Kaletra: Advancing the Fight Against HIV

The world first became aware of clinical implications of human immunodeficiency virus (HIV) in June 1983, when Morbidity and Mortality Weekly Report published a case series describing five previously healthy homosexual Caucasian men who were infected with pneumocystis pneumonia, an opportunistic infection now associated with Acquired Immune Deficiency Syndrome (AIDS). Since that time, it is estimated that over 25 million individuals have died because of AIDS.

Race Against Time to Save Lives

The introduction of protease inhibitors in the mid-1990s revolutionized treatment of HIV, reducing HIV to undetectable levels in many patients and dramatically decreasing the death rate due to HIV/AIDS. However, these drugs were often not well tolerated, had a high occurrence of side effects, and had inconvenient dosing schedules, making it difficult to promote adherence in patients. Moreover, if the therapies did not sufficiently suppress the replication of the virus, it displayed an immense capacity to mutate and quickly became resistant to the drugs. Consequently, while HIV drugs were at least partially effective in most cases, there was a large medical need for more potent and better-tolerated drugs to treat the disease.

Abbott's Quest for a Better HIV Drug

In 1996, after 12 years of searching for a treatment, Abbott scientists were among the first to deliver a potent protease inhibitor to HIV-positive patients. Norvir® (ritonavir) represented a significant step forward in HIV treatment and was the only drug of its class approved for use in both adults and children as young as six months of age.

Drawing on their extensive experience in drug design and knowledge of HIV, our researchers set out to develop a drug that would have all of the features of a durable HIV treatment: strong potency to suppress the virus, the ability to reduce the development of HIV mutations and be well-tolerated. The result was Kaletra® (lopinavir/ritonavir), an antiretroviral agent that has changed the lives of many people living with HIV and helped provide hope even for patients who have failed other anti-retroviral (ARV) therapies. A novel co-formulation, Kaletra contains a potent inhibitor of HIV protease (lopinavir) along with ritonavir, an anti-retroviral agent that helps block the breakdown of lopinavir in the liver. The United States Food and Drug Administration (FDA) granted accelerated approval to Kaletra in September 2000.

Technological Significance: Abbott's Ingenuity and an Advanced Generation Protease Inhibitor

The substantial impact of Kaletra on HIV therapy is based on a key scientific principle that high and steady levels of the drug in the blood are necessary to control the replication of the virus. Drawing on this principle, Abbott scientists introduced two key breakthroughs that provide the foundation for the success of Kaletra.

Protease inhibitors work by binding to their target enzyme, an essential component of the HIV virus, and blocking the action of that enzyme. The first breakthrough was a technological advance made possible by understanding the intimate three-dimensional molecular details of that interaction. To understand how HIV becomes resistant, the Abbott scientists characterized the mutations in the virus that effectively push the drugs out of their binding site, rendering them ineffective. By avoiding the part of the binding site that changed during these mutations, they designed a drug that potentially could be effective against many drug-resistant strains of HIV. Kaletra is the first therapy for HIV to be designed to address the problem of resistance.

The second advance was the recognition that lopinavir and ritonavir competed for the same drug metabolizing enzymes and when given together, allowed lopinavir to enter the patient's bloodstream and remain at high concentrations. Lopinavir, one of the antiviral components of Kaletra, is rapidly removed from the blood by the liver. Our scientists observed that co-administration of ritonavir helped block the metabolism (breakdown) of lopinavir and therefore "boosted" the effectiveness of lopinavir. Co-administration of ritonavir slows the clearance of lopinavir from the body.

The concept of "boosting with ritonavir" that Abbott observed in the development of lopinavir is now adopted widely by the industry, and currently many protease inhibitor therapies are boosted with ritonavir. Lopinavir and ritonavir both bind competitively to the same metabolizing enzyme and hence because of the "ritonavir boosting" lopinavir remains at high concentrations in the blood between doses to help suppress the HIV virus.

Kaletra is an effective anti-ARV medication to treat HIV. Kaletra is always used in combination with other ARV drugs.

Kaletra has provided an important tool for better defining therapeutic paradigms necessary for successful HIV therapy. It is the first antiretroviral agent for which a quantitative pharmacokinetic/pharmacodynamic relationship is defined. Clinical trials with Kaletra have provided a significant advance in our understanding of how potency and blood levels contribute to efficacy and ability to suppress the emergence of resistant virus.

Impact of Kaletra: Children with HIV

Children are susceptible to and suffer from many of the same diseases as adults. One area where there was a great unmet medical need is children with HIV.

According to reports published by the Joint United Nations Programme and HIV/AIDS (UNAIDS) and the World Health Organization in 2006, as many as 2.3 million children around the world are living with HIV/AIDS. Infection with HIV during childhood is associated with challenging virologic and clinical features that interfere with the response to antiretroviral (ARV) therapy. Among these are very high plasma viral loads, the presence of a developing immune system with limited reaction capacity and the lack of suitable, tolerable and palatable ARV therapies for children. As a result, HIV-infected children are more likely to have rapid disease progression and may develop substantial HIV resistance to existing ARV therapies.

In a clinical trial conducted by Abbott, 80 percent of antiretroviral treatment of naive children from 6 months to 12 years of age treated with Kaletra, in combination with reverse transcriptase inhibitors, achieved viral suppression measuring less than 400 copies/mL at week 48 of treatment. The tolerability of the Kaletra liquid formulation is reflected by the observation that only one patient in the study discontinued therapy for adverse events through 48 weeks. Scientists concluded that the liquid co-formulation of lopinavir/ritonavir demonstrated durable antiviral activity and was well-tolerated after 48 weeks of treatment in HIV-positive children. Based on this study, the FDA approved the oral liquid for use in pediatrics from age 6 months to 12 years.The reasons for these results are, in large part, related to the Kaletra formulation, which resulted in convenient twice daily dosing combined with tolerability as noted above.

For bringing health and hope to children with HIV around the world, three Abbott scientists – Dale Kempf, Dan Norbeck and Hing Sham – were honored as 2003 Heroes of Chemistry by the American Chemical Society (ACS), the world's largest scientific organization. ACS President Elsa Reichmanis, Ph.D said, "The broad range of invaluable products that our Heroes of Chemistry 2003 have developed and commercialized has dramatically advanced the health, well-being, and lifestyles of children around the world. The chemical advances made by the honorees serve as testimonials to the valuable role chemists and chemical engineers play in improving lives. It is with pride that the ACS recognizes them as Heroes of Chemistry."

Continuing Efforts to Improve HIV Therapy

Our scientists' work on improving Kaletra has continued. In the spirit of continuing innovation, Abbott succeeded in using Meltrex™, our proprietary melt-extrusion technology, to effect yet another improvement to Kaletra. The original formulation of Kaletra was in soft-gel capsule form, allowing lopinavir and ritonavir, compounds with low solubility, to be uniformly suspended in a solution of inactive ingredients. Meltrex technology helps solve the problem of poor solubility by evenly distributing the active ingredients and inactive ingredients into a solid polymer matrix that is pressed into tablets. Kaletra is the first co-formulated medication manufactured using a melt-extrusion process.

The tablet form of Kaletra, called Aluvia™ in some countries, is equally effective when taken with or without food, and provides the same amount of bioavailable drug in fewer pills per day than the original Kaletra capsules, and does not need to be refrigerated. This latest innovation, in addition to offering added convenience and tolerability, is a major step in improving access to Kaletra in areas where refrigeration or refrigerated transport is not available. In fact, in 2006, the World Health Organization guidelines stated that lopinavir/ritonavir tablets are the preferred protease inhibitor in resource-restricted societies.

Abbott received U.S. Food and Drug Administration (FDA) approval for a new lower-strength formulation of Kaletra. We also recently received European Medicines Agency approval for a lower strength tablet of Kaletra that is suitable for pediatric use.

For important product information, please access:

• Norvir (ritonavir)
  • U.S. Prescribing Information
  • Important Safety Information
• Kaletra (lopinavir/ritonavir)
  • U.S. Prescribing Information
  • Important Safety Information