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Noninferiority and lopinavir/ritonavir monotherapy trials

Pulido, Federicoa; Arribas, José Rb

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doi: 10.1097/QAD.0b013e32830a98ac
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We sincerely appreciate the comments by Richert et al.[1] about the important methodological issues of noninferiority trials. Our answers to their comments related to the OK04 study are as follows:

  1. Richert et al.[1] are concerned about ‘the apparent absence of a consensus regarding the choice of the primary endpoint in trials comparing different strategies of antiretroviral treatment’. However, they fail to realize that the strategy tested in OK04 [2] is completely different from other trials of triple therapy. The differences between lopinavir monotherapy and other simplification strategies still based on triple therapy are so fundamental that new methodological approaches and new endpoints are warranted.
  2. Richert et al.[1] are somewhat surprised about our choice of primary endpoint. In particular, about our decision of not considering successful reinductions as failures. After a pilot study [3], we learned that patients with virological rebound while on monotherapy did not develop resistance, and they could be successfully resuppressed with the same nucleosides without losing therapeutic options. On the basis of the results of our pilot trial, the scientific question we have tried to answer in OK04 is, for a patient without resistance to protease inhibitors who has viral suppression while taking two nucleosides and lopinavir/ritonavir, which strategy is better: to continue triple therapy or stop the nucleosides and use them only if patient fails to maintain suppression? To answer this question our endpoint is appropriate. Not considering successful reinductions as a positive outcome would not allow us to answer our scientific question. Nevertheless, sensitivity analyses with more standard definitions were performed and presented. We disagree with Richert et al.'s comparison with ‘other randomized trials evaluating simplification regimens’ as they mention two lopinavir/ritonavir monotherapy studies that included naïve patients (different to our study) [4,5] and another study using efavirenz for simplification [6] instead of a boosted protease inhibitor (it is well known that the consequences of virological failure with a no-nucleoside are very different to the failure with a boosted protease inhibitor).
  3. Apart from the primary analysis, we have provided six additional sensitivity analyses in our study. Richert et al.[1] ask for even more analyses. In particular, they mention the ‘worst-case’ methodology. This methodology is a way of ‘torturing data until they confess’. This method could be useful when the truth is hidden. However, when reported data have provided all the information clinicians need, we consider such kind of torture unnecessary. Our sensitivity analyses give enough information to obtain a complete picture about the strengths and limitations of the monotherapy strategy. The disposition of patients has been fully detailed and allows the reader to perform other sensitivity analysis if this is considered important. It is now time to discuss from a clinical point of view how this new information has to modify or not our therapeutic approaches.
  4. We agree with Richert et al.[1] that the margin of noninferiority has to be rigorously chosen and justified. The noninferiority margin of OK04 was selected before the study as clinically relevant, taking into account the rates of failure in the clinical trials testing accepted strategies of simplification (with efavirenz, nevirapine, or abacavir) [7]. This margin could be even more appropriate in our trial because the benign nature of the ‘failure’ in the monotherapy group.
  5. OK04 is a real noninferiority trial because, even if monotherapy has a slightly lower probability of maintaining suppression, the added values of the strategy are very clear: reducing cost [8], reducing toxicity [9], and potentially increasing survival [10]. In addition, the consequences of failures do not imply losing therapeutic options [11]. We cannot count how many times we have been criticized because monotherapy does not make sense in the era of ‘safe’ nucleosides. We recommend that these critics look back at to what has happened with ‘safe’ nucleosides during the last 4 months [12].

In summary, we agree with many of the careful points raised by Richert et al.[1], but we have the impression that they have picked the wrong trial to exemplify the many methodological problems inherent to noninferiority trials.


1. Richert L, Bouteloup V, Thiébaut R, Chêne G. Methodological issues of noninferiority trials in HIV-infected patients: a need for consensus? AIDS 2008; 22:996–997.
2. Pulido F, Arribas JR, Delgado R, Cabrero E, González-García J, Pérez-Elias MJ, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV. AIDS 2008; 22:F1–F9.
3. Arribas JR, Pulido F, Delgado R, Lorenzo A, Miralles P, Arranz A, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 2005; 40:280–287.
4. Delfraissy JF, Flandre P, Delaugerre C, Ghosn J, Horban A, Girard PM, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV infected patients. AIDS 2008; 22:385–393.
5. Cameron W, da Silva B, Arribas J, Myers R, Bellos NC, Gilmore N, et al. A two-year randomized controlled clinical trial in antiretroviral-naive subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03–613). In: Program and Abstracts of the XVI International AIDS Conference; 13–18 August 2006; Toronto, Canada; abstract THLB0201.
6. Girard PM, Cabié A, Michelet C, Verdon R, Katlama C, Mercié P, et al. TenofovirDF + efavirenz (TDF + EFV) vs tenofovirDF + efavirenz + lamivudine (TDF +EFV + 3TC) maintenance regimen in virologically controlled patients (pts): COOL Trial. In: Program and Abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 27–30 September 2006; San Francisco, California; abstract H-1383.
7. 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.
8. Escobar I, Pulido F, Pérez E, Arribas JR, García MP, Hernando A. Pharmacoeconomic analysis of a maintenance strategy with lopinavir/ritonavir monotherapy in HIV-infected patients. Enferm Infecc Microbiol Clin 2006; 24:490–494.
9. Cameron DW, da Silva B, Arribas J, Pulido F, Katner HP, Wikstrom K, et al. Significant sparing of peripheral lipoatrophy by HIV treatment with LPV/r + ZDV/3TC induction followed by LPV/r monotherapy compared with EFV + ZDV/3TC. In: Program and Abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; 25–28 February 2007; Los Angeles, California; abstract 44.
10. Schackman BR, Scott CA, Sax PE, Losina E, Wilkin TJ, McKinnon JE, et al. Potential risks and benefits of HIV treatment simplification: a simulation model of a proposed clinical trial. Clin Infect Dis 2007; 45:1062–1070.
11. Pulido F, Delgado R, Pérez-Valero I, González-García J, Miralles P, Arranz A, et al. Long-term (4 years) efficacy of lopinavir/ritonavir monotherapy for maintenance of HIV suppression. J Antimicrob Chemother 2008; 61:1359–1361. doi:10.1093/jac/dkn103.
12. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multicohort collaboration. Lancet 2008; 371:1417–1426.
© 2008 Lippincott Williams & Wilkins, Inc.