It is now fairly obvious to most that treatment of HIV infection has undergone a seismic change. We've witnessed this transformation during the last year as the smorgasbord of different agents within differing classes became unveiled at the clinic. Also as never before, we are now armed with the tools to get nearly most infected individuals to undetectable levels of virus in their bloodstream. This is accomplishable even in patients with exposure and resistance to the traditional three classes of HIV drugs. Integrase inhibitors are from a new class, and have seen their first drug, Isentress, make it into the clinic. Isentress is not just "another drug." Unlike new sleeping pills, stomach antacids, or allergy medicine with their usual fanfare of television commercials and magazine ads, which are all usually a big yawn, the integrase inhibitors have been nothing short of historic, exciting, and mammoth in scope.
Integrase inhibitors work by inhibiting an HIV enzyme (integrase) responsible for HIV becoming incorporated within the human gene. Speaking about the virus, HIV integrase is made up of three areas or domains. A central segment is called the catalytic core, an important part of its domain having properties that enabled the discovery of targets or antiviral integrase inhibitors that can have a major impact on the life cycle of HIV. The catalytic core is also the site where antiviral resistance is born. Additionally and mechanistically, integrase inhibitors act on the strand-transfer point or the last instant whereby the cell becomes "productively infected" and by which the virus inserts viral DNA into host genome. The actual process involves a large complex of proteins and cellular factors that result in an integrated provirus particle.
Both integrase inhibitors have structural features in common. Merck's and Gilead's integrase inhibitor, in addition to GlaxoSmithKline's early phase compound, GSK 364735, all have a bulky hydrophilic group which helps anchor the drug at the active site.
Data from the Phase 2 study of elvitegravir (EVG) was presented last year at both CROI and ICAAC. This Phase 2 study began as a randomized, partially blinded, dose-finding study with four arms. The design of the trial included three integrase inhibitor arms each studying a different dose of EVG plus one protease inhibitor (PI)-containing control arm. As traditional for salvage studies, the patients were required to have triple-class resistance and each participant knew whether they were in an integrase inhibitor treatment arm, but not what dose they were taking. Nukes and +/- Fuzeon could be part of the backbone. The varying doses were 20, 50, and 125 mg, all boosted by ritonavir (Norvir).
The study began with EVG-treated patients not being permitted to take a PI in combination. This was due to lack of drug-drug interaction data for EVG with PIs at that time. At week 16, however, as more information became available, subjects were allowed a PI and the 20 mg dose was stopped due to the emerging demonstration of inferiority of that specific dose. The individuals on 20 mg were all offered 125 mg open label. An additional change in light of knowledge of drug interactions, darunavir (Prezista) or tipranavir (Aptivus) were also allowed to be added in the integrase inhibitor arms. While these changes were good for patients and is sometimes the natural course in early studies, it confounded the data, as the study design was changed midstream. Thus, the only way to honestly look at elvitegravir's effect was during the first 16 weeks and at the 125 mg dose.
The results were as follows: a significant 1.7 log drop in HIV RNA (viral load) was seen overall, but an even more dramatic 2.5 log drop was observed with first use of Fuzeon (T-20) as part of the HAART (highly active antiretroviral therapy) regimen, highlighting the importance of having other active drugs. The actual change of Fuzeon when used for first time with EVG at the 125 mg dose was seen as quickly as the beginning of week 2, showing a staggering -2.9 log drop which persisted though the end of the study. Also, 25% of the control arm achieved viral loads to undetectable or less than 50 copies, versus 74% in the 125 mg dosing arm of EVG. 16 week data of the other integrase inhibitor, raltegravir, when used with T-20 for the first time was very comparable: 72% had less 50 copies. Background therapy always contributes greatly to virologic success, and so notably, as the study design changed and darunavir and tipranavir were allowed to be added, there were more declines in viral load.
At the time of this writing, the current issue of the New England Journal of Medicine (July 24, 2008) reported the findings of treatment with raltegravir (RLV) in a combined analysis of both Benchmark studies, which looked at treatment-experienced patients. Also common to the Gilead study, only patients who were resistant to three classes of HIV drugs were included. Overall the results showed a caliber of viral suppression being among the best ever seen for patients with triple-class resistance. At week 16, the combined analysis of both studies showed 72% of patients on raltegravir achieved viral loads below 400 copies, compared with 37% in the control group. Also at week 48, 62% of patients treated with RLV achieved a level of HIV-RNA to below 50 copies, compared with 33% in the placebo arm. It's worth noting that when patients were also treated with either darunavir (Prezista) or enfurvitide (Fuzeon), or both, the rates of HIV suppression were even greater.
Although the rates of side effects and adverse events were low during the 48 weeks of RLV treatment, part of the journal's article was devoted to the issue of new malignancies and cancers seen in the raltegravir group. Cancer in this study was seen early during the trial (average time of diagnosis was at 68 days) and was observed at a rate of 3.5% in the RLV treated patients versus 1.7% in the control arm. It is well worth noting that cancers are increasing among patients with HIV disease and are of a different type than was seen prior to HAART. Also, new malignancies have now been seen in other studies, as well. Historically, we witnessed Kaposi's sarcoma (KS) and non-Hodgkins Lymphoma to be the most common of cancers in this population. Presently, anal cancer, liver cancer, and Hodgkin's lymphoma are becoming increasingly more common. This is probably due in part to patients having damaged immune systems and individuals who have had detectable virus in the blood (persistent viremia). Thus, it is the opinion of this author, that treatment of HIV disease be initiated earlier and that detectable viral loads be treated with a more effective regimen at the onset of failure. In other words, not to let continued failing regimens be left untreated, regardless of CD4 T-cell count.
Additionally, the theory of immune system activation (immune reconstitution syndrome) seen commonly when starting or initiating a new regimen has also been invoked as a possible cause of detection of cancer. Herpes zoster (shingles) is one of the most common manifestations of immune reconstitution syndrome. As the immune system goes into overdrive, sometimes unexpected events can happen, that is, new infections, as well as cancers, can occur during this period of new treatment. Physicians should be increasingly on the lookout for new problems when patients' immune systems are challenged with new therapy.
Raltegravir is currently dosed at 400 mg twice daily, while elivitegravir is dosed once daily but at 150 mg plus 100 mg of ritonavir as its booster. Gilead Sciences has often been shown to be a leader in development of HIV treatment (i.e., Vistide, Viread, Truvada, and Atripla, all keystone accomplishments); most were surprised with the recent announcement of their development of a new compound that can serve as a booster (like Norvir) to EVG, and to other protease inhibitors. The compound known presently as GS 9350 is purely a pharmacokinetic enhancer and does not have antiviral effects. As such, it is not expected to cause the metabolic side effects that have been associated with Norvir. GS 9350 has the potential of permanently replacing Norvir as a booster, especially if it is priced properly, which one would expect.
This begs me to refer to the movie "Eraser" with Arnold Schwarzenegger. Among Arnold's one liners are "You've just been erased," or referring to being erased, "Next time you're dead ... this only happens once." One of these greetings may eventually be handed to Norvir, if development of GS 9350 goes according to plan. Anyhow, Gilead will eventually combine their enhancer or booster with EVG to be formulated into a one dosing tablet. Also, look on the horizon for EVG combined with GS 9350 plus Truvada, as a new one pill once-daily treatment cocktail currently being called QUAD, again, if the future studies continue to go smoothly.
When resistance to an antiviral drug occurs, by definition it denotes that the effect or advantage of having that drug as treatment is lost. EVG and RLV, being part of a novel class of HIV drug, are both active when resistance occurs to nukes (NRTI), non-nukes (NNRTI's), and protease inhibitors (PIs). In other words, integrase inhibitors (INIs) retain their effect among other class-resistant viruses.
For readers who are interested in the specifics regarding INI resistance, I will try to summarize some basic integrase genetic changes, although very technical. Resistance to integrase inhibitors themselves, although being structurally diverse, has features in common and binding modes that probably have many mechanistic similarities. Thus INI mutations or genetic codon switches on Q148 and N155 are selected by both EVG and RAL. These two mutations show the greatest mean (phenotypic) fold changes for resistance, or are associated with high-level resistance and cross resistance to each INI. Thus, if one develops any one of these mutations while being on a particular integrase inhibitor, it's likely they'll have cross-resistance to the other INI. Note that other antiviral drugs belonging to other classes retain activity in the presence of these mutations.
Some examples of unique mutations to each INI: Y143 is selected by RAL, and 92Q and T66 are EVG-associated mutations. All of these codon switches or changes occur within the HIV integrase gene and tend to cluster around the binding site within the catalytic domain (explained above). Some specific mutations, called "primary," are able to confer very high fold changes or resistance, so I believe that only one primary mutation is required for resistance. The New England Journal of Medicine article states that two mutations (one primary and one secondary) are generally required for resistance, but I don't necessarily agree with this statement, since the second mutation usually follows very quickly behind the occurrence of the primary; the second will almost always be present at the same time as the primary.
Interestingly, INI-mutated virus showed 50% reduced viral fitness (virus that is less apt to damage immune function), compared to wild type (untreated, un-mutated virus). So if one theoretically develops INI resistance, they may get some consolation prize, but I don't recommend it. Anyhow, we don't know yet whether this has any clinical relevance.
The grand milestone and unprecedented, non-inferiority study comparing the two integrase inhibitors has only just begun. Elvitegravir (GS9137), Gilead Sciences' compound, and raltegravir (Isentress, MK0518), the Merck agent, will confront each other in a colossal study of epic proportions that is both historic and significant by any measure.
Treated patients who have failed a regimen can potentially become a candidate and participate in this trial. Each patient will be randomly assigned to be treated with either EVG or RLV in combination with a physician-selected boosted protease inhibitor plus a third drug. The standard dose of Isentress (400 mg twice daily) will be compared with boosted EVG at 150 mg. However, if a patient is administered one of the two PIs Kaletra or Reyataz, both of which increase EVG exposure by 75% and 100% respectively, then dosing of EVG need only be 85 mg, thus offsetting this interaction. Patients will be allowed to use a third drug, including a nuke, Intelence (etravirine), or Selzentry (maraviroc).
This study is indeed a celebration about the progress in HIV therapy; one can't help but look forward to seeing what the results of this trial will show. Genetic barriers to resistance for integrase inhibitors are low since single mutations can confer greater than 20-1,000-fold reduced susceptibility, therefore adherence to the regimen or taking all doses prescribed is always the key. However, when integrase inhibitors are combined with active drugs, they show high-level potency and the results are ones that we've never observed before. To the physician, no individual should ever be treated with functional monotherapy and a minimum of at least two more active drugs should be included in any regimen. Integrase inhibitor-containing regimens are no exception.
Dr. Daniel Berger is a leading HIV specialist in the U.S. and is assistant professor of medicine at the University of Illinois at Chicago and medical director and founder of Northstar Medical Center, the largest private HIV treatment and research center in the Greater Chicago area. He has published extensively in such prestigious journals as the Lancet and the New England Journal of Medicine and serves on the Medical Issues Committee for the Illinois AIDS Drug Assistance Program and the AIDS Foundation of Chicago. Dr. Berger has been honored by Test Positive Aware Network with the Charles E. Clifton Leadership Award.
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