Nobel Hiv-1 Protease Inhibitors
By - 10/04/2005
Dr. Vishal R.Tandon
The HIV protease is essential for viral infectivity and cleaves the viral polyprotein
(gag-pol) into active viral enzymes (reverse transcriptase, protease and integrase)
and structural proteins. Thus, protease enzyme involved in the production of
structural proteins and enzymes of virus as well as for maturation of new viral
particle. All available protease inhibitors act by binding reversibly to the
active site of HIV protease. This prevents the protease from cleaving the viral
precursor polypeptide and blocks subsequent viral maturation1. Resistance
to these agents is generally by stepwise accumulation of mutations of the protease
gene and is growing rapidly1. Therefore, there is always a need for
newer protease inhibitors for the effective treatment of HIV infections. Atazanvir
and fosamprenavir are two recently approved HIV-1 protease inhibitors.
Atazanavir,( BMS-232632)2-5: is a type of antiretroviral agent called a protease inhibitor (PI). It blocks protease, a protein that HIV needs to make more copies of it. It is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Atazanavir does not care HIV or prevent passing HIV to others.
Mechanism of action: atazanavir, an azapeptide HIV-1 protease inhibitor, selectively inhibits the virus specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, preventing formation of mature virions. Atazanavir exhibits anti-HIV-1 activity with mean EC50 in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. FDA approval of this drug in July, 2003 was based on three randomized phase III studies. First randomized, double-blind, multi-center trial showed that 67% of the subjects in the Atazanavir plus lamivudine/zidovudine group responded to treatment compared with 62% of subjects in the efavirenz plus lamivudine/zidovudine group. Response was based on subjects that achieved and maintained confirmed HIV RNA<400 copies/ml through all 48 weeks. Data also demonstrated that 20% of subjects in the atazanavir plus lamivudine/zidovudine group achieved virologic failure compared with 21% of the subjects in the efavirenz plus lamivudien/zidovudine group. Virologic falure subjects had confirmed viral rebound and failure to achieve confirmed HIV RNA <400 copies/ml through all 48 weeks of the trial. In the second trial the results showed that 67% of subjects in atazanavir plus lamivudine/stavudine group responded to treatment compared with 59% of subjects in the nelfinavir plus lamivudine/stavudine group.Whereas, virologic failure in 24% of subjects with atazanavir plus lamivudine/stavudine group in comparison to 27% in nelfinavir pluse lamivudine/stavudine group was found. The third study was a randomized, open label, multi-center comparing atazanavir (400mg) once a daily to lopinavir plus ritonavir (400/100mg) twice a daily, each in combination with two nucleosides (NRTIs) was studied. The results showed that 54% of subjects in the atazanavir plus two NRTIs group responded to treatment (HIV RNA <400 copies/ml) compared with 75% subjects in the lopinavir plus ritonavir plus two NRTIs group.
Adverse events: associated with the use of atazanavir may include headache, nausea, rash, abdominal pain, jaundice, vomiting and diarrhea.
Atazanavir capsules are available for oral administration in the strength containing the equivalent of 100mg, 150 or 200mg once a daily use.
Fosamprenavir calcium (formely GW433908 or 908)6-9: is a new protease inhibitor (PI) for the treatment approved by Food and Drug Administration (FDA) in October, 2003. It is a pro-drug of amprenavir, an inhibitor of HIV protease. It is indicated for the treatment of HIV infection in adults in combination with other antiretroviral agents.
Mechanism of action: fosamprenavir is rapidly converted to amprenavir, an inhibitor of HIV-1 protease, by cellular phosphatases in vivo. Amprenavir binds to the active site of HIV-1 protease preventing the processing of viral Gag and Gag-Pol polyprotein precursors. This results in the formation of immature non-infections viral particles.
FDA approval of this drug was based on three pivotal phase III trials with both therapies native and experienced. The first trial was design to compare treatment with fosamprenavir (1,400 mg twice daily) against nelfinavir (1,250mg twice a daily). Both groups also received abacavir (300 mg twice a daily) and lamivudine (150 mg twice daily). Results showed that the median increases of CD4+cell counts from baseline were 201 cells/mm3 in the fosamprenavir group and 216 cells/mm3 in the nelfinavir group. The second trial compared treatment with fosamprenavir plus ritonavir versus nelfinavir. Both treatment groups also received abacavir and lamivudine. Results showed that median increase of CD4+cell counts from baseline were 203 cells/mm3 in the fosamprenavir group and 207 cells/mm3 in the nelfinavir group. Whereas the third trial was design to compare fosamprenavir (700mg twice a daily) plus ritonavir (100mg twice a daily) or fosamprenavir (1,400mg once a daily) plus ritonavir (200mg once a daily) versus lopinavir/ritonavir (400/100mg twice a daily) in 315 subjects who had experienced virologic failure to 1 or 2 prior protease containing regimens. Results showed that the time averaged changes in plasma HIV-1 RNA from baseline were 1.4 log 10 copies/ml for twice a daily fosamprenavir/ritonavir and 1.67 log 10 copies/ml for lopinavir/ritonavir group. Data demonstrated that 58% of subjects taking fosamprenavir plus ritonavir twice a daily achieved and HIV-1 RNA of under 400 copies/ml versus 61% of subjects taking lopinavir plus ritonavir. However, this study was not large enough to achieve a definitely conclusion that fosamprenavir/ritonavir and lopinavir/ritonavir are clinically equivalent.
Side effects: associated with the use of fosamprenavir may include diarrhea, nausea, vomiting, headache and rash.
The recommended dosage of fosamprenavir for therapy naive patients is 1,400 mg twice daily. The recommended dosage of fosamprenavir for protease inhibitor experienced patients is 700 mg twice a daily.
In conclusion: HIV infection is one of the biggest challenge today for the medical community because of emergence of multiple drug resistant virus among patients treated with current anti-AIDS treatment. Hence, continuous search is on to find out better drugs therefore, these two newly approved HIV-1 protease inhibitors may prove useful in the treatment of HIV infection in future.
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About Author
Dr Vishal R.Tandon has received his doctorate in Pharmacology from Nagpur University,
Maharashtra (India) in Dec, 2002.He has authored and/or coauthored over 55 publications
in many national and international journals. Two chapters in different national
books are also to his credit. His research interests include herbal drug screening,
especially working on plant Vitex negundo. He is Expertise in designing and
conducting clinical trials. He is currently working as Senior Demonstrator Post
graduate department of pharmacology and therapeutics, GMC, Jammu (J&K)-India.
His current job responsibilities include teaching UG/PG classes as well as supervising
research. He bears following post, a) Editorial Secretary JK-SCIENCE,
Journal of Medical Education & Research. This Journal is indexed in Excerpta
Medica/EMBASE, Ulrich periodical Dictionary& Indian Science Abstract. b)
Secretary-Indian Rheumatology Association-J&K CHAPTER. c) Pear reviewer
World Journal of Medical Science. He is also life Member of Indian Pharmacological
society, Association of Physiologist and Pharmacologist of India, Indian Rheumatology
Association and Indian Menopause Society.
Correspondance address:
Dr. Vishal Tandon, (Senior Demonstrator) (MD)
Post Graduate Department of Pharmacology & Therapeutics
GMC, Jammu (J&K) India - 180001.
Email: dr_vishaltandon@yahoo.com
Phone 09419195126