Safety and antiviral activity of lopinavir/ritonavir-based therapy in human immunodeficiency virus type 1 (HIV-1) infection

Protease inhibitor-based antiretroviral therapy has been shown to decrease the morbidity and mortality associated with human immunodeficiency virus type 1 (HIV-1) infection. However, many of the available agents in this class suffer shortcomings, including poor tolerability, difficult dosing regimens, and variable drug concentrations which may lead to generation of viral resistance. Lopinavir/ritonavir (Kaletra) has been designed specifically to address some of these shortcomings. Excellent therapeutic efficacy has been documented for lopinavir/ritonavir in multiple clinical trials in both antiretroviral-naive and -experienced patients. Development of resistance is a rare event in persons initiating therapy with lopinavir/ritonavir as their first protease inhibitor. The main side effects associated with lopinavir/ritonavir are gastrointestinal disturbances and elevations of serum lipids. Current antiretroviral therapy guidelines list lopinavir/ritonavir as the consensus first-line protease inhibitor recommended in the initial therapeutic regimen in persons infected with HIV-1.     

Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients

BACKGROUND: Lopinavir/ritonavir-containing antiretroviral therapy can cause hyperlipidaemia. However, most statins are contraindicated due to drug-drug interactions. Rosuvastatin undergoes minimal metabolism by CYP450, so no CYP450-based interaction with lopinavir/ritonavir is expected. This study explored the lipid-lowering effect of rosuvastatin and assessed the effect of lopinavir/ritonavir on the pharmacokinetics of rosuvastatin and vice versa. METHODS: HIV-infected patients on lopinavir/ritonavir (viral load < 400 copies/ml) with total cholesterol (TC) > 6.2 mmol/l were treated with rosuvastatin for 12 weeks, starting on 10 mg once daily. If fasting target values (TC < 5.0 mmol/l, high-density lipoprotein-cholesterol > 1.0 mmol/l, low-density lipoprotein-cholesterol [LDL-c] < 2.6 mmol/l and triglycerides < 2.0 mmol/l) were not reached, rosuvastatin was escalated to 20 mg or 40 mg at week 4 and 8, respectively. Plasma lopinavir/ritonavir trough levels (C(min)) were determined at week 0, 4, 8 and 12 and rosuvastatin C(min), at week 4, 8 and 12. RESULTS: Twenty-two patients completed the study. Mean reductions in TC and LDL-c from baseline to week 4 (on rosuvastatin 10 mg once a day) were 27.6% and 31.8%, respectively. Lopinavir/ritonavir concentrations were not influenced by rosuvastatin (P = 0.44 and 0.26, repeated-measures analysis). Median (interquartile range) rosuvastatin C(min) for 10 mg, 20 mg and 40 mg once daily were 0.97 (0.70-1.5), 2.5 (1.3-3.3) and 5.5 (3.3-8.8) ng/ml, respectively. CONCLUSIONS: Rosuvastatin appeared to be an effective statin in hyperlipidaemic HIV-infected patients. Lopinavir/ritonavir levels were not affected by rosuvastatin, but rosuvastatin levels unexpectedly appeared to be increased 1.6-fold compared with data from healthy volunteers. Until safety and efficacy have been confirmed in larger studies, the combination of rosuvastatin and lopinavir/ritonavir should be used with caution.     

Pharmacokinetics of a once-daily regimen of lopinavir/ritonavir in HIV-1-infected children

INTRODUCTION: Lopinavir is an HIV protease inhibitor that is co-formulated with ritonavir. The approved paediatric dose is 230/57.5 mg/m2 twice daily. Once-daily dosing may offer an advantage to adherence. We studied the pharmacokinetics of lopinavir/ritonavir in a once-daily regimen in HIV-1-infected children. METHODS: HIV-1-infected children on stable antiretroviral therapy with a viral load <50 copies/ml for at least 6 months received lopinavir/ritonavir 460/115mg/m2 once daily with zidovudine and lamivudine. Blood samples were collected at 0, 2, 4, 6, 8, 12, 18 and 24 h after observed intake during steady state. Target level for lopinavir Cmin was 1.0 mg/l, based on in vitro IC50 data. RESULTS: Nineteen HIV-1-infected children with a median (range) age of 4.5 (1.4-12.9) years were enrolled. The median (interquartile range) dose of lopinavir was 456 (444-477) mg/m2. The mean (standard deviation) AUC0-24, Cmax and Cmin of lopinavir were 149.8 +/- 58.8 h*mg/l, 10.77 +/- 2.90 mg/l and 2.88 +/- 3.74 mg/l respectively. These values are comparable to data observed in adults using lopinavir/ritonavir 800/200 mg once daily. In 10/19 (53%) children Cmin was considered to be too low (<1.0 mg/l). Younger children more often experienced subtherapeutic trough levels. CONCLUSION: Our findings indicate that 460/115 mg/m2 lopinavir/ritonavir once daily leads to mean pharmacokinetic parameters comparable to data of 800/200 mg lopinavir/ritonavir once daily in adults, although the variability observed in the trough levels is much higher in children. Further research, especially in young children, is necessary to determine whether a higher dosage of lopinavir/ritonavir once daily must be given to reach the target level for Cmin.     

Interactions between amprenavir and the lopinavir-ritonavir combination in heavily pretreated patients infected with human immunodeficiency virus

OBJECTIVE: This pharmacokinetic study was designed to characterize interactions between amprenavir and the lopinavir-ritonavir combination in patients infected with human immunodeficiency virus in whom previous antiretroviral therapy had failed. METHODS: Twenty-seven patients included in a randomized clinical trial (ANRS [National Agency for AIDS Research] Protocol 104) participated in this study. They were randomized to receive ritonavir at a dose of either 100 mg twice daily or 200 mg twice daily. For the first 2 weeks of therapy, they were randomly assigned to receive lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily), amprenavir (600 mg twice daily) plus ritonavir (100 mg twice daily), lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily) plus additional ritonavir (100 mg twice daily), or amprenavir (600 mg twice daily) plus ritonavir (200 mg twice daily). From week 3 onward, all patients received amprenavir plus lopinavir-ritonavir with or without an additional ritonavir dose (100 mg twice daily). The pharmacokinetics of the 3 drugs was studied in weeks 2 and 6 of therapy. RESULTS: Median amprenavir concentrations decreased by 54% (P =.004) when lopinavir was added to the amprenavir-ritonavir regimen. Lopinavir weakly displaced amprenavir from plasma proteins: The average unbound fraction of amprenavir was 0.089 in week 2 and 0.114 in week 6 (P =.03), but this did not fully account for the observed interaction. Increasing the ritonavir dose did not affect the amprenavir concentration. The relationship between lopinavir and ritonavir concentrations fitted a maximum effect (E(max)) model;the average concentration of ritonavir that yielded a lopinavir concentration of 8119 ng/mL (50% of E(max)) was 602 ng/mL (coefficient of variation, 22%). There was a significant relationship between the lopinavir inhibitory quotient and the virologic response in week 2 (P =.005). CONCLUSION: Lopinavir markedly decreases the amprenavir concentration during amprenavir and lopinavir-ritonavir combination therapy. The inhibitory quotients were more predictive of the short-term virologic response than was the level of drug exposure.     

The role of lopinavir/ritonavir (Kaletra) in the management of HIV infected adults

As the HIV pandemic enters its third decade, more sophisticated and efficacious therapies are continually being developed. This article provides an in-depth review of the first coformulated boosted protease inhibitor available on the world market, lopinavir/ritonavir (Kaletra). Included in this review is an overview of the current market place, the chemistry, pharmacokinetics, clinical efficacy and side-effect profile of lopinavir/ritonavir. In addition, an expert opinion and commentary on the clinical applications of this drug is provided.     

CYP3A5 genotype has no impact on plasma trough concentrations of lopinavir and ritonavir in HIV-infected subjects

CYP3A5 genotype has no impact on the trough plasma concentrations of lopinavir and ritonavir in human immunodeficiency virus (HIV)-infected individuals on stable highly active antiretroviral therapy (HAART). This is ascribed to a drug interaction, such that ritonavir by inhibiting CYP3A activity, may occlude the pharmacokinetic consequences of functional polymorphisms in the CYP3A5 gene. In the clinical setting, where lopinavir and ritonavir are always combined, CYP3A5 genotype is of no consequence on the trough plasma concentrations of these drugs.     

Use of lopinavir/ritonavir in HIV-infected patients failing a first-line protease-inhibitor-containing HAART

OBJECTIVES: The long-term virological efficacy of lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART) in HIV-infected patients failing a first-line protease inhibitor (PI)-based regimen is still unclear. METHODS: An observational study was carried out from December 2000-December 2002 on 111 consecutive patients starting lopinavir/ritonavir. The primary end-point was virological success (HIV RNA <50 copies/mL in two consecutive determinations). CD4 outcome, lipid levels and adverse events were recorded. The Kaplan-Meier method and log-rank test were used to estimate the time-dependent probability of reaching the end-point using intention-to-treat and on-treatment approaches. RESULTS: Ninety-six patients obtained virological success during follow-up; Kaplan-Meier analysis showed that the time-dependent probability of obtaining this end-point was 78.4% at month 12 and 85.8% at month 24. The median CD4+cell count increased by 118 cells/mm(3) from baseline to month 12 and by 153 cells/mm(3) to month 24. Thirty-one patients discontinued lopinavir/ritonavir: 16 because of drug-related toxicities, six for simplification, five because of virological failure, one patient was lost at follow-up and three died. An elevation in lipid parameters was observed, but only a minority of patients developed a grade 3 or higher hypertriglyceridaemia and/or hypercholesterolaemia. Among the 15 patients not reaching virological success, five had < or =5 mutations in the protease region known to reduce susceptibility to lopinavir/ritonavir (one discontinued lopinavir/ritonavir because of gastrointestinal intolerance), five had no mutations (two discontinued lopinavir/ritonavir because of gastrointestinal intolerance) and five showed > or =6 mutations (all discontinued lopinavir/ritonavir); however, of the patients who discontinued lopinavir/ritonavir none achieved HIV RNA <50 copies/mL on subsequent regimens. CONCLUSIONS: Lopinavir/ritonavir was highly effective and well tolerated in HIV-infected patients failing a first-line PI-based HAART.     

Fosamprenavir: drug development for adherence

OBJECTIVE: To review the pharmacology, pharmacokinetics, virology, safety, efficacy, and clinical use of fosamprenavir. DATA SOURCES: A MEDLINE (1966-July 2005) search was conducted using fosamprenavir, Lexiva, amprenavir, and GW433908 as key words. Abstracts from infectious diseases and HIV scientific meetings were identified. Bibliographies of cited articles were reviewed. STUDY SELECTION AND DATA EXTRACTION: All publications, meeting abstracts, and unpublished information were reviewed and relevant items included. Information from in vitro, preclinical, and Phase II and III clinical trials was included. DATA SYNTHESIS: Fosamprenavir is a protease inhibitor (PI) prodrug used for the treatment of HIV-1 infection. The active moiety, amprenavir, is extensively metabolized by CYP3A4. In clinical trials, fosamprenavir was at least as effective as amprenavir, with a reduced pill burden. Fosamprenavir was developed with the intention of reducing the pill burden associated with amprenavir. It has demonstrated comparable safety and efficacy with comparator PIs and is associated with limited cross-resistance to other PIs. CONCLUSIONS: Fosamprenavir is a promising antiretroviral agent with favorable efficacy and tolerability. At this time, data indicate the utility of fosamprenavir in treatment-na?ve and PI-experienced HIV-infected patients.     

Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients

This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P-glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. Activities, demographics, and genetic polymorphisms in CYP3A, CYP2D6, and P-glycoprotein were tested as covariates. Oral midazolam clearance (overall CYP3A activity) decreased to 0.19-fold (90% confidence interval (CI), 0.15-0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24-fold (0.20-0.29) and 1.12-fold (1.00-1.26), respectively. In CYP2D6 extensive metabolizers, the plasma ratio AUC(dextromethorphan)/AUC(dextrorphan) increased to 2.92-fold (2.31-3.69). Digoxin area under the curve (AUC)(0-12) (P-glycoprotein activity) increased to 1.81-fold (1.56-2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. In conclusion, CYP3A, CYP2D6, and P-glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection.     

Pharmacologic perspectives for once-daily antiretroviral therapy

OBJECTIVE: To contrast available once-daily antiretroviral agents and combinations of these agents from a clinical pharmacologic viewpoint. DATA SOURCES: Data were extracted from publications and major HIV conference proceedings cited in MEDLINE (1966-March 2004) using the search terms antiretroviral therapy, combination therapy, once-daily therapy, and pharmacokinetics. Additional references were obtained from the bibliographies of these sources. STUDY SELECTION AND DATA EXTRACTION: Information pertaining to pharmacologic perspectives for once-daily antiretroviral agents was selected. DATA SYNTHESIS: Maximal and durable suppression of plasma HIV RNA, the principal goal of therapy, depends on the intrinsic antiviral activity of the antiretroviral regimen. A favorable tolerability/toxicity profile is also fundamentally important. All once-daily agents exhibit some pharmacologic limitations or lack adequate long-term follow-up. Of available agents, efavirenz has a long and distinguished efficacy record, with reasonable safety and moderate tolerability. Lamivudine, and newer agents such as atazanavir (or atazanavir/ritonavir), emtricitabine, fosamprenavir/ritonavir, and tenofovir, may offer pharmacologic advantages in the current state of once-daily therapy. Important considerations exist for coadministering once-daily agents including drug-drug interactions, drug-food incompatibilities, and synergistic toxicities. Few controlled studies have compared once-daily regimens with conventional regimens. CONCLUSIONS: Progress has been made toward once-daily therapy, but more clinical experience with available agents is needed, including comparative studies of entirely once-daily regimens versus conventional regimens. Limitations of currently available agents signify a need for improved antiretroviral utilization or new alternative agents.     

The CASTLE study: atazanavir/r versus lopinavir/r in antiretroviral-naive patients

With the introduction of combination antiretroviral therapy (cART), there have been dramatic reductions in mortality and morbidity of HIV-1-infected patients. Protease inhibitor-based regimens remain a cornerstone of cART owing to their potency and high genetic barrier to resistance. The comparison of atazanavir/ritonavir in naive subjects in combination with tenofovir–emtricitabine versus lopinavir/ritonavir in combination with tenofovir–emtricitabine to assess safety and efficacy (CASTLE) study is a noninferiority trial in which the efficacy, safety and tolerability of atazanavir–ritonavir and lopinavir–ritonavir were compared in antiretroviral therapy-naive patients. The aim of this paper is to review the CASTLE study and the role of atazanavir–ritonavir as an initial treatment in HIV-1-infected patients.     

Steady-state pharmacokinetics of a double-boosting regimen of saquinavir soft gel plus lopinavir plus minidose ritonavir in human immunodeficiency virus-infected adults

Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 85.1 microg/ml . h; maximum concentration of drug in serum (C(max)), 10.0 microg/ml; trough concentration of drug in serum (C(trough)), 7.3 microg/ml; and minimum concentration of drug in serum (C(min)), 5.5 microg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC(0-12), 22.9 microg/ml . h; C(max), 2.9 microg/ml; C(trough), 1.6 microg/ml; and C(min), 1.4 microg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.     

Exploratory study comparing the metabolic toxicities of a lopinavir/ritonavir plus saquinavir dual protease inhibitor regimen versus a lopinavir/ritonavir plus zidovudine/lamivudine nucleoside regimen

OBJECTIVES: To assess the safety, efficacy and metabolic toxicity of lopinavir/ritonavir + saquinavir or zidovudine/lamivudine and evaluate the pharmacokinetics of lopinavir/ritonavir + saquinavir. METHODS: HIV-1-infected, antiretroviral-naive subjects were randomized to lopinavir/ritonavir (400/100 mg) twice daily + saquinavir (800 mg) or zidovudine/lamivudine (150/300 mg) in a Phase II, 48 week study. Subjects receiving lopinavir/ritonavir + zidovudine/lamivudine initiated escalating doses of saquinavir (400, 600 and 800 mg) weekly for 3 weeks. RESULTS: By intent-to-treat (non-completer = failure) analysis, 10/16 (63%) lopinavir/ritonavir + saquinavir-treated and 7/14 (50%) lopinavir/ritonavir + zidovudine/lamivudine-treated subjects achieved plasma HIV-1 RNA <50 copies/mL (P=0.713) at week 48. Safety, tolerability, metabolic changes and truncal fat increases were similar between groups. Small decreases in the lower extremity fat in the zidovudine/lamivudine group (-6%) and a statistically significant increase in the lower extremity fat in the saquinavir group (+19%) were observed. Lopinavir/ritonavir co-administered with saquinavir 600 or 800 mg twice daily produced saquinavir concentrations similar to those previously reported for saquinavir/ritonavir 1000/100 mg twice daily. CONCLUSIONS: Treatment regimens had similar efficacy and tolerability. Metabolic parameters suggested lipoatrophy in the zidovudine/lamivudine treatment group. Saquinavir 600 and 800 mg twice daily produced concentrations similar to those previously reported for saquinavir/ritonavir 1000/100 mg twice daily.     

Enfuvirtide: a novel agent for the treatment of HIV-1 infection

OBJECTIVE: To review the pharmacology, virology, pharmacokinetics, efficacy, safety, and clinical use of enfuvirtide. DATA SOURCES: English-language MEDLINE and AIDSline searches were performed (1966-January 2003) using enfuvirtide, T-20, gp41, and fusion inhibitors as key words. Abstracts from infectious diseases and HIV scientific meetings were identified. DATA EXTRACTION: All publications and meeting abstracts were reviewed and relevant items included. In vitro and preclinical studies were included, as well as Phase II and III clinical trials. DATA SYNTHESIS: Enfuvirtide is a fusion inhibitor used for the treatment of HIV-1 infection. Given its unique mechanism of action, most HIV-1 isolates are susceptible to enfuvirtide. Enfuvirtide is administered by subcutaneous injection twice daily. In clinical trials with antiretroviral-experienced patients, enfuvirtide was effective at suppressing HIV-RNA and increasing CD4+ T-cell counts. Enfuvirtide should be used in combination with other active antiretroviral agents to optimize its efficacy and limit resistance. Injection site reactions associated with administration of the drug are experienced in the majority of patients. Availability of enfuvirtide may be limited by a complex manufacturing procedure. CONCLUSIONS: Enfuvirtide is an effective treatment option for HIV-1-infected individuals when used in combination with other antiretroviral agents. It may be used as part of a regimen for treatment-experienced patients.     

Lopinavir/ritonavir monotherapy as a simplification strategy in routine clinical practice

OBJECTIVES: The efficacy and safety of lopinavir/ritonavir monotherapy has been explored with promising results in well-controlled, randomized clinical trials. However, less information about its clinical usefulness in routine clinical practice is currently available. The objective of this study was to assess the effectiveness and safety of monotherapy with lopinavir/ritonavir as a treatment simplification strategy in HIV-infected patients with viral suppression outside a clinical trial setting. METHODS: Fifty-one subjects who were switched to lopinavir/ritonavir monotherapy and whose HIV-1 RNA was <50 copies/mL were included in this retrospective study. Data were obtained from a prospectively compiled database. The primary endpoint was the percentage of subjects who maintained viral suppression after 48 weeks of follow-up. Secondary endpoints included the incidence of adverse events and changes in CD4+ T cell count and in lipid profile. RESULTS: Two patients lost viral suppression, seven patients interrupted lopinavir/ritonavir monotherapy because of adverse events and four patients were lost before completing 48 weeks of follow-up. Thus, 38/40 (95.0%) patients maintained viral suppression when only subjects whose outcomes were available up to week 48 were considered and 38/51 (74.5%) patients maintained viral suppression when subjects who discontinued therapy or who were lost to follow-up were considered as treatment failures. The mean CD4+ T cell count significantly increased, from 541 (280) cells/mm3 at baseline to 609 (212) cells/mm3 at week 48 of follow-up (P=0.034). This increase was similar to that observed in the 48 weeks prior to lopinavir/ritonavir monotherapy (P=0.792). Although total cholesterol remained unchanged, there was a significant decrease in triglyceride levels during follow-up (P=0.029). CONCLUSIONS: Monotherapy with lopinavir/ritonavir is safe and effective as a treatment simplification approach in HIV-1-infected patients with sustained viral suppression in routine clinical practice, particularly in those patients already receiving a lopinavir/ritonavir-based antiretroviral regimen.     

Atazanavir

OBJECTIVE: To review the pharmacology, virology, pharmacokinetics, resistance profile, clinical efficacy, safety, and drug interactions of atazanavir. DATA SOURCES: A PubMed and NLMGateway search (1966-June 2004) utilizing the key words atazanavir and BMS-232632 was performed. Abstracts from scientific meetings, including the Conference on Retroviruses and Opportunistic Infections, International AIDS Society Conference on HIV Pathogenesis and Treatment, Interscience Conference on Antimicrobial Agents and Chemotherapy, and the Infectious Diseases Society of America, were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All publications and meeting abstracts were reviewed, and information relevant to the formulary decision-making process was selected. DATA SYNTHESIS: Atazanavir is a once-daily protease inhibitor (PI) that received approval by the Food and Drug Administration in June 2003. In clinical trials in antiretroviral (ARV)-na?ve patients, atazanavir had efficacy similar to that of efavirenz or nelfinavir. In ARV-experienced patients, atazanavir was inferior to lopinavir/ritonavir unless atazanavir was coadministered with low-dose ritonavir. Following failure of an atazanavir-containing regimen in ARV-na?ve patients, a unique 150L mutation was seen. Atazanavir resistance is likely when resistance to >/=3 PIs is present. Atazanavir can cause increases in unconjugated bilirubin levels, which rarely leads to jaundice or scleral icterus. In contrast to comparators, atazanavir did not negatively impact the lipid profile. Similar to other PIs, atazanavir is metabolized by and inhibits CYP3A at clinically relevant concentrations; therefore, many potential drug interactions exist. CONCLUSIONS: Atazanavir is a once-daily PI that, unlike other PIs, does not negatively impact the lipid profile. Atazanavir may be particularly desirable in patients with hyperlipidemia or other coronary artery disease risk factors.