Safety and efficacy of raltegravir in patients co‐infected with HIV and hepatitis B and/or C virus: complete data from Phase III double‐blind studies
Authors: Rockstroh J , Sklar P , Wan H , Teppler H , Harvey C , Strohmaier K , Leavitt R , Nguyen B 
Published: November 2012

Purpose of studySafety and efficacy of raltegravir (RAL) in patients (pts) with HIV and hepatitis B and/or C (HBV/HCV) co‐infection were evaluated in a double‐blind fashion for 5 years in STARTMRK and 3 years in BENCHMRK‐1&2.MethodsIn STARTMRK, treatment‐naïve pts received RAL 400 mg bid or efavirenz (EFV) 600 mg qhs, both with tenofovir+emtricitabine (TDF/FTC), for up to 240 weeks. In BENCHMRK‐1&2, highly treatment‐experienced pts with multidrug‐resistant virus and failing other therapies received double‐blind RAL 400 mg bid or placebo, both with optimized background therapy (OBT), for up to 156 weeks. Pts with stable chronic HBV/HCV could enroll if baseline AST and ALT were=5×upper limit of normal.Summary of results743 pts received RAL and 519 received comparator. Hepatitis co‐infection was present in 6% (34/563) of treatment‐naïve pts (HBV=4%, HCV=2%, HBV+HCV=0.2%) and 16% (114/699) of treatment‐experienced pts (HBV=6%, HCV=9%, HBV+HCV=1%). Safety and efficacy results at the end of double‐blind treatment are shown by study, treatment group and co‐infection status. Liver enzyme elevations were more common in pts with HIV+HBV/HCV co‐infection than in pts with HIV infection alone, in the RAL and control groups. Most liver enzyme changes occurred in the first 48 weeks of treatment, with minimal further increases (data not shown).ConclusionRAL was efficacious and generally well tolerated for up to 5 years in pts with HIV+HBV/HCV co‐infection. The majority of grade 3 and grade 4 liver enzyme elevations occurred during the first year of treatment and were more common among co‐infected pts than among HIV mono‐infected pts, irrespective of treatment group.

STARTMRK (treatment‐naive), 240 weeks
BENCHMRK (treatment‐experienced), 156 weeks

RAL+TDF/FTC
EFV+TDF/FTC
RAL+OBT
Placebo+OBT

HBV or HCV positive N=18 %
HBV … HCV negative N=263%
HBV or HCV positive N=16%
HBV … HCV negative N=266%
HBV or HCV positive N=77 (PYR=182) % (rate/100 PYR)†
HBV … HCV negative N=385 (PYR=869) % (rate/100 PYR)†
HBV or HCV positive N=37 (PYR=43) % (rate/100 PYR)†
HBV … HCV negative N=200 (PYR=280) % (rate/100 PYR)†

Aspartate aminotransferase (AST) increased

Grade 3‡
5.6
4.6
0
3.0
9.1 (3.8)
3.4 (1.5)
2.7 (2.3)
3.0 (2.1)

Grade 4‡
5.6
0.8
6.3
0
2.6 (1.1)
0.3 (0.1)
0
1.5 (1.1)

Alanine aminotransferase (ALT) increased

Grade 3‡
0
1.9
6.3
1.9
10.4 (4.4)
3.6 (1.6)
8.1 (7.0)
1.5 (1.1)

Grade 4‡
5.6
1.5
6.3
0.4
3.9 (1.6)
0.8 (0.3)
0
2.0 (1.4)

Bilirubin increased

Grade 3‡
0
0.8
0
0
3.9 (1.6)
2.9 (1.3)
5.4 (4.7)
2.0 (1.4)

Grade 4‡
0
0.4
0
0
1.3 (0.5)
0.8 (0.3)
0
0

Clinical adverse events, %

Any clinical AE
94.4
96.6
93.8
98.1
93.6
94.0
86.5
90.5

Discontinued
5.6
4.9
6.3
8.3
3.8
4.7
2.7
6.0

Hepatobiliary AE
5.6
5.7
0
3.4
7.8
4.2
5.4
5.5

Discontinued
5.6
0.4
0
0.4
0
0.5
0
0.4

Efficacy: % with HIV RNA<50 copies/mL (Observed Failure approach)

90.9
89.1
91.7
80.0
62.3
57.9
14.7
26.3

Exposure‐adjusted rates per 100 patient‐years at risk (PYR); shown for BENCHMRK studies only, due to longer exposure in RAL group.
Division of AIDS toxicity criteria.