HAART has dramatically improved the prognosis of HIV disease . 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 .
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 , 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 .
Patients were recruited from centres in France, Poland, Italy, Germany and Spain and were eligible if they were infected with HIV-1, aged 18 years or older, naive to antiretroviral therapy, had a CD4 cell count above 100 cells/μl, a plasma HIV-RNA level below 100 000 copies/ml, and if they required the initiation of anti-HIV therapy according to the International AIDS Society guidelines [14,15]. Patients with an HIV primary infection status, or having received any investigational drug within 30 days before study drug administration, or having an abnormal laboratory test greater than grade 2 could not be included. Patients with viruses harbouring one mutation among positions V32I, I47V/A, G48V, I50V, V82A/F/T/S, I84V, L90M of the protease gene, or more than three mutations among positions L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54V/L/A/M/T/S, L63P, A71T/V of the protease gene, or one mutation at position T215Y/F or M184V of the reverse transcriptase gene were not eligible. All patients received 100 mg ritonavir and 400 mg lopinavir twice a day with the fixed co-formulation of LPV/r soft gel capsules (kaletra) throughout all the study period. Patients randomly assigned to LPV/r triple therapy also received zidovudine 300 mg and lamivudine 150 mg, both twice a day in the fixed combination combivir.
The study protocol was approved by the ethics committees in each participating country (France: Comité d'Ethique de l'Hôpital de Bicêtre; Germany: Ethik-Kommission der Aerztekammer Berlin, Ethikkommission Charité Universitätsmedizin Berlin, Ethikkommission Heinrich Heine-Universitaet Dusseldorf, Ethikkommission Bayerische Landesaerztekammer Muenchen; Spain: Comité Ético de Investigación Clínica Barcelona; Italy: Comitato Etico Brescia, Comitato Etico Torino, Comitato Etico della Fondazione Milano, Comitato Etico Locale per la Sperimentazione Clinica dell'Ospedale Luigi Sacco di Milano, Comitato EticoR Roma; and Poland: Komisja Bioetyczna Warsaw). All patients provided written informed consent.
Randomization and study design
Patients were randomly assigned to receive LPV/r monotherapy or LPV/r in combination with zidovudine/lamivudine (LPV/r triple therapy). The study was initially planned to include 60 patients in a 1: 1 randomization ratio for a follow-up of 48 weeks. Subsequent amendments allowed an extension of the number of participants up to 130 patients for a follow-up of 96 weeks, and a change to a 2: 1 randomization ratio so as to focus on efficacy results in the single-drug regimen.
Patients were evaluated at screening, at day 0 (baseline), and at weeks 1, 2, 4, 8, 12, 16, 20, and 24, then every 8 weeks until week 48, and then every 12 weeks until week 96. Follow-up until week 96 is ongoing for an evaluation of the safety and efficacy of the LPV/r monotherapy arm.
At each study visit, patients underwent routine safety monitoring, including haematology and chemistry evaluations, CD4 cell count, and plasma HIV-RNA level. In addition, patient adherence to the study drug regimen was assessed by compliance evaluation (pill count) at each study visit. Lopinavir and ritonavir trough concentrations were determined by a validated reversed phase high performance liquid chromatography assay with C18 chromatographic and ultraviolet detection (lower limit of quantification 75 and 25 ng/ml, respectively) on blood samples collected before the morning dose of LPV/r at weeks 4, 24 and 48.
The suboptimal virological response was defined according to the following criteria: (i) failure to achieve a decline in viral load of at least 1.0 log10 copies/ml by week 4; (ii) failure to achieve a viral load below 400 copies/ml by week 24; and (iii) any viral rebound of 1 log, after HIV RNA less than 400 copies/ml, confirmed by a second measurement at least 14 days later. In the case of suboptimal virological response, those patients randomly assigned to LPV/r monotherapy with genotype showing susceptibility to lopinavir had their treatment intensified with combivir. Those patients randomly assigned to LPV/r triple therapy with suboptimal virological response were discontinued and alternative treatments were left to the investigator's judgement. All patients with alteration or intensification to the randomized treatment arm were analysed as failures.
HIV-1 drug resistance testing was performed in a centralized laboratory at screening to determine study eligibility, and at the time of suboptimal virological response or study discontinuation. Drug resistance testing was also performed when the HIV-RNA level exceeded 500 copies/ml after achieving a postbaseline nadir value below 400 copies/ml.
In addition to standard case report form adverse event collection, patients reported symptoms via the AIDS symptoms distress module (ASDM) and the WHO-QOL HIV Bref. Assessments were made at baseline (day 1), weeks 4, 12, 24 and 48. The ASDM is a validated list of 22 symptoms known to occur during HAART . The WHO-QOL Bref is an instrument that surveys quality of life. It consists of 31 items designed to measure patients' perception related to the past 2 weeks. Five of the items are specific to patients living with HIV/AIDS .
The primary endpoint was the proportion of patients with plasma HIV-RNA levels below 400 copies/ml at week 24 and below 50 copies/ml at week 48. Secondary endpoints were the proportion of patients with plasma HIV-RNA levels below 50 and 400 copies/ml from baseline over 48 weeks, correlation of early virological response (HIV-RNA below 400 copies/ml at week 4) during the first 4 weeks and LPV/r trough concentration, and the occurrence of resistance mutations in patients with suboptimal virological response.
The design of the study was pilot in nature, with the goal of providing preliminary safety and efficacy data on the concept of initiating therapy with LPV/r monotherapy. It 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. The sample size was computed to obtain a moderate size for the 95% confidence interval: 71–89% if there are 80% responders in the LPV/r monotherapy arm. No alpha-level adjustment was made because of the pilot nature of the study.
All patients who received at least one dose of the study medications were included in the intent-to-treat exposed (ITT-E) population. In the ITT-E analysis, missing HIV-1-RNA data, patients who discontinued the study or made any treatment changes were regarded as failures according to the protocol-defined endpoint. The on-treatment analysis considered only available HIV-1 RNA for patients still under the randomized treatment. A logistic model was used to search for significant prognostic factors of the primary endpoint in patients randomly assigned to receive LPV/r alone. The variables investigated include baseline and demographic characteristics (HIV-1 RNA, HIV-DNA, CD4 cell count, age, sex), early response (decrease in HIV-1 RNA at weeks 1, 2 and 4; HIV-1 RNA levels at weeks 1, 2 and 4), lopinavir and ritonavir trough concentrations at weeks 4, 24 and 48, and missing doses reported by compliance evaluation (patients who declare having missed at least two doses versus less than two doses). Both baseline HIV-1-RNA levels and CD4 cell counts were calculated as the mean of the two measurements obtained at screening (4 weeks before randomization) and at randomization (day 0). Fisher's exact test was used to compare categorical variables whereas the Kruskal–Wallis test was used for continuous data.
Time to discontinuation was analysed using the Kaplan–Meier and log-rank methods. All statistical analyses were performed with the use of SAS software, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA). All reported P values are two-sided and were not adjusted for multiple testing.
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.
Equation (Uncited)Image Tools
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.
Equation (Uncited)Image Tools
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.
Equation (Uncited)Image Tools
Equation (Uncited)Image Tools
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.
Equation (Uncited)Image Tools
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].
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 . 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  or boosted atazanavir . 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 . 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 . 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 .
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) . 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.
The authors wish to acknowledge the study participants and study staff at MDS Pharma Services, France. They are also grateful to the Independent Data Monitoring Committee (Jean Pierre Aboulker, Frederic Lucht, Marianne L'Henaff, Isabelle Pellegrin, Didier Sicard), and to Richard Rode, statistician, Abbott Laboratories.
Centre Hospitalier du Kremlin Bicetre: Jean-François Delfraissy, Cecile Goujard, Pascal Robquin, Yann Quertainmont, Olivier Segeral; Hopital Antoine Beclere, Clamart: François Boue, Veronique Chambrin, Gaelle-Anne Estocq, Isabelle Luquet-Besson, Carole Pignon; Hopital de l'Archet, Nice: Pierre Dellamonica, Francine De Salvador, Jacques Durand, Laurence Heripret, Veronique Rahelinirina; Hopital de la Conception, Marseille: Herve Gallais, F. Tomei, Herve Tissot Dupont, Isabelle Ravaux; Hopital Saint-Antoine, Paris: Pierre-Marie Girard, Diane Bollens, Franck Besse, Benedicte Lefebvre, Zineb Ouazene; Hopital Chalucet, Toulon: Alain Lafeuillade, Stephane Chadapaud, Gilles Hittinger; Hopital St Andre, Bordeaux: Philippe Morlat, Mojgan Bonarek, Marie-Carmen Pertusa, Caroline Nouts, Fabrice Bonnet; Hopital Haut Leveque, Pessac: Jean-Luc Pellegrin, Olivier Caubet, Caroline Perlemoine, Jean-François Viallard; Hopital Hotel Dieu, Nantes: François Raffi; Hopital Gui de Chauliac, Montpellier: Jacques Reynes, Vincent Baillat; Centre Hospitalier Intercommunal de Villeneuve Saint Georges: Olivier Patey, Sophie Dellion, Manuella Podani; Hopital Saint Joseph, Paris: Jacques Gilquin; Hopital Albert Michallon, Grenoble: Pascale Leclercq, Myriam Blanc; Hopital Saint Louis, Paris: Caroline Lascoux, Claire Pintado, Florence Vincent, Olivier Taulera; Hopital de Brabois, Vandoeuvre les Nancy: Thierry May, Christian Rabaud, Laurence Boyer, Thanh Lecompte; Hopital Ambroise Pare, Boulogne Billancourt: Elisabeth Rouveix; Centre Hospitalier Sud Francilien, Corbeil Essonnes: Alain Devidas, Pascale Kousignian, Pierre Chevojon; Hopital Delafontaine, Saint Denis: Marie-Aude Khuong, Nacira Khelil, Denis Mechali; Hopital Henri Mondor, Creteil: Yves Levy, Anne-Sophie Lascaux, Alain Sobel, Fabrice Chaix; Hopital de la Pitie-Salpetrière, Paris: Marc Antoine Valantin.
HIV Research and Clinical Care Centre, München: Hans Jäger, Andrea Eberhad, Eva Jägel-Guedes, Tim Theobald, Eva Wolf; Charité, Universitätsmedizin, Berlin: Dirk Schürmann, Thomas Wünsche, Hans Wesselmann; Klinik fur Gastroenterologie Hepatologie und Infektiologie, Düsseldorf: Mark Oette,Klaus Göbels, Stefanie Koch, Ruth Leidel, Arne Kroidl; EPIMED, Berlin: Keikawus Arastéh.
Osp. S. Raffaele, Milano: Adriano Lazzarin, Antonella Castagna, Nicola Gianotti; Az. Osp. Polo Universitario ‘L. Sacco’, Milano: Mauro Moroni, Antonella D'Arminio Monforte, Teresa Bini, Patrizia Biasi; Ospedale ‘Amedeo di Savoia’, Torino: Giovanni Di Perri, Stefano Bonora, Lorenzo Veronese, Laura Ladetto; A.O. Spedali Civili di Brescia, Brescia: Giampiero Carosi, Giusseppe Paraninfo, Paola Nasta; Univ. Degli Studi ‘La Sapienza’, Roma: Vincenzo Vullo, Anna Paola Massetti, Claudio Maria Mastroianni, Miriam Lichtner, Azzura Ginevra Miccoli.
Wojewodzki Szpital, Warszawa: Andrzej Horban, Piotr Pulik, Anna Ignatowska; Katedra I Oddzia, Wroc. Aw: Andrzej Gladyzs, Brygida Knysz, Jacek Gasiorowski.
Hospital Santa Creu, Barcelona: Pere Domingo, Montserrat Fuster, Mar Gutierrez, Gracia Mateo, Mercedes Gurgui, Ma Antonia Sambeat, Jose Cadafalch; Hospital Germans Trias, Badalona: Bonaventura Clotet, Angel Ballesteros, Jose Miranda, Jordi Puig Pla; Hospital San Jaume de Calella, Calella: Josep Ma Llibre, Silvia Valero.
Sponsorship: This study was sponsored by Abbott Laboratories.
Registration of randomized trial at clinicaltrials.gov under identifier NCT 00234923.
Conflicts of interest: None.
1. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al
. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853–860.
2. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998; 12:1735–1744.
3. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999; 354:1112–1115.
4. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, et al
. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999; 13:1659–1667.
5. Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 2000; 14:1309–1316.
6. Carr A, Emery S, Law M, Puls R, Lundgren JD, Powderly WG. An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet 2003; 361:726–735.
7. Duran S, Saves M, Spire B, Cailleton V, Sobel A, Carrieri P, et al
. Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS 2001; 15:2441–2444.
8. Kahlert C, Hupfer M, Wagels T, Bueche D, Fierz W, Walker UA, Vernazza PL. Ritonavir boosted indinavir treatment as a simplified maintenance “mono”-therapy for HIV infection. AIDS 2004; 18:955–957.
9. Swindells S, DiRienzo AG, Wilkin T, Fletcher CV, Margolis DM, Thal GD, et al
. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA 2006; 296:806–814.
10. Campo RE, Lalanne R, Tanner TJ, Jayaweera DT, Rodriguez AE, Fontaine L, Kolber MA. Lopinavir/ritonavir maintenance monotherapy after successful viral suppression with standard highly active antiretroviral therapy in HIV-1-infected patients. AIDS 2005; 19:447–449.
11. Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, et al
. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002; 346:2039–2046.
12. Hicks C, King MS, Gulick RM, White AC Jr, Eron JJ Jr, Kessler HA, et al
. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study. AIDS 2004; 18:775–779.
13. Ebrahim O, Hill A. Short-course induction with boosted saquinavir monotherapy for naive patients with late-stage infection. AIDS 2005; 19:211–212.
14. Yeni PG, Hammer SM, Hirsch MS, Saag MS, Schechter M, Carpenter CC, et al
. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society – USA Panel. JAMA 2004; 292:251–265.
15. Hammer S, Saag M, Schechter M, Montaner J, Schooley R, Jacobsen D, et al
. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society – USA panel. JAMA 2006; 296:827–843.
16. Justice A, Holmes W, Gifford A. Development and validation of a self-completed HIV symptom index. J Clin Epidemiol 2001; 54:S77–S90.
17. WHOQOL. HIV for quality of life assessment among people living with HIV and AIDS: results from the field test. AIDS Care
18. Eron J Jr, Yeni P, Gathe J Jr, Estrada V, DeJesus E, Staszewski S, et al
. The KLEAN study of fosamprenavir–ritonavir versus lopinavir–ritonavir, each in combination with abacavir–lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised noninferiority trial. Lancet 2006; 368:476–482.
19. Malan N, Krantz E, David N, Kastango K, Frederick D, Matthew M, et al
. Efficacy and safety of atazanvir-based therapy in antiretroviral naive HIV-1 infected patients, both with or without ritonavir: 48-week results from AI24-089. In: 13th Conference on Retroviruses and Opportunistic Infections
. Denver, CO, USA; 5–8 February 2006. Abstract 107 LB.
20. Cameron W, da Silva B, Arribas J, Myers R, Bellow N, Gillmore N, et al
. A two-year randomized controlled clinical trial in antiretroviral-naive patients using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). In: XVIth International AIDS Conference
. Toronto, Canada; 13–18 August 2006. Abstract THLB0201.
21. Arribas J, Pulido F, Delgado R, Lorenzo A, Miralles P, Arrantz A, et al
. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV-viral suppression: forty eight week results of a randomized, controlled, open label, clinical trial (OK04 study). In: XVIth International AIDS Conference
. Toronto, Canada; 13–18 August 2006. Abstract THLB0203.
22. King MS, Brun SC, Kempf DJ. Relationship between adherence and the development of resistance in antiretroviral-naive, HIV-1-infected patients receiving lopinavir/ritonavir or nelfinavir. J Infect Dis 2005; 191:2046–2052.
23. Mo H, King MS, King K, Molla A, Brun S, Kempf DJ. Selection of resistance in protease inhibitor-experienced, human immunodeficiency virus type 1-infected patients failing lopinavir- and ritonavir-based therapy: mutation patterns and baseline correlates. J Virol 2005; 79:3329–3338.
24. Kempf DJ, King MS, Bernstein B, Cernohous P, Bauer E, Moseley J, et al
. Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J Infect Dis 2004; 189:51–60.
25. Kempf DJ, Isaacson JD, King MS, Brun SC, Xu Y, Real K, et al
. Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients. J Virol 2001; 75:7462–7469.
26. Karlström O, Josephson F, Sönnerborg A. Early virological rebound in a pilot trial of ritonavir-boosted atazanavir as maintenance monotherapy. J Acquir Immune Defic Syndr 2007; 44:417–422.
27. Sungkanuparph S, Manosuthi W, Kiertiburanakul S, Piyavong B, Chumpathat N, Chantratita W. Options for a second-line antiretroviral regimen for HIV type 1-infected patients whose initial regimen of a fixed-dose combination of stavudine, lamivudine, and nevirapine fails. Clin Infect Dis 2007; 44:447–452.
© 2008 Lippincott Williams & Wilkins, Inc.