Kaletra monotherapy: small studies and early data
Simon Collins, HIV i-Base
At last year’s IAS conference in Paris, several studies reported on ritonavir boosted PI monotherapy using either indinavir or lopinavir/r both as maintenance therapy and first-line therapy.
In an oral session, Joe Gathe presented 48-week results from lopinavir/r monotherapy in 30 treatment naive patients (28 male, 2 female) treated at a public hospital in Texas. It was emphasised that a large part of the rationale for this choice of treatment was the cost of standard therapy for these patients. 
18 patients were white, 6 black and 6 Hispanic. Mean age was 36 years, mean viral load was 262,000 copies/mL (17 subjects had viral load > 100,000 copies/mL) and mean CD4+ cell count, 170 cells/mm3.
The 24-week results reported last year were generally maintained out to 48 weeks.
By intent-to-treat analysis, 20/30 patients (67%) achieved viral load < 400 copies/mL and 18 (60%) achieved viral load < 50 copies/mL. Mean increase in CD4 cell count was 317 cells/mm3. Ten subjects discontinued treatment: loss to follow-up 2; adverse events (GI related) 2; non-adherence 2; virologic failure 2; deportation from the US 1; hepatitis B 1.
Several case histories were provided for treatment that failed on various occasions, often due to interruption related to health insurance or cost of treatment, and universal treatment access is still clearly a major issue in the US.
Four patients received intensification with tenofovir/3TC/ and/or saquinavir, including 1 with hepatitis B who used tenofovir/3TC. Potential explanations for incomplete suppression to < 50 copies/mL on lopinavir/r alone included poor adherence, incomplete absorption/metabolisation/bioavailability of lopinavir/r and possible development of resistance not detected by assays used.
In conclusion, Gathe emphasised that this was not an approach that is ready for general clinical application but that it is should continue to be studied in clinical trials.
The interest in boosted monotherapy was shown by other studies in the poster sessions with similar study designs.
Arribas and colleagues reported on a study carried out in four hospitals in Madrid, that randomised (1:1) 42 patients on maximally suppressed LPV/r-based treatment (50 copies/mL for at least six months) to either use lopinavir/r monotherapy or continue lopinavir/r with two background RTIs. 
Baseline characteristics were similar: median CD4 cells/mm3 (662 vs 585), CD4 nadir (146 vs 145), HIV log10 viraemia prior to HAART (5.11 vs 4.85) or months with HIV RNA < 50 c/mL (11 vs 9), in the mono and triple therapy arms respectively.
Table 1: Results at 24-weeks
|LPV/r mono||LPV/r + 2RTIs|
|% < 50 copies/mL (ITT, NC=F)||81%||100%|
|Mean change in CD4||+50||+3|
The three failures were: at week 12 (VL 3,600, after a 3-month period of 59% compliance; L63P present at rebound but also present in a pre-HAART sample, subsequently patient discontinued treatment), at week 24 (VL= 1,270, no mutations, results of reinduction pending) and week 24 (VL=564, no mutations, HIV-RNA < 50 copies/mL after 4 weeks of reinduction). Patients with viral rebound had shorter time with VL < 50 than patients without failure (218 vs 1095 days; p=0.002).
One patient in each arm was on lipid lowering agents at the start of the study, and by week 24, this increased to two patients in the monotherapy arm and three in the triple arm. It was suggested in a separate poster analysing lipids changes in this study, that d4T discontinuation was a cofounding factor in lipid changes. 
Pierone and colleagues from AIDS Research and Treatment Center of the Treasure Coast, Ft. Pierce, United States, looked at LPV/r monotherapy as maintenance therapy for patients previous suppressed on an NNRTI + dual RTI combination. With only 18 patients and a mean follow-up of 18 weeks (range 4-24 weeks) this is too early to be presenting these results. 
Nevertheless, four patients have already discontinued (three due to diarrhoea at or before week 8, one with virologic failure with viral load 1,067 at week 12).
Two patients with baseline impaired glucose tolerance developed diabetes mellitus. Both are controlled and continue on study and three patients have added lipid-lowering therapy on study.
Based on these preliminary results this writer would disagree with the researchers conclusion that ‘this is one of the first prospective studies showing effectiveness and tolerability of simplification to LPV/r monotherapy’. In this instance, the intervention in a small group of patients on stable NNRTI-based therapy led to both virological failure and new toxicity.
Finally, Ruane and colleagues from private practice in Los Angeles, switched 18 patients with a history of viral suppression <50 copies/mL for at least nine months to lopinavir/r monotherapy.  An additional safety consideration in this study was to use therapeutic drug monitoring to ensure that all patients had sufficiently high trough levels (> 3.0 μg/mL) prior to the switch.
Table 2: Percentages of patients with viral suppression using monotherapy with LPV/r
|B/line||Wk4||Wk8||Wk 16||Wk 24|
* Pt 7-blip to 185, returned to <50 next visit;
^Pt 14-blip to 387, next visit 150;
#Pt 7- blip to 79, pt 10-blip to 327
Mild to moderate GI complaints were the most frequently reported adverse event. Although viral rebound is reported as ‘blips’ the long term significance of this has not been established. Only having six patients at week 24 must question the value of presenting this early data.
The lack of a control arm to evaluate frequency of blips in triple therapy will also make the results difficult to interpret.
Although there were several posters on use of lopinavir/r monotherapy, apart from the Gathe study, these were generally too small and short term to contribute much new insight into this approach.
If boosted-PI monotherapy can produce or maintain sustained viral suppression in a large group of patients, the additional contribution of nucleosides in traditional three-drug regimens needs to be understood. While issues of drug penetration and sanctuary sites cannot be addressed in short studies, continued suppression <50 copies/mL after a year becomes very interesting. If this was a short term effect, and resistance developed in sanctuary sites, you would expect to see viral rebound in plasma RNA by 48 weeks.
Conflicting results have been reported looking at maximizing the slope of viral load reduction in the first days and weeks of treatment. Using more potent regimens to reduce viral load more quickly to <50 copies/mL, reducing also the potential exposure to the development of resistance, has scientific plausibility and was supported by early studies. Other research has suggested that viral dynamics may include a maximum rate limited reduction, and that recommended efavirenz- and lopinavir/r- based combinations provide this maximum potency.
The appeal of nucleoside-sparing regimens is largely to avoid side effects associated with nucleoside analogues associated with higher levels of mitochondrial dysfunction. This may be less of an issue with more recent approved drugs in this class. Tolerability of the boosted-PI approach is just as important to consider, shown by significant discontinuation rates in the some of these studies.
- Gathe JC, Washington MY, Mayberry C, Piot D, Nemecek J. IMANI-1 TC3WP single drug HAART — proof of concept study. Pilot study of the safety and efficacy of Kaletra (LPV/r) as single drug HAART in HIV+ ARV-naive patients — interim analysis of subjects completing final 48 week data. XV Intl AIDS Conference, Bangkok. Abstract MoOrB1057.
- Arribas JR, Pulido F, Lorenzo A et al. Simplification to lopinavir/r single-drug HAART: 24 weeks results of a randomised, controlled, open label, pilot clinical trial (OK Study). XV Intl AIDS Conference, Bangkok. Abstract TuPeB4486.
- Arribas JR, Pulido F, Lorenzo A et al. Lipid changes in a randomised trial of simplification with lopinavir/r single -drug HAART (OK Study): 24 weeks results. XV Intl AIDS Conference, Bangkok. Abstract TuPeB5925.
- Pierone G, Mieras J, Fontaine L et al. Simplification to lopinavir/ritonavir monotherapy from NNRTI-based HAART in HIV-infected patients with complete viral suppression. XV Intl AIDS Conference, Bangkok. Abstract TuPeB4595.
- Ruane P, Luber A, Gaultier C et al. Maintenance therapy using Lopinavir/ritonavir (LPV/r) alone with well-controlled HIV Infection. XV Intl AIDS Conference, Bangkok. Abstract TuPeB4577.