HIV Treatment: State of the Art 2013 Daniel R. Kuritzkes, MD Chief, Division of Infectious Diseases Brigham and Women s Hospital Professor of Medicine Harvard Medical School Success of current ART Substantial reduction in AIDS-related mortality Source: www.cdc.gov October 2, 2009; accessed September 6, 2010.
FDA-Approved Antiretroviral Agents and Fixed-dose Combinations NRTI Zidovudine Didanosine Stavudine Lamivudine Abacavir Tenofovir* Emtricitabine ZDV/3TC ABC/3TC TDF/FTC ZDV/3TC/ABC NNRTI Nevirapine Efavirenz Etravirine** Rilpivirine TDF/FTC/EFV TDF/FTC/RPV *Nucleotide RT inhibitor **Approved only for treatment-experienced patients Protease Inhibitors Saquinavir Ritonavir Indinavir Nelfinavir Fosamprenavir Lopinavir/ritonavir Atazanavir Tipranavir** Darunavir Fusion Inhibitors Enfuvirtide (T-20)** CCR5 antagonists Maraviroc Integrase inhibitors Raltegravir Elvitegravir/cobicistat/TDF/ FTC Dolutegravir HIV-1 lifecycle: points of drug action Fusion inhibitors Co-receptor inhibitors Reverse transcriptase inhibitors Protease inhibitors Integrase inhibitors
DHHS Guidelines 2013: When to start antiretroviral therapy Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression ART also is recommended for HIV-infected individuals to prevent HIV transmission Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors. DHHS Antiretroviral Treatment Guidelines, February 12, 2013 Available at: http://aidsinfo.nih.gov/guidelines. WHO guideline changes Recommend ART for all patients with CD4 counts <500/mm 3 Prioritize ART for patients with CD4 <350/mm 3 Initiate ART in all patients regardless of CD4 count with TB; HBV; serodiscordant couples For pregnant/nursing women Initiate ART and continue through period of MTCT risk In generalized epidemics initiate ART as lifelong treatment Consider stopping ART after MTCT risk ended if women not otherwise eligible based on local country criteria Fixed-dose TDF/3TC/EFV preferred first-line ART in all situations AZT/3TC and/or NVP are alternatives Second line therapy: 2 NRTI + boosted PI (FDC ATV/r or LPV/r)
HPTN 052 early ART prevents HIV transmission and clinical events Cohen et al NEJM 2011 Considerations in choosing ART Potency Tolerability Co-morbid conditions Convenience Pregnancy Risks for toxicity Drug resistance
DHHS Guidelines: What to start Types of preferred regimens: NNRTI + 2 NRTI Ritonavir-boosted PI + 2 NRTI INSTI + 2 NRTI Preferred regimens: Efavirenz/tenofovir/emtricitabine* Ritonavir-boosted atazanavir + tenofovir /emtricitabine* Ritonavir-boosted darunavir + tenofovir/emtricitabine* Raltegravir + tenofovir/emtricitabine* *Fixed-dose combination Available at: http://aidsinfo.nih.gov/guidelines. Updated February 12, 2013. DHHS Guidelines: What to start Alternative EFV +ABC/3TC RPV + TDF/FTC or ABC/3TC ATV/r or DRV/r + ABC/3TC FPV/r (QD or BID) + TDF/FTC or ABC /3TC LPV/r (QD or BID) + TDF/FTC or ABC/3TC RAL + ABC/3TC EVG/Cobi/TDF/FTC Available at: http://aidsinfo.nih.gov/guidelines Updated February 12, 2013.
Toxicities of first-line NRTIs Tenofovir Renal insufficiency/tubular nephropathy Reduction in bone mineral density Emtricitabine Hyperpigmentation Abacavir Hypersensitivity in patients with HLA-B*5701 Lamivudine Rare neutropenia, neuropathy Toxicities/limitations of NNRTIs Efavirenz CNS toxicity Rash Teratogenicity (neural tube defects) Increased cholesterol (HDL>LDL) Nevirapine Hepatotoxicity Hypersensitivity Rash Rilpivarine Less active in patients with VL>100,000 copies/ml 1,2 1 Molina et al. Lancet 2011; 378: 238 46. 2 Cohen et al. Lancet 2011; 378: 229 37.
ECHO and THRIVE: Study Designs Randomized, double-blind, double-dummy, multicenter, 96-week study ECHO (TMC278-C209) RPV 25mg QD + FTC/TDF (N=346) N=690 patients + EFV placebo QD ARV-naïve HIV RNA 5,000 c/ml No NNRTI RAMs Sensitivity to the NRTIs THRIVE (TMC278-C215) N=678 patients EFV 600mg QD + FTC/TDF (N=344) + RPV placebo QD RPV 25mg QD + 2NRTIs* (N=340) + EFV placebo QD EFV 600mg QD + 2NRTIs* (N=338) + RPV placebo QD *Investigator s choice: TDF/FTC (60%); ZDV/3TC (30%); ABC/3TC (10%) Primary objective: non-inferiority (12% margin) vs. EFV in confirmed virologic response (viral load <50 copies/ml, ITT-TLOVR) at Week 48 ITT = intent-to-treat; TLOVR = time-to-loss of virologic response Pooled analyses were pre-planned Cohen C, et al. JAIDS 2012 13 Pooled ECHO and THRIVE: VL <50 copies/ml Over 96 Weeks (ITT-TLOVR) Cohen C, et al. JAIDS 2012
ECHO and THRIVE: Association baseline VL on of Virologic response * *TMC278= rilpivirine Cohen et al XVIIIth Intl AIDS Conf, Vienna, 2010 Abstract THLBB206 Principles of protease inhibitor therapy Ritonavir (RTV) boosting Most PIs metabolized by CYP3A4 Ritonavir potently inhibits CYP3A4, PGP activity Co-administration of PI + RTV enhances efficacy Metabolic effects (variable) Hyperlipidemia Insulin resistance Visceral adiposity Increased cardiovascular risk Decreased risk of resistance at time of virologic failure for boosted regimens
Cobicistat CYP3A4 inhibitor No anti-hiv activity in vitro Phase 1 and 2 trials show boosting effects similar to ritonavir Plans underway to co-forumulate with atazanavir and darunavir Study Design Study 114 Randomized, double-blind, double dummy, active-controlled, international study (n=350) Treatment Naïve HIV-1 RNA 5000 c/ml Any CD4 cell count egfr 70 ml/min 1:1 ATV + COBI + FTC/TDF Placebo: RTV (n=350) ATV + RTV + FTC/TDF Placebo: COBI Randomization stratified by screening HIV-1 RNA ( vs >100,000 c/ml) 48 Weeks 192 Weeks Gallant et al J Infect Dis 2013 Primary Endpoint Snapshot analysis (HIV-1 RNA < 50 c/ml) Non-inferiority margin: 12%
Study 114 FDA Snapshot Week 48 (ITT) Percentage of Subjects (%) 100 80 60 40 20 0 ATV + COBI (n=344) 85 87 Virologic Success 6 4 Virologic Non- Suppression ATV + RTV (n=348) 9 9 No W48 Data* -12% 95% CI for Difference Favors ATV + RTV -2.2-7.4 3.0 0 Favors ATV + COBI 12% ATV + COBI + FTC/TDF was non-inferior to ATV + RTV + FTC/TDF at Week 48 Gallant et al J Infect Dis 2013 Common Adverse Events Study 114 ATV + COBI (n=344) ATV + RTV (n=348) AEs (all Grades) 10% of subjects in either group Bilirubin-related AEs * 41% 36% Nausea 18% 16% Diarrhea 15% 20% Headache 11% 16% Nasopharyngitis 11% 15% Upper respiratory infection 10% 8% * Bilirubin-related AEs include jaundice, ocular icterus, hyperbilirubinemia, and blood bilirubin increased. Increase in serum creatinine (mg/dl) 0.13 0.09 Gallant et al J Infect Dis 2013
Elvitegravir Integrase strand-transfer inhibitor Requires boosting by CYP3A4 inhibition for once daily dosing Overlapping resistance profile with raltegravir Co-forumulated as elvitegravir/cobicistat/ tenofovir/emtricitabine ( quad ) Study Design 236-0102 (n=350) Treatment naive (N = 700 planned) US & Puerto Rico Randomized 1:1 Stratification by HIV-1 RNA (>100,000 c/ml) Quad QD EFV/FTC/TDF Placebo QHS (n=350) EFV/FTC/TDF QHS Quad Placebo QD Week 48 Week 192 Primary Endpoint: Proportion with HIV-1 RNA < 50 c/ml at Week 48 FDA snapshot analysis, 12% non-inferiority margin HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5 Sax P, et al. CROI 2012; Seattle. Poster 101LB 22
Study Design 236-0103 (n=350) Treatment naive (N = 700 planned) International Randomized 1:1 Stratification by HIV-1 RNA (>100,000 c/ml) Quad QD ATV/r+FTC/TDF Placebo QD (n=350) ATV/r + FTC/TDF QD Quad Placebo QD Week 48 Week 192 Primary Endpoint: Proportion with HIV-1 RNA < 50 c/ml at Week 48 FDA snapshot analysis, 12% non-inferiority margin HIV-1 RNA: Amplicor HIV-1 Monitor Test, version 1.5 DeJesus E, et al., CROI 2012; Seattle. Poster 627. 23 236-0102 and 236-0103: Results Sax et al Lancet 2012; DeJesus et al Lancet 2012
Change in serum creatinine Sax et al Lancet 2012; DeJesus et al Lancet 2012 Dolutegravir Once-daily integrase strand-transfer inhibitor (INSTI) Limited cross-resistance between dolutegravir and raltegravir or elvitegravir Active against viruses carrying INSTI resistance mutations at codons 143, 155 and single 148 mutants
SINGLE study design + TDF/FTC/EFV TDF/FTC/EFV Walmsley et al ICAAC 2012 SINGLE: primary endpoint analysis TDF/FTC/EFV: TDF/FTC/EFV QD to TDF/FTC/EFV at week 48 (primary endpoint) TDF/FTC/EFV, median (TDF/FTC/EFV; p<0.0001) Walmsley et al ICAAC 2012
SINGLE: Resistance at virologic failure TDF/FTC/EFV Walmsley et al ICAAC 2012 SAILING study design Pozniak et al, 20 th CROI, 2013; Abstract, 179LB
SAILING study results Pozniak et al, 20 th CROI, 2013; Abstract, 179LB Persistent low-level viremia in patients on suppressive ART Palmer et al PNAS 2008 DRK/3.5.13/Perth
Persistence of latently infected CD4+ cells Siliciano et al Nat Med 2003 DRK/3.5.13/Perth Persistent immune activation Hunt et al J Infect Dis 2003 DRK/3.5.13/Perth
Immune activation is associated with increased risk of death and CVD Biomarker All-Cause Mortality (N=85) Fatal or Non-fatal CVD (N=136) OR P-value OR P-value hs-crp 3.5 0.004 1.6 0.20 IL-6 12.6 <0.0001 2.8 0.003 Amyloid A 2.3 0.08 1.6 0.12 Amyloid P 1.1 0.90 2.8 0.002 D-dimer 13.3 <0.0001 2.0 0.06 F1.2 1.4 0.45 0.8 0.56 Kuller et al PLoS Med 2008 DRK/3.5.13/Perth Why search for a cure? Need for life-long ART Side-effects and long-term toxicities Burden of life-long adherence Cost Sustainability Adverse effects of HIV-1 persistence Inappropriate immune activation Cardiovascular, CNS, other end-organ damage Potential risk for transmission Ongoing stigma of HIV infection DRK/3.5.13/Perth
Opportunity Better understanding of HIV persistence Identification of novel targets for drug development Novel approaches have led to testable hypotheses Potential utility of animal models DRK/3.5.13/Perth Possible approaches to HIV-1 cure Drugs to activate HIV-1 in latently infected cells SAHA, romidepsin, panobinostat, others (HDACi) Drugs to transcriptionally silence HIV-1 in productively infected cells Ruxolitinib (JAK/STAT inhibitor) Immune-based therapies to boost HIV-specific immunity or blunt immune activation Cytokines, mabs, therapeutic vaccines Genetically modified CD4+ T-cells or bone marrow-derived stem cells sirna, Zn-finger nucleases, CCR5-deleted cells DRK/3.5.13/Perth
Summary AIDS and AIDS-related mortality have decreased dramatically since the introduction of effective combination antiretroviral therapy (ART). ART should be started in all patients regardless of disease stage or CD4 cell count. Combinations of two NRTI plus a NNRTI, two NRTI plus a ritnoavir-boostsed PI, or two NRTI plus an integrase inhibitor (raltegravir) are preferred first-line regimens. Considerations in choosing an initial regimen include potency, patient preference, toxicities, comorbid conditions, dosing convenience, presence of transmitted resistance.