Protease inhibitor monotherapy as a maintenance regimen: are we edging towards acceptance?

An entire session at the 12th European AIDS Conference was devoted to trials of different ritonavir-boosted protease inhibitors (PI/r) used as the sole drug in an antiretroviral regimen.

Several trials of protease inhibitor therapy have produced long-lasting viral suppression statistically non-inferior to two-class therapy. Most successful trials have switched patients to PI monotherapy as a maintenance regimen after starting with combination therapy but some success continues to be seen in trials using monotherapy from the start.

The failure of a trial using a single protease inhibitor as initial regimen, however, was a warning that it is possible to take this approach too far, and doubts remain about the long-term safety of the approach in terms of its ability to suppress HIV in places like the central nervous system and genital mucosa.

The most impressive results came from the 48 week results of the MONET trial of boosted darunavir monotherapy (DRV/r). This has already been covered by Aidsmap: see this report. In this trial of 256 darunavir-naive patients the proportion of patients with viral loads under 50 copies/ml, excluding protocol violations (i.e. patients who should never have been in the study) was 87.8% in the patients taking combination therapy and 86.2% in those taking monotherapy.

According to different analyses, monotherapy resulted in between 1.5% and 3.3% fewer patients remaining virally undetectable than patients taking standard therapy, but this difference was in no case statistically significant.

As well as avoiding NRTI toxicity and resistance, it has to be acknowledged that the primary interest in PI monotherapy is to save money. A separate poster presentation found putting patients on darunavir monotherapy would be 44% cheaper than keeping them on NRTIs plus PIs or NRTIs plus efavirenz (for some reason, other NNRTIs were excluded from this analysis).

This would mean that 108 patients could be treated for one million Euros on monotherapy versus 61 on combination therapy (78% more) and that given the success rates for each approach, the cost per successful viral suppression would be about €9,900 a year for monotherapy versus €17,350 for combination therapy.

The first boosted PI ever used as monotherapy was lopinavir (Kaletra ) and Dr Pedro Cahn presented a study of lopinavir monotherapy in patients mainly from Argentina and Mexico (a few came from Canada). This randomised 80 patients to lopinavir or lopinavir plus NRTIs. All patients were initially on PI-based therapies and 56% were already taking lopinavir. These patients were relatively recently diagnosed (median 3.3 years) and all on their first ARV regimen, and virally suppressed (under 50 copies/ml) for at least six months.

There were nine discontinuations, seven in the standard therapy arm and two in monotherapy, but only one in each arm was a virological failure.

On an intent-to-treat analysis 30 patients in the standard therapy arm and 37 in the monotherapy arm had viral loads under 50 copies/ml at week 48, giving success rates of 93.8% and 94.9%.

However in this study monotherapy patients who had viral load blips, were given NRTIs and successfully re-suppressed were not counted as failures. This happened to four patients, all in the first nine weeks, and if these had been counted as failures the success rate for monotherapy would only have been 84.6%.

Despite the fact that all patients were on lopinavir, there were greater rises in cholesterol in patients on lopinavir monotherapy, and 71% of monotherapy patients exceeded the upper limit of normal value for LDL-cholesterol versus 44% on standard therapy.

A third study looked at boosted atazanavir as a maintenance therapy. This has already been investigated in the USA: see this report. In the Spanish OREY study, 61 patients were switched from atazanavir plus two NRTIs to atazanavir monotherapy; there was no standard-of-care comparison arm. This is a 96-week study and the 48-week data were presented.

To join the study, patients had to have had a viral load under 50 copies/ml for six months and to have been on atazanavir for at least two months: in fact the median time on prior therapy with a viral load under 50 was four years.

The definition of treatment failure in this study was a viral load over 400 copies/ml at week 48 and in fact over one in five (21%) subjects did have viral loads over this level at this time. If ‘failure’ had been defined as viral loads under 50 copies/ml, then one third of patients (33%) would have failed. Twelve per cent met the definition of viral rebound, i.e. two successive viral load tests over 400 copies/ml, and 27% had two successive viral loads over 50 copies/ml.

Fifteen patients (26%) discontinued monotherapy, with eight dropping out of the study and seven, all virological failures, resuming triple therapy. One of these patients turned out to have a new primary atazanavir mutation (N88S). Another subject with poor adherence developed more than one mutation including N88S.

An audience member asked why drug monitoring had not been done on atazanavir levels in patients, given earlier studies that show that levels of this drug can be highly variable – see this report.

There were also two studies presented of monotherapy as initial therapy for drug-naive patients, with no combination therapy lead-in. The first was IMANI 3, the third in a series of lopinavir/ritonavir monotherapy studies by Dr Joe Gathe of Houston, USA, who pioneered the concept in 2003. In fact four of his IMANI 1 subjects were also in IMANI 3 and had been on successful lopinavir/ritonavir monotherapy for six years. Twenty-seven patients from IMANI 2 joined them.

The purpose of IMANI 3 was to find out if lopinavir/ritonavir monotherapy was as successful if patients took the Kaletra ‘Meltrex’ formulation tablets once a day as it was when taking the older capsules twice a day, as in the other two studies.

Twenty-eight out of these 31 patients reached week 48. Twenty-one of them maintained an undetectable viral load (in this case under 75 copies/ml) throughout the study, and at week 48, 84% were under 75 copies/ml. Five of the ten patients who had blips re-achieved viral suppression after adherence counselling. Switching to triple therapy was not allowed within this study’s protocol.

Two patients who remained viremic were put on a trial of a new Gilead drug and one chose to stay on lopinavir monotherapy despite viremia.

Only three patients had viral loads high enough for resistance testing and two of these turned out to have accumulated 5-6 lopinavir resistance mutations, although they would still be susceptible to darunavir, saquinavir and tipranavir in both cases and to atazanavir and fosamprenavir in one case each.

One member of the audience commented that “a third of these patients spend time with viremia with no obvious advantage in toxicity”, but Dr Gathe said that although there was no obvious benefit of once- versus twice-daily therapy he thought the strategy “conveyed huge advantages in terms of NRTI sparing and potential toxicity.”

Finally, Dr Pedro Cahn also reported on a monotherapy trial that was stopped due to high failure rates. This was a trial of darunavir monotherapy as initial therapy in just eleven ARV-naive subjects with baseline viral loads above 10,000 and below 100,000 copies/ml. The original intention had been to make this an escalation study: if at least seven of the eleven had a viral load below 400 copies/ml by week eight, then 13 more subjects with higher viral loads would have been added.

The trial had initial recruitment difficulties because out of 48 subjects screened, 38 failed the criteria; 16 had viral loads over 100,000 and five under 10,000 copies/ml, and 20 turned out to have HIV drug resistance mutations. Four subjects also dropped out before week eight.

At week eight, four of the seven subjects remaining had a viral load under 400 copies/ml and at week 24, two of the four who made it this far had viral loads under 50 copies/ml. It was decided to stop the trial because of inadequate viral suppression. All subjects who rebounded were given NRTIs and successfully re-suppressed their HIV.

Dr Cahn commented that the researchers had been unlucky in that three out of eleven patients screened with viral loads under 100,000 copies/ml turned out to have viral loads over 100,000 copies/ml by the time of starting therapy. He also felt that the criterion of viral suppression by week eight was unduly strict when this was only reached in a minority of patients in combination therapy. Nonetheless, darunavir monotherapy could not be recommended in naive patients on the basis of this study.

Do any of these studies bring us nearer to PI monotherapy, at least as maintenance, being recommended as standard of care? The new EACS Guidelines – see separate report – say that monotherapy “might represent an option with intolerance to NRTIs or treatment simplification, but only applies to patients without a history of treatment failure.”

A couple of audience members also questioned whether PI monotherapy might result in too many patients having viremia in their cerebro-spinal fluid and their genital tract, with implications for brain impairment and transmission. Studies were urged to address these issues.