Lopinavir/r monotherapy: less potent than triple therapy with higher risk of resistance
Simon Collins, HIV i-Base
Four oral presentations – three of them late-breakers – and at least four posters presented results from various strategies looking at lopinavir/r monotherapy (see Table 1).
The most successful approach was reported for treatment naive patients reducing to monotherapy after previous suppression <50 copies/mL for >/= 6 months on triple therapy. However, results were not very dissimilar for treatment-naive patients starting with monotherapy outright, though the numbers in these studies were also small.
While few patients failed outright, or showed lopinavir-associated mutations, at least one of the studies highlighted a major difference: a significantly greater proportion of patients receiving monotherapy experienced viral rebound to between 50-400 copies/mL, compared to patients receiving triple therapy. This is the one factor that has historically been shown to impact on long-term durability of other ARV triple regimens.
Bill Cameron from the University of Ottawa presented two-year results from 155 treatment naive patients randomised 2:1 to lopinavir/r plus AZT/3TC for at least 6 months followed by lopinaivr/r maintenance therapy, or to a control arm of efavirenz plus AZT/3TC triple therpay. In the primary analysis, 50% of the monotherapy arm compared to 61% of the triple therapy suppressed viral load to <50 copies/mL at week 96 (ITT, p=0.23). 
However, Kaplan-Meier analysis showed that the proportion maintaining <50 copies/mL was 62% vs 91%, in favour of efavirenz-based triple therapy was statistically significant (p=0.002). Although most patients on the lopinavir/r arm re-suppressed on continued monotherapy (11/12) or with addition of RTIs (1/12), new PI mutations (generally only very rarely reported with lopinavir/r triple therapy) were seen in (2/15) 13% lopinavir/r-blipping patients.
Also as a late breaker, Jean-Francois Delfraissy and colleagues from the Kremlin Bic鳲e Hospital Paris, presented 48-week results from the Monark study that randomised 136 treatment naive patients to initial lopinavir/r monotherapy (n=83) or lopinavir/r plusAZT/3TC (n=53). 
Similar to the first study, lopinvir/r monotherapy was associated with more episodes of viremia compared with triple-drug therapy, with approximately 10-15% patients at any point after week 16 having viral load 50-400 copies/mL, (84% vs 98% patients had viral load <50 copies/mL in the on-treatment analysis, p=0.03).
CD4 responses and tolerability were similar between the two groups, but protease-associated mutations again occurred more frequently in the monotherapy arm (2/83) compared to a single RT mutation (M184V) in the triple therapy arm.
Jos矁rribas presented results from a Spanish study that randomised 198 patients suppressed on current lopinaivr/r-based treatment <50 copies/mL for the previous 6 months, and who had no previous history of protease resistance, to continue triple therapy or reduce to lopinavir/r monotherapy. 
After 48 weeks, there were no statistically significant differences between the monotherapy vs triple-therapy groups: the percentage of patients without therapeutic failure >400 copies/mL (94% vs 90%), % suppressed to <500 copies/mL (89% vs 90%) and <50 copies/mL (85% vs 90%). PI resistance however was detected in 2/2 monotherapy vs 1/3 triple therapy patients with confirmed viral rebound.
Several other smaller studies looked at boosted PI-monotherapy. In an oral presentation in the main conference programme, Nunes and colleagues reported on interim 48-week results of a 96-week reduction therapy trial in 60 patients in Brazil, with similar response rates to the studies above, but this study included no resistance data. 
Two small non-controlled studies from the UK reported on results from lopinavir/r monotherapy in specific patients with restricted options for triple therapy, and perhaps best described real world settings where individualised may show a role for lopinavir/r monotherapy.
A poster by L Waters and colleagues from the Chelsea and Westminster Hospital in London reported on 35 treatment-experienced patients in their database who were using lopinavir/r and who had previously had low adherence on triple combinations. 
At switch, patients had mean CD4 and viral load of 248 cells/mm3 and 54,866 copies/mL respectively, and had used a median of 5 previous drug regimens. 14/28 (50%) achieved VL<50 copies/ml and 73% a >1 log reduction. Mean CD4 rise was +115 and +73 cells/mm3in the undetectable and viraemic groups respectively. Of the 5 patients with major PI mutations at baseline, 3 experienced satisfactory responses (CD4 increase; 2 undetectable, 1 <400 copies/mL). 2/10 patients with genotype results on monotherapy developed new minor mutations. 8/28 subjects switched therapy (3 virological failure, 2 for blips, 1 immunological failure and 2 unclear reasons) and 20 remain on lopinavir/r monotherapy, 12/20 remaining undetectable after a mean of 13.5 months (range 3-34).
In a second small study from London, N Martin and colleagues from Mortimer Market Centre, presented retrospective results from a database review of 13 patients using monotherapy with lopinavir/r (n=13) or atazanavir/r (n=3). 
Median age was 41 (range 3-54) years. Reasons for choosing monotherapy over alternative regimens included co-existing medical conditions [renal failure, TTP, lymphoma and hereditary mitochondrial toxicity (n=8)], drug toxicity (n=6), known genotypic resistance (n=6), and known poor adherence (n=2).
Median CD4 and viral load at baseline were 190 cells/mm3 and 5,100 copies/mL respectively. Although at the start of monotherapy only 4/16 patients had VL<50 copies/mL, after 12 weeks 7/14 (50%) and 9/14 (64%) achieved virological suppression to <50 copies/mL and <400 copies/mL, respectively. Of the remaining five, 2 stopped therapy due to intolerance and 3 failed to suppress, with VL between 1000 and 8200 copies/mL after a mean of 10 weeks.
An example of where lopinavir/r was clearly unsuccessful was in a small study by Falci and colleagues from Brazil, where 3/3 treatment experienced patients suppressed to <50 copies/mL for the previous 6 months, failed when switched to lopinavir/r once-daily compared to 2/12 (20%) on twice-daily lopinavir/r (p=0.02). Median time for failure was 10(6-16) months. 
Table 1: Selected lopinavir/r monotherapy studies at Toronto
|Study reference||Design||No. pts in study||Tx experience||VL results (mono vs triple)||Follow-up||New PI resistance|
|Cameron ||Triple Tx >6mo, randomised to monotherpy||155||Tx-naive||50 vs 61% <50 c/mL (NS), but 62 vs 91% with no rebound (p=0.002)||96 weeks||Yes. New PI mutations in 2/15 (13%)|
|Delfraissy JF ||Mono vs triple||136||Tx-naive||84%vs 98% (OT, p=0.03)||48 weeks||2/83 (mono) vs 1/53 (triple)|
|Arribas ||Reduction||198||Tx-experienced, no PI resistance||89 vs 90% <50 c/mL||48 weeks||2/2 failures|
|Nunes ||Reduction||60||On-treatment||86 vs 83% (NS) <80 c/mL||48 weeks||No data. IxVF in each arm|
|Waters ||Reduction||35||Tx-experienced||50% <50 copies/mL||13 mo (3-34)||2/10 (20%)|
|Matin ||Reduction||16||Tx-experienced||7/14 (50%) <50 c/mL||12 weeks||Not given|
|Falci ||Reduction||15||Tx-experienced||3/3 Tx-exp failed QD vs 2/12 LPV/r mono BID (20%) BID||10 mo (6-16)||No new PI Rx|
These results are important because of the early hopes for lopinavir/r monotherapy and many people may still interpret these studies as not a bad option for some patients. However, apart from cost, there are few reasons not to use the additional benefit from RTIs given the reduced pill count and side effect profile of recent formulations.
Reports from the Resistance Workshops in the July edition of HTB provided greater detail about the resistance for the M-613 and Monark studies. It was notable both that resistance to lopinavir/r occurred and that 20% patients experience viral rebound 50-500 copies/mL over during follow-up. The effect in the CNS and other compartments is unknown (see report on atazanivir/r monotherapy below).
The durability of other regimens has is limited by low level viral load <50-<500 copies/mL and this is also likely to impact on longer term use of monotherapy. Although not yet shown in studies, this is likely to progressively increase the risk of resistance and treatment failure over several years.
Several commentators, including James McIntyre, the lead rapporteur for Track B studies, have suggested that these risks may be acceptable as a holding strategy, in resource-poor settings where access to second-line treatment is limited, even though additional nucleosides clearly provide optimal results. However, the higher cost of any second line treatment is currently prohibiting use of lopinavir/r in most settings, despite the reduced price of $500 pa in the poorest countries.
The UK case reports, while uncontrolled and retrospective, provide examples of where monotherapy may provide an option in highly individualised care.
Unless stated otherwise, all references are to the Programme and abstracts from the XVI International AIDS Conference, Toronto, Canada. 13-18 August 2006.
- Cameron W, da Silva B, Arribas J et al. A two-year randomized controlled clinical trial in antiretroviral-naive subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). Late breaker abstract THLB0201.
- Delfraissy J-F, Flandre P, Delaugerre C et al. MONARK Trial (MONotherapy AntiRetroviral Kaletra): 48-Week analysis of lopinavir/ritonavir (LPV/r) monotherapy compared to LPV/r + zidovudine/lamivudine (AZT/3TC) in antiretroviral-naive patients. Late breaker abstract THLB0202.
- Arribas J, Pulido F, Delgado R et al. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: forty eight week results of a randomized, controlled, open label, clinical trial (OK04 Study). Late breaker abstract THLB0203.
- Nunes EP, Oliveira MS, Almeida MM et al. 48-week efficacy and safety results of simplification to single agent lopinavir/ritonavir (LPV/r) regimen in patients suppressed below 80 copies/mL on HAART – the KalMo study. Oral abstract TUAB0103.
- Waters L, Gazzard B, Bower M et al. Kaletra monotherapy a real-life experience. Poster abstract THPE0132.
- Matin N, Garrett N, Benn P et al. Boosted PI monotherapy; does it have a role in treatment of HIV infection? Poster abstract CDB0528.
- Falci D, Bay M, Marques L et al. HAART simplification therapy with lopinavir/r once or twice a day in chronic HIV infection: a pilot study. Poster abstract CDB0600.