The Ethics of Switch/Simplify in Antiretroviral Trials: a rebuttal

Arribas JR(1), Hill A(2), and Pulido F(3)

Affiliations: (1) HIV Unit, Internal Medicine Service, Hospital Universitario La Paz, IdiPAZ and (3) HIV Unit, Internal Medicine Service, Hospital Universitario 12 de Octubre, i+12. Madrid, Spain. (2) Pharmacology Research Laboratories, University of Liverpool, Liverpool, UK
A number of cohort studies have demonstrated that antiretroviral therapy (ART) modification during the first year treatment is still a very common event [1]. Many of these treatment changes occur in patients who have already achieved virological suppression. To make ART changes safely, clinicians base their decisions on the results of important switch/simplify trials.

Despite its benefits, Carr, Hoy and Pozniak [2] take issue with the ethics of switch/simplification trials. We would like to offer a balanced reply to many of the alarming points raised in their essay.

Introduction
Claim: “One response to fewer patients with virological failure is to evaluate new ART drugs in patients receiving effective ART, with undetectable plasma HIV”.
Rebuttal: Relevant switch trials started well before the difficulty in enrolling patients in rescue trials [3]. The main reason to change ART nowadays is not virological failure but toxicity events [1]. Following Carr and colleagues logic, trials of ART naïve patients would be also unethical since the rate of virologic failure of modern first-line regimens is very low.

Claim: “One of us (AC) participated in one such trial that yielded adverse patient outcomes”
Rebuttal: Apart from participating as an investigator in SWITCHMRK [4], Dr. Carr is the senior author of the STEAL study (Dr. Hoy was also an investigator) [5], which also yielded adverse patients outcomes. The STEAL trial included suppressed patients not experiencing adverse events. The primary endpoint was virologic. Unfortunately, patients randomized to the abacavir plus lamivudine arm suffered more cardiovascular events. Dr. Carr was also the first author of the PILLR trial that showed worsening lipoatrophy in patients switched to an experimental regimen [6].

Switching and Simplifying Antiretroviral Therapy in Clinical Trials
Claim: “More commonly, one ART drug is switched to a new drug under development, the primary end point being virological non-inferiority, i.e., that virological suppression can be maintained to a similar degree as with current ART”.
Rebuttal: No antiretroviral “under development” has been evaluated with this type of design. New antiretrovirals have been approved based on the results of clinical trials of ART-naïve patients or clinical trials of rescue therapy.

Claim: “A similar virological non-inferiority trial involves ART simplification, which takes one of two forms. A new co-formulation can replace the same two or three drugs
taken separately”
Rebuttal: There is no switch/simplification trial that has evaluated a new coformulation replacing the same two/three drugs taken separately.

Claim: “Because of the similar outcomes expected, non-inferiority trials are less likely than superiority trials to improve patient health”
Rebuttal: This is a misleading claim that appears to affect only switch/simplification trials. Not a single recent trial of ART naïve patients has been designed as a superiority trial.

Claim: “First, neither type of study reduces the risk of virological failure.
Indeed, simplification with protease inhibitor monotherapy can increase this risk [7]”
Rebuttal: Misleading claim referred to the OK04 trial [7]. Readers might interpret that due to virologic failures patients included in the monotherapy arm of OK04 lost therapeutic options. Despite more episodes of low-level viral rebound the risk of resistance was not increased in the monoherapy arm. At 96-week, lopinavir/ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy. Incidence of adverse events leading to treatment discontinuation was significantly lower with monotherapy. This is precisely what Carr and colleagues envision as the optimal outcome of switch/simplification: non-inferior efficacy and less adverse events. Due in part to these results EACS guidelines recommend lopinavir/ritonavir monotherapy in selected patients [8]

Claim: “Second, non-inferior results in a switch trial have sometimes created the incorrect perception that these investigational regimens are as potent as more proven regimens, only to be found inferior when formally evaluated in patients initiating ART for the first time”
Rebuttal: Authors fail to quote the evidence supporting that the antiretroviral “potency” needed to maintain suppression is lower than the potency needed for initial therapy. The ARIES trial [9] has convincingly proven that unboosted atazanavir can maintain suppression as well as boosted atazanavir. Interestingly, patients receiving unboosted atazanavir experienced lower bilurribin and trygliceride increases.

Risks and Benefits for Clinical Trial Participants
Claim: “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”
Rebuttal: We are startled that the PILLR trial [6], in which patients switched to a poorly tolerated regimen of abacavir, nevirapine, adefovir and hydroxyurea that worsened lipoatrophy is quoted as an example of good clinical trial design. We recognize that when any clinical trial is conducted, there is uncertainty about the final results. It is hard fully to anticipate the results of the trial in patient informed consent documents. The Etravirine trial [10] that is also supports the claim was also completely unpowered to prove non-inferior virological efficacy.

Claim: “A switch or simplification study, however, 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”.
Rebuttal: Continued virological suppression should be a primary endpoint. A less toxic drug with an unacceptable rate of virological failure leading to resistance would be useless. Long-term toxicity might take decades to appear. Trials of this duration are simply not feasible. Nevertheless, one-two year duration trials have provided useful information regarding reasonable proxy endpoints such a total limb fat, bone mineral density or glomerular filtration rates changes.

Claim: “Participants must be informed about all potential advantages and disadvantages
and which is the primary focus of the study”.
Rebuttal: Carr and colleagues do not offer examples of trials with poor informed consents despite their full access to the STEAL [5] and PILLR [6] trial documents.

Claim: “Lastly, some laboratory parameters commonly reported as key positive outcomes of switch or simplification trials may not represent significant toxicities”.
Rebuttal: Investigator would not offer to participate in a switch/simplification trial to a patient with high cardiovascular risk when the investigator already knows that there are better options. Interestingly, this knowledge is based on the results of laboratory parameters of trials, which included low risk patients.

The SWITCHMRK Switch Trials
Claim: “Patients with prior treatment failure were eligible, thus permitting some patients with pre-existing antiretroviral resistance to change to what was effectively raltegravir monotherapy”
Rebbutal: Therefore Carr and colleagues imply that, as the OK04 trial has shown [7], these patients were well controlled on effective Lopinavir/ritonavir monotherapy.

Claim: “Although serum cholesterol levels significantly declined with raltegravir, patients were not required to have an elevated cardiovascular risk at baseline, and the total cholesterol to high-density lipoprotein cholesterol ratio did not decline”.
Comment: Following Carr and colleagues logic we believe they would enroll patients in a clinical trial of high cardiovascular risk patients randomizing them to Lopinavir/ritonavir or Raltegravir. Prudent clinicians wouldn’t participate in such a trial

The MONET Simplification Study
Claim: “The MONET trial is an example of a simplification study with limitations”
Rebuttal: In the three main reports of the MONET clinical trial [11, 12, 13] the study has never been described as a simplification trial since a substantial number of patients increased their daily pill burden after the switch. It is difficult to understand why MONET is chosen as an example of trial with limitations. In contrast with SWITCHMRK [4] not a single patient randomized to darunavir/ritonavir monotherapy in MONET lost therapeutic options and the trial met its primary endpoint [11]. Results of MONET and MONOI [14] are the basis for the EACS guidelines recommendations for using darunavir/ritonavir monotherapy in selected patients [8].

Claim: “Reduced toxicity, improved quality of life, and reduced health-care costs were all cited in the MONET publication as potential benefits of the trial’s strategies, but none of these parameters was reported”.
Rebuttal: It is disturbing that Carr and colleagues have not reviewed the published literature. We have reported on safety events in the three main updates of MONET [11, 12, 13]. In addition we have published detailed reports of CNS [15], vitamin D [16], and inflammatory biomarkers outcomes [17]. Pharmacoeconomic analysis for the Spanish [18] and the United Kingdom scenarios [19] have been presented in meetings and subsequently published.

Elephants in the Room
Carr and colleagues make also claims about the motivations of researchers to conduct and participate in switch/simplification trials that are unfair for the majority of researchers. The DHHS guidelines [20] in their regimen simplification section support their recommendations in 16 published clinical trials. It is hard to believe that trials performed “by the opportunity to use new therapy, by academic acclaim, and/or by remuneration” form the basis of evidence-based recommendations. Carr and colleagues also criticize the tenuous science underlying switch/simplification trials. Below we offer examples of key findings of switch trials that are relevant for current clinical practice.

Switching and Simplifying Therapy in Clinical Practice
Finally, Carr and colleagues recommend that switch/simplification be restricted to “those who have a toxicity or are at high risk, and where the toxicity is clinically meaningful, not just an abnormal laboratory parameter”. These are precisely the patients who would be very difficult to randomize to the control arm where treatment is not changed

We hope these rebuttals would help researchers, clinicians, patients and potential clinical trial volunteers to have more balanced information of the benefits of switch/simplification clinical trials.

Findings relevant for patient care that have been proven in switch/simplification trials.
1. Protease inhibitors (mainly unboosted) can be switched to Abacavir, Nevirapine or Efavirenz. Patients with prior nuclesoside resistance more likely to fail on abacavir. [3]
2. Lopinavir/ritonavir should not be switched to Raltegravir if the nucleosides are not fully active [4]
3. A fusion inhibitor can be safely switched to Raltegravir [21]
4. Unboosted atazanavir can mantain suppression as well as boosted atazanavir [9]
5. Lopinavir/ritonavir BID monotherapy can mantain suppression in the majority of patients without losing therapeutic options [7]
6. Darunavir/ritonavir QD monotherapy can mantain suppression in the majority of patients without losing therapeutic options [11,14]
7. In patients without previous virologic failure, two nucleosides plus an NNRTI or a boosted PI can be replaced to coformulated Tenofovir/Emtricitabine/Efavirenz [22]
8. Stavudine or zidovudine can be safely replaced by abacavir or tenofovir. Switch is associated with subclinical limb fat improvement [23,24]
9. Switching from a boosted PI to unboosted atazanavir, an NNRTI, or raltegravir improves total cholesterol, non-high density lipoprotein cholesterol, and triglyceride levels. [25, 9, 3, 4]

REFERENCES
1. Elzi L, Marzolini C, Furrer H, Ledergerber B, Cavassini M, Hirschel B, et al. Treatment modification in human immunodeficiency virus-infected individuals starting combination antiretroviral therapy between 2005 and 2008. Arch Intern Med 2010; 170:57–65.
2. Carr A, Hoy J, Pozniak A. The Ethics of Switch/Simplify in Antiretroviral Trials: Non-Inferior or Just Inferior? PLoS Med 2012; 9:e1001240.
3. Martínez E, Arnaiz JA, Podzamczer D, Dalmau D, Ribera E, Domingo P, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med 2003; 349:1036–1046.
4. Eron JJ, Young B, Cooper DA, Youle M, DeJesus E, Andrade-Villanueva J, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. The Lancet 2010; 375:396–407.
5. Martin A, Bloch M, Amin J, Baker D, Cooper DA, Emery S, et al. Simplification of Antiretroviral Therapy with Tenofovir‐Emtricitabine or Abacavir‐Lamivudine: A Randomized, 96‐Week Trial. Clinical Infectious Diseases 2009; 49:1591–1601.
6. Carr A, Hudson J, Chuah J, Mallal S, Law M, Hoy J, et al. HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. AIDS 2001; 15:1811–1822.
7. Arribas JR, Delgado R, Arranz A, Muñoz R, Portilla J, Pasquau J, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. JAIDS Journal of Acquired Immune Deficiency Syndromes 2009; 51:147–152.
8. European AIDS Clinical Society (EACS) guidelines. Version 6.1. November 2011. Available online at: http://www.europeanaidscl...
9. Squires KE, Young B, DeJesus E, Bellos N, Murphy D, Zhao HH, et al. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients. AIDS 2010; 24:2019–2027.
10. Waters L, Fisher M, Winston A, Higgs C, Hadley W, Garvey L, et al. A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS 2011; 25:65–71.
11. Arribas JR, Horban A, Gerstoft J, Fätkenheuer G, Nelson M, Clumeck N, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS 2010; 24:223–230.
12. Clumeck N, Rieger A, Banhegyi D, Schmidt W, Hill A, Van Delft Y, et al. 96 week results from the MONET trial: a randomized comparison of darunavir/ritonavir with versus without nucleoside analogues, for patients with HIV RNA. Journal of Antimicrobial Chemotherapy 2011; 66:1878–1885.
13. Arribas J, Clumeck N, Nelson M, Hill A, Delft Y, Moecklinghoff C. The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load. HIV Med 2012; :n/a–n/a.
14. Katlama C, Valantin MA, Algarte-Genin M, Duvivier C, Lambert-Niclot S, Girard PM, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS 2010; 24:2365.
15. Winston A, Fätkenheuer G, Arribas J, Hill A, Van Delft Y, Moecklinghoff C. Neuropsychiatric Adverse Events With Ritonavir-Boosted Darunavir Monotherapy in HIV-Infected Individuals: A Randomised Prospective Study. HIV Clinical Trials 2010; 11:163–169.
16. Fox J, Peters B, Prakash M, Arribas J, Hill A, Moecklinghoff C. Improvement in Vitamin D Deficiency Following Antiretroviral Regime Change: Results from the MONET Trial. AIDS Research and Human Retroviruses 2011; 27:29–34.
17. Arribas J, Hill A, Van Delft Y, et al. Interleukin-6 and C-reactive protein levels after 144 weeks of DRV/r monotherapy versus DRV/ r + 2NRTIs in the MONET trial, for patients with HIV RNA <50 copies/mL at baseline [abstract PS 10/2]. European AIDS Clinical Society Conference, Belgrade, Serbia, October 2011
18. Pasquau J, Gostkorzewicz J, Ledesma F, Anceau A, Hill A, Moecklinghoff C. Budget impact analysis of switching to darunavir/ritonavir monotherapy for HIV-infected people in Spain. Appl Health Econ Health Policy 2012; 10:139–141.
19. Gazzard B, Hill A, Anceau A. Cost-efficacy analysis of the MONET trial using UK antiretroviral drug prices. Appl Health Econ Health Policy 2011; 9:217–223.
20. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. March 27, 2012. http://www.aidsinfo.nih.g... (accessed June 10, 2012).
21. De Castro N, Braun J, Charreau I, Pialoux G, Cotte L, Katlama C, et al. Switch from Enfuvirtide to Raltegravir in Virologically Suppressed Multidrug‐Resistant HIV‐1–Infected Patients: A Randomized Open‐Label Trial. Clinical Infectious Diseases 2009; 49:1259–1267.
22. DeJesus E, Young B, Morales-Ramirez JO, Sloan L, Ward DJ, Flaherty JF, et al. Simplification of antiretroviral therapy to a single-tablet regimen consisting of efavirenz, emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected patients. JAIDS Journal of Acquired Immune Deficiency Syndromes 2009; 51:163–174.
23. Moyle G, Sabin C, Cartledge J, Johnson M, Wilkins E, Churchill D, et al. RAVE (Randomized Abacavir versus Viread Evaluation) Group UK. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 2006; 20:2043–2050.
24. Fisher M, Moyle GJ, Shahmanesh M, Orkin C, Kingston M, Wilkins E, et al. A randomized comparative trial of continued zidovudine/lamivudine or replacement with tenofovir disoproxil fumarate/emtricitabine in efavirenz-treated HIV-1-infected individuals. JAIDS Journal of Acquired Immune Deficiency Syndromes 2009; 51:562.
25. Gatell J, Ceron DS, Lazzarin A, Wijngaerden EV, Antunes F, Leen C, et al. Efficacy and Safety of Atazanavir-Based Highly Active Antiretroviral Therapy in Patients with Virologic Suppression Switched from a Stable, Boosted or Unboosted Protease Inhibitor Treatment Regimen: The SWAN Study (AI424-097) 48-Week Results. Clinical Infectious Diseases 2007; 44:1484–1492