Advertisement covers The 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012)

State of ART at CROI: New Concepts and New Integrase Inhibitors

March 8, 2012

Benjamin Young, M.D., Ph.D.

Benjamin Young, M.D., Ph.D.

For years, one of the most anticipated and best-attended sessions at CROI has covered new medications. Wednesday's session was no exception. A standing-room-only crowd listened to presentations that covered preclinical molecules, molecular genetics and clinical trials. I was lucky to arrive early and get a seat.

The session started with a presentation by Frauke Christ (Belgium) describing intriguing in vitro data on inhibitors of a new drug target called LEDGF/p75 -- one of the components of the HIV integration process (abstract 98). These molecules, called LEDGINs, appear to work by blocking the dimerization of the HIV integrase, and may work additively with current integrase inhibitors.

Peter Ruane, M.D., (Los Angeles) presented the results of a dose-ranging, 10-day, monotherapy study of GS-7340 (abstract 103). GS-7340 is a phosphoramidite prodrug of tenofovir (TDF, Viread) -- I love it when clinicians talk organic chemistry -- that is proposed to have lower plasma levels, but concentrates in target cells. Cynics could say that this might be a strategy to extend the patent life of tenofovir, but could the drug offer clinical or safety benefits?

In this study of 38 individuals, patients received either placebo, standard (300-mg) tenofovir or GS-7340 (8, 25 or 40 mg, once daily). Compared with the patients on tenofovir, patients who received 25 or 40 mg of GS-7340 had larger declines in HIV RNA levels (-0.97 log10 versus -1.46 log10 and -1.73 log10, respectively). Intracellular PBMC lymphocyte levels of the active drug metabolite (tenofovir diphosphate) were about seven to 20 times higher for GS-7340 patients compared with tenofovir patients. Questions were asked about the selectivity of this increased intracellular drug concentration; if this could also cause increased levels in hepatocytes (a good thing if you're thinking of treating hepatitis B), bone or kidney cells (not a good thing, if you're concerned about osteoporosis or renal injury).


It appeared that most of the audience was in attendance to hear about studies focused on the investigational HIV integrase inhibitors elvitegravir and dolutegravir. Dolutegravir is of interest because it retains activity against some HIV strains that are resistant to the first integrase inhibitor, raltegravir (RAL, Isentress). Of note, an expanded access program for dolutegravir was announced this week for individuals with raltegravir-resistant HIV.

Integrase-inhibitor-based treatments have become widely utilized in the U.S., as well as in our clinic. Part of the reason for this is the concern over low-grade intolerance for efavirenz (EFV, Sustiva, Stocrin), so studies that compare new integrase inhibitors to the reference standard would be notable. Raltegravir has proved to be extremely well tolerated, but requires twice-daily dosing and is not coformulated. Both of the new integrase inhibitors offer once-daily dosing and the potential for coformulation.

Paul Sax, M.D., (frequent and contributor) presented results from the Gilead Science study GS-US-236-0102, the first fully powered study to compare two once-daily single tablet regimens (abstract 101). This was a placebo-controlled trial of 700 individuals who were randomized to take efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC, Atripla) or the Quad pill (cobicistat + elvitegravir + emtricitabine + tenofovir). Overall, the results demonstrate the non-inferiority of the two single tablet regimens; there were no apparent differences in virologic responses and rates of virologic failure (or resistance rates).

There was a statistically significantly greater CD4+ cell count rise with the Quad (239 cells) compared with efavirenz/tenofovir/emtricitabine (206 cells). Both were relatively well tolerated, though Quad recipients more frequently reported nausea (21% versus 14%) and efavirenz/tenofovir/emtricitabine patients, not surprisingly, had more efavirenz-related side effects (i.e., abnormal dreams, insomnia, dizziness and rash). Quad, as seen in prior cobicistat studies, was associated with small artifactual and not clinically relevant increases in serum creatinine. Most of these side effects were of grade 1 intensity. 1.4% of patients receiving Quad discontinued due to renal side effects.

Quad was also found to be non-inferior to a regimen of the boosted protease inhibitor atazanavir (ATV, Reyataz) in a separate powered phase 3 study, with 90% versus 87% virologic suppression (abstract 627). There were few discontinuations for renal events -- 0.3% in both arms.

The Shionogi-ViiV group and Hans-Juergen Stellbrink, M.D., presented the final 96-week results of the phase 2 study of dolutegravir in treatment-naive persons (abstract 102LB). About 200 individuals received either efavirenz or dolutegravir (with two NRTIs, selected by the site investigators). Protocol-defined virologic failure was not reported in any of the patients initially randomized to the 50-mg arm (the dose selected for phase 3 studies) and there were fewer grade 2-4 adverse events reported in the dolutegravir arms (11%) compared with the efavirenz arm (24%). Like Quad, dolutegravir was associated with small increases in serum creatinine (0.1-0.15 mg/dL) that may be related to inhibition of tubular reabsorption, mediated by OCT2. There were no apparent differences when results were analyzed by NRTI backbone.

I expect that we'll soon have once-daily HIV integrase inhibitors in the clinic. Quad has been submitted for approval to the U.S. Food and Drug Administration; I'd expect its approval before the end of the summer. Quad seems to address the limitations of efavirenz-based treatments, namely psychological side effects, but it may have a mild gastrointestinal side effect profile.

Dolutegravir data also was received with much interest, as it does not require pharmacologic boosting and might offer coformulation with either tenofovir (unlikely) or abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa) (probable, since ViiV manufactures both). The effect of both laboratory measurements of kidney function (creatinine) may be a source of confusion and the company will need to assist clinicians in understanding how to optimally evaluate this, particularly in light of the known, but relatively, rare rates of tenofovir-associated renal injury.

Both Quad and dolutegravir will be born into a treatment world with a growing concern regarding the price of medications and the impending availability of entirely generic preferred regimens. How Gilead and ViiV will deal with these challenges remains to be seen, but I hope for a day when the same innovation in the discovery of new drug molecules will apply to the production, distribution and pricing of HIV medicines.

Copyright © 2012 Remedy Health Media, LLC. All rights reserved.

This article was provided by TheBodyPRO. It is a part of the publication The 19th Conference on Retroviruses and Opportunistic Infections.


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