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).
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.
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.
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.
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).
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  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  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  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  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  and as maintenance therapy after patients have achieved viral suppression for at least 3 months with triple therapy . 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 . 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.
We thank the patients who participated in the study.
In addition to the authors, the study OK04 group includes the following:
Hospital Doce de Octubre, Madrid — C. Cepeda, R. Hervás, V. Moreno, A. Hernando, J.R. Costa; Hospital La Paz, Madrid — F. Gaya, R. Muñoz, A. Lorenzo, J.M. Peña; Hospital Ramón y Cajal, Madrid — F. Dronda, A. Antela, S. Moreno; Hospital Príncipe de Asturias, Alcalá de Henares — J. Sanz, J. De Miguel, E. Casas; Hospital General de Alicante, Alicante — V. Boix, E. Merino, S. Reus; Hospital Virgen de las Nieves, Granada — M.A. López, M.C. Hidalgo, M.R. Javier, A. Tapia, M. López; Hospital Donostia, San Sebastián — X. Camino, M.A. von Wichmann, J. Arrizabalaga, F.J. Rodríguez-Arrondo; Hospital Xeral Cíes, Vigo — A. Ocampo, A. López, C. Miralles, P. Vázquez; Hospital Gregorio Marañón, Madrid — P. Miralles, M. Sánchez, J. Berenguer, J.C. López, J. Cosín; Hospital del Mar, Barcelona — H. Knobel, G. Vallecillo; Hospital de la Princesa, Madrid — J. Sanz, R. Carrillo, I. Santos; Hospital La Fe, Valencia — J. López-Aldeguer, M. Salavert, J. Lacruz, M. Blanes, V. Navarro; Hospital Miguel Servet, Zaragoza — P. Arazo, J.M. Aguirre, M.A. Pascual; Fundación Jiménez Díaz, Madrid — M. Górgolas, A. Goyeneche; Hospital de Tenerife, Tenerife — J.L. Sirvent, R. Alemán, A.M. López, M.M. Alonso; Hospital Civil de Basurto, Bilbao — J.M. Santamaría, R. Teira, O. Ferrero; Z. Zubero, J. Muñoz, J. Baraiaetxaburu; Hospital de Valme, Sevilla — F. Lozano, J. Gómez, J.A. Pineda, J. Corzo, E.M. León, G. Sebastián; Hospital Santa Creu I Sant Pau, Barcelona — P. Domingo, M. Gutiérrez, G. Mateo, M. Fuster, M.A. Sambeat, J. Cadafalch, M. Gurgí; Hospital Germans Trias i Pujol, Badalona — B. Clotet, A. Tuldrá, A. Ballesteros, J. Moltó, J.R. Santos, A. Bonjoch; Hospital de Bellvitge, Hospitalet de Llobregat — D. Podzamczer, P. Robres, E. Ferrerr, M. Olmo; Hospital Clinic Universitari, Barcelona — J.M. Gatell, A. Milinkovic, J. Mallolas, E. Martínez; Hospital San Carlos, Madrid — V. Estrada, M. Fuster, M.J. Téllez, J. Vergas; Hospital de Elche, Elche — F. Gutiérrez, M. Masía, S. Padilla, E. Bernal; Hospital Clínico de Valencia, Valencia — G. García, M.J. Galindo; Hospital Insular de Canarias, Las Palmas — A. Francés; Hospital Virgen Macarena, Sevilla — M.A. Muniaín, J. Gálvez, L. Orbea, J. Rodríguez, A. Domínguez, D. Morales, G. Ollero; Hospital General de Valencia — V. Abril, E. Ortega, A. Martín.
Source of funding: Supported with an unrestricted grants from Abbott Laboratories and the Fundación de Investigación Médica Mutua Madrileña (MUTUA 2005-066). The funding source had no role in the study design, data collection, analysis and interpretation of the data, preparation of the manuscript, or the decision to submit the manuscript for publication. FP is the recipient of a BAE grant from the Instituto de Salud Carlos III, Spanish Ministry of Health (BA06/90001).
1. Panel on Clinical Practices for the Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services and Henry J. Kaiser Foundation, October 10, 2006. Available at: http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
. Accessed August 30th, 2007.
2. Hammer SM, Saag MS, Schechter M, Montaner JS, Schooley RT, Jacobsen DM, et al
. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA 2006; 296:827–843.
3. Panel de expertos de GESIDA y Plan Nacional sobre el SIDA. Recomendaciones de GESIDA/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana (actualización enero de 2007)
. Enferm Infecc Microbiol Clin
4. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996; 271:1582–1586.
5. Havlir DV, Marschner IC, Hirsch MS, Collier AC, Tebas P, Bassett RL, et al
. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. N Engl J Med 1998; 339:1261–1268.
6. Pialoux G, Raffi F, Brun-Vezinet F, Meiffrédy V, Flandre P, Gastaut JA, et al
. A randomised trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. N Engl J Med 1998; 339:1269–1276.
7. Reijers MH, Weverling GJ, Jurriaans S, Wit FW, Weigel HM, Ten Kate RW, et al
. Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study. Lancet 1998; 352:185–190.
8. Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, et al
. Lopinavir-ritonavir vs. nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002; 346:2039–2046.
9. 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.
10. van den Brande G, Marquie-Beck J, Capparelli E, Ellis R, McCutchan A, Hermes A, et al
. Kaletra (LPV/r) independently reduces HIV replication in cerebrospinal fluid. Twelfth Conference on Retroviruses and Opportunistic Infections. Boston, MA, 22–25 February 2005. Abstract 403.
11. Gathe JC, Washington MY, Mayberry C, Piot D, Nemecek J. IMANI-1 TC3WP single drug HAART: proof of concept study. Pilot study of the safety and efficacy of Kaletra (Lopinavir-ritonavir) as single drug HAART in HIV+ ARV naive patient - interim analysis of subjects completing final 48 week data. XV International AIDS Conference, Bangkok, Thailand 189, 11–16 July, 2004. Abstract MoOrB1057.
12. Arribas JR, Pulido F, Delgado R, Lorenzo A, Miralles P, Arranz A, et al
. Lopinavir-ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept, pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 2005; 40:280–287.
13. Knobel H, Alonso J, Casado JL, Collazos J, González J, Ruiz I, et al
. Validation of a simplified medication adherence questionnaire in a large cohort of HIV-infected patients: the GEEMA Study. AIDS 2002; 16:605–613.
15. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: antiretroviral drugs using plasma HIV RNA measurements— clinical considerations for accelerated and traditional approval. Washington, D.C.: Department of Health and Human Services, October 2002. (http://www.fda.gov/cder/guidance/3647fnl.pdf
.) Accessed August 30th, 2007.
16. McKinnon JE, Arribas JR, Pulido F, Delgado R, Mellors JW. The Level of Persistent Plasma Viremia Does Not Increase after Simplification of Antiretroviral Therapy to Lopinavir-ritonavir Alone. AIDS 2006; 20:2331–2335.
17. Shuter J, Sarlo J, Kanmaz T, Rode R, Zingman B. HIV-infected patients receiving Lopinavir/Ritonavir-based antiretroviral therapy achieve high rates of virologic suppression despite adherence rates less than 95%. J Acquir Immune Defic Syndr 2007; 45:4–8.
18. Cameron DW, da Silva BA, Arribas JR, Pulido F, Katner HP, Wikstrom K, et al.
Significant sparing of peripheral lipoatrophy by HIV treatment with Lopinavir/ritonavir (LPV/r) + ZDV/3TC induction followed by LPV/r monotherapy compared to efavirenz (EFV) + ZDV/3TC. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; Feb 22–28, 2007; Los Angeles. Abstract # N-1004.
19. Delfraissy JF, Flandre P, Delaugerre C, Horban A, Girard PM, Rouzioux C, et al
. MONARK Trial (MONotherapy AntiRetroviral Kaletra): 48-week analysis of lopinavir-ritonavir (Lopinavir-ritonavir) monotherapy compared to Lopinavir-ritonavir + zidovudine/lamivudine (AZT/3TC) in antiretroviral-naive patients. Program and abstracts of the XVI International AIDS Conference; August 13–18, 2006; Toronto, Canada. Abstract THLB0202.
20. Cameron W, da Silva BA, Arribas J, Myers R, Bellos NC, Gilmore N, et al.
A two-year randomized controlled clinical trial in antiretroviral-naive subjects using lopinavir-ritonavir (Lopinavir-ritonavir) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0201.
© 2008 Lippincott Williams & Wilkins, Inc.
21. Escobar I, Pulido F, Perez E, Arribas JR, Garcia MP, Hernando A. Análisis farmacoeconómico de una estrategia de mantenimiento con lopinavir-ritonavir como monoterapia en pacientes con infección por el VIH. Enferm Infecc Microbiol Clin 2006; 24:490–494.