JAIDS Journal of Acquired Immune Deficiency Syndromes:
Lopinavir/Ritonavir Plus Nevirapine as a Nucleoside-Sparing Approach in Antiretroviral-Experienced Patients (NEKA Study)
Negredo, Eugènia MD, PhD*; Moltó, José MD*; Burger, David PhD†; Côté, Helene PhD‡; Miró, Oscar MD, PhD§; Ribalta, Josep PhD∥; Martínez, Eva PhD*; Puig, Jordi PhD*; Ruiz, Lidia PhD*; Salazar, Juliana BSc∥; López, Sònia PhD§; Montaner, Julio MD‡; Rey-Joly, Celestino MD, PhD¶; Clotet, Bonaventura MD, PhD*¶
From the *Department of Internal Medicine, Lluita contra la SIDA and Irsicaixa Foundations, Germans Trias i Pujol Hospital, Badalona, Universitat Autònoma de Barcelona, Barcelona, Spain; †Nijmegen University Hospital, The Netherlands; ‡British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada; §Mitochondrial Research Laboratory, Muscle Research Unit, Internal Medicine Department, Hospital Clínic de Barcelona, Barcelona, Spain; ∥Sant Joan University Hospital, Rovira i Virgili University, Reus, Tarragona, Spain; and ¶Department of Internal Medicine, Germans Trias i Pujol Hospital, Badalona, Universitat Autònoma de Barcelona, Barcelona, Spain.
Received for publication March 10, 2004; accepted August 11, 2004.
José Moltó was supported by contract SCO/1620/2003 from the Fundació per a la Recerca Biomédica Germans Trias i Pujol in collaboration with the Spanish Health Department. Oscar Miró and Sònia López were supported by Fundación para la Investigación y la Prevención del Sida en España (FIPSE 3102-00), Fundació La Marató de TV3 (020210), Suport als Grups de Recerca (2001/00379), and Redes de Investigación en Mitocondrias (V-2003-REDG011-O) y en Sida (Redg173) del Fondo de Investigaciones Sanitarias.
The co-authors Eugenia Negredo and José Moltó have contributed equally to the manuscript.
Reprints: Eugenia Negredo, Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet, s/n. 08916 Badalona, Barcelona, Spain (e-mail: firstname.lastname@example.org).
Objectives: To compare the efficacy and safety of a nucleoside-sparing approach with a conventional highly active antiretroviral therapy (HAART) regimen in antiretroviral-experienced patients with prolonged viral suppression.
Methods: Pilot study including 31 antiretroviral-experienced patients with HIV RNA <80 copies/mL. Subjects were randomly assigned to lopinavir/ritonavir (LPV/rtv) 400/100 mg BID plus nevirapine (NVP) 200 mg BID (NVP group, n = 16) or LPV/rtv plus the 2 previous NRTIs (NRTI group, n = 15). The primary endpoint was the percentage of subjects who maintained viral suppression at week 48. Changes in lipid metabolism, mitochondrial parameters, and LPV trough levels were also assessed.
Results: All patients maintained viral suppression after 48 weeks. No subject discontinued therapy because of adverse events. HDL cholesterol increased by 28% at week 24 (P < 0.0001) and 10% after 48 weeks of follow-up (P = 0.319) in the NVP group. In the NRTI group, LDL cholesterol increased by 14% at week 48 (P = 0.076). Mitochondrial DNA/nuclear DNA ratio and mitochondrial respiratory chain complex IV activity showed a trend toward increasing in the NVP group. Mean (SD) LPV trough levels were 6340 (2129) ng/mL in the NRTI group and 5161 (2703) ng/mL in the NVP group (P = 0.140).
Conclusions: In antiretroviral-experienced subjects with sustained viral suppression, dual therapy with NVP plus LPV/rtv at standard dosage was as potent and safe as standard-of-care HAART at 48 weeks of follow-up. This approach may reduce mitochondrial toxicity and improve LPV/rtv-associated lipid abnormalities. The results of this pilot study support the study of this approach in a larger, randomized trial.
Limitations on achieving complete HIV eradication render it necessary to maintain highly-active antiretroviral treatment (HAART) over long periods,1 which may lead to the development of antiretroviral-associated toxicities.2-4 The current standard-of-care HAART regimens include a backbone of 2 nucleoside reverse transcriptase inhibitors (NRTIs). This antiretroviral family inhibits the mitochondrial gamma-DNA polymerase, and previous studies have shown decreases in mitochondrial DNA content to appear soon after starting NRTI-based treatments.5 In addition, mitochondrial dysfunction has been recognized as one of the pathogenic mechanisms of NRTI-related side effects such as peripheral neuropathy, pancreatitis, liver dysfunction, or even lipoatrophy, which is one of the most stigmatizing features related to antiretroviral therapy.6-10 Conversely, a relationship has been reported between protease inhibitor (PI)-based antiretroviral regimens and metabolic disorders such as hyperlipidemia, glucose intolerance, and changes in body shape, mainly fat accumulation.2,3
All these antiretroviral drug-derived toxicities may compromise treatment compliance and may represent a major obstacle for achieving durable control of viral replication.4,11-13 Thus, different strategies aimed at avoiding or delaying these toxicities are currently under evaluation. Although NRTI-sparing regimens may be an adequate approach for this purpose, data currently available on this strategy are rather scarce.14-16
The objective of this study was to assess the efficacy and safety of a standard dosage of lopinavir/ritonavir (LPV/rtv) in combination with nevirapine (NVP), as an NRTI-sparing simplification approach in antiretroviral-experienced subjects with long-term viral suppression.
PATIENTS AND METHODS
Design and Study Population
The Nevirapine-Kaletra Study (NEKA) study is a pilot, prospective, randomized, and open-label study conducted in antiretroviral-experienced patients with long-lasting viral suppression.
Patients included in this study had been on a PI- or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen for at least 9 months and had plasma HIV-1 RNA <80 copies/mL in at least 2 determinations within the previous 6 months. Subjects with previous experience with LPV/rtv, suspected or documented NNRTI resistance, or intolerance to NVP were excluded from the study. Transaminase levels >5 times above the upper normal limit, active opportunistic infection in the previous 6 months, poor treatment compliance, and pregnant or breast-feeding women were other exclusion criteria. The ethical committee of our hospital approved the trial and all subjects gave written consent before inclusion in the study.
Subjects were randomly assigned to replace the current PI or NNRTI with LPV/rtv (Kaletra, Abbott Lab, Abbott Park, IL, USA, 400/100 mg BID), maintain the 2 NRTIs (NRTI group), or switch therapy to NVP (Viramune, Boehringer, Ingelheim Gmbh, Ingelheim am Rheim, Germany, 200 mg BID) plus LPV/rtv (400/100 mg BID) (NVP group). Patients without previous exposure to NVP received a daily dose of 200 mg for the first 2 weeks, increasing to 200 mg of NVP twice daily thereafter.
The primary endpoint of the study was the percentage of subjects from each group who maintained viral suppression at week 48. Secondary endpoints included changes in CD4 and CD8 cell counts as well as in liver enzymes, lipid metabolism, and mitochondrial parameters during follow-up. Plasma LPV and NVP trough levels were also assessed at steady-state conditions.
Follow-up and Assessments
Adverse events and physical examination were assessed at baseline, at weeks 4 and 12, and every 12 weeks thereafter. Blood samples for HIV-1 RNA quantification, CD4+ and CD8+ T-cell count, hematology, clinical chemistry, and lipid profile evaluations (including total cholesterol, high- and low-density lipoprotein [HDL and LDL] cholesterol, triglycerides, and apopoproteins A and B) were taken after at least 8 hours' fasting, at baseline and every 12 weeks. Self-perceived and dual-energy x-ray absorptiometry (DEXA)-assessed lipodystrophy was evaluated at baseline and every 24 weeks during the follow-up, as well as anthropometric measurements (weight, body mass index, waist-hip ratio, and circumferences by Harpenden anthropometric tape). Lipodystrophy was defined by patients' report of peripheral fat wasting (upper and lower extremities, face, or buttocks) or central fat accumulation (abdominal, dorsocervical, or breast) and confirmed by physician.
HIV-1 RNA was quantified by NASBA assay (Organon, Teknika, Barcelona, Spain; limit of detection of 80 copies/mL). Flow cytometry was used to perform CD4+ and CD8+ T-lymphocyte counts.
Peripheral blood mononuclear cells (PBMCs) were obtained at baseline and at week 48 in the first 11 recruited patients. The ratio between mitochondrial (mt) and nuclear (n) DNA was quantified using real-time polymerase chain reaction with fluorescent detection17 (LightCycler, Fact Sheet DNA Meter, SYBR Green I, Roche Molecular Biochemicals®, Mannheim, Germany). Additionally, changes from baseline in respiratory mitochondrial chain (RMC) complex III and IV activities were spectrophotometrically assessed at week 48. mtDNA content and RMC enzyme activities were expressed both by cell (normalizing by protein content measured through Bradford's methodology) and by mitochondria (normalizing by citrate synthase). In all cases, results were expressed as percentages of activity with regard to baseline (100%).
LPV and NVP plasma trough levels were determined in steady-state conditions by high-performance liquid chromatography and were considered to be suboptimal if they were <5000 and 3400 ng/mL, respectively.18-21
Comparisons between groups were performed using SPSS Version 10.0 statistical software (Cary, NC). Variable distribution was explored by the Kolmogorov-Smirnov test. Variables with a normal distribution were described as mean (SD) and compared with the Student t test. Median and interquartile range (IQR) were employed to describe variables that did not follow a normal distribution, which were compared by using Mann-Whitney nonparametric test. Proportions were compared by a χ2 test or Fisher exact test, where appropriate. Differences were considered statistically significant at P < 0.05.
Only patients whose outcomes were measured at specific time points were included in the on-treatment analysis. The intention-to-treat analysis involved all patients enrolled in the study, and those who discontinued treatment were considered as failures. Missing plasma viral load observations were considered as failures unless they had been <80 copies/mL immediately before and after the missing value, in which case it was assumed to be undetectable.
A total of 31 patients were included into the study between May and December 2001. Sixteen subjects were randomly assigned to receive NVP plus LPV/rtv (NVP group), and 15 maintained their current 2-NRTI backbone and only replaced the PI or NNRTI by LPV/rtv (NRTI group). Baseline characteristics were similar between the 2 groups (Table 1). Two subjects, both assigned to the NVP group, were lost to follow-up.
Virologic and Immunologic Assessments
At week 48 of follow-up, all patients maintained viral suppression in the on-treatment analysis. Likewise, in the intention-to-treat analysis, plasma viral load was <80 copies/mL in 87.5% of the subjects in the NVP group and in 100% of the patients in the NRTI group (P = 0.484).
Absolute CD4+ T-cell count increased in both study groups during follow-up while CD8+ T-cell count remained stable (Fig. 1). At week 48, mean (SD) increase from baseline in CD4 cell count was 300 (124) cells/mm3 in the NVP group (95% CI 37-563; P = 0.028), and 155 (197) cells/mm3 in the NRTI group (95% CI −328 to +639; P = 0.462). There were no significant differences between the 2 arms in absolute CD4+ T-cell count at week 48 (P = 0.813).
The proportion of patients who developed adverse events during follow-up was similar in both study groups (37.5% in the NVP group and 33.3% in the NRTI group; P = 0.894). Gastrointestinal complaints (diarrhea, vomiting, and abdominal disturbances) were the most frequently observed adverse events. They mainly appeared during the first 12 weeks of therapy, were usually mild (grade I or II) and transient in all the subjects, and no patient discontinued the study medication because of them.
Mean transaminase levels did not show any significant change from baseline, and no patient developed acute clinical hepatitis during follow-up. Likewise, mean GGT values did not significantly vary in patients in the NVP group (from 100 U/L at baseline to 72 U/L at week 48; P = 0.365) or in the NRTI group (from 76 U/L at baseline to 35 U/L at week 48; P = 0.540), without statistically significant differences between the 2 arms after 48 weeks of follow-up (P = 0.082).
Lipid Profile and Lipoprotein Assessment
Total cholesterol levels increased in both arms during follow-up (Fig. 2). At week 48, percentage augmentation in total cholesterol levels was 14% in the NVP group (P = 0.039) and 13% in the NRTI group (P = 0.036), without significant differences between the groups (P = 0.400). HDL cholesterol increased by 28% at week 24 (P < 0.0001) and by 10% at week 48 (P = 0.319) in the NVP group but decreased by 13% at week 48 in the NRTI group (P = 0.138). The same was observed for apoprotein AI levels, with a mean increase of 12.6% at week 24 (P < 0.0001) and 6.8% at week 48 (P = 0.452) in the NVP group, while it did not vary in the NRTI group (mean increase of 0.8% at week 48, P = 0.843). As for the LDL cholesterol and apoprotein B levels, there were no significant changes among the patients in the NVP group during the study. On the contrary, subjects assigned to the NRTI group presented a percentage increase of 14% in LDL cholesterol (P = 0.076) and of 37% in apoprotein B levels (P = 0.004) at week 48 of follow-up (Fig. 2).
Although mean LDL/HDL cholesterol ratio increased in the NRTI group during follow-up (from 2.07 at baseline to 2.5 at week 48; P = 0.02), it decreased slightly in the NVP group (from 2.1 at baseline to 1.8 at week 48; P = 0.10) (Fig. 2).
Fasting triglyceride levels augmented from baseline in both study groups. In the NRTI group the percentage increase from baseline was 103.8% (P = 0.017) and 18% (P = 0.120) at weeks 24 and 48, respectively. Likewise, patients in the NVP group experienced a mean increase in triglyceride levels of 25.8% (P = 0.048) and 56% (P = 0.056) at weeks 24 and 48, respectively. There were no significant differences regarding the fasting triglyceride levels at week 48 between groups (Fig. 2).
Two patients in the NVP group and 1 in the NRTI group were receiving lipid-lowering agents at baseline. However, 1 subject in the NVP group was able to stop pravastatin during follow-up. On the contrary, 2 patients in each group had to start statins during the study, following the National Cholesterol Education Program criteria.
Mitochondrial Toxicity and Lipodystrophy Assessments
After 48 weeks of NRTI discontinuation, mtDNA/nDNA ratio reached a median increment of 36 and 117% according to whether the results were considered by cell or by mitochondria, respectively, although such increases did not reach statistical significance (P = 0.22 and P = 0.17, respectively). On the contrary, no substantial changes in the mtDNA/nDNA ratio were observed among subjects who continued NRTI therapy by cell (P = 0.68) or by mitochondria (P = 0.66). Regarding the mitochondrial respiratory chain, complex III and IV activity remained quite stable throughout the study in both groups of patients, but a trend toward increased complex IV activity expressed by mitochondria was observed for patients who discontinued NRTIs (P = 0.05).
A new case of self-perceived lipoatrophy was reported during follow-up in the NRTI group. A loss of fat in lower extremities and buttocks was evidenced through the study in this subject, who was receiving didanosine, lamivudine, and LPV/rtv. On the contrary, 2 subjects assigned to the NVP group had a marked improvement in peripheral lipoatrophy after the cessation of NRTIs, zidovudine and lamivudine in both cases, which was confirmed by anthropometric measurements. However, DEXA scans did not show any significant change in fat in any of the study groups.
Mean NVP trough level was 6611 (2207) ng/mL in patients assigned to the NVP group, and no subject presented suboptimal NVP trough levels.
Mean (SD) lopinavir trough levels were 6340 (2129) and 5161 (2703) ng/mL in the NRTI and in the NVP group, respectively (P = 0.140). Although 44% of the patients in the NRTI group and 58% of the subjects in the NVP group presented LPV trough levels <5000 ng/mL (P = 0.369), all patients maintained LPV trough levels above the previously reported protein-binding corrected 95% CI for wild-type HIV-1.19,20
NVP plus standard doses of LPV/rtv showed similar antiviral potency to that of conventional HAART regimens in HIV-infected patients with prolonged viral suppression. Additionally, this dual NRTI-sparing approach was safe and well tolerated, improved lipid profile, and showed a trend toward increasing mtDNA content and RMC enzyme activities.
Despite 48 weeks of dual antiretroviral therapy, the maintenance of viral suppression in all our patients may be accounted for by the high antiviral activity of this drug combination. Previous studies with LPV/rtv monotherapy have reported a similar antiretroviral potency to that of conventional 3-drug antiretroviral regimens, as well as a high proportion of patients maintaining viral suppression.22,23 In addition, lopinavir reaches high enough plasma levels to provide an elevated inhibitory quotient, precluding the development of viral resistance.24 These issues may have contributed to the virologic success of this strategy.
Although it is currently recommended to increase LPV/rtv dosage when it is combined with NNRTIs,25 our patients received a standard dosage of LPV/rtv to preserve comparability between the treatment groups regarding LPV/rtv-associated toxicity. The proportion of our patients with suboptimal LPV plasma trough levels was similar between the 2 study groups. In addition, all patients showed LPV levels above the protein-binding corrected 95% CI described for the wild-type HIV-1 strains.19,20 These data agree with a previous study showing successful antiviral efficacy in patients receiving standard dosage of LPV/rtv plus NVP and 2 NRTIs.26 The high LPV inhibitory quotient may help to maintain viral suppression in patients with limited PI exposure and undetectable viral load despite the drugs being given at standard doses. Nevertheless, until more experience in this regard is available, monitoring lopinavir plasma levels should be recommended in all patients receiving NVP plus LPV/rtv at standard dosage.
In our study no differences were found regarding body shape changes between groups. Interestingly, only patients who discontinued the NRTIs tended to improve mitochondrial parameters. These data agree with other data reported5 and encourage considering NRTI-sparing approaches to limit NRTI-induced mitochondrial damage and the consequent development of lipoatrophy.
In our study, the heterogeneity of NRTI combinations received at enrollment should be taken into account due to the different impact of each nucleoside analogue on mitochondrial toxicity. The continuation of stavudine in almost one-third of patients in the NRTI group may have had a strong influence in the lack of improvement of mitochondrial parameters in this group. However, none of the 3 patients who reported changes in fat redistribution during the study were receiving stavudine at baseline. This supports the significant impact on mitochondrial function of other nucleosides beside stavudine. Although this remains to be confirmed, our results suggest an association between the improvement in mitochondrial parameters in PBMCs and the recovery of fat loss. The easiness and reproducibility of the PBMC mitochondrial study should prompt further studies to confirm its clinical usefulness.
In addition, increased adipocyte apoptosis in subcutaneous fat, which has been proposed as the final pathogenic mechanism of lipoatrophy, could render the morphologic changes in subcutaneous fat irreversible.27 As a consequence, NRTI-sparing regimens might be offered to HIV-infected patients ideally before or at the very beginning of lipoatrophy development.
Lipid disorders such as hypercholesterolemia or hypertriglyceridemia have been related to the use of LPV/rtv and some NRTIs.22,28,29 We observed an increment in fasting total cholesterol and triglyceride levels in both study groups after enrollment. Nonetheless, only the subjects in the NVP group experienced an increase in HDL cholesterol and apoprotein AI levels, both related to a lower vascular risk. In contrast, LDL cholesterol increased in subjects assigned to the NRTI group, which may favor the development of atherosclerosis. Previous studies, including either antiretroviral-naive patients starting an NVP-based HAART regimen30 or those switching from PIs to NVP,31-34 sustain the beneficial effect of this NNRTI on lipid profile. Our study revealed a similar benefit on lipid metabolism even when NVP is combined with a PI. This better atherogenic profile in patients receiving NVP plus LPV/rtv may imply a lower risk of developing cardiovascular events in this population.
In conclusion, dual antiretroviral therapy with NVP plus LPV/rtv at standard dosage was as potent and safe as standard HAART care regimens after 48 weeks in antiretroviral-experienced subjects with prolonged viral suppression. Our results support the suitability of this NRTI-sparing approach to prevent mitochondrial damage and NRTI-related adverse events, as well as to ameliorate PI-associated lipid abnormalities. Nevertheless, due to the small size of the study, the benefits of this approach should prompt a larger, randomized trial.
1. Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997;278:291-295.
2. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999; 353:2093-2099.
3. Behrens G, Dejam A, Schimidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS. 1999;13:F63-F70.
4. d'Arminio Monforte A, Cozzi Lepri A, Rezza G, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. ICONA Study Group. AIDS. 2000;14:499-507.
5. Côté H, Brumme Z, Craib K, et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med. 2002;346:811-820.
6. Brinkman K, Smeitink JA, Romijn JA, et al. 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.
7. Kakuda TN, Brundage RC, Anderson PL, et al. Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy. AIDS. 1999;13:2311-2312.
8. Savès M, Raffi F, Capeau J, et al. Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin Infect Dis. 2002;34:1396-1405.
9. Saint Marc T, Partisani M, Poizotmartin I, et al. A syndrome of peripheral wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS. 1999;9:595-599.
10. Van der Valk M, Gisolf EH, Reiss P, et al. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV infection. AIDS. 2001;15:847-855.
11. Proctor VE, Tesfa A, Tompkins DC. Barriers to adherence to highly active antiretroviral therapy as expressed by people living with HIV/AIDS. AIDS Patient Care STDS. 1999;13:535-544.
12. Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis. 2000;30(Suppl 2):S171-S176.
13. Staszewski S, Morales-Ramírez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med. 1999;341:865-873.
14. Alavella C, Lafeuillade A, Bentata M, et al. Lopinavir/ritonavir-efavirenz: preliminary assessment of a potent nucleoside-sparing dual antiretroviral regimen (the BIKS study). Paper presented at: XIV International AIDS Conference; July 7-12, 2004; Barcelona, Spain.
15. López-Cortés LF, Viciana P, Ruiz-Valderas R, et al. Pharmacokinetics, efficacy, and safety of once-daily saquinavir-sgc plus low-dose ritonavir (1200/100 mg) in combination with efavirenz in HIV-pretreated patients. Paper presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle.
16. Cooper CL, Fraser C, Seguin I, et al. Increased initial anti-HIV activity and decreased initial CD4 T-cell response with efavirenz (EFV) added to ritonavir (RTV) and saquinavir (SQV) treatment. Paper presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle.
17. López S, Miró O, Martínez E, et al. Mitochondrial effects of antiretroviral therapies in asymptomatic patients. Antivir Ther. 2004;9:47-55.
18. Hugen PW, Verweij-van Wissen CP, Burguer DM, et al. Simultaneous determination of the protease inhibitors indinavir, nelfinavir, saquinavir and ritonavir by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 1999;727:139-149.
19. Molla A, Vasavanonda S, Kumar G, et al. Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. Virology. 1998;250:255-262.
20. Kaletra [prescribing information]. Abbott Laboratories, Abbott Park, Illinois, USA; 2002.
21. Veldkamp AI, Weverling GJ, Lange JMA, et al. High exposure to nevirapine in plasma is associated with an improvement virological response in HIV-1-infected individuals. AIDS. 2001;15:1089-1095.
22. Murphy RL, Brun S, Hicks C, et al. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. AIDS. 2001;15:1-9.
23. Gathe JC, Washington M, Piot D, et al. Preliminary pilot data on the safety and efficacy of Kaletra (LPV/r) dosed alone for the treatment of HIV in ARV-naive patients: greater or equal 24 data. Paper presented at: 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago.
24. Kempf D, King M, Bauer E, et al. Comparative incidence and temporal accumulation of PI and NRTI resistance in HIV-infected subjects receiving lopinavir/ritonavir of nelfinavir as initial therapy. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003; Boston.
25. Degen O, Kurowsky M, van Lunzen J, et al. Steady state pharmacokinetic (PK) of lopinavir (LPV) in combination with nevirapine (NVP) or efavirenz (EFV). Paper presented at: XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain.
26. Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis. 2002;185:599-607.
27. Domingo P, Matias-Guiu X, Pujol R, et al. Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitors-associated lipodystrophy. AIDS. 1999;13:2261-2267.
28. Domingo P, Labarga P, Llibre JM, et al. Evolution of dyslipidemia in virologically suppressed HIV-infected patients switching from stavudine to tenofovir DF. Paper presented at: 9th European AIDS Conference; October 25-29, 2003; Warsaw, Poland.
29. Ribera E, Sauleda S, Paradiñeiro JC, et al. Increase in mitochondrial DNA in PBMCs and improvement in lipid profile and lactate levels in patients with lipoatrophy when stavudine is switched to tenofovir (LIPOTEST). Paper presented at: 9th European AIDS Conference; October 25-29, 2003; Warsaw, Poland.
30. Van de Valk M, Kastelein J, Murphy R, et al. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in a antiatherogenic lipid profile. AIDS. 2001;15:2407-2414.
31. Martínez E, Conget I, Lozano L, et al. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS. 1999;13:805-810.
32. Negredo E, Ribalta J, Paredes R, et al. Reversal of atherogenic lipoprotein profile in HIV-1 infected patients with lipodystrophy after replacing protease inhibitors by nevirapine. AIDS. 2002;16:1383-1389.
33. Martínez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med. 2003;349:1036-1046.
34. Ruiz L, Negredo E, Domingo P, et al. Antiretroviral treatment simplification with nevirapine in protease inhibitor-experienced patients with HIV-associated lipodystrophy: 1-year prospective follow-up of a multicenter, randomized, controlled study. J Acquir Immune Defic Syndr. 2001;27:229-236.
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