Over|More than} 2 years back, 4 new antiretrovirals were approved: Two of these introduced new classes of treatment, and 2 others offered new hope for previously resistant viruses. These were added to the 20 existing antiretrovirals and have provided even more potent combos that confer less resistance and long-term toxicities. In spite of these powerful, cleaner regimens, resistance and intolerance are inevitable in a number of cases. Therefore, there is a necessity for both new classes of antiretrovirals and enhancement of existing classes. There are over 50 new compounds in many different phases of development. This article will focus on medications currently in Phase II and III development.
Integrase Inhibitors
Integrase Inhibitors stop the action of the integrase enzyme, that is responsible for viral insertion into the DNA of the CD4+ cell. One such Integrase Inhibitor is Elvitegravir, Gilead's competitor to Isentress (raltegravir, Merck). However, elvitegravir can be dosed once daily when combined with a pharmacokinetic (PK) enhancer (i.e. ritonavir or cobicistat). Elvitegravir is one component of Gilead's "Quad," a 4-in-1 coformulation of elvitegravir, GS-9350 (cobicistat) and emtricitabine/tenofovir (Truvada). Phase II analyses saw the Quad regimen meet the primary endpoint of non-inferiority in head-to-head trials versus Atripla (efavirenz/emtricitabine/tenofovir). Phase III trials are underway as of April 2010, with the "Quad" regimen going head-to-head alongside Reyataz (efavirenz and ritonavir-boosted atazanavir) in treatment-naive individuals.
Another Integrase Inhibitor presently in Phase II trials is S/GSK1349572 (Viiv, Shlongi), which showed a major viral load reduction over a 10 day phase IIa dosing trial even in the absence of a PK enhancer. Resistance numbers showed this compound maintains activity in spite of integrase cross-resistance, which does not hold true for elvitegravir. Phase IIb trials are underway, with Phase III trials to begin in late 2010.
Pharmacokinetic Enhancer
Ritonavir (Norvir) is the only "booster" approved by the Food and Drug Administration used to raise levels of antiretrovirals, most particularly protease inhibitors. Although boosting is indicated in treatment-experienced patients, ritonavir carries side effects which make it intolerable in patients, such as gastrointestinal intolerance and lipid elevations. Cobicistat (GS-9350) is a "pharmacoenhancer" that possesses no antiretroviral activity. It raises drug levels through inhibition of Cytochrome P4503A -- the identical mechanism as ritonavir. Phase II trials comparing cobicistat and ritonavir saw similar gains in CD4+ cell counts and decreases in viral load in their respective arms. Side effects were comparable, albeit less common, in the cobicistat arm. Phase III trials will start later on this year, comparing cobicistat versus ritonavir with an assortment of combinations. One point of unease in the cobicistat arm was a decrease in estimated glomerular filtration rate (GFR), through a false rise in serum creatinine. Fortunately, this does not occur via the same pathway as most other nephrotoxic drugs. Further investigation is necessary to better understand the means by which this occurs.
Currently, the NNRTI preferred by the Department of Health and Human Services is efavirenz. NNRTIs job to prevent DNA synthesis of the retrovirus through structural alteration of the Reverse Transcriptase enzyme. When resistance is an issue, nearly all NNRTIs are rendered inactive with the exception of etravirine ilpivirine (TMC 278, Tibotec), a 2nd generation NNRTI which demonstrates antiretroviral activity in the presence of the K103N mutation -- the signature efavirenz mutation. Rilpivirine demonstrated virologic efficacy similar to efavirenz at week 48 (76.9% v. 80%) and sustained effectiveness at week 96. The most commonly reported moderate to severe adverse events perhaps linked to study medication (e.g., nausea, dizziness, abnormal dreams, rash, somnolence and vertigo) occurred less often with rilpivirine than with efavirenz. In general, rilpivirine demonstrates efficacy similar to efavirenz with a lesser incidence of neurological and psychiatric effects. Current Phase III trials are underway to replicate bioequivalence in the coformulation of riplivirine and emtricitabine/tenofovir. If approved, rilpivirine will be utilized as part of a first-line course of therapy -- unlike its Tibotec counterpart, etravirine, which is not indicated as such. Other NNRTIs in Phase II development include GSK2248761 (Viiv) and RDEA806 (Ardea). Both possess antiretroviral action in spite of efavirenz resistance.
CCR5 Antagonists
Presently, maraviroc is the only FDA-approved CCR5 antagonist available. Maraviroc blocks the CCR5 coreceptor which HIV uses to bind and enter a human macrophage. It recently received indication for treatment in naive individuals and serves as an additional option in the presence of certain viral strains when other classes are not an option.4 Vicriviroc (Merck/Schering-Plough) is another CCR5 Inhibitor currently in Phase II/III trials. However, it has experienced obstacles. The first Phase II trials failed to establish an adequate dose. As of May 2008, two phase III trials (VICTOR-E3 and VICTOR E4) in treatment-experienced patients were initiated. Late phase clinical trials did not meet key efficacy endpoints and Merck decided not to seek approval for the medication in treatment-experienced patients. However, trials in treatment-naive individuals will resume. Like maraviroc, several drug interactions with other antiretrovirals exist and side effects, such as increased danger of respiratory infection, may occur.
NRTIs are considered the backbone of antiretroviral treatment. Unlike their NNRTI counterparts, NRTIs structurally resemble compounds used in viral DNA chain elongation, essentially tricking the virus into incorporating these analogues and terminating the growing chain. First-line combination(s) generally consist of lamivudine (Epivir) or emtricitabine (Emtriva) and an additional nucleoside, such as tenofovir or abacavir (Ziagen). While the regimens are highly potent, resistance to lamivudine and emtricitabine happens quite frequently. Among the other nucleosides, multi-drug resistance or long-term morphological changes warrant the need for newer agents.
Amdoxovir (DAPD, RFS Pharmaceuticals) is presently in Phase II trials. Although it demonstrates activity against the main lamivudine/emtricitabine mutation, M184V, amdoxovir must be taken twice every day. In addition, visual troubles can occur, but resolve upon discontinuation.
Elvucitabine (ACH-126, Achillon) is virologically equivalent to lamivudine (3TC) when combined with efavirenz and tenofovir as a first-line regimen taken for ninety six weeks. Yet, because of the small size of this phase II trial, and the high dropout rate, elvucitabine lagged 3TC from a statistical standpoint. More research is needed to see where elvucitabine fits in treatment. Similar to lamivudine and tenofovir, elvucitabine also possess anti-Hepatitis B activity.
Maturation Inhibitors
Maturation inhibitors, in later phases of viral replication, interfere with protease processing of a newly translated HIV polyprotein precursor known as gag. This molecule contains a number of HIV proteins in a single polypeptide, that is then cleaved by an enzyme, called protease, to make functional structural proteins. However, unlike the protease inhibitors, bevirimat binds to the gag protein, not protease. Two agents currently in Phase II trials include Bevirimat (PA457, MPC-4326, Myriad) and Vivecon (MPC-9055). Although these agents offer a new opportunity, the potential for cross-resistance among previous protease inhibitor use is possible. Thus, baseline resistance testing might be warranted.
Monoclonal Antibodies
Similar to CCR5 antagonists, these compounds use monoclonal -- that is, all identical -- antibodies, rather than a drug molecule, to stop the CCR5 co-receptor. PRO140 (Progenics) is currently in Phase II trials and has shown promise in terms of strength and duration of action. It is administered by subcutaneous injection, but only requires dosing every other week, which could offer an option for patients where adherence may be an issue. PRO140 is usually well-tolerated, with injection site reactions (e.g., swelling, irritation, and pain) being the major side effects. In addition, Phase II studies of ibilazumab (TNX-355, Genetech) are scheduled to finish by late 2010.12-17 Both compounds have been granted fast-track status by the FDA, and might offer "salvage" in patients with a very resistant virus, a lot like enfuvirtide (Fuzeon) did in 2003.
Author Resource:
Article written by Michael Modzelewski and posted courtesy of www.hivandsingle.com . HIV and Single is the best HIV Dating site on the web and also offers a number of great articles and supportive resources for people living with HIV. Joint today for free.
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