Top 10 HIV Clinical Developments of 2012

Tenofovir/FTC/Elvitegravir/Cobicistat (The Drug Previously Known as the QUAD)

A review of:

Paul Sax, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012 Jun 30;379(9835):2439-48.

Edwin DeJesus, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012 Jun 30;379(9835):2429-38.

Okay, yes, the Quad was on last year's top stories list, and it does seem odd to recycle a "top 10," but in 2012, the story for the third single-tablet regimen got better. Foremost, the results of head-to-head trials of the drug (versus efavirenz/TDF/FTC and atazanavir/ritonavir/TDF/FTC) were published.

These trial results showed efficacy for the Quad that was non-inferior to these two first-line therapy workhorses. The studies also made clearer the effects of the drug on measures of renal function and lipids, as well as gastrointestinal tolerability.

Importantly, in August, the Quad was considered by the U.S. DHHS guidelines panel and was designated an "alternative" to the preferred agents. The rationale for alternative status included relatively short-term data (only 48-week clinical trial information was available), as well as lingering questions regarding the renal effects of the combination.

The cobicistat component is known to block MATE-1, a transporter of creatinine from the blood to the urine across the proximal tubule. Inhibition of this and similar transporters lead to less clearance of creatinine. This in and of itself does not cause any reduction in kidney function or harm, but it does mess with the most commonly used assessment of kidney health, the serum creatinine, by causing an artificially elevated value. With tenofovir also part of the Quad's four-drug mix, confusion regarding serum creatinine bumps is a worry.

The new clinical trial data helped a bit, showing that the artifactual increase in serum creatinine occurs within first two to four weeks of therapy and generally plateaus. The study comparing the Quad to atazanavir/ritonavir demonstrated how a similar but smaller increase in serum creatinine also occurs with the boosted protease inhibitor, as ritonavir has some (albeit weaker) inhibitory effects on MATE-1.

Still, some study participants did develop true tubulopathy, and although the numbers were small, this was more common among those on the Quad. As to longer-term data, we now have 96 weeks of follow-up from these trials presented at the 11th International Congress on Drug Therapy in HIV Infection in Glasgow, and this affirms the one-year results. (You read the abstracts for the 96-week comparison to atazanavir/ritonavir/TDF/FTC as well as the 96-week comparison to efavirenz/TDF/FTC.)

It is notable that there has not been more enthusiasm for this four-drugs-in-one therapy, despite it being a marvel of drug engineering and the finding that it is as efficacious as NNRTI- and boosted PI-based regimens. That said, there are many existing options for the treatment of treatment-naive patients, including two other once-daily, single-tablet regimens, so the field is increasingly crowded. It could also be that there remains some apprehension regarding the longer-term renal picture: In addition, in some states, the pace of adding the drug to AIDS Drug Assistance Program formularies has been slow, and a few insurance companies are now starting to require prior authorization for certain HIV therapies, including the Quad. Lastly, the absence of the "preferred" imprimatur from the DHHS guidelines can't be helping.

As more data emerge, it is likely we will see more attention paid to this drug -- but the competition is only getting stiffer (read on).