 100,000 - < 250,000 copies/ml < 100,000 copies/ml ABC/3TC (n = 49) TDF/FTC (n = 48) Smith KY, Patel P, Fine D, et al; HEAT Study Team. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23(12):

94 Dolutegravir Trials (SINGLE, FLAMINGO) No differences between abacavir or tenofovir in virologic efficacy, even at high viral loads (>100k)

95 Abacavir in DHHS Guidelines Recommended in patients taking dolutegravir (extensively tested) Use in efavirenz or atazanavir based regimens only if viral load is <100k ***Considered as alternative *** Probably ok with darunavir based regimens (not tested) Not much data with rilpivirine or raltegravir

96 Abacavir and Cardiovascular Risk D:A:D cohort study has thousands of patients on multiple regimens Found that patients recently started (within 6 months) associated with increased risk of MI, particularly in patients with CV risk factors

97 Summary of Clinical Trial and Cohort Analyses of ABC Use and CVD Risk Study Design CV Events Effect of ABC? D:A:D [1] (N = 33347) Observational cohort Prospective, predefined Yes FHDH [2] (N = 1173) Case control study MI retrospectively validated SMART [3] (N = 2752) RCT, observational analyses Prospective, predefined Yes 1st yr of exposure STEAL [4] (N = 357) RCT Prospective Yes GSK analysis [5] (N = 14174) ALLRT ACTG A5001 [6] (N = 3205) 54 RCTs Retrospective database search No 5 RCTs All or majority of pts antiretroviral-experienced at ABC initiation All or majority of pts antiretroviral-naive at ABC initiation Retrospective by 2 independent reviewers Yes No 1. Lundgren JD, et al. CROI Abstract 44LB. 2. Lang S, et al. CROI Abstract 43LB. 3. SMART. AIDS. 2008;22:F17-F Carr A, et al. CROI Abstract Cutrell A, et al. IAC Abstract WEAB Benson C, et al. CROI Abstract 721. Reiss P. CROI Abstract 152.

98 Cardiovascular Risk of Abacavir Bedimo et. al (CID (1): 84-91) used Veterans Association data to calculate risk of MI and stroke in patients on abacavir and other combinations Controlled for chronic kidney disease, smoking, lipids etc. Observed NO association between abacavir use and MI or CVA once CKD accounted for

99 Cardiovascular Risk and Abacavir Meta-analysis of randomized, controlled treatment trials and manufacturer data found no evidence that abacavir-containing regimens carry greater risk of MI Cruciani M. AIDS 2011; 25(6):

100 DHHS and IAS Guidelines No consensus has been reached on the association between abacavir use and MI risk or the mechanism for such an association. Abacavir should be used with caution or avoided in patients with known high cardiovascular risk

101 Concerns About Tenofovir

102 Spine BMD Percent Change From Wk 0 Spine BMD Percent Change From Wk 0 ACTG 5224s: Change in Bone Mineral Density Substudy of ACTG 5202 Tenofovir versus abacavir and efavirenz vs atazanavir/ritonavir Primary endpoint Changes in bone mineral density by DXA TDF/FTC ABC/3TC 192 At week 96, significantly greater losses in BMD with Tenofovir vs abacavir in both hip and spine Atazanavir/ritonavir vs efavirenz in spine P =.035* EFV ATV/RTV McComsey GA, et al. J Infect Dis. 2011;203:

103 Tenofovir: Concerns for Renal Toxicity Fanconi s syndrome known potential toxicity of tenofovir Multiple case studies and clinical experience of proximal tubular dysfunction and impaired GFR; several observational cohort studies show rates of renal failure with tenofovir use Meta-analysis showed significantly greater decrease of ml/min and increased risk of acute renal failure (0.7%) in patients receiving tenofovir as compared to other regimens Cooper R. CID 2010:

104 Tenofovir alafenamide (TAF) TAF (GS-7340), prodrug of tenofovir with lower tenofovir plasma concentrations, increased delivery to hepatocytes, lymphoid cells Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF Cathepsin A TFV TFV-MP TFV-DP

105 Use of Tenofovir Alafenamide vs TDF in Treatment-Naive Pts Studies 104/111 Compared elvitegravir/cobicistat and tenofovir alefenamide versus disproxil Similar virologic suppression Smaller egfr decline with TAF (but decline noted) Decreased rates of bone loss with TAF Higher lipid levels with TAF due to absence of TDF lipid lowering effect 1. Sax PE, et al. Lancet. 2015;385: Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72:58-64.

106 Tenofovir versus Abacavir Regimen Advantages Disadvantages Abacavir Similar efficacy to tenofovir in HEAT and dolutegravir trials Hypersensitivity can be safely avoided with HLA-B*5701 assay Potential for hypersensitivity reaction Inferior response high viral load in ACTG 5202 Association with risk of myocardial infarction in some studies Tenofovir DF Tenofovir AF High level of efficacy in clinical trials Active against hepatitis B Comparable efficacy to tenofovir DF in clinical trials Less effect on bone and renal Active against hepatitis B Can use in patients with CKD to GFR >30 ml/min Caution in pts with renal insufficiency Long-term nephrotoxicity and tubular toxicity not fully understood Should not be coadministered with other nephrotoxic drugs Bone toxicity Does have some effects on bone and kidney Higher cholesterol levels than TDF

107 Really Alternative Regimens if Cannot Use Tenofovir or Abacavir Darunavir/ritonavir plus raltegravir (BID) if HIV RNA <100,000 copies/ml and CD4 >200 cells/mm 3 (NEAT) Lopinavir/ritonavir + lamivudine (GARDEL) Raffi F, et al. Lancet. 2014;384: Cahn P, et al. Lancet Infect Dis. 2014;14:

108 Other Regimens for Naïve Patients (Not in the Guidelines) ANDES: Small study comparing darunavir/lamivudine and darunavir/lamivudine/tenofovir DF showed similar virologic suppression ATLAS: atazanavir/lamivudine open label trial Cahn P et al. Dual therapy with darunavir/ritonavir plus lamivudine for HIV-1 treatment initiation: week 24 results of the randomized ANDES study. 9th International AIDS Society Conference on HIV Science, Paris, abstract MOAB0106LB, 2017.

109 Other Regimens For Naïve Patients (Not in the Guidelines Yet) Dolutegravir monotherapy NOT recommended PADDLE, ACTG A5353 trial: dolutegravir + lamivudine open label looked good but small, not randomized GEMINI-1 and 2: compared dolutegravir + lamivudine to dolutegravir/lamivudine/tdf in treatment naïve patients Similar virologic efficacy, no development of resistance (capped at VL <500k) Cahn P. Program and abstracts of the 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands. Abstract TUAB0106LB.

110 New Antiretrovirals Doravirine, novel NNRTI Comparison trials against efavirenz/emtricitabine/tenofovir and darunavir/ritonavir/tenofovir/emtricitabine Just released coformulated doravirine/lamivudine/tenofovir DF (DELSTRIGO) PIFELTRO = doravirine alone Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5:e211-e220.

111 A Little Farther on the Horizon Cabotegravir, novel integrase inhibitor Trial of oral medication Injectable formulation In combination with oral or IM rilpivirine