Australasian Society for HIV Medicine

According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), in 2006, an estimated 2.3 million children under the age of 15 were living with HIV/AIDS worldwide; a vast majority - 2 million children with HIV/AIDS - were living in Africa. Last year alone, an estimated 530,000 children were infected with HIV, and 380,000 children died of AIDS (1).

The European Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), has recently issued a positive opinion recommending approval of a new, lower-strength tablet formulation of Abbott's leading HIV protease inhibitor, Kaletra® (lopinavir/ritonavir) (2). In addition, the CHMP has adopted a positive opinion, in coordination with the World Health Organization (WHO), for Aluvia® (lopinavir/ritonavir), the trade name of the same lower-strength tablet formulation in developing countries. Lopinavir/ritonavir tablet is the first and only co-formulated protease inhibitor tablet approved for use in children with HIV. The new lower-strength formulation is suitable for paediatric use and represents a significant breakthrough for clinicians and patients in developing countries, where more than 2 million of the estimated 2.3 million children worldwide with HIV/AIDS live. The first and only co-formulated protease inhibitor tablet that can be used in children, the tablets do not require refrigeration and can be taken with or without a meal - an important advance in delivering HIV medicine in developing countries.

The European Commission will review the CHMP's positive opinion for Kaletra and is expected to issue a final decision for marketing authorisation for the lower-strength Kaletra in the European Union within the next 60-90 days. The regulatory review processes in many developing countries require products to receive positive opinion from the CHMP, the scientific committee of the EMEA. The positive opinion is necessary for obtaining a Certificate of Pharmaceutical Product (CPP) - often a prerequisite for regulatory filing in developing countries. In order to expedite review in developing countries, Abbott is working with regulatory agencies on a country-by-country basis to negotiate submissions before the CPP is available. The price of the recently approved lower-strength tablet will be half the price of the original-strength tablet everywhere it is available.

Based on the US Food and Drug Administration (FDA) approval on 9 November  2007, Abbott is shipping the lower-strength tablets to countries that have issued approved waiver orders. On 1 December 2007, Uganda, the first country to issue such a waiver order, was one of the first countries in the world - and the first country in Africa - to receive the lower-strength tablets. The Ugandan Government's early approval of the waiver allowed Dr Victor Musiime of the Joint Clinical Research Centre in Kampala to write the first prescription for the lower-strength tablet just days after the product received marketing authorisation in the United States. Other African governments are now also talking to Abbott about the possibility of waiver shipments. According to UNAIDS, an estimated 110,000 Ugandan children were living with HIV in 2005.

The WHO recommends lopinavir/ritonavir as the preferred treatment for children who no longer respond to first-line HIV medicine. The US Department of Health and Human Service recommends lopinavir/ritonavir for the initial treatment of children with HIV.

The new tablet formulation will complement Kaletra oral solution, which has been available for paediatric use since its approval in September 2000 in the United States. For paediatric patients, lower-strength Kaletra tablets will offer more dosing flexibility and contains 100mg of lopinavir and 25mg of ritonavir, compared with the original tablet strength of 200mg of lopinavir and 50mg of ritonavir, most commonly used by adults. Kaletra is indicated for the treatment of HIV-1 infected adults and children above the age of two years. It is used in combination with other antiretroviral agents.
Kaletra Important Safety Information (3).

Globally, prescribing information varies; refer to the individual country product label for complete information. Kaletra should not be taken by patients who have had an allergic reaction to any of its ingredients, including lopinavir or ritonavir, or any of the excipients, or by patients with severe liver problems. Taking certain medications with Kaletra could cause serious side effects that could be life threatening. Do not take Kaletra with astemizole, terfenadine, midazolam, triazolam, pimozide, cisapride, ergotamine, dihydroergotamine, ergonovine, and methylergonovine, rifampicin, amiodarone, vardenafil and products containing St. John's Wort (Hypericum perforatum). Medical advice and approval must be sought before Kaletra is taken with medicines that lower blood cholesterol (e.g. lovastatinor simvastatin), some medicines affecting the immune system (e.g. cyclosporin, sirolimus (rapamycin), tacrolimus), various steroids (e.g. dexamethasone, fluticasone propionate, ethinyl oestradiol), other protease inhibitors, certain heart medicines such as calcium channel antagonists, (e.g. felodipine, nifedipine, nicardipine) and medicines used to correct heart rhythm (e.g., bepridil, systemic lidocaine, quinidine), antifungals, (e.g., ketoconazole, itraconazole), morphine-like medicines (e.g. methadone) anticonvulsants (e.g. carbamazepine, phenytoin, phenobarbital), warfarin, certain antibiotics (i.e., rifabutin, clarithromycin), certain antidepressants (e.g. trazodone) and voriconazole. Kaletra may interact with erectile dysfunction agents (e.g. sildenafil or tadalafil). Lower doses of these medicines should be prescribed in patients taking Kaletra. Kaletra may interact with digoxin (heart medicine); monitoring by a physician is recommended. Taking Kaletra with certain medicines can cause increased levels of these other medicines in the body. This could increase or prolong their effects and/or adverse reactions, which may result in serious or life-threatening problems. Because of this, patients must tell their doctor about all medicines they are taking or planning to take, including those medicines that can be bought without a prescription and herbal preparations. Patients using an oral contraceptive or using a patch contraceptive to prevent pregnancy should use an additional or alternative type of contraception since Kaletra may reduce the effectiveness of these products. Pregnant or nursing mothers should not take Kaletra unless specifically directed by their doctor. Kaletra oral solution contains 42% alcohol. While taking Kaletra oral solution, patients should not take any medicines that may cause a reaction with alcohol such as disulfiram. It is important that Kaletra oral solution is taken with food. Kaletra tablets may be taken with or without food.

Cases of pancreatitis have been reported in patients taking Kaletra. Liver problems, which can be fatal, have also been reported. Patients should tell their doctor if they have had liver disease such as chronic hepatitis B or C as they are at increased risk for severe and potentially fatal liver adverse events. These patients may require blood tests for control of liver function.
Redistribution, accumulation or loss of body fat may occur in patients receiving combination antiretroviral therapy. Patients should contact their doctor if they notice changes in body fat. In patients taking protease inhibitors, increased bleeding (in patients with hemophilia type A and B) has been reported. Combination antiretroviral therapy may cause new cases of diabetes and high blood sugar or worsening of existing diabetes, as well as increased fats and raised lactic acid in the blood. The long-term risks for complications due to increases in triglycerides and cholesterol are not known at this time. In addition, large amounts of triglycerides have been considered a risk factor for pancreatitis.

In some patients with advanced HIV infection and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. Symptoms of infection should be reported to a doctor immediately.

Some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis. Signs and symptoms are joint stiffness, aches and pains (especially in the hip, knee and shoulder) and difficulty in movement. These symptoms require that patients contact their doctor.
In lopinavir/ritonavir lopinavir/ritonavir adult clinical trials, the very commonly reported (>1 out of 10 persons treated) and commonly reported (less than 1 out of 10 but more than 1 out of 100 persons treated) side effects of moderate to severe intensity were diarrhea, insomnia, headache, nausea, vomiting, abdominal pain, abnormal stools, dyspepsia, flatulence, gastrointestinal disorder, rash, lipodystrophy, weakness, and abnormal liver enzymes. This is not a complete list of reported side effects. In children two years of age and older, the safety profile is similar to that seen in adults. In children two years of age and older, the safety profile is similar to that seen in adults.

References and links

(1) Joint United National Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO) AIDS epidemic update December 2006 Link to resource: http://data.unaids.org/pub/EpiReport/2006/2006_EpiUpdate_en.pdf

(2) Abbott's Kaletra® and Aluvia® (lopinavir/ritonavir) New Lower-Strength Tablet for Pediatric Use Receives Positive Opinion from EMEA Press release link: http://www.abbott.com/global/url/pressRelease/en_US/60.5:5/Press_Release_0569.htm

(3) Indication and Important Safety Information about KALETRA
Resource link: http://www.kaletra.com/

Footnote: ASHM Members are invited to contribute to ASHM Latest News page with articles under headings of Education, Training, Clinical Issues, Conferences, Resources, International and Research. Please forward information to Paul McQueen (email: paul.mcqueen@ashm.org.au).