HIV/AIDS Therapy Express Report
The 5th International Conference on Drug Therapy and HIV Infection
Glasgow, Scotland

Kaletra (Lopinavir/Ritonavir): A New Option for the PI- and ARV-Experienced Patient

This report was reviewed for medical and scientific accuracy by Mark B. Feinberg, MD, PhD , Associate Professor of Medicine and Microbiology and Immunology, Emory University School of Medicine; Attending Physician, HIV/AIDS Service, Grady Memorial Hospital, Atlanta, Georgia.


Mark Bennett Feinberg, MD, PhD, Emory University School of Medicine, Atlanta, Georgia

The advent of potent drugs to treat HIV and the development of increasingly effective treatment strategies have resulted in dramatic improvements in the prognosis and quality of life for HIV-infected persons. However, two major challenges exist in developing more effective treatments. First, regimens typically require the use of three or more antiviral drugs, resulting in complex medication schedules, and requiring patients to take multiple pills at multiple times each day. As the relative complexity and inconvenience of a specific treatment regimen is likely to impact a patient's adherence to and their ultimate chance for long-term therapeutic success, the development of effective, but convenient, antiviral drugs is an essential goal. Second, there remains a great need to develop alternative antiretroviral (ARV) treatment regimens for patients who develop resistance to the antiviral drugs included in their initial (or subsequent) ARV therapy combinations. In particular, there is substantial "cross-resistance" seen among different ARV drugs of the same class. As a result, none of the drugs currently available have been shown to durably suppress the replication of HIV-variants that arise in individuals who had been previously and unsuccessfully treated with other protease inhibitors (PIs). The development of PIs that select for distinct mutations in the HIV protease gene-unlike previously available PIs-would provide one useful path to successful treatment of patients who develop drug resistant HIV-variants as a result of prior unsuccessful PI therapy. In addition, growing evidence indicates that strategies to alter the metabolism of PIs can result in substantially increased concentrations of the drug in the blood and appreciably prolong the half-life of the drug. Because the antiviral effect of any ARV drug is influenced by its associated resistance pattern and by the level of the drug attained during treatment of HIV-infection, maintenance of high concentrations of a potent PI may, in certain instances, be able to successfully inhibit the replication of even those HIV-variants that already harbor a number of mutations associated with PI resistance.

For these reasons, the development of the combined formulation of the potent PIs lopinavir (LPV) and ritonavir (RTV), known as Kaletra™ (formerly called ABT-378/ritonavir), represents a promising addition to the available ARV treatments for HIV infection. Lopinavir/ritonavir acts as a potent inhibitor of the HIV protease, and its pharmacologic properties yield high levels of the drug in vivo, permitting a simple, twice a day treatment schedule. Furthermore, this combination therapy has proven itself to be an important component in the formulation of successful regimens for patients who have failed prior therapy. While recent data on lopinavir/ritonavir indicate that it likely represents a valuable advance in HIV therapy, important questions remain concerning how and when to best exploit the drug's favorable properties. Should the drug become a routine component of initial combination therapy regimens, or should it be reserved for those individuals who fail their initial ARV treatments? What will be the long-term consequences of the lipid abnormalities seen in many lopinavir/ritonavir-treated patients, and how can these best be managed to minimize their clinical significance? Nevertheless, many patients who exhaust options for successful ARV therapy may now be able to obtain substantial benefit through the carefully considered formulation of salvage therapy regimens that include lopinavir/ritonavir as an active constituent drug.


Based on the results of recent clinical trials, lopinavir/ritonavir (Kaletra™) was granted accelerated approval by the United States Food and Drug Administration (US FDA) on Sept. 15, 2000, for the treatment of HIV infection in adults and children six months and older, in combination with other ARV medications. Findings presented at the 5th International Congress on Drug Therapy in HIV Infection, indicate that lopinavir/ritonavir represents a promising new ARV agent-its favorable pharmacologic properties and pattern of resistance mutations may enable PI-experienced patients whose resident HIV populations harbor multiple baseline mutations to achieve durable suppression of HIV replication.

The rationale for the selective combination of LPV with RTV is found in the ability of RTV to potently inhibit the cytochrome system and alter its own metabolism, as well as those of other PIs. RTV has been proved effective in favorably altering the pharmacokinetics of other PIs, such as saquinavir (Fortovase®, Invirase®) and indinavir sulfate (Crixivan®). As a result of the RTV-mediated increases in plasma drug levels and drug half-lives, a simplified dosing schedule is possible, and drug concentrations can be reached in treated patients that are in excess of the concentrations needed to inhibit the replication of many PI-resistant HIV-variants. It is recommended that lopinavir/ritonavir be given with a patient's choice of food, twice daily for adults, using either three capsules or five milliliters of a liquid formulation (total of 400 mg lopinavir/100 mg ritonavir for each of the two daily doses). The dose for children six months to 12 years is based on weight.

"Within this regimen, lopinavir really provides the antiviral activity, and ritonavir is only there to boost its pharmacokinetics," stated Dr. Kempf, a researcher from Abbott Laboratories. "But because lopinavir is very sensitive to ritonavir, we can achieve very high blood levels with good tolerability." Dr. Anthony Japour, MD, Medical Director for the HIV Franchise at Abbott Laboratories, and closely associated with the design and execution of the clinical studies, stated that "the aggregate clinical studies have demonstrated that Kaletra™ is an important advance for the treatment of HIV-infected persons."

Clinical Trial Results

Adult Studies in Antiretroviral-Naпve Patients

A large, randomized, double-blind, Phase III study compared lopinavir/ritonavir (Kaletra™)-as a component of the initial ARV treatment regimen in ARV-naпve patients-with nelfinavir (Viracept®), both of which are used in combination with stavudine (Zerit®) and lamivudine (Epivir®). In this study the 653 participants enrolled had a mean plasma HIV RNA level of 4.9 log10 copies/mL and a mean CD4+ T-cell count of 259 cells/µL. Data from this study were evaluated using "intent-to-treat" (ITT) analysis (which incorporates data on all study participants, including those who left the study early for any reason and those who were considered treatment failures) and "on-treatment" (OT) analysis, (which includes data for patients who remained on treatment and for whom results were available at a particular timepoint.)

Important endpoints for the study were the suppression of plasma HIV levels to undetectable levels and the extent of durability of antiviral effectiveness. After 48 weeks of therapy, plasma HIV RNA levels, according to ITT analysis, were less than 400 copies/mL in 75% (lopinavir/ritonavir) and 63% (nelfinavir) recipients; according to the same analysis, HIV RNA levels of less than 50 copies/mL were achieved in 67% of lopinavir/ritonavir subjects, and in 52% of nelfinavir recipients (p < 0.001). According to OT analysis, plasma HIV RNA levels were less than 400 copies/mL in 93% versus 82% with lopinavir/ritonavir and nelfinavir, respectively (p < 0.001) and HIV RNA levels < 50 copies/mL achieved by lopinavir/ritonavir and nelfinavir were 83% and 68%, respectively (p < 0.001). Tolerability of the two regimens was similar in both treatment groups, with only 2% (lopinavir/ritonavir) and 4% (nelfinavir) of patients citing adverse events (AEs) as their reason for discontinuation. AEs experienced include: diarrhea, nausea, asthenia, abdominal pain, vomiting, and headache. Genotypic and phenotypic analyses were done on patients with incomplete virologic suppression at week 24. Of those samples analyzed, 0/31 lopinavir/ritonavir and 20/40 nelfinavir subjects showed evidence of phenotypic or genotypic resistance to the PI.

In a second study of treatment-naпve, HIV-infected patients, the combination of lopinavir/ritonavir with stavudine and lamivudine exhibited durable antiviral activity beyond two years of treatment. One hundred ARV-naпve patients were enrolled in a study presented by R. Stryker, MD, Pacific Oaks Research. Median baseline viral load and CD4 cell count were 4.9 log10 copies/mL and 334 cells/µL. Group 1 consisted of 32 patients randomized to either 200/100 mg or 400/100 mg BID lopinavir/ritonavir; 68 patients (Group 2) received either 400/100 mg or 400/200 mg BID lopinavir/ritonavir. After 48 weeks, all patients began open-label dosing of lopinavir/ritonavir 400/100 mg BID.

Kaplan-Meier analysis was performed with loss of response defined as a confirmed viral load ≥400 copies/mL. Ninety seven percent (76/78) of patients who reached week 108 had viral loads <400 copies/mL. According to Kaplan-Meier analysis, 83% of patients were still responding to treatment at week 108.

Only 3 patients discontinued the study on or before week 108 due to drug-related AEs (AST/ALT increases, diarrhea, and arthralgia). Other AEs cited include diarrhea, nausea, abdominal pain, abnormal stools, asthenia, headache, vomiting, and rash. Increases in cholesterol levels (>300 mg/dL) and in triglycerides (>750 mg/dL) were seen in 15% and 13% of participants, respectively.

A study presented by S. Brun, Abbott Laboratories, suggests that lopinavir/ritonavir has a high inhibitory quotient (IQ, Ctrough/EC50 ratio) in wild-type HIV and that it displays antiviral activity in ARV-naпve patients, and in experienced subjects who have demonstrated PI-resistant HIV. Although selection of resistance to lopinavir in vivo in treatment-naпve patients has not been documented, in vitro 11 protease mutations have been associated with decreased susceptibility to lopinavir in viral isolates under selective pressure by other PIs.

Investigators examined the genotype (population sequencing) and phenotype (Antivirogram™ or PhenoSense™) of baseline and rebound viral isolates from adult and pediatric patients, previously treated with other PIs, who initiated combination therapy with lopinavir/ritonavir, an NNRTI, and NRTIs. Subsequently, these patients experienced either a lack of complete response or viral rebound. Four adult and 5 pediatric patients had confirmed baseline lopinavir mutation scores of 0-2. (A mutation score for each baseline isolate is determined by counting the number of protease mutations [10, 20, 24, 46, 53, 54, 63, 71, 82, 84, 90] previously associated with reduced sensitivity to lopinavir/ritonavir). Upon rebound, isolates from each subject were NNRTI-resistant, but remained phenotypically susceptible to lopinavir. These subjects displayed no evidence of genetic selection by lopinavir/ritonavir. The lack of resistance to lopinavir/ritonavir in PI-experienced patients with low mutation scores is consistent with the absence of detectable resistance in ARV-naпve subjects.

Contrasting this result, rebound isolates from 5 treatment-experienced patients who began therapy with baseline mutation scores of 4-5 displayed the concomitant development of resistance to both the NNRTI and to lopinavir/ritonavir. These results suggest that the development of resistance is more likely in the presence of 4-5 mutations. Also important to note is that isolates that developed resistance to lopinavir/ritonavir retained susceptibility or displayed slightly reduced susceptibility to amprenavir (Agenerase™) and saquinavir (Fortovase®, Invirase®). In addition, all post-rebound isolates tested against tipranavir were fully sensitive. This suggests that amprenavir and tipranavir-which demonstrate resistance patterns not similar to lopinavir-may be useful agents to examine with ritonavir's pharmacokinetic enhancement for salvage therapy, especially when lopinavir resistance is present.

In these studies, viral rebound in treatment-naпve, HIV-infected subjects treated with lopinavir/ritonavir has not been associated with the development of resistance. These observations are indicative of the potency of the drug, of a high genetic barrier to resistance to lopinavir/ritonavir, and of the existence of sufficient tolerability to encourage long-term adherence in the population studied.

Pediatric Studies

A Phase I/II open-label study of coformulated lopinavir/ritonavir (Kaletra™) was conducted with 100 HIV-infected ARV-naпve and experienced (but NNRTI-naпve) pediatric (six months to 12 years) patients. Study participants were placed into three categories: Naпve (44), NRTI-experienced (32), and NRTI- and PI-experienced (24). Subjects were randomized to 230/57.5 mg/m2 BID or 300/75 mg/m2 BID of lopinavir/ritonavir. Treatment-naпve patients received stavudine and lamivudine concurrently, and experienced subjects took nevirapine (Viramune®) and one to two NRTIs to supplement lopinavir/ritonavir treatment. After week 12, all subjects switched to the 300/75 mg/m2 BID dose; the switch was due to an interim analysis of tolerability, safety, antiviral activity, and pharmacokinetics.

Treatment-naпve patients were a median age of five years, had a median CD4 count of 920 cells/mm3, and had a median viral load of 4.9 log10 copies/mL at baseline. At week 48, according to ITT (intent-to-treat) analysis, in antiretroviral-naпve, pediatric patients 84% (37/44) achieved HIV RNA levels of < 400 copies/mL. From baseline, these patients experienced a decrease in HIV RNA of 2.21 log10 copies/mL and an increase in CD4 counts of 404 cells/mm3. PI-experienced patients had an average age of six years, a mean baseline CD4 count of 773 cells/mm3, and viral load of 4.5 log10 copies/mL. At week 48, 58% (14/24) had < 400 copies/mL and 54% (13/24) had < 50 copies/mL. From baseline, subjects experienced a decrease in HIV RNA of 1.5 log10 copies/mL and an increase in CD4 count of 238 cells/mm3.

By week 48, only 2/100 subjects discontinued the study-1 participant discontinued due to a drug-related adverse event (pancreatitis). The other discontinuation was due to an HIV-related event (Burkitt's lymphoma). Other AEs noted were: allergic reaction, fever, viral infection, constipation, hepatomegaly, dry skin, and vomiting.

Lopinavir/ritonavir and Relevant Non-PI CYP3A Interactions

As a potent inhibitor of the P450 3A isoenzyme (CYP3A), lopinavir/ritonavir (Kaletra™) has the potential to interact with other drugs that are dependent on the same enzyme for clearance, including those that may be used to counteract the metabolic side effects of its use, such as the observed elevations of cholesterol and triglyceride levels. Noting that the use of various statins is increasingly common among HIV patients for the treatment of dyslipidemias, Dr. Robert Carr, a senior pharmacokineticist at Abbott Laboratories, explored the potential for drug interactions with atorvastatin calcium (Lipitor®) and pravastatin sodium (Pravachol®). Twelve volunteers received four days of treatment with atorvastatin calcium, 20 mg/day, or pravastatin sodium, 20 mg/day, given together both in the presence and absence of lopinavir/ritonavir, in standard doses of 400/100 mg twice a day for 14 days.

"Pharmacokinetic assessments were obtained over a dosing interval for each parent drug, as well as each drug's metabolites," Dr. Carr noted. The statins were taken 30 minutes before breakfast, while lopinavir/ritonavir was taken 30 minutes after breakfast and dinner.

Results indicate that there was a "very significant interaction" with atorvastatin calcium. Specifically, plasma levels of atorvastatin calcium increased approximately six-fold in the presence of lopinavir/ritonavir. "Clinically, this means that if you give atorvastatin in doses of ten milligrams a day, the concentration of [the] parent drug in the blood would be equivalent to a dose of about 60 mg a day, and that does not take into account the effect lopinavir/ritonavir had on the active metabolites," Dr. Carr commented. In contrast, plasma levels of pravastatin sodium increased by approximately 30%, which is not likely to be clinically significant, he added.

"Our advice is to stay with ten milligrams a day if you're using atorvastatin [Lipitor®, with lopinavir/ritonavir] or use another statin [that lopinavir/ritonavir doesn't affect that much], like pravastatin," Dr. Carr concluded.

Dr. Richard Betz, another pharmacokineticist at Abbott Laboratories, in turn, reported that the co-administration of lopinavir/ritonavir with efavirenz (Sustiva®) can reduce the concentrations of lopinavir, and, in particular, the trough concentrations by 40 to 45%. "Efavirenz concentrations were not affected by the co-administration of lopinavir/ritonavir," Dr. Betz noted. Given the high plasma concentration achieved with lopinavir/ritonavir, this interaction may not be that important, Dr. Betz suggested. But in patients who are highly ARV therapy experienced, with multiple genotypic or phenotypic resistance to lopinavir, "the dose [of lopinavir/ritonavir] should probably be increased," Dr. Betz said.

For heavily pre-treated HIV patients, Dr. Betz suggested physicians increase the dose to four capsules twice a day, or 533/133 mg twice a day when lopinavir/ritonavir is combined with efavirenz or nevirapine. "It's up to [a] clinician's judgment to increase the dose or not, but we think that it is most important to do so in highly experienced patients," he confirmed.

Finally, Dr. Betz and colleagues assessed bioequivalence between the liquid and soft gel capsule co-formulations, both of which are approved for HIV therapy in the United States.

"When we looked, in healthy volunteers, at blood concentrations of these two formulations in a cross-over fashion, we found that the liquid and the capsule produced very similar concentrations at the same dose, so they are interchangeable," Dr. Betz said.

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