A number of small studies presented results at IAS 2013 on combinations that are not widely used or recommended in first or second line therapy.
The studies were small, underpowered and often without comparator arms but they show an interest in broadening options which may become possible with drugs approved from five classes. None will change guidelines that are currently based on using 2NRTIs plus an NNRTI/boosted PI/integrase inhibitor.
Maraviroc + raltegravir maintenance
Although this study plans to enroll 40 patients, an interim analysis of the first ten patients at week 24 was required prior to enrolling the full group.
Median baseline CD4 cell count and viral load was 457 cells/mm3 [range 366-929] and 4.0 log copies/mL [range 2.7-4.5]. All patients were men with median age 41 years [range 25-54]. Entry criteria included CCR5 tropism and no drug resistance.
All patients had undetectable viral load at week 24 and remained suppressed out to week 48 on the reduced combination. One blip result at week 44 (56 copies/mL) was re-suppressed without treatment change.
Raltegravir + darunavir/r
In another NRTI-sparing approach, the RADAR study included 85 treatment-naive patients starting on darunavir/ritonavir (800 mg/100mg once-daily) who were randomised to include either raltegravir (400 mg twice daily) or tenofovir/FTC (300 mg /200 mg once-daily).
A high rate of drop out/loss to follow-up (~20%) resulted in poorer virological responses in the primary endpoint for the raltegravir vs tenofovir/FTC arm in the ITT analysis (62.5% vs 83.7% achieved viral load <50 copies/mL at week 48; p=0.045). However, most of the virological failures in the raltegravir arm had viral load <200 copies/mL. 3
A secondary endpoint looking at bone changes favoured the NRTI-sparing arm (sub-total BMD: +1.02% vs. -0.76%, p=0.002). Changes in bone formation and resorption markers at week 16 were predictive of these BMD changes at week 48.
Boosted PI monotherapy: darunavir/r vs lopinavir/r
A small randomised study in treatment-naive patients compared boosted PI monotherapy with darunavir/r (n=40) and lopinavir/r (n=33). 6
At week 48, by ITT analysis, 77.5% (31/40) and 66% (22/33) patients respectively had viral load <50 copies/mL (p=0.302, treatment difference 10.8% [IC95% -12.6;34.2]). Side effects were similar to the expected profiles for each drug. The median (IQR) change of CD4 cell count seemed numerically lower with darunavir: +3 (-204, 99) vs 71 (-49, 144) cells/mm3 although this was not statistically significant (p=0.164).
Switch to etravirine plus raltegravir
Results from a single-arm observational study reported on 91 patients stable on standard three-drug combination and without NNRTI resistance at a single centre in France who from 2008 switched to etravirine plus raltegravir. Reasons for switching included metabolic toxicity/lipodystrophy, renal impairment or toxicity prevention. 7
Median (IQR) follow-up was 11.5 months (4.6-22.7) with 65 and 48 patients reaching 6 and 12 months of follow-up respectively, generally maintaining viral suppression.
Five patients had virological failure, after a median (IQR) 7 months (6-16) following the switch. These five patients had previously used NNRTIs and 4/5 reported prior NNRTI treatment failure. Of the 18 other discontinuations, five were associated with side effects related to either drug.
Once-daily etravirine plus darunavir/ritonavir
Although combinations including etravirine and darunavir/r plus optimised background regimens were the basis for regulatory approval (the DUET 1 and DUET 2 studies) their use without other drugs and specifically without NRTIs has not been previously reported.
This study also notably used etravirine at a 400 mg once-daily dose (although approved as a twice-daily drug, recent PK data may support once-daily use). 8
This was a 48-week single arm study included 42 treatment experienced patients and 12 patients who were treatment naive with transmitted drug resistance. All patients had to show genotypic sensitivity to both drugs.
Virological response rate at week 48 was 89% by ITT analysis that did not include resuppressed blips as treatment failure. However, response rates were lower by standard ITT (74%), TLOVR (72%) and FDA snapshot (69%) analyses. Seven patients discontinued due to virologic failure (2/2 with resistance results had etravirine mutations) and four due to side effects.
Although the numbers are small, the study from Cotte et al sounds interesting for people unable to take NRTIs. However, this is a twice-daily combination for first treatment, when once-daily combinations are usually preferred. This combination is unlikely to offer any cost saving.
The RADAR study is similar to the earlier ACTG 5262 single arm study of darunavir/ritonavir plus raltegravir that reported a 16% failure rate at week 24 and 26% failure at week 48, with poorer outcomes for patients who had baseline viral load >100,000 copies/mL.
However, given the higher effectiveness of darunavir/ritonavir monotherapy (88% <50 copies/mL at week 96 in the MONOI study and 82% at week 48 in the MONET study) these differences may have been related to more difficult to treat US patients. 4,5
Unless stated otherwise, references are to the Programme and Abstracts for the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 30 June 3 July 2013, Kuala Lumpur.
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