Integrated analysis shows 'Quad' pill has potent activity with fewer side-effects

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An integrated analysis of data from phase II and III trials showed that the 'Quad' single-tablet regimen has antiviral efficacy at least as good as comparison regimens and is associated with fewer adverse events than Atripla or ritonavir-boosted atazanavir (Reyataz), researchers reported on Monday at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.

Gilead Science's four-in-one 'Quad' coformulation contains the next-generation integrase inhibitor elvitegravir, the novel boosting agent cobicistat, and tenofovir DF/emtricitabine (FTC; the latter two are the drugs in Truvada). It was approved by the US Food and Drug Administration in August 2012 for adults starting HIV treatment for the first time and is marketed under the brand name Stribild in the US.

Approval was based on study data showing that Stribild suppresses HIV viral load as effectively as two widely used, guidelines-recommended antiretroviral regimens. At ICAAC, David Ward from Dupont Circle Physicians Group presented findings from a pre-specified integrated analysis of safety and efficacy in three of these trials:

  • Study 102: a phase III head-to-head comparison of Stribild versus Atripla (efavirenz/tenofovir/emtricitabine single-tablet regimen) in 700 treatment-naive people.
  • Study 103: a phase III comparison of Stribild versus ritonavir-boosted atazanavir plus tenofovir DF/emtricitabine in 700 previously untreated patients.
  • Study 104: a smaller phase II study comparing Stribild versus Atripla in 75 treatment-naive patients.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

creatinine

Breakdown product of creatine phosphate in muscle, usually produced at a fairly constant rate by the body (depending on muscle mass). As a blood test, it is an important indicator of the health of the kidneys because it is an easily measured by-product of muscle metabolism that is excreted unchanged by the kidneys.

phase II

The second stage in the clinical evaluation of a new drug or intervention, in which preliminary data on effectiveness and additional information about safety is collected among a few hundred people with the disease or condition.

naïve

In HIV, an individual who is ‘treatment naïve’ has never taken anti-HIV treatment before.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

The combined analysis included a total of 749 participants taking Stribild, 375 taking Atripla, and 355 taking boosted atazanavir.

Baseline characteristics were similar across the three regimen groups. About 90% were men, two-thirds were white, the median age was about 38 years and the median CD4 T-cell count was approximately 380 cells/mm3.

The Quad pill demonstrated a high rate of virological suppression in all studies, matching that of comparison regimens. At 48 weeks, 89% of Stribild recipients, 84% of Atripla recipients and 87% of atazanavir recipients achieved virological response, defined as HIV RNA less than 50 copies/mL.

CD4 cell increases at week 48 were also similar in all three regimen arms: 224, 203 and 211 cells/mm3, respectively. Virological suppression and CD4 cell gains were consistent across subgroups stratified by demographic characteristics, baseline HIV viral load and baseline CD4 count.

Stribild was generally safe and well tolerated, with mostly mild-to-moderate side-effects. Overall rates of study discontinuation were similar in all regimen arms at around 12%. Rates of serious adverse events (9, 7 and 9%, respectively) and adverse events leading to drug discontinuation (4, 5 and 5%) were also statistically equivalent. Mortality was less than 1% in all groups.

However, Stribild recipients reported significantly fewer neuropsychiatric side-effects such as abnormal dreams and dizziness (43 vs 62%) and less skin rash (18 vs 28%) than those taking Atripla, and less bilirubin elevation than those taking boosted atazanavir.

Stribild was associated with significantly smaller increases in total, LDL and HDL cholesterol compared with Atripla, and smaller triglyceride increases compared with boosted atazanavir.

Stribild recipients experienced an early increase in serum creatinine – a potential marker of impaired kidney function – but levels soon stabilised. At 48 weeks, the increase in the Stribild arm was greater than that seen with Atripla, but similar to that of atazanavir (median +0.13, +0.01 and +0.08 mg/dL, respectively). Less than 1% of participants across arms discontinued therapy due to kidney problems. People who stopped Stribild for this reason showed improvement after discontinuation, but not necessarily to baseline levels, according to Ward.

The researchers concluded that the Stribild single-tablet regimen "demonstrated high rates of virologic suppression comparable to [Atripla] and [atazanavir/ritonavir + tenofovir/emtricitabine] with potential to overcome toxicities, such as neuropsychiatric symptoms, rash, and hyperlipidemia".

"[An] early small increase in creatinine that stabilizes is expected" with Stribild due to inhibition of renal tubule secretion by cobicistat, they added.

While this is not thought to be problematic itself, Ward explained that it raises the issue of how to differentiate cobicistat-related creatinine increases from uncommon kidney toxicity associated with tenofovir. Stribild prescribing information will include a threshold level indicating when the regimen should be stopped.

References

Ward D et al. Efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF from an integrated analysis of phase 2 and 3 clinical trials. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, abstract H-555, 2012. View the abstract on the conference website.