WHO guidelines recommend the use of boosted protease inhibitors second line in resource-limited settings. Findings from strategies looking at using lopinavir/ritonavir (LPV/r) have been uncertain to date, both in limited and richer resourced settings.
Two posters at CROI 2011 presented data from studies evaluating LPV/r monotherapy, with showed further conflicting results.
ACTG 5230 evaluated lopinavir/ritonavir (LPV/r) monotherapy in a pilot study. It was a single arm multinational trial with sites in Malawi, Tanzania, South Africa, Thailand and India.
Participants had previously received first line NNRTI-containing regimens for at least six months and had detectable viral load 1,000-200,000 copies/mL. All participants received LPV/r monotherapy BID. The primary endpoint was remaining on monotherapy without virological failure at 24 weeks. This was defined as: failure to suppress viral load to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression.
People with virologic failure received intensification with emtricitabine (FTC) 200 mg/tenofovir (TDF) 300 mg.
There were 123 participants enrolled in this trial. About 60% were women and they were a median of 39 years of age, with a median CD4 of 164 cells/mm3 and viral load of 4.34 log10 copies/mL (17% were >100,000 copies/mL).
Other baseline characteristics included: 93% with >1 year HAART, 98% with >1 NNRTI mutation and 95% with >1 NRTI mutation (87% M184V, 84% TAM, 11% K65R, 4% Q151M/L).
The majority, of participants completed 24 weeks of follow-up with the exception of one death at week 20 with a viral load of <400 copies/mL.
The investigators reported, at week 24, 107 (87%; 95% CI 80-92%) of participants remained on LPV/r monotherapy without virologic failure.
Of the remaining, 15 met the criteria for virologic failure and one added FTC/TDF before failure. Of 13 participants with data after intensification, 11 (85%) suppressed viral load to <400 copies/mL.
At virologic failure, 2/11 participants who were successfully sequenced had selected new resistance mutations (both had A71T and V82F). The overall mean CD4 count increase from baseline to week 24 was 107 cells/mm3. Overall 31 (25%) of participants experienced grade 3 or 4 toxicities. The most commonly reported grade 3 or 4 toxicities (9% of participants) were metabolic (mostly elevated lipids). Self reported adherence was high; at week 24, 83% of participants reported no missed doses.
The investigators concluded that LPV/r monotherapy showed promising preliminary activity as second-line HAART following failure of first-line NNRTI-containing regimens at 24 weeks. The lower bound of the 90% CI (81-92%) of the observed success rate (87%) was above 65%.
Torsak Bunupuradah and colleagues from the HIV STAR Study in Thailand looked at LPV/r monotherapy as second line but they also evaluated viral suppression to <50 copies/mL and included a comparison arm with triple therapy.
The STAR investigators enrolled 200 participants with viral load >1000 copies/mL on NNRTI-containing first line therapy. Participants were randomised to receive either LPV/r monotherapy ot LPV/r + TDF + 3TC.
Treatment failure was defined as viral load >400 copies/mL at >24 weeks. Participants meeting these criteria in the monotherapy arm received intensification with TDF + 3TC.
Participants in this study were about 60% men with a median age of 37 years, CD4 of 188 cells/mm3, and viral load of 4.1 log10 copies/mL.
Prior to switching, 92% of participants were receiving 3TC, 63% d4T, 23% AZT and 5% TDF. Nevirapine and efavirenz were received by 86% and 14% participants, respectively. Without significant differences between arms, 15% of participants had ≥3 TAMS, 82% had M184V/I, 6% had Q151M, and 7% had K65R.
By intent-to-treat analyses at 48 weeks, the proportion of patients with viral load <400 copies/mL the LPV/r monotherapy arm was 75% vs. 86% in the TDF/3TC/LPV/r arm, p=0.53. But, only 61% of the LPV/r monotherapy arm vs. 83% in TDF/3TC/LPV/r arm had a viral load <50 copies/mL, p<0.01.
Major PI mutations were detected in 1 of 2 LPV/r monotherapy and 0 of 3 TDF/3TC/LPV/r treated participants with genotype results following treatment failure. There was no significant difference in CD4 count increase between arms: 114 vs. 137 cells/mm3 in the LPV/r monotherapy and TDF/3TC/LPV/r arms respectively. One death (unrelated to study drugs) was reported in each arm. Serious adverse events were reported in two patients in the LPV/r monotherapy arm and seven patients in the TDF/3TC/LPV/r arm.
The investigators concluded that LPV/r monotherapy should be used with caution as a second-line option, particularly in settings where close viral load monitoring is not available.
The ongoing EARNEST Trial (NCT00988039) will answer the question whether or not lopinavir/r monotherapy is a sufficiently potent regimen compared to lopinavir/r combined with two NRTIs or raltegravir.
Results from this trial are expected in 2013.
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