Lopinavir/ritonavir monotherapy after 24 weeks of second-line antiretroviral therapy in Africa: a randomized controlled trial (SARA).
BACKGROUND
Boosted protease inhibitor (bPI) monotherapy (bPImono) potentially has substantial cost, safety and operational benefits. It has never been evaluated as second-line antiretroviral therapy (ART) in Africa.


METHODS
After 24 weeks of lopinavir/ritonavir-containing second-line therapy, DART participants were randomized to remain on combination therapy (CT), or change to bPImono maintenance (SARA trial; ISRCTN53817258). Joint primary end points were CD4(+) T-cell changes 24 weeks later and serious adverse events (SAEs); retrospectively assayed viral load (VL) was a secondary end point. Analyses were intention-to-treat.


RESULTS
A total of 192 participants were randomized to CT (n=95) or bPImono (n=97) and followed for median 60 weeks (IQR 45-84). Participants received median 4.0 years (IQR 3.5-4.4) first-line ART. Median CD4(+) T-cell count at first-line failure was 86 cells/mm(3) (47-136), increasing to 245 cells/mm(3) (173-325) after 24-week induction when 77% had VL<50 copies/ml. Overall, 44 (23%) were receiving second-line therapy with bPI and nucleoside reverse transcriptase inhibitors (NRTI) only, and 148 (77%) with bPI plus non-NRTI (NNRTI) with or without NRTI. At 24 weeks after randomization to CT versus bPImono, mean CD4(+) T-cell increase was 42 (CT, n=85) versus 49 cells/mm(3) (bPImono, n=88; adjusted difference 13 [95% CI -15, 43], P=0.37; non-inferior compared with predetermined non-inferiority margin [-33]). Virological suppression was greater for CT versus bPImono (trend P=0.009): 77% (70/91) versus 60% (56/94) were <50 copies/ml, and 5% (5) versus 14% (13) were ≥1,000 copies/ml, respectively. A total of 0 (0%) versus 5 (5%) participants had major protease inhibitor mutations and 3 (3%) versus 0 (0%) new NNRTI/NRTI mutations were detected during follow-up. Two participants (1 CT and 1 bPImono) died >24 weeks after randomization, and 5 (2 CT and 3 bPImono) experienced SAEs (P=0.51).


CONCLUSIONS
bPImono following a 24-week second-line induction was associated with similar CD4(+) T-cell response, but increased low-level viraemia, generally without protease inhibitor resistance. Longer-term trials are needed to provide definitive evidence about effectiveness in Africa.
Imperial College, London, UK. gilksc@unaids.org
Charles F
CF
Gilks
A Sarah
AS
Walker
David T
DT
Dunn
Diana M
DM
Gibb
Ben
B
Kikaire
Andrew
A
Reid
Hellen
H
Musana
Ivan
I
Mambule
Ronnie
R
Kasirye
Val
V
Robertson
Francis
F
Ssali
Moira
M
Spyer
Deenan
D
Pillay
David
D
Yirrell
Pontiano
P
Kaleebu
D000328:Adult; D000349:Africa; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D006678:HIV / Q000472:pathogenicity; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D061466:Lopinavir / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D014766:Viremia / Q000473:pathology / Q000821:virology
D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D061466:Lopinavir; D019438:Ritonavir