Antiretroviral Treatment PDF Free Download

Activity Code FM285

Antiretroviral Treatment 2014 Rajesh Gandhi, MD Masssachusetts General Hospital Disclosures: Educational grants to my institution from Janssen, Viiv, Abbott

Learning Objectives Upon completion of this presentation, learners should be better able to: To review the most recent guidelines regarding when to start antiretroviral therapy To review the most recent guidelines regarding initial therapy of HIV infection To review the most recent guidelines regarding monitoring HIV-infected patients on antiretroviral therapy

Case Scenario # 1 55 yo white M with newly diagnosed HIV History of hypertension, depression Good adherence with medications (lisinopril, paroxetine). Smokes 1 ppd. Regular meals Exam: obese man. BP 130/80 CD4 count 550. HIV RNA 16,000 Estimated GFR 70. Lipids: TC 210. LDL 160 HLA-B5701 negative He says he s interested in treatment with a single-pill combination

Which regimen would you start? A. Dolutegravir + ABC/3TC B. Dolutegravir + TDF/FTC C. EFV/TDF/FTC D. RPV/TDF/FTC E. EVG/cobi/TDF/FTC F. DRV/r + TDF/FTC G. RAL + TDF/FTC 0% 0% 0% 0% 0% 0% 0% A. B. C. D. E. F. G. 10

Case Scenario # 2 55 yo African-American F with GERD, allergic rhinitis, newly diagnosed with HIV CD4 count 150, HIV RNA 250,000 Nurse. Irregular meal-times Medications: omeprazole, fluticasone Estimated GFR 60. HLA-B5701 negative She is interested in starting therapy

Updated: May 1, 2014

What s New in the Guidelines? New section on cost considerations: cost-sharing (co-pays), generic ART, targeted lab testing to reduce costs Change in recommendation re: frequency of CD4 count monitoring Change in classification of recommendations for initial therapy from Preferred to Recommended Regimens, and updated list of recommended regimens Addition of table that provides recommendations on ARV options when switching drugs because of adverse events

What s Not New in the DHHS Guidelines? HCV section not revised Check www.hcvguidelines.org for the latest: This website is constantly being updated. Please remember to always refresh your page.

When to Start What to Start What to monitor

When to Start ART recommended for all HIV+ individuals. Strength of recommendation varies based on CD4 count: CD4 Cell Count < 350 350-500 >500 Recommendation AI AII BIII AI: strong recommendation, data from randomized clinical trials AII: strong recommendation, non-randomized or observational cohort studies BIII: moderate recommendation, expert opinion 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. US DHHS Guidelines, January 2011.

When to Start Therapy Favors delayed ART Drug toxicities Risk of resistance if patient non-adherent Cost Favors early ART potency, simplicity, safety of current regimens transmission May prevent complications of untreated HIV: neurocognitive decline, CV disease, cancer Decreased HIV reservoirs Decreased immune activation, inflammation in blood and CSF Decreased neuronal injury Slide adapted from one by J. Eron, M.D. Jain et al, JID, 2013; Persaud D et al, CROI 2014, #75LB Peterson J et al, CROI 2014, #30 Peluso, CROI 2014, #31

Acute HIV and Elite Controllers Early HIV infection (acute or recent) Most acutely infected patients will reach CD4 threshold for ART initiation within short time (~ 1 yr) Early ART may lower VL set point, delay CD4 cell decline, and enhance CD4 recovery ART recommended although definitive evidence lacking Elite controllers ART recommended for controllers with declining CD4 counts or HIV-related complications My opinion: refer controllers to clinical trials, e.g. ACTG A5308 Hogan et al., JID, 2012; Le T, et al, NEJM, 2013; Lodi S, et al. CID, 2011; Grijsen et al, PLOS Medicine, March 2012; SPARTAC NEJM, January 17, 2013

What to Start 15

What to start DHHS guidelines Feb. 12, 2013 NNRTI + 2 NRTI PI + 2 NRTI INSTI + 2 NRTI Preferred regimens Efavirenz/tenofovir/emtricitabine Darunavir/ritonavir + tenofovir/emtricitabine Atazanavir/ritonavir + tenofovir/emtricitabine Raltegravir + tenofovir/emtricitabine http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0

What to Start: Preferred Recommended Oxford English Dictionary: Prefer: Put in a privileged and more eminent position Recommend: Put forward... with approval as being suitable for a particular purpose or role The era of individualized therapy is here! 17

What to start DHHS guidelines NNRTI + 2 NRTI PI + 2 NRTI May 1, 2014 Recommended Regardless of VL, CD4 count Efavirenz/tenofovir/emtricitabine Darunavir/ritonavir + tenofovir/emtricitabine Atazanavir/ritonavir + tenofovir/emtricitabine Raltegravir + tenofovir/emtricitabine INSTI + 2 NRTI Elvitegravir/cobicistat/tenofovir/emtricitabine Dolutegravir + tenofovir/emtricitabine Dolutegravir + abacavir/lamivudine

Recommended but only for patients with pretherapy VL <100,000 NNRTI- Regimen What to start DHHS guidelines May 1, 2014 Rilpivirine/tenofovir/emtricitabine* Efavirenz + abacavir/lamivudine * PI Regimen Atazanavir/ritonavir + abacavir/lamivudine * Only if patient s CD4 count is >200

PI Regimens INSTI-Regimen Alternative Regimen Options Darunavir-ritonavir + abacavir/lamivudine Lopinavir-ritonavir + abacavir/lamivudine Lopinavir-ritonavir + tenofovir/emtricitabine Raltegravir + abacavir/lamivudine Effective and tolerable but have potential disadvantages or fewer data than Recommended Regimens.

Medications Removed from List of Options for Initial Therapy Zidovudine Nevirapine Ritonavir-boosted saquinavir Ritonavir-boosted fosamprenavir Unboosted atazanavir Maraviroc

Recent Trials of Initial ART EFV RPV EVG/cobi EFV EVG/cobi ATV/r DRV/r ATV/r DTG RAL DTG EFV DTG DRV/r RAL ATV/r

ECHO/ THRIVE Double-blind, double dummy RPV vs. EFV RPV + 2 NRTI* EFV + 2 NRTI* *ECHO: TDF/FTC; THRIVE: investigator selected NRTI RPV EFV Wk 96 VL <50 78% 78% More discontinuations due to AE in EFV gp Pts with pre-art VL >100 K, CD4<200: more virologic failures with RPV STaR Open label N=786 RPV/TDF/FTC SPC EFV/TDF/FTC SPC Wk 48 VL <50 86% 82% *SPC: single-pill combination RPV non-inferior to EFV overall and in pts with pre-art VL >100K; RPV superior to EFV in pts with pre-art VL 100K; more virologic failures and resistance in RPV gp as VL increases, esp. if VL >500K Cohen CJ et al, JAIDS, 2012; Cohen CJ et al, AIDS 2013; CJ Cohen, AIDS 2014

EVG/cobi vs. EFV or ATV/r + TDF/FTC Treatment-naïve patients. CrCL >70 ml/min Randomized, double blind, phase III trials Wk 96 VL <50 Study 102 (n = 700) EVG/cobi/TDF/FTC qd EFV/TDF/FTC qd 84% 82% Study 103 (n = 708) EVG/cobi/TDF/FTC qd ATV/r + TDF/FTC qd 83% 82% Sax P, et al. Lancet. 2012; DeJesus E, et al. Lancet. 2012; Zolopa A et al, JAIDS, 2013; Rockstroh J et al, JAIDS, 2013

EVG/cobi/TDF/FTC Advantages Well-tolerated: fewer CNS and rash events than with EFV Smaller increase in TC, LDL, HDL than with EFV Smaller increase in TGs than with ATV/r Disadvantages/considerations Cobi inhibits tubular secretion of Cr; early increase serum Cr (~0.14 mg/dl; typically < 0.4) Not recommended if CrCl <70 Cobicistat (CYP3A4 inhibitor) can affect metabolism of commonly used meds Separate from antacids (Mg, Al, Ca) by >2 hrs

DTG: Treatment Naïve Studies Wk 48 VL <50 SPRING-2 n=822 double blind DTG (qd) + 2 NRTI* RAL (bid) + 2 NRTI* *investigator selected ABC/3TC or TDF/FTC 88% 85% SINGLE n=833 double blind DTG + ABC/3TC EFV/TDF/FTC 88% 81% FLAMINGO n=484 open-label DTG + 2 NRTI* DRV/r + 2 NRTI* *investigator selected ABC/3TC or TDF/FTC Raffi F et al, Lancet, 2013. Walmsley S et al, NEJM, 2013; Walmsley S et al, CROI, 2014, 543. Clotet B et al. Lancet 2014. 90% 83%

DTG Trials in Treatment-naïve Patients: Summary DTG non-inferior to RAL DTG + ABC/3TC superior to EFV/TDF/FTC More treatment-related discontinuations in EFV/TDF/FTC group: 10% vs. 2% DTG superior to DRV/r Fewer withdrawals in the DTG group Baseline VL >100K: fewer virologic non-responders with DTG In pts receiving DTG for initial therapy, no treatment-emergent mutations detected DTG may have high genetic barrier to resistance Raffi F et al, Lancet, 2013. Raffi et al, IAS, 2013. Walmsley S et al, NEJM, 2013; Walmsley S et al, CROI, 2014, #543; Clotet B et al. Lancet 2014.

Comparing non-efv regimens: ACTG A5257 HIV+ adults, no previous ART (n=1809) Randomized 1:1:1. Open Label Therapy ATV/r + FTC/TDF RAL + FTC/TDF DRV/r + FTC/TDF At 96 wks, RAL superior to both PI/r regimens for combined tolerability and virologic efficacy; DRV/r superior to ATV/r Landovitz RL et al, CROI 2014, #85

Virologic Failure ATV/r: 13% RAL: 10% DRV/r: 15% ATV/r, RAL, DRV/r have equivalent virologic efficacy Landovitz RL et al, CROI 2014, #85

Tolerability Failure : ATV/r: 14% RAL: 1% DRV/r: 5% ATV/r was less well tolerated than DRV/r or RAL (mainly because of hyperbilirubinemia/jaundice) Lipids increased more in PI arm than in RAL arm; no difference between ATV/r and DRV/r arms Bone mineral density losses in spine and hip greater in PI arms than in RAL arm Landovitz RL et al, CROI 2014, #85; Ofotokun I et al, CROI 2014, #746; Brown T et al, CROI 2014, #779LB

Choosing an Antiretroviral Regimen: Two decisions Step 1: Decide which NRTI to use Step 2: Decide which drug to use within the NNRTI, PI or INSTI class

ABC/3TC TDF/FTC or ABC/3TC TDF/FTC NRTI PROS CONS TDF/FTC Single pill options available (with EFV, RPV, EVG/cobi) Active vs. HBV Lowers lipids ABC/3TC Not nephrotoxic When combined with DTG, superior to TDF/FTC/EFV Coformulation with DTG may be available this year Nephrotoxicity (particularly in those receiving other nephrotoxic agents, PIs) Increased loss of bone mineral density Must confirm HLA-B5701 negative VL >100 K: more virologic failures with ABC/3TC than TDF/FTC when used with ATV/r or EFV Some studies, but not all, show association with MI

Can we ditch Nucs? NEAT001? 805 pts randomized to DRV/r + TDF/FTC or DRV/r + RAL At wk 96, RAL non-inferior to TDF/FTC; however: Treatment-emergent resistance: 5/28 (RAL); 0/13 (TDF/FTC) Raffi et al, CROI 2014, # 84LB

Choosing 3 rd drug: NNRTI, PI, INSTI Factor Comorbidities Depression Dyslipidemia Bone disease HCV coinfected Acid lowering Rx CYP3A4-met. drug Considerations Avoid EFV* Favor RPV, DTG, EVG/cobi, RAL INSTI may be better than PI If considering use of simeprevir, favor RAL, DTG, RPV Avoid or caution with RPV, ATV/r Avoid PIs, cobi *In retrospective analysis, increased rate of suicidality in pts randomized to EFV regimens as compared to EFV-free regimens: 8 vs. 3.66/1000 PY. K Mollan et al, IDWeek, 2013

Drug Interactions: Exogenous Steroids Fluticasone 1 & budesonide 2 levels increased by PIs Cushing s syndrome, adrenal insufficiency reported Beclomethasone appears to be a safer alternative 3 1 DHHS guidelines for use of antiretroviral agents in HIV-1-infected adults and adolescents. May 1, 2014. http://aidsinfo.nih.gov 2 http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/hivandaidsactivities/ucm336367.htm 3 Boyd S et al, JAIDS, 2013

Injectable Steroids in Patients on ART 170 HIV+ pts who received steroid injection 81 pts on PI ART 56 pts on non-pi ART 29 pts not on ART 4 pts: insufficient info 9 pts developed Cushings/adrenal insuff. No patient developed Cushings/adrenal insufficiency After steroid injection, 11% of patients on PI-containing ART developed clinical and lab evidence of Cushing s syndrome or secondary adrenal insufficiency Hyle E et al, JAIDS, 2013

What to Monitor 37

Monitoring after Starting ART Chemistries, BUN/Cr, LFTs: wk 2-8, then every 3-6 mo. CBC/diff: every 3-6 mo. Fasting glucose or HbA1c: every 3-6 mo. if previously abnormal; every 12 mo. if normal Lipids: if abnormal, every 6 mo; normal: every 12 mo. U/A every 12 months (every 6 mo. if on tenofovir) Tenofovir Fanconi s syndrome: glucosuria, proteinuria ( 1+), urinary phosphate wasting Cobicistat, dolutegravir inhibit creatinine secretion serum Cr without affecting renal function If >0.4 mg/dl increase in Cr on cobi check for TDF toxicity DHHS guidelines, http://aidsinfo.nih.gov ; Aberg J et al, CID, 2013

Clinical Scenario Before ART After initiating ART After modifying ART in pt with suppressed VL Viral Load Monitoring At entry into care If ART initiation deferred, repeat before initiating ART In patients not initiating ART, repeat testing optional Within 2 to 4 wks; thereafter every 4 to 8 wks until VL suppressed. 4 to 8 wks after modifying ART CD4 Count Monitoring At entry into care If ART deferred, every 3 to 6 mo. 3 mo. after initiation of ART Monitor according to CD4 count and ART duration

Clinical Scenario VL Monitoring CD4 Monitoring First 2 yrs of ART Every 3 to 4 mo. Every 3 to 6 mo. After 2 yrs of ART, VL suppressed, CD4 300-500 --------------------------------- After 2 yrs of ART, VL suppressed, CD4 >500 Change in clinical status, e.g. new HIV clinical sx or drug that may affect CD4 count Can extend to every 6 mo. Every 3 mo. Every 12 mo. ---------------------- Optional Perform CD4 count, repeat as clinically indicated Monitoring of lymphocyte subsets other than CD4 (e.g. CD8, CD19) NOT routinely recommended

CD4 Count Monitoring Patients with VL <200 & CD4 count >300: 99% likelihood CD4 count will stay >200 1 Substantial cost savings with less frequent CD4 cell monitoring 2 1 Gale, CID, 2013; 2 Hyle E et al, JAMA, 2013;

Case Scenario # 1 55 yo white M with newly diagnosed HIV Salient considerations: High risk for cardiovascular disease (HTN, smoking) 2013 AHA risk calculator: 10 yr ASCVD risk is 13% Low VL (16,000), high CD4 count (550) Estimated CrCl 70 Borderline lipids Regular meals Prefers single-pill combination

Which regimen would you start? 1. Dolutegravir + ABC/3TC 2. Dolutegravir + TDF/FTC 3. EFV/TDF/FTC 4. RPV/TDF/FTC 5. EVG/cobi/TDF/FTC 6. DRV/r + TDF/FTC 7. RAL + TDF/FTC

Case Scenario # 2 55 yo F with newly diagnosed HIV Salient considerations GERD, requiring proton-pump inhibitor Allergic rhinitis, on nasal fluticasone Low CD4 count (150), high VL (250,000) Irregular meal-times (nurse) Estimated GFR 60 HLA-B5701 negative

Which regimen would you start? 1. Dolutegravir + ABC/3TC 2. Dolutegravir + TDF/FTC 3. EFV/TDF/FTC 4. RPV/TDF/FTC 5. EVG/cobi/TDF/FTC 6. DRV/r + TDF/FTC 7. RAL + TDF/FTC

Activity Code FM285