The Buzz: Something to CROI About
Three Integrase Inhibitors Offer Great Promise
I went to this year's CROI (Conference on Retroviruses and Opportunistic Infections), like many I've attended over my career, to hear about revelations being presented, if any, and to network among fellow researchers and scientists. I'll admit this 14th session did not hold the eye-opening surprises that several previous meetings had. The newer compounds have already shown efficacy, but integrase inhibitors are unique, fresh, and still inspire.
This article would not be complete without a personal word about the great expenses involved in attending conferences. There's the $600 registration fee, plus hotel stay, air travel, food and miscellaneous costs, not to mention lost clinic time; this is a difficult economic environment. A fellow colleague and I were discussing whether it would be more cost effective to listen to audio podcasts at home and do follow-up conference call discussions with fellow thought-leaders. Not a bad idea, but I digress.
Of the now several integrase inhibitors (INIs) on the table, raltegravir (Isentress) was the first agent in the class to gain approval. Its first indication was in treatment-experienced patients; those who were in great need of newer options were given a true lifeline with this agent, especially as it's combined with darunavir (Prezista), etravirine (Intelence) and/or enfurvitide (Fuzeon).
More recently, Isentress won a broader indication to include naïve patients (individuals starting their first regimen), becoming the first integrase inhibitor to be approved for treatment of all HIV-positive individuals in combination with other effective antiretroviral agents.
This article will approach different issues within each of the three integrase inhibitors that are in varying stages of development. Much data has previously been presented on raltegravir, but large studies with the second integrase inhibitor, elvitegravir, particularly a trial comparing head-to-head effects of two integrase inhibitors (Isentress and elvitegravir), are not yet available. And for the newest compound in the class, GSK 572, broader studies are only now being recruited; therefore, far less is known about this agent than the previous two.
Intensification With Raltegravir
Interesting studies concerned patients who do not achieve full immune reconstitution following good HIV treatment and probed the addition of raltegravir to already optimized regimens.
Approximately 25% of individuals who initiate HAART (highly active antiretroviral therapy) with CD4 counts below 200 cells/mm3 never achieve counts above 500. In other words, they exhibit sub-optimal immune recovery. Personally, it's not uncommon to see patients remain within the less than 200 CD4 cell scale despite excellent treatment, who nevertheless are able to maintain years of undetectable viral loads. Patients who remain in this lower CD4 count, however, may be at greater risk of developing long-term complications such as malignancy (cancer). Attempting immune reconstitution through the use of an integrase inhibitor is based on unique properties specific to the class, their unique mechanism of action (inhibiting viral integration within the human genome), and observations of more potency with more rapid effect of suppressing HIV RNA (viral load). The question posed was, could CD4 counts be augmented further if select patients had the integrase inhibitior raltegravir added to their treatment?
One study examined 30 patients, all undetectable (less than 50 copies/ml) for at least one year, randomized to receive the addition of raltegravir to their regimen versus placebo. At 24 weeks, there was no change in viral activity measured to supersensitive levels, or to below 1 copy of HIV RNA. (Previous to study, baseline values for patients were already at 5 or less copies/ml.) However, no changes were seen with the raltegravir addition to get levels to below 1 copy/ml, nor were there changes in cell-associated RNA (viral particles attached to, or within, the cell) measurements of proviral DNA (virus in a latent stage of its life cycle), nor improvement in CD4 count.
In a different protocol, seven individuals who had undetectable viral loads and less than 40 copies/ml for three to 12 years, were studied as follows: four patients had raltegravir added to their regimen, two patients had raltegravir plus efavirenz (Sustiva) added, and one patient had raltegravir plus boosted darunavir (Prezista) added. Viral and immune system markers were also looked at in intestinal-lining cells by biopsy after upper and lower endoscopies.
In summary, intensification did not result in any decrease in plasma (blood) viral load, viral load in mononuclear cells, nor gut-lining cells. However, there were signs of decreased immune activation (activation is often felt to be harmful), the most being observed in the ileum (third part of the small intestine), as well as trends toward slight increases (1.9-2.9%) in CD4 cell count. Thus intensification had an effect on the ileum of the small intestine, which the authors suggested is a site of ongoing viral replication despite undetectable viral loads in the plasma. These areas within the body (gut-associated lymphoid tissue, or GALT) have been suggested as sanctuary sites for viral activity, and this is one particular reason (among several) that might explain why effective antiviral treatment does not eradicate HIV.
Simply adding more antiviral agents to already optimally suppressed patients is not the miraculous key to further controlling HIV. This work confirms that new avenues in research are needed.
In summary, the results of these studies demonstrate that simply adding more antiviral agents to already optimally suppressed patients is not the miraculous key to further controlling HIV. This work confirms that new avenues in research are needed to exert broader control of viral activity and agents are needed to manage hazardous hyper-activation; I believe it is possible to do so with current technology.
It's worth noting that we have been awaiting the data of a large study, also being conducted at Northstar in Chicago, that is comparing the administration of Isentress in its currently approved dosing of one 400 mg tablet, twice daily versus taking both 400 mg tablets once daily (in combination with Truvada). Although preliminary data may suggest that this is a viable option, we do not feel the need to encourage patients to switch their habits and we warn of the risks for developing possible integrase inhibitor resistance. It is prudent to wait until final results of this trial become available.
Elvitegravir and the Quad
In a presentation that had its entertaining moments, Cal Cohen discussed results from two Phase 2 studies involving Gilead Sciences' new booster agent cobicistat, a replacement candidate for Norvir (ritonavir). Cobicistat has no antiviral activity, but is used to boost the levels of an integrase inhibitor, elvitegravir, in the blood. The first study randomized 71 patients (2 to 1) to the Quad (a new one-pill regimen, taken once daily) or Atripla. The Quad consists of Truvada plus elvitegravir (integrase inhibitor) plus the new pharmacoenhancer/booster cobicistat, previously known as GS 9350. Atripla was the first one-pill cocktail and combines Sustiva with Truvada, taken once a day. The second study highlighted the effects of cobicistat versus Norvir, as a booster for atazanavir (Reyataz).
Virologic results were similar in Quad-treated patients versus the Atripla arm with 90% versus 83% achieving undetectable viral loads to below 50 copies, demonstrating non-inferiority of the Quad to Atripla. Among side effects, the differences in the two arms were due to central nervous system side effects or sleep disorders, not unexpectedly higher in Sustiva- (Atripla) treated patients (48% versus 10%). Sleep disorders and psychedelic dreams are well known with efavirenz; some have likened their Sustiva experience to dropping acid. There were no lipid level (blood fat) advantages for cobicistat-treated patients over ritonavir, however.
Concerns regarding cobicistat's safety profile, specifically regarding renal issues (kidney-related), were raised due to observed elevations in creatinine. Creatinine is a waste product the kidneys should be responsible for clearing; elevated levels suggest kidney malfunction. This is paramount, as patients are already taking Viread, which is in itself a concern for some patients at high risk for renal disease.
The approximate 10% increase in creatinine associated with cobicistat use was seen within the first one to two weeks of the trial and did not continue into the duration of study (24 weeks). In a separate study conducted by the sponsor, calculated glomerular filtration rates (GFR) based on creatinine changes increased; however, actual GFR did not increase, after IOHexol administration. Cohen indicated that cobicistat had no more impact on renal (kidney) function than, perhaps, Tagamet, and he hypothesized the change was due to an increase in tubular secretion of creatinine.
To summarize, at the moment, the Quad looks good going into Phase 3 studies and cobicistat (GS 9350) hopefully moves forward to eventually replace ritonavir (Norvir). The co-formulation of cobicistat with elvitegravir and the Quad lessens pill burdens for patients, but at present does not appear to have a better lipid side effect profile compared to Norvir. The replacement is welcomed by many clinicians and the community based on a general consensus of malcontent with Abbott Labs and their history on the pricing of Norvir.
GSK's Integrase Inhibitor GSK 572
ViiV, being called a "new" company, is a joint venture between the HIV franchises of GlaxoSmithKline (GSK) and Pfizer; ViiV is owned primarily by GSK. A new integrase inhibitor, acquired by GSK, is the latest agent in the class and is moving into Phase 3 studies. The compound is often referred to as "572" (short for S/GSK1349572) and was shown to be a very potent, once-daily administered integrase inhibitor that does not require pharmacokinetic enhancement or boosting.
Earlier test tube studies indicated limited cross-resistance to other INIs with 572. At CROI, further information was presented on the antiviral effects of 572, in the presence of integrase inhibitor mutations or substitution at various codons that normally have been able to confer resistance in clinical trials to either ralegravir (Isentress) or elvitegravir (the Gilead compound, also a component of the Quad pill).
For the purposes of this article, and to simplify, data presented at CROI continues to be hopeful in suggesting that 572 has a resistance profile distinct from the other two integrase inhibitors and that it may indicate a higher genetic barrier to resistance.
572 will be studied for use in both treatment-naïve patients (first-line therapy), as well as in those having already developed resistance to the other integrase inhibitors. Perhaps the easiest route for an antiviral to gain approval is in the treatment-naïve population. There are far fewer available individuals who are not able to achieve a fully suppressive regimen in this era, thus fewer patients to enroll in clinical trials who've failed or may have treatment resistance to INIs. However, 572's current use is truly most important for patients who indeed have integrase inhibitor experience, since a true second-generation agent is needed. Moreover, there will already be two integrase inhibitors available for naïve patients. Further, as this candidate agent continues to look good through development, it will also help clinicians have more confidence in using integrase inhibitors up front; they'll be cognizant of a back-up available within this class. It is early and we'll need clinical data and experience in patients to make any final judgment on 572.
Recent data presented at CROI this year gave us an opportunity to see and discuss progress with three leading developers of integrase inhibitors. Only one is currently approved, and we'll have to wait for further studies on continued development of the remaining two integrase inhibitors. The first two have similar resistance profiles, and patients who develop resistance will be cross-resistant to the other. ViiV's drug may hold promise for patients who may need a new and novel agent.
Dr. Daniel S. Berger is Clinical Associate Professor of Medicine at the University of Illinois at Chicago and founder and medical director of Northstar Healthcare, the largest private HIV treatment and research center in the greater Chicago area. Dr. Berger has published extensively in 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's Board of Directors. Dr. Berger has been honored by Test Positive Aware Network with the Charles E. Clifton Leadership Award. He can be reached at DSBergerMD@aol.com and www.nstarmedical.com.
The New Quad on the Block: Gilead's Four-Drug, Fixed-Dose Combination With a Novel Booster Sails Through Phase 2 Trials
This article was provided by Test Positive Aware Network. It is a part of the publication Positively Aware. Visit TPAN's website to find out more about their activities, publications and services.
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