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A competitive edge

Advances in fixed-combination antiretrovirals are key to improving the treatment of HIV

Men running a race with the leader in the middleHuman immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). The virus is transmitted via semen, blood and breast milk, and can also be transmitted from an infected mother to her baby at birth via the placenta. AIDS has killed tens of millions of people since it was discovered in 1981, and is now one of the leading causes of death worldwide.

HIV infects cells of the immune system, destroying or impairing their function. HIV searches for cells that have CD4 surface receptors, because this particular protein enables the virus to bind to the cell. Although HIV infects a variety of cells, its main target is the T lymphocyte (also called the helper T cell), a type of white blood cell that is abundant with CD4 receptors. The HIV virus cannot be destroyed and lives undetected in the body for months or years before any signs of illness appear.

According to the US Centers for Disease Control and Prevention (CDC), a person is considered to have AIDS when they have a CD4+ cell count of no more than 200 cells/μL (normal CD4+ cell counts range from 500-1500 cells/μL) or when they have an AIDS-defining condition. Guidelines have been published by the CDC to indicate the commencement of treatment according to viral load and CD4+ cell count.

There is no cure for HIV, but antiretroviral drugs are used to slow the reproduction of the virus. When used in combination, these drugs are known as Highly Active Antiretroviral Therapy (HAART). HAART combines three or more antiretrovirals in a daily regimen. There have been three classes of antiretrovirals available for some time: HIV protease inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several newer antiretroviral classes have also been developed.

Antiretroviral regimens can be extremely complicated, requiring patients to take several pills every day. The development of antiretroviral resistance is also a considerable problem which leads to virological failure and, in many cases, necessitates a change in drug regimen. Hence, the focus in recent years has been on improving adherence to therapy and delaying the occurrence of antiretroviral resistance.

HIV entry inhibitors
Treatment options continue to improve as new drugs enter clinical trials. Entry inhibitors are a newer class of antiretroviral which interfere with the binding, fusion and entry of the virus to a new cell. There are two currently approved entry inhibitors: enfuvirtide (Fuzeon; Roche) and maraviroc (Selzentry; Pfizer). Enfuvirtide is also known as a fusion inhibitor, and binds to an HIV protein called gp41. Maraviroc binds to CCR5, a chemokine receptor found on the surface of CD4+ cells. It is also known as a CCR5 receptor antagonist. Maraviroc has been launched in Canada, Japan, the US and the European Union (EU) for the treatment of HIV-1 infections in antiretroviral-experienced patients.

Two other CCR5 antagonists are currently being developed: vicriviroc and TBR 652. Vicriviroc is in phase III development with Merck & Co in treatment-experienced patients with HIV-1 infections. Vicriviroc will also be used in combination with ritonavir-boosted atazanavir in phase II/III trials in treatment-naïve patients.

TBR 652 is currently being developed by Tobira Therapeutics. A phase IIa proof-of-concept trial evaluated the antiviral activity, safety and pharmacokinetics of TBR 652 in treatment-experienced, CCR5-naïve patients with HIV-1 infections. The study took place in Argentina and the US, with results presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI). Lead investigator David Martin said: "These data demonstrate a clear and consistent relationship between TBR 652 plasma concentrations and antiviral activity. TBR 652's potent, dose-dependent decreases in viral load, obtained without the need for a ritonavir-boost, illustrate the potential for this compound in fixed-dose antiretroviral drug combinations for the treatment of HIV disease".

 

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HIV integrase inhibitors
HIV integrase inhibitors are another relatively new antiretroviral drug class designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Raltegravir (Isentress; Merck & Co) was the first integrase inhibitor to be approved, and has been launched for the treatment of HIV-1 infections in treatment-experienced patients. Two ongoing pivotal phase III trials (BENCHMRK-1 and -2) are comparing raltegravir and placebo as an adjunct to optimised background therapy. A phase I/II trial (IMPAACT) is currently underway to investigate the efficacy and tolerability of raltegravir in treatment-experienced children and adolescents with HIV-1 infections.

Two other HIV integrase inhibitors currently being developed are elvitegravir and GSK 1349572. Elvitegravir is being developed by Gilead Sciences and Japan Tobacco. Elvitegravir is currently undergoing phase III development in Australia, Canada, the EU, Puerto Rico, Switzerland and Japan.

GSK 1349572 is being developed by Shionogi-GlaxoSmithKline Pharmaceuticals and ViiV Healthcare. A phase IIb trial has been planned and phase III trials are expected to begin before the end of 2010. In vitro data suggest that GSK1349572 has a resistance profile distinct from raltegravir and elvitegravir. At the 17th CROI, Dr Dominique Limet, chief executive officer of ViiV Healthcare said: "We are committed to advancing GSK1349572, as integrase inhibitors represent an important new class of medications for treating patients with HIV."

Fixed Combinations
Fixed-dose combinations are multiple antiretroviral drugs combined into a single pill. Their use helps to reduce pill burden, improve patient adherence and enhance the effectiveness of antiretroviral therapy over the long-term. There are several licensed fixed-dose combinations currently available, including lamivudine/zidovudine (Combivir; GSK), lopinavir/ritonavir (Kaletra; Abbott Laboratories) and emtricitabine/tenofovir disoproxil fumarate (Truvada; Gilead Sciences).

An exciting new four-in-one fixed-dose tablet, known as "Quad", has been developed by Gilead Sciences. Quad combines elvitegravir, emtricitabine 200mg, tenofovir disoproxil fumarate 300mg and GS 9350. GS 9350 is a potent inhibitor of cytochrome P450 3A and does not have any anti-HIV activity. As such, Gilead is developing GS 9350 as a booster to increase plasma concentrations of concomitant antiretroviral in an effort to allow once-daily dosing. According to Dr Norbert Bischofberger, Research and Development and chief scientific officer at Gilead Sciences: "GS 9350 holds promise as a stand-alone alternative to ritonavir for patients receiving boosted HIV protease inhibitor-based treatment regimens."

Interim results from a phase II trial comparing Quad with efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla; Gilead, Bristol-Myers Squibb) in treatment-naïve HIV-infected patients were presented at the 17th CROI. These results demonstrated that the Quad regimen exhibited antiretroviral activity comparable to that of Atripla. At 24 weeks, the proportion of patients who achieved a viral load less than 50 copies/mL was 90 per cent in the Quad group and 83 per cent in the Atripla group.

"Simplified treatment regimens of co-formulated, fixed-dose medicines have become the standard of care in HIV therapy because they can help patients adhere to dosing schedules," said principal investigator Dr Calvin Cohen.

"These positive efficacy and safety results indicate that the Quad has the potential to become an important new treatment option in HIV therapy."

Financial forecast data have indicated that from 2013 to 2018, Quad will make significant inroads in the HIV market, and by 2018, will become the highest-selling antiretroviral drug in the world's major markets. Plus let's not forget the potential for GS 9350 to finally break ritonavir's rock-solid hold on the antiretroviral booster market.

The Author
Pipeline was written by Hannah Blair of Adis International - part of Wolters Kluwer Pharma Solutions - using data derived from Adis R&D Insight and Clinical Trials Insight.

For further information on Adis services, please contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email Kuljeet.Sohanpal@wolterskluwer.com

To comment on this article, email pm@pmlive.com

6th May 2010

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