WO2002092095A1

WO2002092095A1 - Use of nevirapine to treat or prevent lipid pathology in patients with hiv that is resistant to nevirapine

Info

Publication number: WO2002092095A1
Application number: PCT/EP2002/005151
Authority: WO
Inventors: Carl-Heinz Pommer; Julio Sergio González MONTANER
Original assignee: Boehringer Ingelheim International Gmbh; The University Of British Columbia
Priority date: 2001-05-11
Filing date: 2002-05-10
Publication date: 2002-11-21

Abstract

A method for treating or fully or partially preventing lipid abnormalities in patients with HIV that is resistant to nevirapine.

Description

NEVIRAPINE TO TREAT OR PREVENT LIPID PATHOLOGY IN PATIENTS WITH HIV THAT ESISTANT TO NEVIRAPINE

Background of the Invention

( 1 ) Field of the Invention

The invention relates to a method for treating or folly or partially preventing lipid abnormalities in patients with HIV that is resistant to nevirapine. Furthermore, the invention relates to the use of nevirapine for the manufacture of a medicament for treating or folly or partially preventing lipid abnormalities in patients with HIV that is resistant to nevirapine.

(2) Description of the Related Art

The human disease, acquired immunodeficiency syndrome (AIDS), is caused by the human immunodeficiency virus (HIV).

Three classes of drugs are currently known to be effective for the treatment of HIV. The first are the nucleoside reverse transcriptase inhibitors, also known as NRTIs. Exemplars of this class are zidovudine (AZT, Retro vir®.), stavudine (d4T, Zerit®), lamivu- dine (3TC, Epivir®) and didanosine (ddi, Nidex®). Next are the non-nucleoside reverse transcriptase inhibitors, or NNRTIs. Exemplary of this class are nevirapine (Niramune®) and efavirenz (Sustiva®). Finally, there are the protease inhibitors, also known as Pis, typified by, lopinavir (Kaletra®), nelfinavir (Niracept®), indinavir (Crixivan®), ritonavir (Νorvir®), and saquinavir (Invirase®). The NNRTI nevirapine, which is the subject of the present invention, is also known by the chemical name ll-cyclopropyl-5,ll-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'- e][l,4]diazepin-6-one. The synthesis and use of nevirapine as an agent for the treatment of HIV-1 are described in various publications including, inter alia, U.S. Patent No. 5,366,972 and granted European Patent 0429987B1.

HIV mutates rather readily, and mutant strains arise that are resistant to (have reduced sensitivity to) each of the above-mentioned chemotherapeutic agents. Chemotherapy with a given agent will effectively suppress wild-type virus but may permit strains having resistance to that agent to proliferate. Should this happen, further treatment of the infection with that agent, and quite often other members of its class will be ineffective and pointless.

The problem of viral resistance can be avoided to a great degree by using the above- . described chemotherapeutic agents in combination. Thus, monotherapy with these agents is generally to be avoided. Current treatments for HIV typically combine two NRTIs with either a PI or an NNRTI. But even when these agents are used in combination, drug resistance is sometimes seen to emerge over time. According to current best medical practice, when a patient's virus becomes resistant to a given agent, that agent is removed from the therapy regimen and another agent, to the which the virus is not resistant, is added in its place or the regimen may be changed entirely.

Thus, an HIV-infected patient receiving a combination of an NNRTI (such as but not limited to nevirapine) and two NRTIs who develops a virus resistant to the NNRTI would be taken off of the NNRTI and be placed instead on a regimen employing other chemotherapeutic agents. According to current best practices, continued administration of the NNRTI would be contraindicated and there would be no reason for continued therapy with it.

There are various known per se phenotypic and genotypic test methods for determining whether a patient has developed an HIV infection that is resistant to treatment with nevirapine. A typical phenotypic test is marketed by Virco under the servicemark Antivirogram™. HIV isolates of nevirapine resistant patients show a 100 to 150-fold reduced susceptibility to nevirapine.

Typically, a patient who becomes resistant to an NNRTI would be moved to a combination regimen including a PI.

Moving an NNRTI-resistant patient to a treatment regimen employing a PI can, however, be problematic. Treatment with a PI can induce a syndrome that is sometimes loosely termed lipodystrophy. This condition has two distinct aspects. First is an altered deposition of fat in the body, wherein there is a loss of subcutaneous fat from some areas, notably the upper arms and thighs, and increased fat deposition in others, notably the lower adomen and behind the neck and upper back. Second, there are changes in blood chemistry, including increases in total cholesterol and triglycerides, decrease in HDL cholesterol, increases in LDL cholesterol and increases in blood sugar. The changes in cholesterol and triglycerides are of particular concern, as they may lead to atherosclerosis, heart disease and stroke.

Studies have shown that pathological changes in a patient's lipid profile that have been induced by PI administration can be reversed by discontinuation of treatment with the PI and subsequent treatment with nevirapine. Thus, as reported by Gatell, (http://www.thebodv.com/confs/eacs/gatell.html. The 7^th European Conference on Clinical Aspects and Treatment of HIV-Infection, Satellite Symposium: Clinical Advances in the Treatment of HIV Disease, October, 1999) one study showed that patients receiving a combination of of two NRTIs and a PI, who had elevated lipid levels, when switched to a combination of two NRTIs and nevirapine experienced a significant improvement in total cholesterol, which dropped from 230 to 196. Another study confirmed this observation and also showed that triglycerides dropped by 57% after replacement of the PI with nevirapine. Studies have also shown that Pi-induced lipid pathologies can simply be avoided by using a drug combination that employs an NNRTI instead of a PI, and that nevirapine can actually improve a patient's lipid profile even in patients not having been exposed to prior PI usage or any other antiretroviral drug. Thus, Van Der Valk et al. (http://www.thebodv.com/confs/retro2001/saxl0.html The 8th Conference on Retro- viruses and Opportunistic Infections, "Nevirapine Containing Potent Antiretroviral Therapy Results in Ananti-Atherogenic Plasma Lipid Profile: Results from the Atlantic Trial (Poster 654B)", February 4-8, 2001) has reported that in the "Fat Redistribution and Metabolic Sub-study (FRAMS)", a substudy of the so called "Atlantic Study", nevirapine (at a dosage of 400 mg, once per day for 70% of the enrolled patients and at 200 mg twice per day for the remaining 30% of patients) was shown to have a potentially cardio-protective effect on plasma lipids. This study randomized antiretroviral therapy- naive, asymptomatic HIV-positive patients to d4T/ddI plus one of the following: indi- navir, 3TC, or nevirapine. A profile including a striking 38% increase in HDL-c, a decrease in the total cholesterol/ HDL-C ratio, and an increase in HDL size, was ob- served in patients on nevirapine at 24 weeks, but not in patients on indinavir or 3TC.

While Pl-induced lipid pathologies can be treated by switching patients from Pis to NNRTIs, such treatment regimens are not options for patients who have infections that are resistent to the NNRTIs due to prior NNRTI use. In such patients, the antiviral activity previously afforded by the PI cannot be replaced by the NNRTI. The present invention provides a method for treating or folly or partially preventing Pi-induced lipid abnormalities in patients who have HIV that is resistant to nevirapine. The invention further provides a method for treating lipid abnormalities in patients with HIV that is nevirapine resistant wherein the lipid abnormalities is not drug-induced, or wherein it is induced by an agent other than a PI. In a second aspect the invention relates to the use of nevirapine for the manufacture of a medicament for treating lipid abnormalities in patients with HIV that is nevirapine resistant wherein the lipid abnormalities is not drug- induced, or wherein it is induced by an agent other than a PI. Description of the Invention

The present invention provides a method for treating or fully or partially preventing the development of lipid pathologies in an HIV-positive patient with an infection that is resistant to nevirapine. The lipid abnormality may be due to or induced by the administration of an HIV protease inhibitor, some other drug agent, or it may be due to factors not related to the administration of any drug agent. In accordance with the method of the invention, nevirapine is administered to such patient, even though use of nevirapine in patients harbouring a nevirapine-resistant virus is not expected to provide antiretroviral efficacy and therefore not recommended by current medical practice. Used in this manner, nevirapine serves to treat or folly or partially prevent the development of lipid pathologies, whether such lipid abnormalities are due to or induced by the administration of some drug agent, such as but not limited to an HIN protease inhibitor, or due to some other cause not involving the administration of a drug agent. Used for this pur- pose, nevirapine acts to maintain or elevate serum HDL cholesterol, large HDL cholesterol, apoprotein Al and/or lipoprotein Al. Furthermore, for this purpose nevirapine may act to normalize pathological serum triglycerides, e.g. decrease elevated serum triglycerides or prevent increase of triglycerides.

An appropriate patient to receive treatment in accordance with the invention will be a human who is infected with a strain of HTV that is resistant to antiviral therapy with nevirapine. The patient may be resistant to nevirapine because of prior treatment with nevirapine, prior treatment with another ΝΝRTI, or for any other reason. Various strains of HIN are known to be resistant to nevirapine. These include the Y181C mutant [in which the tyrosine (Y) at codon 181 has been mutated to a cysteine (C) residue], which has been the most commonly observed mutant in clinical studies following therapy with many non-nucleoside reverse transcriptase inhibitors, as well as K103Ν, N106A, G190A, Y188C, and P236L. Whether a patient is infected with virus that is resistant to nevirapine therapy can be assessed by way of genotypic or phenotypic testing. An appropriate patient to receive treatment in accordance with the invention will be one who has already developed a lipid abnormality, regardless of the cause of the lipid abnormality. Such lipid abnormalities may be due to, for example, genetic predisposition, diet, or the administration of some drug substance such as but not limited to an HIN- protease inhibitor. In such case, nevirapine is administered to treat the pre-existing lipid abnormality.

Alternatively, an appropriate patient to receive treatment in accordance with the invention will be one who is currently undergoing treatment for HIN infection with a drug that is known to induce lipid abnormalities. Such drugs include but are not limited to the class of HIV-protease inhibitors. In turn, this class includes but is not limited to lopinavir (Kaletra®), nelfinavir (Viracept®), indinavir (Crixivan®), ritonavir (Νorvir®), and saquinavir (hivirase®). For best antiviral effectiveness, a protease inhibitor will typically be administered in combination with one or more drugs be- longing to the class of nucleoside reserve transcriptase inhibitors (ΝRTIs), although, co- administration of an ΝRTI does not constitute a necessary part of treatment in accordance with the present invention. In such case, nevirapine will be administered to folly or partially prevent the induction of a lipid abnormality by the other drug or to treat it if it has already arisen.

A patient will be considered to have a lipid abnormality if his level of serum high density lipoprotein-bound cholesterol (HDL-c) is below 40 or if the ratio of total cholesterol to HDL exceeds 4.5.

When used in accordance with the present invention, nevirapine may be administered in manners that are known per se or conventional. That is to say, nevirapine may be administered in the manner described in U.S. Patent No. 5,366,972 or European Patent No. 0 429 987B1.

For the purpose of practicing the present invention, nevirapine may be most conveniently administered orally in the form of tablets, such those approved for sale in the United States under NDA 020636, or in the form of an oral suspension, such as that approved for sale in the United States under NDA 020933. Thus, a typical tablet dosage form might comprise 200 mg of nevirapine and, as inactive ingredients, microcystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. A typical oral suspension would be one made in accordance with the teachings of US Patent 6,172,059.

When used in accordance with the present invention, nevirapine may be administered at the same dosages that have been clinically determined to be optimal for treatment of infection by HIV. In accordance with current practice, a patient receiving nevirapine as antiviral therapy would be given 200 mg per day (4 mg/kg in pediatric patients) for 14 days, and thereafter 200 mg twice per day (4 or 7 mg/kg twice daily, according to age, for pediatric patients). However, as nevirapine is being used in the present context for the purpose of correcting a patient's lipid profile, and not primarily for its antiviral effect, it may be admimstered at a dosage that is lower than that ordinarily considered optimum for treatment of infection by HIV. Employing such a lowered dosage may serve to avoid side effects sometimes encountered at optimum antiviral dosages. The dosage used need only be sufficient to therapeutically elevate HDL-c, large HDL cholesterol, apoprotein Al and/or lipoprotein Al, to normalize pathological serum triglycerides, e.g. decrease elevated serum triglycerides or prevent increase of triglycerides. Thus, the daily dosage of nevirapine maybe as low as 25 mg per day (0.5 mg/kg in pediatric patients).

In accordance with the present invention, nevirapine may be administered at a dosage in the range between 25 and 400 mg per day for an adult patient. Preferred dosage subranges are 25 to 200 mg per day, 25 to 150 mg per day or 50 to 150 mg per day for an adult patient.

Pharmaceutical compositions suitable for the method in accordance with the present invention may be specially adapted to the dosage requirements mentioned hereinbefore. For example, such pharmaceutical compositions comprise tablet dosage forms com- prising nevirapine in an amount of 25 up to 150 mg, optionally together with inactive ingredients such as microcystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate.

In order to folly or partially prevent the development of lipid pathologies in an HIV- positive patient with an infection that is resistant to nevirapine and who is undergoing antiviral therapy that includes the administration of an HIV protease inhibitor, a kit of parts could be used comprising

(a) a first containment containing a pharmaceutical composition comprising nevirapine in an amount of 25 up to 400mg;

(b) a second containment comprising an HIV protease inhibitor.

Preferred kit of parts comprise in the first containment 25 to 200 mg of nevirapine, more preferred 25 to 150 mg or especially preferred 50 to 150 mg of nevirapine.

Normally, nevirapine should not be administered to patients infected with strains of HIV that are known to be resistant to treatment using nevirapine. Nevirapine will not effectively treat the infection in such patients, and such use would not be in accordance with accepted medical practice. Although it would seem to contravene such accepted medi- cal practice , nevirapine may be beneficially administered in accordance with the present invention to a patient infected with a strain of HIV that is resistant to therapy with nevirapine. This is possible because in the context of the present invention nevirapine acts to alter the lipid profile and is not relied upon for its antiviral effect. The antiviral activity is supplied by the protease inhibitor and other co-administered antiviral agents.

Claims

What is claimed is:

1. A method for treating or folly or partially preventing the development of a lipid pathology in an HIV-positive patient with an infection that is resistant to nevirapine, which method comprises administering nevirapine in an amount sufficient to maintain or elevate serum levels of HDL cholesterol, large HDL cholesterol, apoprotein Al or lipoprotein Al .

2. The method of claim 1 wherein nevirapine is administered at a dosage in the range between 25 and 400 mg per day for an adult patient or between 0.5 and 4 mg/kg for a pediatric patient.

3. The method of claim 1 wherein the patient has a preexisting lipid abnormality and nevirapine is administered for the purpose of treating such lipid abnormality.

4. The method of claim 3 wherein the lipid abnormality is due to or induced by the administration of an HIV protease inhibitor.

5. The method of claim 1 wherein the patient does not have a preexisting lipid abnormality but is undergoing treatment with an agent or drug known to induce lipid abnormalities and wherein nevirapine is administered to folly or partially prevent the induction of lipid abnormalities by such other agent or drug.

6. The method of claim 5 wherein the other agent or drug is an HIV protease inhibitor.

7. Use of nevirapine for manufacturing a medicament for treating or folly or partially preventing the development of a lipid pathology in an HIV-positive patient with an infection that is resistant to nevirapine wherein the medicament comprises an amount of nevirapine sufficient to maintain or elevate serum HDL cholesterol, large HDL cholesterol, apoprotein Al and/or lipoprotein Al.

8. The use of claim 7 wherein the medicament is adapted for the administration of nevirapine in an amount of 25 up to 400 mg per day for an adult or between 1 and 4 mg/kg for a pediatric patient.

9. The use of claim 7 or 8 wherein the patient has a preexisting lipid abnormality and nevirapine is administered for the purpose of treating such lipid abnormality.

10. The use of claim 9 wherein the lipid abnormality is due to or induced by the ad- ministration of an HIV protease inhibitor.

11. The use of claim 7 or 8 wherein the patient does not have a preexisting lipid abnormality but is undergoing treatment with an agent or drug known to induce lipid abnormalities and wherein the medicament comprises an amount of nevirapine suffi- cient to folly or partially prevent the development of lipid pathologies.

12. The use of claim 11 wherein the agent or drug known to induce lipid abnormalities is an HIN protease inhibitor.

13. Tablet dosage form comprising nevirapine in an amount of 25 up to 150 mg, optionally together with inactive ingredients, suitable for folly or partially preventing the development of a lipid pathology in an HIV-positive patient with an infection that is resistant to nevirapine.