Are antiretroviral switch or simplification studies of benefit for patients?

The attitude of physicians, ethics committees and medical journals to antiretroviral switch and simplification studies needs to be radically reappraised, according to an article published in PLoS Medicine.

Before approval, studies of this type must show a clear potential advantage to patients and the risks and benefits need to be explicitly outlined to participants during recruitment, state the authors.

They add that commercial advantage for a pharmaceutical company is not a valid reason for approving a switch or simplification study.

The recent SWITCHMRK studies (substitution of raltegravir for lopinavir/ritonavir) and MONET trial (a simplification study exploring darunavir/ritonavir monotherapy) are highlighted by the authors as studies whose design and reporting failed to show any benefit to patients or healthcare systems. Indeed, for some patients participation in the study led to loss of virologic control.

Outcomes for patients taking HIV therapy in the UK and similar countries are hugely impressive. The majority of patients treated with antiretroviral drugs, regardless of their past treatment history and resistance profile, have an undetectable viral load, the primary goal of HIV therapy.

The safety and efficacy of antiretroviral treatment is demonstrated in phase III clinical studies. In these studies, a new drug is generally required to show virological superiority over either a placebo or the current standard of care.

Because of the substantial improvements seen in virological outcomes over the part 15 years, it is becoming increasingly difficult to recruit patients to clinical trials.

One solution has been to evaluate new drugs and treatment strategies in individuals whose existing therapy is effective and suppressing viral load. Many of these studies involve switching treatment to see if a new drug is non-inferior to an existing therapy, or if it leads to the simplification of treatment.

Switching studies have intended to show the non-inferiority of a new drug (no more than 10 to 12% worse than the existing therapy). If non-inferiority is proved, then the secondary end-points of these studies, such as the impact of the switch on quality of life and side-effects, can be of great interest.

Treatment simplification studies should also show that a new therapy is non-inferior to the pre-existing therapy. Simplification of treatment can include the replacement of two or three drugs with a co-formulation of these agents to reduce pill burden, or the cessation of one drug without the introduction of a new therapy.

There are undoubted benefits from switching or simplifying treatment. These can include reduced pill burden, greater tolerability and lower cost. However, there are also potential disadvantages. For instance, an effective and tolerable treatment may be abandoned.

Moreover, it has become clear that neither switching nor simplifying treatment reduces the risk of virological failure. Nor does a non-inferior finding in a study show that new agents or strategies are as potent as existing drugs. This can only be demonstrated in patients starting HIV therapy for the first time.

According to the Declaration of Helsinki, the benefits of a clinical trial should outweigh the potential risks.

“A switch or simplification study…with a primary end point of continued virological suppression and with no clinically useful impact on toxicity, costs, or quality of life cannot have any benefit to the participant,” write the authors. However, they found that 42% of HIV switch or simplification studies registered on clinical-trials.gov “had virological non-inferiority as the primary end point.”

Rather, they believe that a particular disadvantage of a current treatment should be an explicit and well-defined entry criteria for the study. “Good examples of this approach are trials that evaluated the ability of drug switching to reverse objectively defined lipoatrophy and efavirenz-related central nervous symptoms.”

Moreover, the authors emphasise that the possible potential disadvantages of the switch should be “measured, analysed and reported.”

Patients must therefore be informed about the potential advantages and disadvantages and which is the primary focus of the study. If cost is the main focus, then the consent form must make it clear that the patient is not expected to derive any benefit from the study.

The authors also question whether some laboratory improvements reported as a benefit of a treatment switch are really of any clinical relevance. For instance, they suggest that reductions in cholesterol levels are likely only to be of meaningful benefit for patients with cardiovascular risk factors. “No lipid switch study specifically enrolled patients with elevated cardiovascular risk,” note the authors.

Ethics committees should only approve studies if they are “convinced the potential gain is both clearly anticipated and clinically relevant to all participants and confident that patients are not likely to be at risk of virological failure,” write the investigators. “Trials that primarily benefit a pharmaceutical company should not be contemplated or approved.”

In terms of design, switch studies should be double-blind and have subjective endpoints. Any large switch study with a primary focus on toxicity should be preceded by a smaller pilot study. The virological efficacy of therapy should be assessed in trials involving treatment-naive patients, not in switch studies.

Journal editors are asked by the authors to consider making it compulsory to submit patient information and consent forms with manuscripts reporting the findings of switch and simplification research. They would enable editors to “determine whether patients were fully informed about the risks and benefits of a trial, all risks and benefits were reported, and the principles of the Helsinki Declaration were upheld.”

Switching HIV treatment can be appropriate, conclude the authors, but it is essential to determine the full risks and benefits before and to communicate these to patients.

“The diminishing antiretroviral drug pipeline suggests greater care will need to be given in coming years to extending the benefits of existing drugs for what is likely to remain lifelong therapy.”

Carr A et al. The ethics of switch/simplify in antiretroviral trials: non-inferior or just inferior? PLoS Medicine, 9:7. e1001240, 2012.