The elvitegravir Quad pill: the first once-daily dual-target anti-HIV tablet

Abstract

Anti-HIV combination therapies in a single formulation currently target only HIV-1 reverse transcriptase via two different mechanisms of action by associating a nucleoside and a non-nucleoside reverse transcriptase inhibitor. These combination therapies are therefore referred to as multi-class combination products. The elvitegravir Quad pill (Gilead Sciences), when approved by the Food and Drug Administration for the treatment of HIV/AIDS, will become the first once-daily dual-target anti-HIV tablet. This “4 in 1” tablet targets HIV-1 integrase by elvitegravir boosted by the pharmaco-enhancer cobicistat and HIV-1 reverse transcriptase by the two nucleoside reverse transcriptase inhibitors emtricitabine + tenofovir disoproxil fumarate. A second pill referred to as the 572-Trii pill (Shionogi-ViiV Healthcare, LLC), also based on the dual inhibition of integrase and reverse transcriptase, is currently in late-phase clinical trials. The availability of these novel once-daily anti-HIV tablets will improve treatment adherence and offer new perspective for patient failing existing antiviral regimens.

Keywords::

• dolutegravir
• elvitegravir
• HIV-1 integrase
• raltegravir

1. Introduction

With the approval by the Food and Drug Administration (FDA) of the first anti-HIV integrase agent raltegravir in 2007, the highly active antiretroviral therapy (HAART) has now the potential of targeting the three retroviral enzymes, reverse transcriptase, protease and integrase (Table 1). Introducing a new drug in the therapeutic arsenal had a major impact on the outcome of HIV/AIDS and provided new therapeutic options for heavily treated patients with multidrug resistance. Novel anti-HIV integrase drugs are currently in late-phase clinical trials with the goals of overcoming raltegravir clinical resistance and increasing treatment adherence by a once-daily oral administration. These new agents will also be co-formulated with reverse transcriptase inhibitors (RTIs) to become the first anti-HIV tablets targeting two of three enzymes, integrase and reverse transcriptase in a single formulation.

Table 1. List of the FDA-approved anti-HIV drugs and formulations (www.fda.gov).

Approval date	Brand name	Generic name	Manufacturer
Multi-class combination products
2006	Atripla	Efavirenz + emtricitabine + tenofovir disoproxil fumarate	Bristol-Myers Squibb & Gilead Sciences
2011	Complera	Emtricitabine + rilpivirine + tenofovir disoproxil fumarate	Gilead Sciences
Nucleosides reverse transcriptase inhibitors (NRTIs)
1997	Combivir	Lamivudine + zidovudine	GlaxoSmithKline
2003	Emtriva	Emtricitabine (FTC)	Gilead Sciences
1995	Epivir	Lamivudine (3TC)	GlaxoSmithKline
2004	Epzicom	Abacavir + lamivudine	GlaxoSmithKline
1992	Hivid	Zalcitabine (dideoxycytidine, ddC) – No longer marketed	Hoffmann-La Roche
1987	Retrovir	Zidovudine (ZDV, azidothymidine, AZT)	GlaxoSmithKline
2000	Trizivir	Abacavir + lamivudine + zidovudine	GlaxoSmithKline
2004	Truvada	Emtricitabine + tenofovir disoproxil fumarate	Gilead Sciences
2000	Videx EC	Enteric coated didanosine	Bristol-Myers Squibb
1991	Videx	Didanosine (dideoxyinosine, ddI)	Bristol-Myers Squibb
2001	Viread	Tenofovir disoproxil fumarate (TDF)	Gilead Sciences
1994	Zerit	Stavudine (d4T)	Bristol-Myers Squibb
1998	Ziagen	Abacavir sulfate (ABC)	GlaxoSmithKline
Non-nucleosides reverse transcriptase inhibitors (NNRTIs)
2011	Edurant	Rilpivirine	Tibotec Therapeutics
2008	Intelence	Etravirine	Tibotec Therapeutics
1997	Rescriptor	Delavirdine (DLV)	Pfizer
1998	Sustiva	Efavirenz (EFV)	Bristol-Myers Squibb
1996	Viramune	Nevirapine (NVP)	Boehringer Ingelheim
2011	Viramune XR	Extended release nevirapine	Boehringer Ingelheim
Protease inhibitors (PIs)
1999	Agenerase	Amprenavir (APV)	GlaxoSmithKline
2005	Aptivus	Tripranavir (TPV)	Boehringer Ingelheim
1996	Crixivan	Indinavir (IDV)	Merck & Co., Inc.
1997	Fortovase	Saquinavir - No longer marketed	Hoffmann-La Roche
1995	Invirase	Saquinavir mesylate (SQV)	Hoffmann-La Roche
2000	Kaletra	Lopinavir + ritonavir (LPV/RTV)	Abbott Laboratories
2003	Lexiva	Fosamprenavir calcium (FOS-APV)	GlaxoSmithKline
1996	Norvir	Ritonavir (RTV)	Abbott Laboratories
2006	Prezista	Darunavir	Tibotec Therapeutics
2003	Reyataz	Atazanavir sulfate (ATV)	Bristol-Myers Squibb
1997	Viracept	Nelfinavir mesylate (NFV)	Agouron Pharmaceuticals
Fusion inhibitors
2003	Fuzeon	Enfuvirtide (T-20)	Hoffmann-La Roche & Trimeris
Entry inhibitors – CCR5 co-receptor antagonist
2007	Selzentry	Maraviroc	Pfizer
Integrase inhibitors
2007	Isentress	Raltegravir	Merck & Co., Inc.

2. Comparison between elvitegravir and the two other clinical integrase inhibitors, raltegravir and dolutegravir

Raltegravir (Merck & Co., Table 1) was originally approved for the treatment of experienced patients with multidrug resistance [1]. Due to its excellent efficacy and safety profile, it was approved 2 years later for the treatment of naïve HIV-infected patients [2]. The use of raltegravir is now being extended to HIV-1-infected pediatric patients [3] and to patients co-infected with hepatitis B or C virus [4]. Raltegravir-based regimen contains raltegravir 400 mg twice daily in combination with other inhibitors such as emtricitabine + tenofovir disoproxil fumarate (both nucleoside RTIs, NRTIs, Table 1) once-daily [5]. Raltegravir inhibits selectively the strand transfer reaction; the second step of integration and is therefore referred to as an integrase strand transfer inhibitor (INSTI) [6]. Raltegravir was co-crystallized with the integrase of the prototype foamy virus (PFV) in the presence of retroviral DNA and shown to bind in the active site of the enzyme [7]. Raltegravir interacts with the enzyme, the viral DNA and the two catalytic magnesium atoms, which makes it a perfect example of an interfacial inhibitor [8]. Despite its strong clinical success, the use of raltegravir is impacted by the appearance of resistance mutations. These mutations are categorized in three major pathways involving the integrase residues G140/Q148, N155, and Y143 [9]. Novel integrase inhibitors which could alleviate partially or completely raltegravir resistance are therefore being investigated.

Elvitegravir (Gilead Sciences) is currently in Phase III clinical trials and should become the next INSTI to be approved by the FDA for the treatment of HIV/AIDS. Elvitegravir exhibits the same interfacial mechanism of inhibition than raltegravir [8] but it does not interact with the Y143 residue of the enzyme and therefore overcomes raltegravir resistance involving the 143 pathway [10]. One major advantage of elvitegravir over raltegravir is that its blood concentration can be boosted by the proteinase inhibitor ritonavir (Table 1) or by the pharmaco-enhancer cobicistat (GS9350). Therefore, elvitegravir can be administered at 150 mg once daily with an efficacy and safety comparable to raltegravir 400 mg twice daily [11]. The administration of raltegravir once daily has recently been evaluated and is not recommended as a substitute to the current twice daily regimen [5]. The once-daily administration of elvitegravir represents a significant improvement for heavily treated patients and treatment adherence.

Dolutegravir (formerly S/GSK1349572, Shionogi-GlaxoSmithKline Pharmaceuticals, LLC, now Shionogi-ViiV Healthcare, LLC) is the most recent INSTI in clinical development with an effective 50 mg once-daily unboosted administration [12]. Dolutegravir seems to have a higher barrier to resistance when compared to raltegravir as demonstrated by in vitro work [13] and suggested by preliminary in vivo data [12]. Dolutegravir was co-crystallized with the PFV integrase and retroviral DNA and was found to bind similarly to raltegravir and elvitegravir [14]. The improved resistance profile of dolutegravir may only be structurally explained by an increased interaction with the viral DNA, which would therefore allow the drug to be less sensitive to structural protein rearrangements [14].

3. The Quad pill

In October 2011, Gilead Sciences requested FDA approval of its “4 in 1” once-daily tablet (Quad pill) consisting of a combination of elvitegravir boosted with cobicistat, emtricitabine, and tenofovir disoproxil fumarate (Table 1) for the treatment of HIV-1 infection in adults. This Quad pill with its combination of one INSTI and two NRTIs represents the first once-daily dual-target anti-HIV tablet and is on its way to be approved by the FDA in 2012. It was first evaluated in a Phase II clinical study in comparison to the multi-class once-daily tablet Atripla (Bristol-Meyers Squibb & Gilead Sciences, Table 1) containing the NRTIs emtricitabine and tenofovir disoproxil fumarate in combination with the non-nucleoside RTI (NNRTI) efavirenz (Table 1). Both NRTI and NNRTI inhibit RT by two different mechanisms of action. NRTI are often viewed as chain terminators, whereas NNRTI are allosteric RTIs binding outside the catalytic site. These multi-class combination therapies have long been considered the golden standards for anti-HIV therapy. When compared to the multi-class once-daily tablet Atripla, the Quad pill achieved and maintained high rate of virologic suppression with a lower rate of central nervous system and psychiatric adverse events [15].

4. The 572-Trii pill

The 572-Trii pill (Shionogi-ViiV Healthcare, LLC), a once-daily tablet combining the INSTI dolutegravir with the two NRTIs lamivudine and abacavir (Table 1), recently entered a Phase III clinical non-inferiority study in comparison to the multi-class once-daily tablet Atripla [16]. This 48-week study for which the results have not yet been released will seek to demonstrate the antiviral activity of the 572-Trii pill in comparison to Atripla. Secondary objectives will include assessment of tolerability, long-term safety, antiviral and immunologic activities of the 572-Trii pill over 96 weeks. Investigators will also evaluate viral resistance in patients experiencing virologic failure [16].

5. Expert opinion

Current HAART regimens are mainly based on the use of NRTI, NNRTI and protease inhibitors (PIs) in combination (Table 1) and the complexity of these regimens has a direct negative impact on treatment adherence. For several years, the pharmaceutical industry has been trying to combine inhibitors in single formulations (Table 1). There are currently two multi-class combination products approved by the FDA for the treatment of HIV/AIDS. These multi-class once-daily tablets are Atripla (see above, Table 1) and Complera (Gilead Sciences, Table 1) based on the combination of two NRTIs and one NNRTI to target two distinct pharmacological sites on RT. The approval by the FDA of the Quad pill would bring to the HAART drug arsenal a first once-daily tablet targeting two HIV enzymes (integrase and reverse transcriptase). This new once-daily regimen should simplify greatly drug administration and promote patient treatment adherence with an efficacy and toxicity similar to twice daily raltegravir-based regimens.

If the efficacy and safety of the 572-Trii pill is confirmed, both of these once-daily dual-target pills will have to be compared side-by-side in clinical studies. Due to the presence of dolutegravir, currently the INSTI with the best resistance profile, the 572-Trii pill may offer a real advantage over the Quad pill to overcome clinical resistance in patients failing raltegravir-based regimens. Nevertheless, these two once-daily dual-target tablets will be important assets to the 35 anti-HIV already FDA-approved drugs or formulations (Table 1).

Now that a once-daily dual-target tablet has proven its efficacy and safety in the HIV/AIDS treatment, one could envision a once-daily pill targeting the three retroviral enzymes: reverse transcriptase, protease, and integrase. This could be the next step to improve treatment efficacy and adherence. As shown in Table 1, combination formulations arise generally from within the catalog of a given company. The only pharmaceutical company which currently has FDA-approved inhibitors against the three retroviral enzymes is GlaxoSmithKline (Table 1). The next once-daily pill could potentially be a 572-Trii pill supplemented with the protease inhibitors fosamprenavir or amprenavir.

Declaration of interest

This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The author has no competing interests to declare.

Acknowledgments

The author wishes to thank Y Pommier, M Métifiot and K Maddali for insightful discussions and editorial suggestions.