Episodes of low-level viremia (between 50 and 500 HIV RNA copies/mL) were more common in the monotherapy group than in the triple therapy group (Fig. 2). During the first 48 weeks of the trial, 6 patients in the monotherapy group were reinduced with nucleosides (5 due to an HIV RNA >500 copies/mL and 1 due to HIV RNA >50 but <500 copies/mL). From week 48 to week 96, 6 additional patients in the monotherapy group had to be reinduced with nucleosides (all because HIV RNA >50 but <500 copies/mL). Of the 12 (12%) patients needing reinduction with baseline nucleosides, 10 remain with HIV RNA <50 copies per milliliter and 2 have experienced subsequent virologic rebound after reinduction. At week 96, proportion of patients without therapeutic failure according to our primary end point definition (for which the 10 patients with successful reinductions are not considered failures) was 78% in the triple therapy group and 87% in the monotherapy group (difference: −9%; 95% CI: −20% to +1.2%, P = 0.09). The upper limit of the CI for the difference (+1.2%) fulfilled the preestablished criteria for noninferiority of the monotherapy group.
The mean increase from baseline in CD4 cell counts at week 96 was 71 cells per microliter in the monotherapy group and 47 cells per microliter in the triple therapy group (difference not statistically significant).
Using the GEEMA adherence questionnaire, 35% of patients in the monotherapy group and 38% of patients in the triple therapy group were categorized as fully adherent both to daily number and timing of doses in all visits up to week 96. If the item in GEEMA adherence questionnaire related to timing of doses was excluded from the analysis, then 52% of patients in the monotherapy group and 50% of patients in the triple therapy group were classified as fully adherent to the daily number of doses through week 96. The proportion of patients missing at least 1 day of medication since the prior visit were 33% in the monotherapy group and 31% in the triple therapy group. The proportion of patients with at least 1 missed dose of medication during the week before study visits was 38% in the monotherapy group and 37% in the triple therapy group. None of these comparisons were statistically significant.
At week 96, 29 samples from 16 patients in the monotherapy group had been examined by genotypic resistance testing compared with 9 samples from 4 patients in the triple therapy group. During the first year of follow-up, 2 patients in the monotherapy group and 1 patient in the triple therapy group had loss of virological suppression with HIV isolates containing major protease inhibitor mutations. Details of these 3 patients had been previously described.3 From week 48 to week 96, resistance genotyping did not show new isolates containing major protease inhibitor mutations in the monotherapy group. In the triple therapy group, 1 new patient had an isolate with major protease inhibitor mutations. For this patient, ultrasenstitive genotypic and phylogenetic analysis could not rule out superinfection with a resistant virus. In total, after 2 years of follow-up, proportion of patients rebounding with isolates containing major protease inhibitor mutations was 2% in the monotherapy group and 2% in the triple therapy group.
Safety and Tolerability
At week 96, 8 patients had discontinued randomized therapy due to adverse events in the triple therapy group vs. none in the monotherapy group (P = 0.003). Detailed types of adverse events and the nucleoside combinations received by patients who discontinued triple therapy are shown in Table 2.
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 hypertriglyceridemia was seen in 8 patients (8%) in the monotherapy group and in 6 patients (6%) in the triple therapy group.
Grade 3 hypercholesterolemia was seen in 11 patients (11%) in the monotherapy group and 7 patients (7%) in the triple therapy group. Grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations were seen in 7 patients (7%) in the monotherapy group and in 4 patients (4%) in the triple therapy group. Of the 11 patients with grade 3 or 4 aspartate aminotransferase/alanine aminotransferase elevations, 10 were coinfected with hepatitis C virus. No patient discontinued the study because of elevated lipid or aminotransferase levels.
After 2 years of follow-up, the OK04 study shows that lopinavir-ritonavir monotherapy can maintain HIV viral suppression in a very large proportion of patients. Of the 100 patients initially randomized to lopinavir-ritonavir monotherapy, 77% remain on monotherapy with an HIV viral load of less than 50 HIV RNA copies per milliliter at week 96. This result support the durability of lopinavir-ritonavir monotherapy and is consistent with the long-term follow-up of our pilot clinical trial in which 66.7% of patients randomized to lopinavir-ritonavir monotherapy remain on monotherapy and with HIV RNA <50 copies per milliliter after 4 years of follow-up.9 The durability of lopinavir-ritonavir monotherapy might be explained by the fact that residual replication below 50 HIV RNA copies per milliliter does not seem to be increased in patients receiving this single-drug regimen.10
As it happened during the first 48 weeks of the trial, episodes of low-level viral rebound were more frequent in patients receiving monotherapy than in patients receiving triple therapy. This difference is better appreciated in the on-treatment analyses (Fig. 1B) in which successful reinductions, missing data, or changes (for toxicity or other reasons) are censored. In this analysis, there is a trend toward better virologic control in the triple therapy group. The most likely explanation for these episodes of low-level viremia is suboptimal adherence. In the 2 OK trials11 and in the M03-613 trial,12 treatment adherence was a significant risk factor for loss of virological suppression in patients receiving lopinavir-ritonavir monotherapy. For example, total days without medication between 2 consecutive visits in the OK trials were 1 for patients maintaining suppression and 6 for patients who experienced loss of virological suppression.11
The more frequent incidence of episodes of low-level viremia in patients receiving monotherapy is not incompatible with the long durability of the regimen. With the data, we have so far, we believe that the forgiveness of lopinavir-ritonavir monotherapy could be lower than the forgiveness provided by lopinavir-ritonavir and 2 nucleosides. Consequently, there is a higher risk of episodes of low-level viremia in patients with suboptimal adherence to monotherapy. However, we hypothesize that for the adherent patient, the probability of remaining suppressed on monotherapy might be similar than the probability of patients receiving triple therapy.
A critical aspect of the lopinavir-ritonavir monotherapy strategy is the possibility of regaining virological control by reinduction with nucleosides without loosing therapeutic options. The original protocol allowed reinduction with baseline nucleosides for patients with confirmed viral rebound >500 copies per milliliter if no major protease inhibitor resistance mutation was detected. However, after the first year of follow-up, we identified several patients who experienced sustained viral rebound between 50 and 500 HIV RNA copies per milliliter. To manage these patients, we decided to amend the protocol to allow reinduction after viral rebound between 50 and 500 HIV RNA copies per milliliter that lasted at least 8 weeks. Following this strategy, 6 patients randomized to monotherapy had to be reinduced during the second year of follow-up. It should be highlighted that we have not detected any additional case of protease inhibitor resistance development during the second year of follow-up and that the great majority of patients needing reinduction (83%) have regained viral suppression. Similarly, in our pilot clinical trial, patients reinduced with nucleosides were able to maintain long-term virological suppression up to 4 years after reinduction.9 Taken together, these findings support the safety of the strategy of using lopinavir-ritonavir as maintenance monotherapy followed by reintroduction of nucleosides as needed.
One important finding during the second year of follow-up is that discontinuations of randomized therapy due to adverse events were significantly more frequent in the triple therapy group than in the monotherapy group. Of note, 6 of the 8 patients who discontinued therapy suffered adverse events that are characteristic of nucleoside-induced toxicity. It might be argued that nucleoside combinations for these patients were not the ones recommended by international guidelines as preferred combinations.13,14 However, our clinical trial allowed enrolling patients with nucleoside resistance. Once HIV has already developed the M184V mutation that confers resistance to lamivudine, the ability of clinicians to prescribe “safe” nucleoside combinations is already compromised. We believe that these patients who are receiving a nucleoside combination that is considered toxic might be good candidates to explore the strategy of lopinavir-ritonavir monotherapy.
One important limitation of our findings is that we did not have an objective assessment of lipoatrophy. It is possible that the incidence of lipoatrophy was the same in the monotherapy group, but because those patients were already not receiving nucleosides, clinicians opted to continue monotherapy. Nevertheless, the M03-613 study has already shown that the risk of lipoatrophy is reduced in patients who receive lopinavir-ritonavir monotherapy.4
In summary, the 96 results of the OK04 trial continue to support the efficacy and safety of the lopinavir-ritonavir monotherapy strategy. Although episodes of low-level viremia were more frequent in the monotherapy group, we did not observe an increased risk of resistance development and most of these patients could be resuppressed restarting nucleosides. The toxicity of the monotherapy regimen was lower than the toxicity of the triple regimen.
We are grateful to the patients who participated in the study. In addition of the authors, the study OK04 group includes the following: Hospital Doce de Octubre, Madrid: S. Fiorante, C. Cepeda, V. Moreno, A. Hernando, and J. R. Costa; Hospital La Paz, Madrid: Juan González-García, N. Perez Valero, and F. Gaya; Hospital Ramón y Cajal, Madrid: F. Dronda, A. Antela, and S. Moreno; Hospital Príncipe de Asturias, Alcalá de Henares: J. Sanz, J. De Miguel, and E. Casas; Hospital General de Alicante, Alicante: V. Boix, E. Merino, and S. Reus; Hospital Virgen de las Nieves, Granada: M. A. López, M. C. Hidalgo, M. R. Javier, A. Tapia, and M. López; Hospital Donostia, San Sebastián: X. Camino, M. A. von Wichmann, J. Arrizabalaga, and F. J. Rodríguez-Arrondo; Hospital Xeral Cíes, Vigo: A. López, C. Miralles, and P. Vázquez; Hospital Gregorio Marañón, Madrid: P. Miralles, J. Berenguer, J. C. López, and J. Cosín; Hospital del Mar, Barcelona: G. Vallecillo; Hospital de la Princesa, Madrid: R. Carrillo and I. Santos; Hospital La Fe, Valencia: M. Salavert, J. Lacruz, M. Blanes, and V. Navarro; Hospital Miguel Servet, Zaragoza: J. M. Aguirre, M. A. Pascual; Fundación Jiménez Díaz, Madrid: M. Górgolas and A. Goyeneche; Hospital de Tenerife, Tenerife: J. L. Sirvent, R. Alemán, A. M. López and M. M. Alonso; Hospital Civil de Basurto, Bilbao: J. M. Santamaría, R. Teira, and O. Ferrero; Z. Zubero, J. Muñoz, and J. Baraiaetxaburu; Hospital de Valme, Sevilla: F. Lozano, J. Gómez, J.A. Pineda, J. Corzo, E.M. León, and G. Sebastián; Hospital Santa Creu I Sant Pau, Barcelona: P. Domingo, M. Gutiérrez, G. Mateo, M. Fuster, M. A. Sambeat, J. Cadafalch, and M. Gurgí; Hospital Germans Trias i Pujol, Badalona: B. Clotet, A. Tuldrá, A. Ballesteros, J. Moltó, J. R. Santos, and A. Bonjoch; Hospital de Bellvitge, Hospitalet de Llobregat: D. Podzamczer, P. Robres, E. Ferrerr, and M. Olmo; Hospital Clinic Universitari, Barcelona: J. M. Gatell, A. Milinkovic, J. Mallolas, and E. Martínez; Hospital San Carlos, Madrid: V. Estrada, M. Fuster, M. J. Téllez, and J. Vergas; Hospital de Elche, Elche: F. Gutiérrez, M. Masía, S. Padilla, and E. Bernal; Hospital Clínico de Valencia, Valencia: G. García and 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, and G. Ollero; Hospital General de Valencia: V. Abril, E. Ortega, and A. Martín.
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. Accesed November 1, 2008.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
HIV; lopinavir/ritonavir; monotherapy