help please!!! There are actually 4 now.
The three main classes are nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (nNRTIs), protease inhibitors (PIs). There is a new, fourth class known as Fusion Inhibitors, of which there is only one drug, Fuzeon (aka T-20). It is used primarily in salvage therapy for people with HIV resistant to other more common medications. The 46th ICAAC contained considerable new information in regard to investigational drugs in the field of HIV medicine. Following on the footsteps of the 2 recently approved protease inhibitors, tipranavir and darunavir, the pipeline continues to advance new agents in existing classes of drugs that appear to fill gaps in the existing array of antiretrovirals (ARVs), including the possible addition of new fusion inhibitors. In addition, important information continues to emerge regarding the exciting new classes of ARVs - integrase inhibitors and CCR5 antagonists.
Reverse Transcriptase - In Vitro Results of a Novel Inhibitor
White and coworkers[1] reported in-vitro results on a novel adenine nucleotide analogue, GS-9148, which blocks HIV-1 reverse transcriptase (RT). This compound is orally administered as a prodrug, GS-9131. In-vitro and in-vivo studies have shown that the prodrug is a highly effective vehicle to deliver the active compound, GS-9148 diphosphate (GS-9148-DP), into lymphocytes. The current results have further characterized the active component and have shown that GS-9148-DP inhibits viral replication by acting as a DNA chain-terminator. Of particular interest is the fact that, once incorporated into viral DNA, the excision rate of GS-9148 appears to be extremely poor in RT that contains drug resistance mutations associated with zidovudine (ZDV). The in-vitro results are promising with respect to the safety profile of GS-9148-DP in that they show only weak inhibition of a number of host DNA polymerases, including DNA polymerase gamma. In view of the fact that GS-9131 is a prodrug that appears to be safe for patients, the further development of this compound is warranted, and may lead to approval of a novel nucleotide adenine analogue effective in the treatment of HIV disease. The potential for synergy with zidovudine (ZDV) should not be underestimated on the basis of the excision data reported in this presentation.
HIV Protease - In Vitro and Animal Studies of a Novel Inhibitor
Wu and coinvestigators[2] reported pharmacokinetic data on an experimental protease inhibitor (PI) PL-100. PL-100 is administered as a phosphylated prodrug (PPL-100) that is metabolized to its active drug, PL-100. The active drug possesses both a high genetic barrier to drug resistance and excellent ability to maintain activity against viruses that contain multiple mutations associated with resistance to currently approved members of the PI family of drugs.
Although virologic results on this compound have been reported previously,[3] the current study has extended this work by documenting a very long half-life of PL-100 in primary human hepatocytes. Indeed, studies carried out on both human and rat liver microsomes suggest that PL-100 may have greater in-vivo stability than other currently approved PIs. It appears very significant that the metabolism of PL-100 in human liver microsomes was blocked by ritonavir, a finding consistent with previously obtained in-vivo results suggesting that PL-100 levels in plasma can be boosted by coadministration with ritonavir. At the same time, however, PL-100 did not appear to interfere with either the CYP2C9 or CYP2D6 metabolic pathways in vitro but did inhibit CYP3A4. In studies conducted on fresh primary human hepatocytes, PL-100 was unable to induce activity of either CYP2C9 or CYP3A4. Additional studies revealed that administration of the prodrug, PPL-100, to rats resulted in an approximate 3-fold increase in levels of the active PL-100 compound in plasma compared with direct dosing with the active compound, PL-100, itself. Furthermore, the solubility of PPL-100 is more than 1000-fold greater than the active compound. At the same time, PL-100 is the major metabolic derivative observed in the portal vein, following dosing of rats with PPL-100.
Of potentially greater significance are findings that PL-100 apparently has the ability to boost levels of other PIs, such as atazanavir. This suggests that PL-100 and/or PPL-100 may have the ability to boost levels of other drugs in much the same manner as ritonavir. A potential explanation for the potential ability of PPL-100 to be dosed once daily may be its effects on cytochrome P450 clearance mechanisms. In short, PL-100 and/or PPL-100 might potentially be able to boost itself/themselves. Clearly, further studies on both the antiviral activity of PL-100 in vivo as well as its potential to act as a boosting agent are warranted.
The half-life of PL-100 in humans, following its administration as PPL-100, appears to range between 30 and 37 hours regardless of dose administered over a range of 300-2400 mg per day. This is fortuitous, in view of findings that the half-life of this drug may only be 18 hours in dogs and 8-9 hours in rats. The studies in humans were generated in a dose-ranging study involving 32 healthy volunteers over a period of 14 days, as reported at the 46th ICAAC but not included in the body of the abstract.
All indications are that PPL-100 has the potential to be a novel PI with a novel drug-resistance profile and high antiretroviral activity that will lend itself to once-daily dosing.
Integrase Inhibitors - New and Newer
MK-0518. Further clinical data were presented by Grinsztejn and coworkers[4] on the clinical efficacy of the integrase inhibitor MK-0518 that is being developed by Merck, West Point, Pennsylvania, and which is likely to be the first agent in this new category of ARVs. The study population was treatment-experienced patients whose virus was resistant to currently approved NRTIs, NNRTIs, and PIs. Earlier results on this trial were presented at the13th Conference on Retroviruses and Opportunistic Infections, held February 5-8, 2006 in Denver, Colorado.[5] The current results extend previous observations to a total of 24 weeks and document excellent antiviral activity. Viral load reductions to < 50 copies viral RNA/mL at week 24 were observed in 46%, 62%, 54%, and 0% of individuals who received MK-0518 at 200, 400, 600 mg/daily or placebo, respectively. Thus, MK-0518 continues to deliver impressive clinical results. It should be noted that data presented on this same drug at the XVI International AIDS Conference, held August 13-18, 2006 in Toronto, Ontario, Canada,[6] documented that it caused more precipitous drops in viral loads than had previously been observed with any compound studied to date in terms of antiviral activity.
Additional data on MK-0518 were presented by Teppler and colleagues[7] who evaluated lipid profiles in subjects receiving doses of this compound ranging between 100 and 600 mg twice daily with tenofovir + lamivudine. After 24 weeks of therapy in treatment-naive patients, no significant changes were reported in regard to fasting serum cholesterol, subcutaneous fat levels, low-density lipoprotein cholesterol, or triglycerides. In contrast, use of efavirenz instead of MK-0518 in combination with tenofovir + lamivudine did result in a number of changes in lipids during 24 weeks of evaluation, including increases in serum cholesterol and triglycerides. These data add to the rationale to proceed swiftly with the clinical development of MK-0518, which shows every likelihood of becoming a truly significant addition to our armamentarium of anti-HIV drugs.
Data presented at the 46th ICAAC and other recent conferences have raised hopes very high for MK-0518. MK-0518 targets the viral integrase, an enzyme that had not previously lent itself to successful drug development. There is little reason to believe that any HIV-infected patient has baseline resistance mutations associated with this drug because no compound in this class has yet been approved for therapy. Accordingly, MK-0518 should be expected to work well in all patients, including those who are drug-naive as well as those who have failed all existing classes of antiviral therapy. Moreover, as discussed above, the antiviral activity of MK-0518 appears to be exquisite and yields profound and rapid drops in viral loads in both patients with advanced disease as well as naive patients. In the latter case, the rate of viral load decline has raised conjecture that the integrase family of compounds may somehow be able to prevent the ability of HIV to establish reservoir status in cellular targets more efficiently than the other classes of drugs developed to date.
JTK303/GS-9137: A Novel Integrase Inhibitor. Kodama and coinvestigators[8] reported their in-vitro studies of a newer investigational integrase inhibitor, JTK303/GS-9137. They showed that this compound can inhibit the strand transfer step that is mediated by the HIV integrase enzyme. When the activity of the integrase enzyme is inhibited, unintegrated viral DNA accumulates in the nucleus in the form of 1-long-terminal-repeat (1-LTR) and 2-LTR covalently closed circles. In this report at ICAAC, the investigators also showed that GTK-303/GS-9137, which has been licensed to Gilead Sciences Inc, Foster City, California, can cause a significant accumulation of 2-LTR circles as a consequence of blocking integrase strand transfer.
These scientists also selected for resistance against their compound and demonstrated that 4 mutations in integrase emerged after 80 passages in tissue culture. These mutations were located at positions H51Y, E92Q, S147G, and E157Q, all of which are located within the integrase catalytic core. Furthermore, the ability of these mutations to interfere with the antiviral activity of JTK303/GS-9137 was confirmed by site-directed mutagenesis. The E92Q mutation alone yielded the highest levels of resistance of the mutations studied, conferring 36-fold resistance. However, combinations of E92Q together with other mutations further raised the level of resistance observed. Of interest, HIV variants that possessed the E92Q mutation also displayed resistance to other inhibitors of integrase. Viruses previously shown to contain amino acid substitutions associated with resistance to other integrase inhibitors also showed cross-resistance against JTK-303/GS-9137. The Merck MK-0518 compound was not tested in this study. Thus, it appears as though cross-resistance among compounds that block the HIV integrase enzyme is likely to occur in the clinic. The fact that the mutations identified seem to cluster around the integrase catalytic core suggest that JTK303/GS-9137 probably binds to a relatively conserved region of integrase.
Next-generation Fusion Inhibitors
Finally, there was important information on the sole currently approved fusion inhibitor, enfuvirtide (T-20), and hope for a next-generation member of the class that may be more user-friendly and possess higher levels of antiviral activity than enfuvirtide.
Holguin and coinvestigators[9] showed that both enfuvirtide and a novel compound, termed TRI-999, retain excellent activity against viruses of a multitude of subtypes in tissue culture. This allays concerns that the extensive variability that has been observed in both the HR1 and HR2 regions of gp41 might somehow result in diminished sensitivity of non-B subtype HIV to the fusion-inhibitor family of drugs.
Other studies explored the activity of the novel fusion inhibitor TRI-1144,[11,12] which is a pure peptide that is being developed for clinical use. This compound has a long half-life and may potentially lend itself to being injected on a once-weekly basis in patients with HIV disease. Furthermore, TRI-1144 has excellent activity against a wide array of viruses that possess mutations associated with resistance to enfuvirtide. A related compound, TRI-999,[10] also possesses excellent activity when studied in culture and retains its antiviral effectiveness even when bound to plasma proteins. However, TRI-999 is a structure-activity relationship (SAR) compound - a conjugate of a peptide derived from the HR2 region of gp41 and a pegylated fatty acid motif - that results in improved pharmacokinetics. The decision to move forward with TRI-1144, as discussed with the presenter, is based on the fact that TRI-1144 is a pure peptide that has not been conjugated, but nonetheless retains excellent antiviral activity as well as a long half-life. |
