Paul E. Sax, MD

Disclosures

March 29, 2012

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Hi. This is Dr. Paul Sax from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. Today, I would like to summarize some of the recent presentations from the Conference on Retroviruses and Opportunistic Infections that was just completed in Seattle. These are presentations involving new HIV drugs.

The first 2 studies[1,2] involved the so-called "quad" combination regimen, which is a 4-drug single pill option that contains tenofovir, emtricitabine (FTC), elvitegravir (an integrase inhibitor), and the investigational booster cobicistat. We already know from phase 2 studies that this combination looks quite good compared with the standard of care (tenofovir/FTC/efavirenz). Phase 2 studies are smaller, so these were actually phase 3, fully powered, noninferiority studies.

The first study is paper 101.[1] I had the privilege of presenting these data on behalf of the study team. It compared the quad regimen with the tenofovir/FTC/efavirenz regimen and found that at week 48, virologic responses to the quad regimen were every bit as good, if not a little bit better, than the efavirenz regimen, with 88% of patients with an HIV RNA level < 50 copies/mL vs 84% for the quad and the efavirenz arms, respectively.

Side effects did differ between the 2 groups, and it was a blinded study. There were more rashes and central nervous system side effects in the efavirenz arm and a bit more mild nausea in the quad arm, but rates of discontinuation due to adverse events were very infrequent in both arms. I should also emphasize that the responses were good in the high and the low viral load for the whole range of baseline demographic characteristics.

This study tells us that the quad regimen looks every bit as good as tenofovir/FTC/efavirenz, at least through 48 weeks. It certainly met its noninferiority criteria and was also very well tolerated.

The second study[2] compared the quad regimen with tenofovir/FTC/boosted atazanavir in a very similar study design. Again, responses were excellent in both the quad and the boosted atazanavir arms. The quad success rate was 90%. Side effects differed slightly between the 2 groups. Not surprisingly, there was a bit more jaundice in the tenofovir/FTC/boosted atazanavir arm, but again, rates of study discontinuation were very low in both study arms.

One thing I want to emphasize (because it is actually a bit perplexing or confusing) is that the drug cobicistat appears to raise serum creatinine in most patients rather rapidly, and it does so by inhibiting the tubular secretion of creatinine. In both of these studies, people who received quad had a median of about a 0.1- to 0.15-mg/dL increase in their serum creatinine. This is something that is going to have to be kept in mind when we start patients on this combination. It differs from the tubular toxicity of the tenofovir that we have seen in particular studies where tenofovir is used with a boosted protease inhibitor. In those cases of tubular toxicity from tenofovir, you are more likely to see a greater rise in creatinine, as well as proteinuria, glycosuria, and sometimes a low phosphate level. This is a factor that is going to have to be considered when the drugs are available in clinical practice.

I want to mention 2 other studies briefly. One is on the investigational integrase inhibitor dolutegravir.[3] This is a once-daily, unboosted integrase inhibitor. We have seen the phase 2 data at week 48. The week 96 results also look excellent, and we look forward to seeing the phase 3 data soon.

The last study[4] I want to mention is on a tenofovir prodrug called 7340, a monotherapy study given for just 10 days. Doses as low as 8 mg, 25 mg, and 40 mg were every bit as, if not more, potent than tenofovir. It was also associated with lower plasma levels of tenofovir. What is hoped is that these lower plasma levels will correlate with lower end-organ toxicity. This drug, 7340, is currently being studied in phase 2 and also in coformulations with both elvitegravir/cobicistat/FTC and darunavir/cobicistat/FTC.

These are some of the studies on new drugs from the recent retrovirus conference. Thanks very much for listening.

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