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Does Boosted PI Monotherapy Have Future Utility? Kaletra Monotherapy Studies: the OK Study and MONARK Study
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Written by Jules Levin.
Jan 30, 2008
Following the introduction immediately below are 2 reports on the recently published Kaletra monotherapy studies the MONARK Study and the OK Study, which are very different in design.
For several years now Abbott has been conducting studies examining Kaletra monotherapy. In two publications this month Jan 2008 in the journal AIDS, results of two Kaletra monotherapy studies were published, the MONARK Study and the OK Study. The MONARK Study was designed as a pilot study of 60 patients. MONARK "was not specifically powered to demonstrate either equivalence or non-inferiority but to identify whether LPV/r monotherapy provided adequate safety and efficacy relative to recommended LPV/r triple therapy, so as to allow further evaluation in a larger comparative trial if warranted". While the OK Study was designed as a induction-maintenance study, meaning patients started HAART on triple Kaletra therapy and after being <50 copies for a while were switched to Kaletra monotherapy. Patients who experienced viral failure could re-introduce nukes and were not considered failures if they were resuppressed after adding nukes. With this as a study design the virological response rates were similar for the patients who were randomized to remain on triple therapy compared to those patients who switched to the Kaletra monotherapy maintenance therapy. There were concerns because low-level viral blips were more frequent in the monotherapy arm, and this is discussed in the publication of the study, I suggest reading this discussion. Three years of data from the OK Study are expected to be reported in the next year, and 3 years of data from MONARK are expected to be reported.
So, what is the utility of Kaletra monotherapy?
Abbott has put quite a lot into monotherapy research. The studies are exploring several potential uses including nuke-sparing therapy and HAART simplification and several additional ones. I think the interest of application in the developing world emerged at least in part because of limited availability of secondline therapy, and for the use of Kaletra monotherapy as a secondline therapy. It is my understanding there is quite a bit of interest in using Kaletra monotherapy as a secondline therapy option in the developing world. The interest for Kaletra monotherapy in the developing world is also in part because of the limitations regarding the usefulness and access of secondline nukes . My understanding is that firstline failure in the developing world is identified by the development of infections or CD4 decrease because viral load testing is not usually available. Therefore, patients are often left for too long on failing regimens where nuke resistance can develop, which may reduce the efficacy of secondline nukes. Apparently, it is felt in the developing world that Kaletra monotherapy could reduce costs of HAART and eliminate use of nukes. There appears to be quite a lot of use of and interest for use of Aluvia in the developing world so my understanding is that Abbott is increasing production capacity in anticipation.
Apparently, there are a number of ongoing Kaletra monotherapy studies in several areas of the developing world including Africa, as well as in Mexico and Canada. The Canadian trial is examining Kaletra monotherapy for HCV+ patients who are starting Peginterferon plus ribavirin to eliminate use of HIV nukes while on HCV therapy. There are trials in Nigeria looking at Kaletra monotherapy as secondline therapy, in Tanzania, and in the DART Study Kaletra monotherapy is one of the arms for secondline therapy. It is my understanding that Tibotec is exploring darunavir monotherapy. There were several Reyataz monotherapy studies but it does not appear that BMS is still pushing this.
There is an ongoing monotherapy trial in France trying to duplicate the findings from the OK Study, whose results may be presented at Mexico City. ANRS is conducting in France a Kaletra monotherapy pregnancy trial, which deletes nukes from HAART due to concern for safety/toxicity associated with nukes for newborns. The study is enrolling and has been ongoing and mothers have gone to term in this trial.
Another possible use is to explore two-drug therapy, which would consist of Kaletra plus 1 additional drug, which could be a nuke such as 3TC or another ART drug, perhaps a CCR5 antagonist or an integrase inhibitor, because combining a PI with a NNRTI has concerns.
There has been much controversy regarding the safety of using Kaletra monotherapy, with many in the community concerned that rates of resistance can be higher compared to triple HAART, viral failure, or other safety concerns including CNS effects. Therefore, ongoing research is required to examine safety and efficacy. I do not expect that Kaletra monotherapy or monotherapy with other boosted protease inhibitors will likely be a recommended firstline therapy in the developed world in most scenarios, but ongoing research will examine if it has other usefulness. Whether or not viable alternative uses of Kaletra monotherapy are identified remains to be seen, but the Abbott program has devoted resources to creative ways to look for utility. I think patients have been enrolled in the OK Study for as long as 4 years; safety data from the OK Study has been presented for 2 years and 3 years data is expected to be presented, and 96-week Monark Study data is expected to be presented at Mexico City.
OK Study: Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV
AIDS:Volume 22(2)11 January 2008p F1-F9
Pulido, Federicoa,*; Arribas, Jose Rb,*; Delgado, Rafaela; Cabrero, Estherc; Gonzalez-Garcia, Juanb; Perez-Elias, Maria Jd; Arranz, Albertoe; Portilla, Joaquinf; Pasquau, Juang; Iribarren, Jose Ah; Rubio, Rafaela; Norton, Michaeli; for the OK04 Study Group
From the aUnidad HIV and Laboratorio de Microbiologia Molecular, Hospital 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain
bServicio de Medicina Interna, Hospital La Paz, Universidad Autonoma de Madrid, Madrid, Spain
cAbbott Laboratories, Madrid, Spain
dHospital Ramon y Cajal, Madrid, Spain
eHospital Principe de Asturias, Alcala de Henares, Spain
fHospital General de Alicante, Alicante, Spain
gHospital Virgen de las Nieves, Granada, Spain
hHospital Donostia, San Sebastian, Spain
iAbbott Laboratories, Abbott Park, Ill, USA.
*F. Pulido and J.R. Arribas contributed equally to this study.
"At week 48, the percentage of patients without therapeutic failure was 94% in the monotherapy group versus 90% in the triple therapy group (difference,-4%; upper limit of 95% confidence interval for difference, 3.4%). The percentage of patients with HIV RNA 50 copies/mL at 48 weeks by intention-to-treat, missing data or reinductions considered as failures, were 85% in the monotherapy group versus 90% in the triple therapy group (P = 0.31; 95% upper limit of 95% confidence interval for difference, 14%)....
.... Our trial shows that a substantial proportion of suppressed patients on triple therapy can maintain suppression with lopinavir-ritonavir monotherapy. This is in contrast to previous clinical trials [5-7] that attempted the use of a single antiretroviral drug for maintenance of virologic control. These findings suggest that a single antiretroviral, with a high genetic barrier to resistance, such as lopinavir-ritonavir, could be sufficient to maintain control of HIV replication and therefore challenge the notion that triple drug regimens are an absolute prerequisite for successful anti-HIV therapy....
.... it should be noted that, as happened in our pilot trial, patients receiving monotherapy who had low level viraemia could be successfully reinduced by adding nucleosides again, without loss of therapeutic options. In our opinion this result supports our decision, when we designed the study, of not considering successful reinductions as failures for the primary endpoint. Nevertheless we acknowledge that longer follow-up of reinduced patients is clearly needed to completely rule out negative consequences of a period of low level viraemia in patients receiving lopinavir-ritonavir monotherapy.....
..... At week 48, six out of the 100 patients (6%) in the monotherapy group had developed confirmed loss of virological suppression compared to three out of 98 (3%) in the triple therapy group (P = 0.31). Of the six patients with loss of virological suppression in the monotherapy group, four resumed baseline nucleosides and regained virological suppression which was subsequently maintained for a median of 56 weeks (36-64). In one patient reinduction was not attempted per protocol, as genotypic testing showed lopinavir-ritonavir resistance and one patient did not maintain virological suppression after resuming baseline nucleosides....
..... In an intent-to-treat analysis, 89% of the patients in the monotherapy group and 90% of the patients in the triple therapy group achieved an HIV RNA level of < 500 HIV RNA copies/mL at week 48 (missing HIV RNA level values or change in randomized therapy, including successful reinduction with nucleosides in the monotherapy group, were considered to be > 500 HIV RNA copies/mL)[P = 0.85; Fisher's exact test, 95% CI (Triple-Monotherapy): -7.8 to 9.4]. Using the same analysis but with a cut-off of HIV RNA level of 50 copies/mL proportions were 85% for monotherapy and 90% for triple therapy [P = 0.31; Fisher's exact test, 95% CI (triple-monotherapy): -4.4 to 14].....
..... Fig. 3 shows the point prevalence of discontinuations and virologic response by as-treated analysis using both the < 50 and < 500 HIV RNA copies/mL level cut-offs. At week 48, four patients in the monotherapy group and no patient in the triple therapy group had an HIV RNA level between 50 and 500 copies/mL. Table 2 shows different sensitivity analysis for antiviral efficacy both by intention-to-treat and by an as-treated analysis. By as-treated analysis, a significantly higher proportion of patients in the triple therapy group maintained HIV RNA < 50 HIV RNA copies/mL after 48 weeks of follow-up [97% versus 89% P = 0.0496; Fisher's exact test, 95% CI (triple monotherapy), 0.8-15.5]. There were 15 patients with transitory viral loads > 50 copies/mL (blips) in the monotherapy group and 13 in the triple therapy group....
..... The results of our trial also show that episodes of low level, intermittent viral replication are slightly more common in patients receiving monotherapy than in patients receiving triple therapy. Insufficient antiretroviral potency of lopinavir-ritonavir monotherapy could be an explanation of this finding. However, using an ultrasensitive (3-50 copies/mL) PCR assay, we have shown [16] that the level of persistent plasma viral load < 50 copies/mL does not increase after simplification of triple antiretroviral therapy to lopinavir-ritonavir monotherapy. Consequently, it is unlikely that insufficient antiviral potency of monotherapy could account for the observed difference in low level viraemia between monotherapy and triple therapy......
......Drug adherence might be an important factor to explain the higher incidence of low-level viraemia in the monotherapy group. Adherence scores were not significantly different between groups during the trial. Less than half of the patients in both groups were classified as fully adherent by the GEEMA questionnaire. However, it should be emphasized that this questionnaire might overestimate the level of non-adherence because it gives significant weight to the question related to timing of doses. Although recent data suggest that 95% adherence level might not be absolutely predictive of virological efficacy [17] when lopinavir-ritonavir is used along with two nucleosides, our results suggest that a high level of adherence might be needed when patients receive lopinavir-ritonavir monotherapy. We hypothesize that the short-term consequences of intermittent non-adherence might have a more negative impact in patients receiving lopinavir-ritonavir monotherapy than in patients receiving triple therapy. Since lopinavir-ritonavir has a short terminal half-life [9] it is reasonable to postulate that patients missing doses of lopinavir-ritonavir monotherapy have a greater risk of virological rebound than patients receiving lopinavir-ritonavir and two nucleosides which are characterized by a long intracellular half-life. It would be interesting to evaluate if interventions that can have a benefit in adherence, such as once-daily administration of lopinavir-ritonavir or the new meltrex formulation of lopinavir-ritonavir could improve the results seen in our trial....
.... Being able to treat HIV infection with a single antiretroviral has important implications. Worldwide a significant barrier to treatment of HIV is the cost of antiretrovirals. By decreasing this cost, boosted protease inhibitor monotherapy has the potential to increase access to anti-HIV treatment [21]. Additionally, treating with fewer drugs means avoiding drug related toxicities and resistance to drugs not being taken. Nucleoside sparing regimens might have also an important role in settings such as the treatment of HIV-HCV coinfection in which undesirable interactions with ribavirin should be avoided. Finally although not directly applicable, our results give some support to the use of lopinavir-ritonavir monotherapy after failure of first line regimens in the underdeveloped world.....
In conclusion, in patients who have achieved virological suppression for more than 6 months after receiving triple drug therapy our study supports the use of lopinavir-ritonavir monotherapy followed by reinduction with nucleosides if virological suppression is lost. Since episodes of low-level viral rebound were more frequent in the monotherapy group further studies and longer follow-up of patients treated with lopinavir-ritonavir monotherapy are needed before this strategy can be widely recommended."
Abstract
Background: Prior attempts to reduce the number of drugs needed to maintain viral suppression in patients with suppressed HIV replication while receiving three antiretroviral drugs have been unsuccessful.
Methods: In 205 patients with suppressed HIV replication on lopinavir-ritonavir and two nucleosides, this randomized, open-label, non-inferiority clinical trial compared the strategies of continuation of triple therapy versus lopinavir-ritonavir monotherapy followed by reinduction with two nucleosides if virological rebound occurred without genotypic resistance to lopinavir-ritonavir. The primary endpoint was proportion of patients without therapeutic failure, defined as confirmed HIV RNA higher than 500 copies/mL (with exclusion of patients receiving monotherapy who resuppressed to < 50 copies/mL after resuming baseline nucleosides), or loss to follow-up, or change of randomized therapy other than reinduction.
Results: At week 48, the percentage of patients without therapeutic failure was 94% in the monotherapy group versus 90% in the triple therapy group (difference,-4%; upper limit of 95% confidence interval for difference, 3.4%). The percentage of patients with HIV RNA 50 copies/mL at 48 weeks by intention-to-treat, missing data or reinductions considered as failures, were 85% in the monotherapy group versus 90% in the triple therapy group (P = 0.31; 95% upper limit of 95% confidence interval for difference, 14%).
Conclusion: In this trial, 48 weeks of lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed was non-inferior to continuation of two nucleosides and lopinavir-ritonavir in patients with prior stable suppression. However, episodes of low level viremia were more common in patients receiving monotherapy. (ClinicalTrials. gov number, NCT00114933).
Introduction
A combination of three antiretrovirals is globally recommended for the treatment of HIV disease [1-3]. Three drugs are typically combined from two different classes; two nucleoside reverse transcriptase inhibitors plus one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor. For the adherent patient, taking three drugs from two antiretroviral classes translates into a substantial and durable suppression of HIV replication. The successful viral control achieved by these combinations is mainly due to the high genetic barrier to resistance that is difficult for a population of wild-type HIV to escape from [4].
Despite the success of triple drug regimens, the idea or treating HIV with fewer than three drugs continues to be very attractive, due mainly to issues of cost, convenience and toxicity. Unfortunately, prior attempts at decreasing the number of drugs needed to maintain HIV viral suppression have been unsuccessful [5-7].
Lopinavir-ritonavir is an appropriate candidate for single drug therapy of HIV infection due to its high potency [8], its high genetic barrier to resistance [9] and its ability to reduce HIV replication in the cerebrospinal fluid [10]. We and others have preliminarily tested the hypothesis that lopinavir-ritonavir monotherapy might be sufficient to control HIV replication [11,12]. In a pilot trial [12] we showed that 17 of 21 (81%) patients who simplified from triple therapy to lopinavir-ritonavir monotherapy maintained HIV viral suppression after 72 weeks. None of the patients who failed lopinavir-ritonavir monotherapy in this pilot study developed mutations in the HIV protease gene. Importantly in three patients who failed lopinavir-ritonavir monotherapy, virological suppression could be regained by restarting prior nucleosides. As a follow up to the small pilot trial we conducted a larger clinical trial comparing lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance of HIV viral suppression.
Patients and methods
Study design
This randomized, open-label, investigator-initiated, non-inferiority, multicentre clinical trial was carried out in 28 sites in Spain. Patients were at least 18 years old, had no previous history of suspected or confirmed virological failure while receiving a protease inhibitor, were receiving two nucleoside reverse transcriptase inhibitors (or one nucleoside plus tenofovir DF) and lopinavir-ritonavir soft gel capsule (400/100 mg b.i.d.) for at least 4 weeks and had < 50 copies of HIV RNA/mL for at least the prior 6 months. Patients with a single transitory episode of detectable viral load ('blip', defined as an HIV-RNA viral load >50 copies/mL preceded and followed by one HIV-RNA viral load < 50 copies/mL without changes in antireteroviral treatment) during the prior 6 months could also been included. Exclusion criteria were pregnancy, presence of serum hepatitis B surface antigen in patients treated with lamivudine, emtricitabine or tenofovir DF, need for treatment with agents known to have potential major interactions with lopinavir-ritonavir and major psychiatric disease as assessed by the investigator. The study was approved by the Regional Ethics Committee for Clinical Research of the Community of Madrid, the local ethics committees for clinical research at each site and by the Spanish Agency for Medicines and Healthcare Products. All patients gave dated and written informed consent.
Patients were randomly assigned in a 1: 1 ratio to stop or continue the two nucleosides (or one nucleoside plus tenofovir DF). Randomization was centralized and computer generated (Clin Stat v.08.05.96. Department of Public Health Sciences, St George's Hospital Medical School). Randomization was stratified by CD4 cell count (< or ≥ 200 cells/μL) and months with HIV RNA < 50 copies/mL prior to randomization (< or ≥ 9 months).
Patients were assessed at baseline, week 4, week 12, and every 12 weeks thereafter until week 48. At study visits, clinical data was collected and labs were drawn after an overnight fast. Laboratory analyses included CD4 cell count, measurement of plasma HIV-1 RNA, haematology, plasma chemistry profiles, and a fasting lipid panel.
Plasma HIV-1 RNA and RNA HIV-1 genotyping were performed at the Laboratory of Molecular Microbiology at the Hospital 12 de Octubre in Madrid. All other laboratory determinations were performed locally at each site.
Adherence was assessed using a validated, 6-item, adherence questionnaire (GEEMA) [13]. Patients were classified as non-adherent when there was a positive response to any of the qualitative questions included. Responses to two of the questions in the questionnaire (a) 'Thinking about the last week. How often have you not taken your medicine?' and (b) 'Since the last visit how many days have you not taken any medicine at all?') were also independently quantified and analysed, as they had been associated with the risk of virological rebound in a previous pilot trial [12].
Virologic analysis
HIV-1 plasma viral load was performed by automatized RNA extraction in an Cobas AmpliPrep instrument followed by quantification using the Cobas TaqMan HIV-1 in a TaqMan 48 analyzer (Roche Molecular Systems, Inc., Branchburg, New Jersey, USA).
Any sample with detectable plasma HIV RNA (> 50 copies/mL) was repeated every 2 weeks during the following month, and then monthly until HIV viral load became undetectable again or until viral load increased > 500 copies/mL in two different samples. Viral genotyping was performed in all samples with viral load > 500 copies/mL. Antiretroviral susceptibility studies were performed in circulating virions by sequencing the protease (PR) and reverse transcriptase (RT) (amino acids 1-335) genes using the ViroSeq HIV-1 Genotyping system V2.0 (Celera Diagnostics, Alameda, California, USA). In the present analysis, lopinavir-ritonavir associated resistance mutations are defined according to the list published by the International AIDS Society-USA in 2006 [14]. Phenotypic testing (in selected samples) for antiretroviral resistance was performed by Antivirogram (Virco BVBA, Mechelen, Belgium). Results of phenotypic testing were not available to the investigators during the trial.
Endpoints
The primary objective was to assess the non-inferiority of the strategy of simplification to lopinavir-ritonavir monotherapy versus continuation of triple therapy. Subjects were permitted to restart nucleosides if monotherapy did not maintain virologic suppression as long as the virus remained without genotypic resistance to lopinavir-ritonavir [14].
The primary outcome measure was the proportion of patients without therapeutic failure at 48 weeks. Therapeutic failure was defined as any of the following: (i) two consecutive measurements of HIV RNA > 500 copies/mL separated by at least 2 weeks. A cut-off level of 500 copies/mL was chosen because it is probably a truer measure of virologic failure than a lower cut-off. Patients randomized to lopinavir-ritonavir monotherapy who failed by this definition were not considered therapeutic failures if at the time of failure there was no evidence of lopinavir-ritonavir genotypic resistance, were reinduced with two nucleosides and were suppressed to < 50 copies/mL of HIV RNA at 48 weeks; (ii) change of randomized therapy for reasons different from re-induction in the monotherapy group; (iii) treatment discontinuation; (iv) loss to follow-up; (v) for patients re-induced in the monotherapy group: decrease in HIV RNA < 1 log10 4 weeks after reinduction or failure to reach HIV RNA < 50 copies/mL 16 weeks after reinduction.
Secondary efficacy outcomes included the proportion of patients with virological failure (HIV RNA > 50 or > 500 copies/mL, according to the analysis) through week 48. For these secondary outcomes we used the FDA algorithm for time to loss of virologic response [15]. This algorithm requires consecutive confirmation of a value before assigning failure. Missing data, early termination of participation in the study, or re-induction with nucleosides in the monotherapy group were considered to be failures in these analyses. Additional secondary endpoints were the development of HIV resistance and changes in the CD4 cell count.
Comparisons between the two treatment groups were also made with respect to the frequency and severity of treatment-related adverse events, the incidence of laboratory abnormalities, and changes from baseline in laboratory values.
Statistical analysis
With 100 patients per group, the study has 80% power to show the non-inferiority of the monotherapy group, assuming 10% therapeutic failure rate at 48 weeks in both groups. We based this assumption on the results of our initial monotherapy pilot trial [12]. Per protocol, non-inferiority would be demonstrated if the upper limit of the 95% confidence interval (CI) of the difference in percentage of patients without therapeutic failure (triple therapy - monotherapy) was < 12%.
All randomized patients who received at least one dose of their assigned therapy were included in the analyses and they were followed for the entire 48 weeks regardless of whether they prematurely discontinued or switched their randomized therapy.
Treatment groups were compared using the Fisher exact test and ƒÔ2 test for categorical variables and the Mann-Whitney U test for continuous variables. Time-to-event analyses were performed using Kaplan-Meier survival curves and the log rank test. All reported P values are two-sided and were not adjusted for multiple testing.
Results
Between December 2004 and July 2005, 205 patients receiving lopinavir-ritonavir and two nucleosides were randomly assigned in a 1: 1 fashion to either stop taking their nucleosides or continue taking their nucleosides. All visits for the 48-week study were completed by June 2006. The baseline characteristics were similar in the two study groups (Table 1). Patients included in the trial were receiving treatment with lopinavir-ritonavir mostly as their first or second protease inhibitor and had maintained HIV virological suppression for a median time of 18 months. Prior to randomization, the most common nucleosides combinations used along with lopinavir-ritonavir were zidovudine plus lamivudine and stavudine plus lamivudine. At 48 weeks 94 patients in the monotherapy group and 88 patients in the triple therapy group were still in the study. The disposition of the two treatment groups is shown in Fig. 1. Of the 205 randomized patients, seven (three in the monotherapy and four in the triple therapy group) were not dosed due to consent withdrawal. At 48 weeks, 94/100 subjects randomized to monotherapy were still receiving lopinavir-ritonavir, 89 as monotherapy and five as triple therapy. In the triple therapy group, at 48 weeks 88/98 subjects were still receiving lopinavir-ritonavir and two nucleosides.
Response to treatment
At week 48, 94 of the 100 patients (94%) in the monotherapy group did not develop therapeutic failure compared to 88 of the 98 patients (90%) in the triple therapy group. The 95% CI for the difference between the two groups was -11.8 to 3.4% (P = 0.28), which fulfilled the pre-established criteria for non-inferiority of the monotherapy group. There were six therapeutic failures in the monotherapy group. Three were lost to follow-up. One changed randomized therapy without loss of virologic suppression. One lost virologic suppression and developed protease inhibitor resistance. One patient had loss of virologic suppression and then failed to maintain suppression after reinduction with baseline nucleosides. There were 10 therapeutic failures in the triple therapy group. Four were lost to follow up. Three had confirmed loss of virological suppression. Three discontinued randomized treatment due to adverse events. There were no significant statistical differences in the time to treatment failure between both groups by log-rank test (P = 0.29) (Fig. 2).
At week 48, six out of the 100 patients (6%) in the monotherapy group had developed confirmed loss of virological suppression compared to three out of 98 (3%) in the triple therapy group (P = 0.31). Of the six patients with loss of virological suppression in the monotherapy group, four resumed baseline nucleosides and regained virological suppression which was subsequently maintained for a median of 56 weeks (36-64). In one patient reinduction was not attempted per protocol, as genotypic testing showed lopinavir-ritonavir resistance and one patient did not maintain virological suppression after resuming baseline nucleosides.
In an intent-to-treat analysis, 89% of the patients in the monotherapy group and 90% of the patients in the triple therapy group achieved an HIV RNA level of < 500 HIV RNA copies/mL at week 48 (missing HIV RNA level values or change in randomized therapy, including successful reinduction with nucleosides in the monotherapy group, were considered to be > 500 HIV RNA copies/mL)[P = 0.85; Fisher's exact test, 95% CI (Triple-Monotherapy): -7.8 to 9.4]. Using the same analysis but with a cut-off of HIV RNA level of 50 copies/mL proportions were 85% for monotherapy and 90% for triple therapy [P = 0.31; Fisher's exact test, 95% CI (triple-monotherapy): -4.4 to 14].
Fig. 3 shows the point prevalence of discontinuations and virologic response by as-treated analysis using both the < 50 and < 500 HIV RNA copies/mL level cut-offs. At week 48, four patients in the monotherapy group and no patient in the triple therapy group had an HIV RNA level between 50 and 500 copies/mL. Table 2 shows different sensitivity analysis for antiviral efficacy both by intention-to-treat and by an as-treated analysis. By as-treated analysis, a significantly higher proportion of patients in the triple therapy group maintained HIV RNA < 50 HIV RNA copies/mL after 48 weeks of follow-up [97% versus 89% P = 0.0496; Fisher's exact test, 95% CI (triple monotherapy), 0.8-15.5]. There were 15 patients with transitory viral loads > 50 copies/mL (blips) in the monotherapy group and 13 in the triple therapy group.
Fig. 3. Point prevalence of discontinuations and virologic response by as-treated analysis using both the less than 50 and less than 500 HIV RNA copies/mL level cutoffs. These graphs show the weekly percentage of patients in each viral load stratum. Every viral load remains in the same stratum until it is repeated or until discontinuation.
Immunologic changes
The mean increase from baseline in CD4 cell counts at week 48 was 65 cells/μL for the monotherapy group and 31cells/μL for the triple therapy group (P = 0.31; Mann-Whitney U test).
Adverse events
Study drug-related adverse events of at least moderate severity occurred in three patients in the triple therapy group (3%) and none (0%) in the monotherapy group (P = 0.08). The three adverse events in the triple therapy group were diarrhoea (two patients) and insomnia. These three adverse events resulted in treatment discontinuation.
Laboratory abnormalities
In both treatment groups there were no statistically significant changes from baseline in fasting total cholesterol, high-density lipoprotein cholesterol or triglycerides. Grade 3 or 4 hypertriglyceridaemia was seen in three patients (3%) in each group (P = 0.99). Grade 3 or 4 hypercholesterolemia was seen in 10 patients (10%) in the monotherapy group and four patients (4%) in the triple therapy group (P = 0.1). Grade 3 or 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations were seen in four patients (4%) in the monotherapy group and in two patients (2%) in the triple therapy group. Of the six patients with grade 3 or 4 AST/ALT elevations, five were coinfected with hepatitis C virus. No patient discontinued the study because of elevated lipid or aminotransferase levels.
Genotypic analysis
There were 15 patients (11 in the monotherapy group, four in the triple therapy group) who qualified for genotypic testing due to a HIV RNA > 500 HIV RNA copies/mL. Protease inhibitor associated mutations were detected in three subjects, two (2%) in the monotherapy group, and one (1%), in the triple group (P = 0.56; Fisher exact test). All three subjects had exhibited more than one episode of viraemia > 500 copies/mL. Reverse transcriptase mutations were detected in two subjects, one in the monotherapy group and one in the triple therapy group.
At week 16, subject #VN04 on monotherapy showed protease mutations 10F and 46I. By phenotypic testing the fold change in 50% inhibitory concentration (IC50) to lopinavir-ritonavir was 2.6 (fold change cut-off for normal susceptible range, 1.7). The patient was reinduced with abacavir plus didanosine and reached < 50 HIV RNA copies/mL at week 24. At week 36 there was a new loss of virological suppression and genotypic testing showed protease mutations 10F, 46I and 82A. By phenotypic testing the fold change in IC50 to lopinavir-ritonavir was 2.7. The patient was switched to tenofovir DF plus stavudine plus saquinavir-ritonavir and resuppressed to < 50 HIV RNA copies/mL. This patient died shortly after resuppresion due to complications of a previously diagnosed non-Hodgkin lymphoma.
At Week 48, subject #XC02 on monotherapy showed protease mutations 54V, 77I, 82A. By phenotypic testing the fold change in IC50 to lopinavir-ritonavir was 0.7. After viral failure was switched to tenofovir DF plus emtricitabine plus saquinavir/ritonavir and remains suppressed to < 50 HIV RNA copies/mL 20 weeks after switch.
At Week 36, subject #DO34 on monotherapy had an isolated viral load > 500 copies/mL and showed reverse transcriptase mutations 41L, 74V, 210W, 215Y, without mutations in the protease gene (phenotypic testing not performed). Subject #D034 re-suppressed to <50 copies/mL while remaining on lopinavir-ritonavir monotherapy.
At Week 24, subject #DO05 receiving triple therapy showed reverse transcriptase mutations 41L, 74V, 184V, 210W, 211K, 215Y and protease mutations 54V, 63P, 71V, 82A. By phenotypic testing the fold change in IC50 to lopinavir-ritonavir was 2.8. He was lost to follow-up after viral failure.
Adherence
Using the GEEMA adherence questionnaire 44% of patients in the monotherapy group and 43% of patients in the triple therapy group were classified as adherent both to daily number and timing of doses (P = 0.88). If the item in GEEMA adherence questionnaire related to timing of doses was excluded from the analysis then 62% of patients in the monotherapy group and 55% of patients in the triple therapy group were classified as adherent to the daily number of doses (P = 0.34). The proportion of patients missing at least 1 day of medication since the prior visit were 23% in the monotherapy group and 28% in the triple therapy group (P = 0.42). The proportion of patients with at least one missed dose of medication during the week prior to study visits were 27% in the monotherapy group and 31% in the triple therapy group (P = 0.53).
Discussion
Our data indicate that for subjects who are currently suppressed while receiving lopinavir-ritonavir and two nucleosides, lopinavir-ritonavir monotherapy followed by reintroduction of nucleosides as needed is a therapeutic strategy as effective as continuing triple therapy, fulfilling the pre-established criteria for non-inferiority. The majority of patients who experienced a loss of virologic suppression while on lopinavir-ritonavir monotherapy had no evidence of resistance mutations in the protease gene and were able to resuppress and maintain suppression after resumption of baseline nucleosides. Importantly detection of resistance in the protease gene was uncommon and of little or no clinical significance. It should be noted that these results have been achieved without the need of a very intensive follow-up of the patients. In fact, during most of the trial patients visits were performed every 3 months.
Our trial shows that a substantial proportion of suppressed patients on triple therapy can maintain suppression with lopinavir-ritonavir monotherapy. This is in contrast to previous clinical trials [5-7] that attempted the use of a single antiretroviral drug for maintenance of virologic control. These findings suggest that a single antiretroviral, with a high genetic barrier to resistance, such as lopinavir-ritonavir, could be sufficient to maintain control of HIV replication and therefore challenge the notion that triple drug regimens are an absolute prerequisite for successful anti-HIV therapy.
The results of our trial also show that episodes of low level, intermittent viral replication are slightly more common in patients receiving monotherapy than in patients receiving triple therapy. Insufficient antiretroviral potency of lopinavir-ritonavir monotherapy could be an explanation of this finding. However, using an ultrasensitive (3-50 copies/mL) PCR assay, we have shown [16] that the level of persistent plasma viral load < 50 copies/mL does not increase after simplification of triple antiretroviral therapy to lopinavir-ritonavir monotherapy. Consequently, it is unlikely that insufficient antiviral potency of monotherapy could account for the observed difference in low level viraemia between monotherapy and triple therapy.
Drug adherence might be an important factor to explain the higher incidence of low-level viraemia in the monotherapy group. Adherence scores were not significantly different between groups during the trial. Less than half of the patients in both groups were classified as fully adherent by the GEEMA questionnaire. However, it should be emphasized that this questionnaire might overestimate the level of non-adherence because it gives significant weight to the question related to timing of doses. Although recent data suggest that 95% adherence level might not be absolutely predictive of virological efficacy [17] when lopinavir-ritonavir is used along with two nucleosides, our results suggest that a high level of adherence might be needed when patients receive lopinavir-ritonavir monotherapy. We hypothesize that the short-term consequences of intermittent non-adherence might have a more negative impact in patients receiving lopinavir-ritonavir monotherapy than in patients receiving triple therapy. Since lopinavir-ritonavir has a short terminal half-life [9] it is reasonable to postulate that patients missing doses of lopinavir-ritonavir monotherapy have a greater risk of virological rebound than patients receiving lopinavir-ritonavir and two nucleosides which are characterized by a long intracellular half-life. It would be interesting to evaluate if interventions that can have a benefit in adherence, such as once-daily administration of lopinavir-ritonavir or the new meltrex formulation of lopinavir-ritonavir could improve the results seen in our trial.
One limitation of our study is that there were inconsistencies in the sensitivity analyses of virological outcomes. Although the monotherapy group met the non-inferiority criteria for the primary endpoint, the analysis by observed treatment with a viraemia cut-off of 50 HIV-RNA copies/mL did not prove the non-inferiority of the monotherapy group. This result supports the notion that, in general, triple therapy has a higher probability of maintaining complete viral suppression than does monotherapy. However it should be noted that, as happened in our pilot trial, patients receiving monotherapy who had low level viraemia could be successfully reinduced by adding nucleosides again, without loss of therapeutic options. In our opinion this result supports our decision, when we designed the study, of not considering successful reinductions as failures for the primary endpoint. Nevertheless we acknowledge that longer follow-up of reinduced patients is clearly needed to completely rule out negative consequences of a period of low level viraemia in patients receiving lopinavir-ritonavir monotherapy. Finally it should be acknowledged that it is possible that patients in the triple therapy group who experienced confirmed virological rebound could have resuppressed spontaneously without needing a change in therapy.
Another limitation is that we could not show an improvement in adverse events or laboratory abnormalities in patients receiving monotherapy. However, because our study included patients who were already tolerating a stable antiretroviral regimen, the probability of showing differences in adverse events was a priori low. It is possible that longer follow-up is needed to demonstrate differences in adverse events. In addition recent data [18] have shown that monotherapy with lopinavir-ritonavir prevents development of lipoatrophy, an adverse event which was not been specifically evaluated in our study.
Lopinavir-ritonavir monotherapy has been also studied as initial treatment for antiretroviral naive patients [19] and as maintenance therapy after patients have achieved viral suppression for at least 3 months with triple therapy [20]. In each of these two studies the incidence of low level viral replication was approximately double that in our trial. In our study, all patients had maintained viral suppression for at least 6 months prior to receiving lopinavir-ritonavir monotherapy. This suggests that this period of viral suppression may be a relevant factor to predict the success of lopinavir-ritonavir monotherapy.
Being able to treat HIV infection with a single antiretroviral has important implications. Worldwide a significant barrier to treatment of HIV is the cost of antiretrovirals. By decreasing this cost, boosted protease inhibitor monotherapy has the potential to increase access to anti-HIV treatment [21]. Additionally, treating with fewer drugs means avoiding drug related toxicities and resistance to drugs not being taken. Nucleoside sparing regimens might have also an important role in settings such as the treatment of HIV-HCV coinfection in which undesirable interactions with ribavirin should be avoided. Finally although not directly applicable, our results give some support to the use of lopinavir-ritonavir monotherapy after failure of first line regimens in the underdeveloped world.
In conclusion, in patients who have achieved virological suppression for more than 6 months after receiving triple drug therapy our study supports the use of lopinavir-ritonavir monotherapy followed by reinduction with nucleosides if virological suppression is lost. Since episodes of low-level viral rebound were more frequent in the monotherapy group further studies and longer follow-up of patients treated with lopinavir-ritonavir monotherapy are needed before this strategy can be widely recommended.
MONARK Study: Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients
AIDS:Volume 22(3)30 January 2008p 385-393
Delfraissy, Jean-Francoisa; Flandre, Philippeb; Delaugerre, Constancec; Ghosn, Jadea; Horban, Andrzejd; Girard, Pierre-Mariee; Norton, Michaelf; Rouzioux, Christinec; Taburet, Anne-Marieg; Cohen-Codar, Isabellef; Van, Philippe Ngof; Chauvin, Jean-Pierref
From the aAP-HP, Department of Internal Medicine and Infectious Diseases, Bicetre University Hospital, Le Kremlin-Bicetre, France
bINSERM U 720, Pierre and Marie Curie University, Paris, France
cAP-HP, Virology Department, Necker University Hospital, Paris, France
dDepartment of Infectious Diseases, Warsaw, Poland
eAP-HP, Department of Infectious Diseases, Saint-Antoine University Hospital, Paris, France
fAbbott Laboratories, Rungis, France
gAP-HP, Laboratory of Clinical Pharmacology, Bicetre University Hospital, Le Kremlin-Bicetre, France.
"Currently, the gold standard treatment is a combination regimen that typically includes two nucleoside analogue reverse transcriptase inhibitors (NRTI) plus either one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor. The absence of HIV eradication with those drugs, however, requires their prolonged use for a lifespan, making their long-term cost and cumulative toxicities a critical issue in the treatment of HIV infection. Mitochondrial toxicity and lipoatrophy are well documented adverse effects of NRTI [2-6]. Lipoatrophy in the buttocks, limbs, or face are common and distressing side effects for patients receiving anti-HIV therapy, and can lead to a reduction in patient adherence to therapy [7].....
....It has been hypothesized that monotherapy with a ritonavir-boosted HIV protease inhibitor may offer protection from the long-term toxicities of NRTI while effectively maintaining long-term virological suppression. Different strategies of ritonavir-boosted protease inhibitor monotherapy have been considered. One strategy discontinues the NRTI backbone in patients with full viral suppression on a classic triple combination with two NRTI and one ritonavir-boosted protease inhibitor, and recent results suggest that these strategies are effective [8-10]. Another approach is to use ritonavir-boosted protease inhibitor monotherapy initially as a first line regimen, thereby avoiding NRTI exposure entirely. Lopinavir/ritonavir (LPV/r) monotherapy is hypothetically well suited for evaluation in monotherapy trials on the basis of its virological potency and apparent high barrier to resistance development when employed as first-line therapy [11,12]. Although some pilot studies have suggested that first-line ritonavir-boosted protease inhibitor monotherapy seems effective in some specific populations [13], by the start of the study in October 2003, no randomized study had clearly challenged the notion that a first-line three-drug regimen is a prerequisite for successful anti-HIV therapy. Our objective was therefore to compare the safety and efficacy of a first-line monotherapy with LPV/r with a recommended classic triple regimen combining zidovudine plus lamivudine and LPV/r [14].....
".....It [this study] was thus not specifically powered to demonstrate either equivalence or non-inferiority but to identify whether LPV/r monotherapy provided adequate safety and efficacy relative to recommended LPV/r triple therapy, so as to allow further evaluation in a larger comparative trial if warranted.... Another limitation may be the pilot nature of the study.... This is the first randomized trial comparing LPV/r monotherapy as a first-line regimen with a recommended potent triple regimen of zidovudine, lamivudine and LPV/r [15]. In these antiretroviral-naive patients, using ITT-E analysis, 64% of patients randomly assigned reached the protocol-defined virological response in the LPV/r monotherapy arm compared with 75% in the LPV/r triple therapy arm. This difference was not statistically significant. The on-treatment analysis at week 48, however, shows a larger discrepancy between the two randomized groups with 80 and 98% of patients reaching the primary endpoint in the LPV/r monotherapy arm versus the LPV/r triple therapy arm. LPV/r monotherapy resulted in similar CD4 cell count increases as obtained with the standard triple drug combination. Patients on LPV/r monotherapy reported significantly fewer symptoms than those on triple combination..... We conclude that first-line monotherapy with LPV/r soft gel capsules is virologically less effective than the current standard-of-care triple combination with two NRTI and LPV/r soft gel capsules. Given the requirement for chronic therapy with current antiretroviral treatments, however, and the long-term toxicities associated with all antiretroviral therapies, long-term strategies that limit exposure while providing adequate virological efficacy deserve further study. Future monotherapy studies utilizing the more convenient LPV/r tablet formulation should focus on select patient populations, such as those with extensive reverse transcriptase inhibitor resistance (for example in developing countries where first to second-line switch is often driven by clinical failure and results in extensive NRTI resistance) [27]. Taking into account the long-term rates of lipoatrophy, viral resistance, patient satisfaction and the cost of therapy are also critical to identify clinical scenarios in which LPV/r monotherapy might yet play a significant role in the treatment of HIV infection."
Abstract
Background: Guidelines for the use of antiretroviral agents for HIV-1 infection recommend combining at least three agents. The toxicity, cost, and complexity of such regimens warrant the search for other options.
Methods: MONARK is a prospective, open-label, randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen as an initial treatment regimen in HIV-infected patients with HIV-RNA levels less than 100 000 copies/ml. The primary endpoint was the proportion of patients with HIV-1-RNA levels below 400 copies/ml at week 24 and below 50 copies/ml at week 48.
Results: Eight-three and 53 patients were randomly assigned and exposed in the monotherapy and triple-drug groups, respectively. At week 48, by an intent-to-treat analysis, 53 of 83 patients (64%) in the monotherapy group and 40 of 53 patients (75%) in the triple-drug group achieved the primary endpoint (P = 0.19). The on-treatment analysis indicates that 80 and 95% of patients reached the primary endpoint in the monotherapy and triple-drug groups, respectively (P = 0.02). In the monotherapy arm, protease inhibitor-associated resistance mutations were seen in three of the 21 patients qualifying for genotypic resistance testing, with a modest impact on lopinavir susceptibility. None of the serious reported adverse events were considered to be related to study treatment.
Conclusion: Our results suggest that lopinavir/ritonavir monotherapy demonstrates lower rates of virological suppression when compared with lopinavir/ritonavir triple therapy and therefore should not be considered as a preferred treatment option for widespread use in antiretroviral-naive patients.
Results
Patient characteristics at baseline and patient disposition
Patients were randomly assigned into the study between October 2003 and February 2005. A total of 213 patients was screened for inclusion in the study (Fig. 1). The ITT-E population included 83 and 53 patients randomly assigned to LPV/r monotherapy and LPV/r triple therapy, respectively, who received their allocated treatment. Baseline characteristics were well balanced between the two arms (Table 1). More women, however, tended to be randomly assigned to LPV/r triple therapy (P = 0.10). Thirteen (16%) and twelve (23%) patients randomly assigned to LPV/r monotherapy and LPV/r triple therapy, respectively, discontinued the study before the 48-week visit (Fig. 1). The rate of discontinuation (P = 0.37) and time to discontinuation (log-rank test, P = 0.25) were not significantly different between the two arms, although a larger percentage of patients on LPV/r triple therapy tended to discontinue the study earlier than those on LPV/r monotherapy.
Virological and immunological response
In the monotherapy arm, seven patients (8.4%) had a confirmed viral rebound greater than 1.0 log10. Similarly, suboptimal virological response was reported in seven patients (13%) on LPV/r triple therapy: two patients failed to achieve a decline in HIV RNA of 1.0 log10 or greater by week 4, two patients failed to reach an HIV-RNA level of less than 400 copies/ml by week 24, and three patients had a confirmed viral rebound greater than 1.0 log10 after an HIV-RNA level of less than 400 copies/ml. There was no significant difference between the two arms (P = 0.40). By ITT-E analysis, 53 patients (64%) on LPV/r monotherapy and 40 patients (75%) on LPV/r triple therapy reached the study primary endpoint at week 48 (P = 0.19, Table 2). The point estimate of the difference between the two groups was 11.6% with a 95% confidence interval of -0.04 to 27%. In the on-treatment analysis, the proportion of responders was significantly lower on LPV/r monotherapy than on LPV/r triple therapy (80 versus 98%, respectively, P = 0.02). The difference between the two groups was 17.3% and the 95% confidence interval was 7-28%. Furthermore, fewer patients on LPV/r monotherapy had an HIV-RNA level of less than 50 copies/ml at week 48 compared with those on LPV/r triple therapy (84 versus 98%, respectively, P = 0.03). Treatment response according to study entry HIV-1-RNA levels, discontinuations, missing HIV-1-RNA data and treatment change at all study visits is shown in Fig. 2.
In LPV/r monotherapy, the on-treatment analysis indicates that a baseline HIV-1-RNA decrease in viral load at week 1, and HIV-1-RNA levels both at weeks 2 and 4 were predictive risk factors of the primary endpoint (P < 0.10, Table 3). Among these variables only early virological response at week 4 was an independent significant predictor of achieving the study primary endpoint. Thirty-seven of 41 patients (90.2%) with HIV-1 RNA less than 400 copies/ml at week 4 reached the primary endpoint.
There was no significant difference between the two groups with respect to the median change in the CD4 cell count from baseline to week 48 (P = 0.65). At week 48, the median change (interquartile range) was +151 (+105 to +239) and +159 (+112 to +250) cells/μl in the LPV/r monotherapy and LPV/r triple therapy arms, respectively.
Seventeen (20%) and 15 (28%) patients in the LPV/r monotherapy and LPV/r triple therapy arms, respectively, declared having missed at least two doses during the nine evaluations of the adherence from baseline to week 48. Overall, 34, 48 and 63% of patients who declared having missed none, one or more than two doses, respectively, had at least one low (< 3000 ng/ml) lopinavir trough concentration (test for trend, P = 0.003). Similarly, at least one undetectable value of lopinavir trough concentration was observed in 4, 6, and 22% of patients who declared having missed none, one or more than two doses, respectively (test for trend, P = 0.004). Plasma lopinavir trough concentrations were in the same range in the responder and in the non-responder groups in the monotherapy arm. No therapeutic change decisions were made in any of these patients based on plasma lopinavir concentrations.
Genotypic resistance
Of the 24 patients who qualified for resistance testing, the majority (21/24) received LPV/r monotherapy. Protease inhibitor-associated resistance mutations emerged in three of 21 patients on LPV/r monotherapy (L76V, M46I). Phenotypic changes in lopinavir sensitivity were either not observed or were extremely modest ranging from a 1.13 to 2.69-fold increase compared with reference (Fig. 3). Trough plasma lopinavir concentrations were always above 3500 ng/ml in these three patients (Fig. 3). An NRTI-associated resistance mutation was seen in one of three patients on LPV/r triple therapy who required genotypic testing (M184V at week 24 in patient no. 5102); no patient on triple therapy developed protease inhibitor resistance mutations.
Tolerance
Ten of 83 patients (12%) on LPV/r monotherapy and four of 53 patients (8%) on LPV/r triple therapy experienced a serious adverse event throughout the study. None of the serious reported adverse events was considered to be related to study treatment by the investigator on site. Adverse events of at least moderate severity occurred with similar frequency in the two treatments groups. Diarrhoea was the most common clinical adverse event [five (6%) and four (8%) patients on LPV/r monotherapy and LPV/r triple therapy, respectively], whereas aspartate aminotransferase and alanine aminotransferase elevation was the most common laboratory abnormality [10 (12%) and four (8%) patients on LPV/r monotherapy and LPV/r triple therapy, respectively].
Discussion
This is the first randomized trial comparing LPV/r monotherapy as a first-line regimen with a recommended potent triple regimen of zidovudine, lamivudine and LPV/r [15]. In these antiretroviral-naive patients, using ITT-E analysis, 64% of patients randomly assigned reached the protocol-defined virological response in the LPV/r monotherapy arm compared with 75% in the LPV/r triple therapy arm. This difference was not statistically significant. The on-treatment analysis at week 48, however, shows a larger discrepancy between the two randomized groups with 80 and 98% of patients reaching the primary endpoint in the LPV/r monotherapy arm versus the LPV/r triple therapy arm. LPV/r monotherapy resulted in similar CD4 cell count increases as obtained with the standard triple drug combination. Patients on LPV/r monotherapy reported significantly fewer symptoms than those on triple combination.
In the LPV/r triple therapy arm, by ITT-E analysis, the percentage of patients with HIV-RNA levels below 50 copies/ml at week 48 (67%) is consistent with recent results involving antiretroviral-naive patients receiving two NRTI plus either boosted fosamprenavir [18] or boosted atazanavir [19]. In our trial, the ITT-E analysis penalized the LPV/r triple therapy arm compared with the LPV/r monotherapy arm. At week 48, 16 and 23% of patients discontinued the study for any reason on LPV/r monotherapy and LPV/r triple therapy, respectively. Such a percentage on LPV/r triple therapy is concordant with results found in a recent trial also involving naive patients receiving a similar regimen [18]. Therefore patients receiving LPV/r triple therapy were almost exclusively classified as non-responders as a result of discontinuation; whereas on LPV/r monotherapy, non-response resulted from a mixture of virological failures and discontinuations.
A higher proportion of intermittent viraemia (HIV RNA > 50 but < 400 copies/ml) was seen in the LPV/r monotherapy arm (Fig. 2), not only in this study with antiretroviral-naive patients, but also in maintenance studies in patients with previously undetectable viral loads [20,21]. Prolonged periods of low-level viraemia might favour the development of resistance mutations, as seen in the three patients on LPV/r monotherapy in our study, who developed resistance mutations after several weeks of almost continuous low-level viraemia (Fig. 3). The cause of these episodes of intermittent viraemia is not clearly understood at present. One possible explanation for the intermittent viraemia seen with LPV/r monotherapy is that in the absence of NRTI and their longer intracellular half-life, greater adherence may be required for constant suppression with LPV/r monotherapy. Of note is the fact that the median lopinavir trough concentration was similar between the two randomly assigned groups, although a limitation is that lopinavir trough measurements were recorded only at three timepoints. We observed, however, a correlation between the lopinavir trough concentration and self-reported adherence.
The long-term durability of the antiviral activity of LPV/r with two NRTI has been confirmed [11,12]. Studies with LPV/r in combination with two NRTI showed that the high inhibitory quotient of LPV/r at any time yields a plasma concentration of lopinavir that allows little replication of HIV [22-24]. Moreover, the high genetic barrier of LPV/r against resistance generally requires the accumulation of a high number of protease mutations to confer resistance [25]. Additional mutations that were not present at baseline were detected in the protease gene in three of 83 patients (3.6%) on LPV/r monotherapy, and in the reverse transcriptase gene in one patient on LPV/r triple therapy up to week 48. The absolute risk of resistance over 48 weeks with LPV/r monotherapy does not appear to be high compared with triple non-nucleoside reverse transcriptase inhibitor-based therapy among antiretroviral-naive patients; however, it appears to be higher than has been observed with triple therapy protease inhibitor-associated resistance regimens [18,24]. The mutations selected yielded neither significant phenotypic nor genotypic resistance to LPV/r at the time of failure. In the context of this closely monitored clinical trial, however, the resistance observed does raise caution regarding any widespread usage of LPV/r monotherapy in an antiretroviral-naive population. Whether these results might be extended to the whole protease inhibitor-associated resistance drug class remains to be determined [26].
Importantly, in the LPV/r monotherapy arm, three patients (of which only one experienced a protocol-defined suboptimal response) were intensified with zidovudine and lamivudine, and all three achieved prolonged full viral suppression. This is in keeping with previous LPV/r maintenance therapy studies, in which most patients experiencing virological failure on LPV/r achieved full viral suppression with the addition of their previous NRTI backbone [20,21]. Therefore, in this study, virological failure on LPV/r monotherapy did not jeopardize future therapeutic options over the observed duration of follow-up. Long-term follow-up of LPV/r monotherapy patients will be required to assess the risks relative to resistance over time.
The limitations of this study include its open-label design, which might bias an assessment of tolerability or toxicity, but would be less likely to bias virological, immunological, or resistance endpoints. Another limitation may be the pilot nature of the study, with the limited power and the unbalanced sample size designed to focus on the LPV/r monotherapy arm. Finally, another limitation is that the study employed conservative entry criteria for both HIV-RNA level (< 100 000 copies/ml) and CD4 cell count (> 100 cells/μl). Therefore, results from this study may not be generalizable to the HIV-infected patient population as a whole.
Interestingly, 90% of patients randomly assigned to the LPV/r monotherapy group with HIV RNA below 400 copies/ml at week 4 reached the protocol-defined virological response. Therefore, an early decrease in the plasma viral load below 400 copies/ml might enable clinicians to predict potential responders to LPV/r monotherapy. We conclude that first-line monotherapy with LPV/r soft gel capsules is virologically less effective than the current standard-of-care triple combination with two NRTI and LPV/r soft gel capsules. Given the requirement for chronic therapy with current antiretroviral treatments, however, and the long-term toxicities associated with all antiretroviral therapies, long-term strategies that limit exposure while providing adequate virological efficacy deserve further study. Future monotherapy studies utilizing the more convenient LPV/r tablet formulation should focus on select patient populations, such as those with extensive reverse transcriptase inhibitor resistance (for example in developing countries where first to second-line switch is often driven by clinical failure and results in extensive NRTI resistance) [27]. Taking into account the long-term rates of lipoatrophy, viral resistance, patient satisfaction and the cost of therapy are also critical to identify clinical scenarios in which LPV/r monotherapy might yet play a significant role in the treatment of HIV infection.
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