Antiretroviral UpdateSpring 2008 Lisa M. Chirch, M.D. Stony Brook University - CPHE NY/NJ AIDS Education and Training Center
Objectives • Review DHHS guidelines and most recent changes / additions • Overview of recent significant clinical trial results • Review currently approved, available antiretroviral (ARV) medications and known toxicities, idiosyncrasies • Report on new agents in the pipeline, or under ongoing investigation in Phase II and III trials • Case vignettes and discussion
Indications for initiating ARV therapy for the chronically HIV-1 infected patient * Initiation of ARV also recommended for individuals co-infected with Hepatitis B, HIV-associated nephropathy, and pregnant women;Adapted from “Guidelines for the use of antiretroviral agents in HIV-1 – infected adults and adolescents,” U.S. Dept. of Health and Human Services. 2008.
Predicted 6 month risk of AIDS according to age, CD4, and viral load • Based on Poisson regression model: Phillips A, et al. AIDS 2004 (CASCADE Collaboration- Concerted Action on SeroConversion to AIDS and Death in Europe: www.ctu.mrc.ac.uk/cascade • Examples: • 35 year old with CD4 100, has 6 month risk of progression to AIDS of 4.7% if viral load is 3,000; 9.3% if VL is 30,000; 18% if 300,000. • 55 year old with CD4 of 150 has 4.7% risk if VL 3,000; 18.2% if VL 300,000. • 55 year old with CD4 of 350 has 1.2% risk if VL 3,000, 3.6% if VL 100,000, 5% if VL 300,000.
20 Which of the following fixed dose combinations (FDCs) are designated as preferred initial NRTI options according to the most recent DHHS guidelines? A) TDF/FTC and ZDV/3TC B) ABC/3TC and TDF/FTC C) ZDV/ABC/3TC and TDF/FTC D) ABC/3TC and ZDV/3TC
20 Which of the following ARVs is contraindicated in women with CD4 cell counts above 250? A) Efavirenz B) Nelfinavir C) Nevirapine D) Didanosine
20 Which of the following regimens is not recommended in women who are or may become pregnant? A) EFV/TDF/FTC B) FPV/r plus ABC/3TC C) LPV/RTV plus ZDV/3TC D) All of the above
Preferred and Alternative ARVs in updated DHHS Guidelines Adapted from “Guidelines for the use of antiretroviral agents in HIV-1 – infected adults and adolescents,” U.S. Dept. of Health and Human Services. 2008.
Rationale: recent data (KLEAN) • Inclusion of boosted fosamprenavir in the “preferred” list: • KLEAN: phase 3, open-label, multi-center, non-inferiority study comparing the safety and efficacy of ritonavir-boosted fosamprenavir to lopinavir/ritonavir, both in combination with abacavir/lamivudine • 878 treatment-naïve patients • At week 48, no significant differences between arms in terms of virologic, immunologic, or metabolic response; few adverse events in similar numbers among 2 groups Eron J et al. The Lancet. August 5, 2006; 368(9534):476-482.
BMS-089 • 96-week randomized, open-label study comparing the efficacy and safety of 400 mg atazanavir versus 300 mg of atazanavir boosted with 100 mg of ritonavir, both in combination with lamivudine and stavudine. • 199 naïve patients • Both arms had high rates of virologic response and were well-tolerated Malan E. et al. 13th CROI; Feb 5-8, 2006; Denver, Colorado. Abstract 107LB
BMS-089 • There were 10 virologic failures in the unboosted arm, compared to only 3 in the ritonavir-boosted arm; 7 people in the unboosted arm developed resistance mutations, primarily at the 184 codon, compared to only 1 in the boosted arm. • Patients on ritonavir had higher rate of hyperbilirubinemia • Changes in total cholesterol and triglyceride levels were significantly higher in the ritonavir-boosted arm; HDL also increased nearly identically in both arms.
Gilead 934 • Randomized, open-label, non-inferiority trial comparing tenofovir, emtricitabine to zidovudine, lamivudine, both in combination with Efavirenz. • 517 naïve patients • At week 96 significantly more patients in tenofovir / FTC arm achieved and maintained HIV RNA levels below 400 copies/mL, and had significantly greater limb fat by DEXA. • The groups were similar in terms of patients achieving HIV RNA < 50 copies/mL • Higher toxicity rates in zidovudine / lamivudine arm (esp. anemia), may have contributed Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. Joel E. Gallant et al., for the Study 934 Group. The New England Journal of Medicine. January 19, 2006;354(3):251-260.
Acceptable but inferior options • Nelfinavir • Inferior virologic efficacy • Pregnancy: good tolerability and adequate PK data • Stavudine / lamivudine • Significant toxicities: peripheral neuropathy, lipoatrophy, lactic acidosis and hepatic steatosis, pancreatitis • Use if preferred or alternative dual NRTI combination cannot be used
May 2007 update • For HIV/HBV co-infected patients, entecavir should not be used for the treatment of HBV infection without concomitant treatment for HIV. • Previous in vitro data showed no significant activity against HIV-1; but recent case-series of 3 patients reported decline in HIV-RNA and emergence of M184V mutations in one co-infected patient on entecavir monotherapy. Supplement to the Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents – October 2006.
Why Do Treatments Fail • adherence • side effects – acute and longer-term • baseline resistance or cross-resistance • use of less potent antiretroviral regimens • sequential monotherapy • drug levels and drug interactions • tissue reservoir penetration • other, unknown reasons
M184V • Arises rapidly on 3TC or FTC therapy • Continued antiviral activity in presence of drug and mutation • decreased viral replication fitness • Presence of M184V slows the evolution of thymidine analogue mutations (TAMs) • Increased susceptibility to ZDV, d4T, TDF • Modest decreased susceptibility to ddI and ABC
TAMs • Emerge gradually with ongoing failure of ZDV or d4T • Rare with ddI, TDF, ABC in absence of thymidine analogue • Development of TAMs tends to follow distinct pathways of mutation at either codons 41 and 215, or at codons 67, 70, 219 McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.
K65R • Selected by TDF and less frequently ABC in the absence of thymidine analogue • Decreased susceptibility to TDF, ABC, and ddI • Activity of TDF may be partially retained with M184V present • Increases susceptibility to ZDV McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.
L74V • Selected by ABC or ddI in the absence of a thymidine analogue • Decreases susceptibility to ABC and ddI • Does not decrease susceptibility to TDF or thymidine analogues McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.
NNRTI mutations • Long term virologic response to sequential NNRTI use is poor, particularly when 2 or more mutations are present • K103N, Y188L, or G190A mutations likely prevent the clinical utility of all NNRTI’s currently approved • Importance of most mutations depends on the presence of Y181C, which has an impact only in the presence of at least 1 other mutation (important for Etravirine) Johnson VA et al. Topics in HIV Medicine 2007; 15(4): 119-125.
NNRTI hypersusceptibility • Longer duration of NRTI use, prior use of zidovudine, and abacavir or zidovudine resistance have been associated with enhanced susceptibility to NNRTIs (defined as IC50 of >2.5-fold less than that of wild-type reference strain) • Greater short term reductions in viral load in patients with hypersusceptibility to efavirenz, who received that drug as salvage therapy Hirsch M. CID 2003;37:113-128.
Protease gene mutations • Major mutations • Selected first in the presence of drug, or shown at the virologic or biochemical level to lead to an alteration in drug binding or an inhibition of viral replication • Effect on drug susceptibility phenotype • Minor mutations • Emerge later, by themselves do not have significant effect on phenotype, but may improve replicative fitness in the presence of major mutations • Presence of at least 2 key mutations (e.g., D30N, G48V, I50V, V82A/F/T/S, I84V, and L90M) generally confers broad cross-resistance to most currently available PIs • “boosting” with low dose ritonavir may result in higher and more prolonged drug concentrations and greater suppression of viral variants that contain a limited number of mutations Hirsch M. CID 2003;37:113-128.
Envelope gene mutations • Entry of HIV-1 into cell involves attachment mediated by gp120 binding to CD4, chemokine coreceptor binding, and association of 2 trimeric helical coils (HR-1 and HR-2) located in the ectodomain of gp41 into a 6-helix bundle that brings virus and cell membranes closer together, allowing fusion • T-20 (enfuvirtide) binds HR-1 and blocks association with HR-2, inhibiting fusion and viral entry Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125.
Entry inhibitors • Mutations at gp41 codons 36-45 are associated with an average 20-fold increase from baseline IC50 • CCR5 inhibitors: Maraviroc activity is limited to patients with only R5-using virus detectable; some cases of failure during therapy are associated with outgrowth of X4 virus that pre-exists as a minority population below the level of detection • Mutations in the gp120 molecule that allow the virus to bind R5 receptors in the presence of drug have been described Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125.
Integrase mutations • Raltegravir failure was associated with integrase mutations in 2 distinct genetic pathways defined by 2 or more mutations including: • A major mutation at either Q148H/K/R or N155H, and • 1 or more minor mutations
20 The potential for nephrotoxicity with tenofovir is an important consideration in patients who have A) hyperpigmentation B) severe anemia C) baseline renal insufficiency D) none of the above
Tenofovir – renal issues • Several case reports noting development of renal insufficiency in patients on tenofovir, some without prior history of renal dysfunction • Nephrotoxicity involving tubular dysfunction with Fanconi syndrome noted in toxicological studies, dose-limiting toxicity in animal studies
Tenofovir – renal issues • Two similar nucleotide analogues, cidofovir and adefovir, have been associated with dose-limiting, renal tubular cell toxicity in patients in infectious hepatitis or cytomegalovirus infection • Renal toxicity is mediated by proximal tube epithelial cells that express human renal organic anion transporter (hOAT1) and actively uptake these drugs
Figure 1. Renal biopsy image by light microscopy showing acute tubular injury with loss and irregularity of tubular epithelial cells (hematoxylin and eosin strain; original magnification, ×100). Inset, prominent nuclear enlargement with hyperchromatic and smudged chromatin (hematoxylin and eosin stain; original magnification, ×400).
Tenofovir – renal issues • Package insert revision 2005: dose should be adjusted for patients with creatinine clearance of <50 mL/min. • Cockcroft-Gault equation: • (140-age) x (lean body weight in kg) x 0.85 (females) / 72 x plasma creatinine • CD4 and viral load seem not to be predictors of renal toxicity • Patients on tenofovir should be monitored closely for early signs of tubulopathy (glycosuria, proteinuria, acidosis, mild creatinine increases) every 2 weeks for the first 2 months; therapy should be stopped if any signs of tubulopathy develop Karras et al. CID 2003; 36: 1070-1073; Zimmerman et al. CID 2006; 42: 283-90.
More important clinical trials • The SMART study • ACTG 5142 • TITAN
SMART • Strategies for Management of AntiRetroviral Treatment • Randomized, prospective study: 33 countries, 80% in North America and Europe • Median CD4 597, 72% had viral load <400 copies/mL • 5,472 HIV-infected adults with CD4 >350 • Control group took ART continuously “viral suppression group” • “drug conservation group” took therapy episodically (initiated when CD4 <250, stopped when >350) El-Sadr W et al. N Engl J Med 2006; 355(22):2283-2296
SMART • Results: • Trial halted by DSMB with a mean follow up time of only 16 months • Greater risk of clinical disease progression events and overall death in drug conservation group • Greater risk of serious renal, hepatic, and cardiovascular events • Rather than protect patients, the withdrawal of therapy increased risk of death from any cause, including that of opportunistic infections. Cardiovascular, hepatic, and renal disease, which are often associated with ART, were greater in the treatment interruption arm.
ACTG 5142 • Phase 3, randomized, open-label study comparing three regimens: lopinavir/ritonavir + 2 NRTI; Efavirenz vs. 2 NRTI; lopinavir/ritonavir + efavirenz • 753 ART-Naive patients with viral load >2,000 • NRTIs were chosen by clinicians and patients; initially only one provided at no cost (extended-release stavudine…later tenofovir was added)
ACTG 5142 • Week 96 • Proportion of patients with VL < 50 copies/mL statistically significantly greater in Efavirenz arm • Median increase in CD4 count was significantly higher in the lopinavir arm • Those patients in the NRTI-sparing arm had significantly higher fasting triglyceride levels (14% grade 3, compared to 6% in lopinavir arm, 3% in efavirenz arm); 45% moderate of severe laboratory abnormality • No resistance to lopinavir was observed; however, resistance to efavirenz was detected in nearly half of patients who failed this regimen; NRTI resistance was more common with virologic failure on efavirenz as well Riddler S. et al. New England Journal of Medicine, May 15, 2008.
TITAN • Phase 3 study comparing darunavir/r and lopinavir/r in patients with VL < 1000 copies/mL, on stable but failing regimen for at least 12 weeks • 604 patients randomized to open label lopinavir/r or darunavir/r, both with optimized background selected based on resistance testing (T-20 and investigational drugs excluded) • Previous lopinavir therapy exclusion criteria • Data from week 48 present at IDSA 2007, San Diego
TITAN • Both PIs were well tolerated, only 7% discontinued due to toxicity • Lipid level elevation similar between the groups; higher incidence of diarrhea in lopinavir arm (42% vs. 32%), rash in darunavir arm (16% vs. 7%) • Significantly more patients in darunavir arm achieved VL <50; fewer patients in darunavir arm had virologic failure (10% vs 22%), and had primary PI mutations (21% vs. 36%) • **among patients with baseline lopinavir fold-change of greater than 10-fold, only 28% achieved VL <50 (greater virologic failure driven by baseline phenotypic resistance to lopinavir??)
TITAN – 48 weeks efficacy results Adapted from Hardy WD et al. IDSA 2007; San Diego, CA. Abstract 1209.
Newly available ARVs • MERIT • MOTIVATE • BENCHMRK • MERCK 004 • Integrase cross-resistance • Effects on lipid parameters • DUET
MERIT: Maraviroc vs Efavirenz in Treatment-Naive Patients Stratified by HIV-1 RNA < or 100,000 copies/mL and by Northern or Southern Hemisphere Week 48 primary endpoint Week 96 MVC 300 mg twice daily + ZDV/3TC (n = 360) Antiretroviral-naive patients infected with CCR5-tropic HIV-1 and HIV-1 RNA 2000 copies/mL (N = 740) EFV 600 mg once daily + ZDV/3TC (n = 361) MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at end of phase IIB (Week 16) • Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CI Saag M, et al. IAS 2007. Abstract WESS104.
MERIT: Patients With VL < 50 Copies/mL by baseline VL • EFV patients more likely to discontinue due to AE • Overall : 25.2% • AE: 13.6% • Efficacy: 4.2% • MVC patients more likely to discontinue due to lack of efficacy • Overall: 26.9% • AE: 4.2% • Efficacy: 11.9% EFV MVC 100 90 80 71.6 69.6 66.6 70 59.6 60 50 Patients, % 40 30 20 10 0 n = 211 204 150 156 BL VL < 100,000 copies/mL BL VL ≥ 100,000 copies/mL Saag M, et al. IAS 2007. Abstract WESS104.
MOTIVATE: Maraviroc in Treatment-Experienced Patients With R5 Virus • Randomized, double-blind, placebo-controlled, parallel phase IIb/III studies • 44% failed screening with X4 or dual/mixed virus detected • Primary endpoint: mean change in HIV-1 RNA at Week 24 • Based on MOTIVATE data FDA approved MVC in August 2007 for use in treatment-experienced patients with R5-tropic virus only 2:2:1 randomization; stratified by ENF use and VL Week 24 planned interim analysis Week 48 Patients infected with R5; HIV-1 RNA ≥ 5000 copies/mL; stable ART or no ART for ≥ 4 weeks; previous ART experience with ≥ 1 agent (≥ 2 for PIs) from 3 of the 4 antiretroviral drug classes for ≥ 6 months or documented resistance to members of 3 of 4 classes (MOTIVATE 1: N = 601, Canada, US; MOTIVATE 2: N = 475, Europe, Australia, US) MVC 150 mg or 300 mg* twice daily + OBR† MVC 150 mg or 300 mg* once daily + OBR† Placebo + OBR† *Patients receiving PI (other than TPV) or DLV received 150 mg; all others received 300 mg. †OBR: 3-6 ARVs. Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.
MOTIVATE 1 and 2: Combined Virologic and Immunologic Efficacy • MVC + OBR associated with significantly greater virologic suppression than placebo plus OBR in treatment-experienced patients • Increased activity observed with de novo use of enfuvirtide, LPV/RTV *HIV-1 RNA value imputed as baseline if patient discontinued before 24 weeks.†Patients with missing values were classified as failures unless they were responders at Weeks 20 and 32.‡P = .0001 vs placebo group. Gulick RM, et al. IAS 2007. Abstract WEPEB116LB.