ARTEMIS: First-Line Darunavir/Ritonavir Effective and Well

Tolerated Irrespective of Sex, Age, or Race

Posting Date: August 07, 2008

Post hoc subgroup analysis of Antiretroviral Therapy With TMC114 Examined in Naive
Subjects (ARTEMIS): multinational, randomized, phase III trial [1]

Summary of Key Conclusions

48-week efficacy and tolerability of darunavir/ritonavir 800/100 mg once daily in
treatment-naive individuals comparable across sex, age, and racial subgroups
Efficacy at Week 48 in subgroups comparable to overall study population
Most adverse events and laboratory abnormalities observed in subgroups
mild/moderate in severity and similar in frequency to overall study population
 No clinically meaningful differences in tolerability observed across
subgroups

Background
ARTEMIS, 48-week trial that showed darunavir/ritonavir noninferior to
lopinavir/ritonavir as first-line treatment in patients also receiving tenofovir plus
emtricitabine (Capsule Summary)[2]
HIV-1 RNA < 50 copies/mL at Week 48: 84% for darunavir/ritonavir vs 78%
for lopinavir/ritonavir
Lopinavir/ritonavir associated with higher incidence of gastrointestinal
toxicities and lipid abnormalities vs darunavir/ritonavir, but lower incidence of rash
Current study evaluated efficacy and safety of darunavir/ritonavir at Week 48 among
ARTEMIS participants subgrouped by age, sex, and race

Summary of Study Design

Randomized, phase III ARTEMIS trial compared 2 treatment arms in antiretroviral-
naive patients with HIV-1 RNA > 5000 copies/mL and any CD4+ cell count
o Darunavir/ritonavir 800/100 mg once daily (n = 343)
o Lopinavir/ritonavir 400/100 mg twice daily or 800/200 mg once daily,
depending on patient preference (n = 346)
o All patients also received tenofovir 300 mg plus emtricitabine 200 mg
Subgroup analyses performed on ARTEMIS patients in darunavir/ritonavir arm
according to sex, age, and race
Primary endpoint
o HIV-1 RNA < 50 copies/mL
Secondary endpoint
o Safety
Intent-to-treat, time-to-loss-of-virologic-response analysis

Baseline Characteristics
 N = 343 patients who received darunavir/ritonavir in ARTEMIS
o Mean age: 34 years
o Female: 30%
o Nonwhite: 60%
 Baseline disease characteristics similar between subgroups

Subgroup % Mean Duration of Mean HIV-1 RNA, Median CD4+ Cell

HIV Infection, log10 copies/mL Count, cells/mm3
yrs

Age, yrs  
 Subgroup % Mean Duration of Mean HIV-1 RNA, Median CD4+ Cell
HIV Infection, log10 copies/mL Count, cells/mm3
yrs
 ≤
34 2.10 4.75 268
 30
 3
51 2.44 4.95 218
1-45
 >
15 3.24 4.82 227
45

Sex        
 M
70 2.50 4.94 226
ale
 F
30 2.33 4.69 240
emale

Race        
 W
40 2.86 4.97 228
hite
 B
23 2.92 4.81 225
lack
 L
22 1.67 4.71 246
atino
 A
13 1.82 4.91 196
sian
 O
1 1.27 4.59 153
ther
Main Findings
 Proportion of patients with HIV-1 RNA < 50 copies/mL similar across all subgroups and
consistent with overall trial population who received darunavir/ritonavir (84%)
 High response rate observed in Asians (100%) may be due to small subgroup size (n =
44)

Subgroup n HIV-1 RNA < 50 Copies/mL at Week 48, %

Age, yrs    
 ≤ 30 115 82
 31-
175 85
45
 > 45 53 85

Sex    
 Male 239 84
 Fem
104 84
ale

Race    
 Whit
137 80
e
 Blac
80 83
k
 Latin
77 82
o
 Subgroup n HIV-1 RNA < 50 Copies/mL at Week 48, %
 Asia
44 100
n

 Most frequent adverse events (regardless of severity or causality) observed in these

subgroups similar to those seen in overall population that received darunavir/ritonavir in
ARTEMIS
o Diarrhea, nausea, headache, upper respiratory tract infection,
nasopharyngitis, abdominal pain, vomiting, cough
 Slight difference in frequency of adverse events observed for certain age subgroups,
but these differences not considered clinically relevant
o For laboratory abnormalities, slightly higher incidence of grade 3 amylase
increases (9% vs 1% to 2%), low density lipoprotein (LDL) cholesterol increases (6%
vs 1%), and total cholesterol increases (6% vs 0% to 1%) observed in patients older
than 45 years of age, but not deemed clinically relevant

Safety Outcome, % Age Group

≤ 30 Yrs 31-45 Yrs > 45 Yrs

(n = 115) (n = 175) (n = 53)

Adverse events*      
 Diarrhea 30 37 28
 Nausea 20 14 13
 Abdominal pain 10 7 17
 Headache 12 19 25
 Upper respiratory tract infection 12 17 19
 Nasopharyngitis 15 13 8
 Rash 10 7 4

Grade 3/4 laboratory abnormalities      

 Increased amylase 1 2 9
 Increased ALT 6 2 2
 Increased AST 6 3 4
 Increased LDL cholesterol 1 1 6
 Increased total cholesterol 1 0 6
 Increased triglycerides 2 2 0
 Hyperglycemia 0 2 0
 Hypophosphatemia 2 1 2
 Decreased neutrophils 1 4 0
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
*≥ 10% incidence in any subgroup, regardless of severity or causality.

 Incidence of adverse events and laboratory abnormalities similar between males and
females, except for
 Higher frequency of diarrhea in males vs females (37% vs 26%)
 Higher frequency of vomiting in females vs males (11% vs 4%)
 Safety Outcome, % Sex

Male Female
(n = 239) (n = 104)

Adverse events*    
 Diarrhea 37 26
 Nausea 15 18
 Headache 18 17
 Upper respiratory tract infection 15 17
 Nasopharyngitis 13 11
 Abdominal pain 9 11
 Vomiting 4 11
 Rash 9 5

Grade 3/4 laboratory abnormalities    

 Increased amylase 4 0
 Increased ALT 3 4
 Increased AST 4 3
 Increased LDL 2 1
 Increased total cholesterol 1 1
 Increased triglycerides 2 0
 Hyperglycemia 0 2
 Hypophosphatemia 1 2
 Decreased neutrophils 2 4
*≥ 10% incidence in any subgroup, regardless of severity or causality.

 Although not considered clinically relevant, some differences in incidence of adverse

events and laboratory abnormalities observed in certain racial subgroups
o Lower incidence of urinary tract infections in whites and Asians (0% to 1%
vs 8% to 14%)
o Higher incidence of back pain (13% vs 0% to 8%) and grade 3 neutrophil
decreases (9% vs 0% to 1%) in blacks
o Rash more frequent in Latinos (14% vs 5% to 7%)
o Lower incidence of headache (2% vs 17% to 23%), diarrhea (23% vs 32%
to 37%), and abdominal pain (2% vs 9% to 11%) and higher incidence of upper
respiratory tract infections (27% vs 9% to 19%) in Asians

Safety Outcome, % Racial Group

White Black Latino Asian

(n = 137) (n = 80) (n = 77) (n = 44)

Adverse events*        
 Diarrhea 37 35 32 23
 Nausea 20 9 18 14
 Abdominal pain 11 11 9 2
 Headache 23 18 17 2
 Upper respiratory tract
9 19 16 27
infection
 Safety Outcome, % Racial Group

White Black Latino Asian

(n = 137) (n = 80) (n = 77) (n = 44)
 Nasopharyngitis 14 11 13 9
 Urinary tract infection 1 14 8 0
 Back pain 4 13 8 0
 Rash 6 5 14 7

Grade 3/4 laboratory abnormalities        

 Increased amylase 4 1 4 0
 Increased ALT 5 3 4 2
 Increased AST 5 1 7 0
 Increased LDL 1 3 1 2
 Increased total cholesterol 1 3 1 0
 Increased triglycerides 3 0 0 2
 Hyperglycemia 1 1 1 0
 Hypophosphatemia 2 1 0 0
 Decreased neutrophils 1 9 0 0
*≥ 10% incidence in any subgroup, regardless of severity or causality.

 No meaningful differences observed across subgroups regarding incidence of serious

adverse events or rate of treatment discontinuation

References
1. Andrade-Villanueva J, Hererra G, Chiliade P, Van Baelen B, Lefebvre E, Lavreys L. ARTEMIS:
week 48 safety and efficacy of darunavir/r by gender, age and race. Program and abstracts of the
17th International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. Abstract TUPE0064.

2. DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety of darunavir/ritonavir vs

lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at Week 48: ARTEMIS. Program
and abstracts of the 47th Annual Interscience Conference on Antimicrobial Agents and
Chemotherapy; September 17-20, 2007; Chicago, Illinois. Abstract H-718b.