There is, however, much inconsistency in the design and interpretation of HIV noninferiority trials . In this review, we describe the design of these studies and their interpretation, and discuss the implications of this design for the choice of endpoints and sample size calculations. Our aim is both to educate and review the use of such trials in the HIV setting.
The present review includes data from company-sponsored Phase 3 noninferiority trials conducted between 2000 and 2007, defined as Phase III/IV trials conducted with company sponsorship for both trial conduct and study drugs. Only the company-sponsored trials were included as they normally follow US Food and Drug Administration (FDA) guidelines on design and reporting of HIV RNA endpoints , and could therefore be interpreted in a standardized way. We used a MEDLINE search with the search terms of each antiretroviral, followed by ‘clinical trial’ (e.g. ‘lamivudine clinical trial’). In addition, we searched the FDA product labels for registrational trials of each approved antiretroviral, and searched for abstracts on clinical trials presented at the following conferences: Annual Conference on Retroviruses and Opportunistic Infections, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), European AIDS Clinical Society, International AIDS Conference (including IAS Pathogenesis Conference) and International Conference on Drug Therapy in HIV Infection.
The search identified 17 randomized trials with a noninferiority design that used an endpoint of HIV RNA suppression below either 400 or 50 copies/ml (the design of these trials and summary efficacy data are shown in Table 1). In two cases [10,11], the trials were powered to show equivalence but can be interpreted in terms of noninferiority. All but three of the trials [11–13] were conducted in treatment naive patients. The BMS-034 trial (atazanavir versus efavirenz in naive patients) was excluded from this analysis owing to problems in validation of the HIV RNA assays used . There were four additional trials which were powered on noninferiority but used continuous log reduction as the primary endpoint [15–18].
Standard superiority trials are designed to ensure that the smallest true difference between the new and standard treatments thought to be clinically relevant has a high chance of being detected as statistically significant. For clinical trials of antiretrovirals, the most commonly used endpoint is HIV RNA suppression below 50 copies/ml without treatment discontinuation. Decisions about the likely efficacy of the new treatment are generally based on a standard hypothesis test and the resulting p-value (with confidence intervals provided to aid the clinical interpretation of the findings). In contrast, noninferiority trials are designed to show that a new treatment is not substantially inferior to the current standard. Instead of focussing on the results of a statistical test, emphasis is placed on ensuring that the lower limit of the confidence interval for the observed difference in outcomes between the two regimens does not cross the prespecified ‘delta’ .
The choice of an appropriate delta may be problematic: delta is usually chosen to reflect the largest difference in outcomes between the arms that could reasonably be assumed to be clinically equivalent . A few trials have been designed with a high delta – for example the BI 118.33 trial was designed to show that tipranavir/ritonavir was no more than 15% worse than lopinavir/ritonavir ; the design of the Abbott 418 trial of once versus twice daily lopinavir/ritonavir also included a delta of 15%  (Table 1). Trials powered with a delta of this size may not, however, be able to exclude the possibility that a true difference exists between the arms which may be considered to be clinically significant. For example, if a noninferiority trial showed that the efficacy of first-line tenofovir/emtricitabine/efavirenz was 80% but that the true efficacy of a new combination treatment may be as low as 65%, would this convince clinicians to choose the new combination over the current standard, even if it were deemed to be noninferior? In addition, the noninferiority margin (delta) should be smaller if the control arm is already highly efficacious (i.e. with response rates above 90%).
In future, differences between treatment arms of less than 10% may be considered clinically significant, and therefore a delta of 10–12% could be considered too large. For example in the Gilead 934 trial, there was a 7% advantage in efficacy of tenofovir/emtricitabine/efavirenz over the control arm of zidovudine/lamivudine/efavirenz at week 48 , driven mainly by higher rates of anaemia and gastrointestinal toxicties in the zidovudine arm. As a result, zidovudine is no longer recommended for first-line use in Europe . Once the delta falls below 10%, however, Phase III trial sample sizes could rise to levels where the economics of HIV drug development become unsustainable. For example if a new experimental drug was compared to tenofovir/emtricitabine/efavirenz with a predicted success rate of 80%, and a delta of 5%, the trial sample size would be 1005 patients per arm for a power of 80%, and 1345 patients per arm for a power of 90%.
When performing a superiority trial, the primary analysis uses the intent-to-treat population, including all patients randomized, irrespective of whether they have taken their study medication as randomized. Such an approach tends to bias the results towards the null hypothesis (i.e. no difference in outcome between the treatment arms). Thus, if there is still a difference in outcome when the trial is analysed in this way, it is likely that the real difference (if all patients were able to take the drugs as planned) would be greater.
Unlike a superiority trial, noninferiority trials usually favour a ‘per protocol’ analysis. This analysis excludes patients with major protocol violations, such as not receiving at least one dose of study drug or using a disallowed medication in the background regimen . By excluding these patients (who would be expected to make the two groups more alike), it is thought that analysis of the per protocol population may be more likely to show differences between treatments. For noninferiority trials, demonstration that the new treatment is noninferior on both the intention-to-treat and per protocol populations is usually required.
There is, however, no standard predefined list of the exclusions for a per protocol analysis. Some per protocol analyses only exclude patients with the strongest protocol violations, such as not taking one dose of randomized treatment [12,24], whereas other analyses exclude from the analysis all individuals experiencing a nonvirological endpoint .
In addition, in order for the results from the per protocol analysis to be of value, it is important that a large proportion of the patients randomized in the trial fall into the per protocol population - demonstration of noninferiority on only a small minority of randomized patients is unlikely to convince many clinicians that the new regimen is genuinely noninferior. Furthermore, poorly conducted trials also tend to obtain results that are biased towards ‘no effect’. Therefore, both careful support for patient adherence and attendance, including documentation to support this, and evidence of strict adherence to the study protocol, are of utmost importance in a noninferiority trial.
HIV RNA suppression <50 copies/ml has been adopted as the primary objective of antiretroviral treatment in the most recent guidelines reflecting the sensitivity of most currently available commercial assays. The FDA TLOVR (time to loss of virological response) algorithm has been used to analyse HIV RNA data from registrational trials . This algorithm classifies patients either as virological successes while taking randomized treatment (with HIV RNA below the detection limit on two consecutive study visits around the 48 week timepoint), or treatment failure, divided into three categories:
When using composite endpoints such as this, it is assumed that all components of the endpoint are viewed as being equally detrimental – it can be argued that discontinuation of treatment due to withdrawal of consent may have less clinical relevance for future virological suppression than a virological failure. One particular limitation with composite endpoints such as these is that it can be difficult to interpret intent-to-treat analyses where the virological and nonvirological endpoints are imbalanced across treatment arms. For example in the MERIT trial the experimental treatment of zidovudine/lamivudine/maraviroc showed an excess of virological failure endpoints, whereas the zidovudine/lamivudine/efavirenz arm showed an excess of discontinuations for adverse events .
In a recent survey, only 27% of endpoints in trials of naive patients were due to virological failure, with the remaining 73% being due to discontinuation of study medication (32% for adverse events and 41% for loss to follow up) . Given that trial outcomes can be dominated by nonvirological endpoints when analysed by the FDA TLOVR algorithm, it is important for HIV clinical trials to be re-analysed including only virological endpoints. The FDA guidelines state that, in addition to analyses using the TLOVR algorithm, an analysis comparing only the documented virological failures should be presented and any inconsistencies between the different analyses should be explored . This is also called a ‘nonvirological failures censored’ analysis. Data from patients is censored after discontinuation for reasons other than virological failure.
Another potential outcome is if a treatment is shown to be significantly worse than the control, but the confidence intervals of the difference fall within the limits for noninferiority (ie. not overlapping zero or the noninferiority margin). We are not aware of an example of this in Phase III HIV efficacy trials, although this outcome has been seen in bioequivalence studies .
The outcomes described above may arise when a trial has been designed to show noninferiority. A further possible outcome of a trial, where noninferiority is demonstrated in a study originally designed to show superiority, is not recommended by European guidelines [8,28].
There needs to be well controlled data to show that the comparator arm is in itself an effective treatment, with proven benefits over placebo or current standard of care. In addition, the performance of the comparator arm needs to be similar to that seen in previous reference trials [8,28]. This is to minimize the chance of the ‘outcome drift’ that may be seen if successive noninferiority trials are performed that each use as a comparator the regimen shown to be noninferior in the previous trial. For treatment of naive patients, a recent meta-analysis has suggested gradual improvements in the efficacy of HAART over the past 10 years . It is important to compare new treatments with control arms that have shown the strongest efficacy, and have not been superseded. For example, once lopinavir/ritonavir showed efficacy benefits over nelfinavir in the Abbott 863 trial , nelfinavir was no longer used as a control arm. In treatment-experienced patients, new treatments with proven efficacy benefits are added to the optimized background regimen, which should lead to incremental improvements of efficacy in control arms. The efficacy of control arms has improved between the TORO, POWER and DUET trials, as the use of first enfuvirtide and then darunavir/ritonavir was allowed in the control arms [31–34].
There are examples of noninferiority trials with control arms which are either not approved by regulatory authorities, or no longer recommended in international treatment guideline documents. For example, the SOLO trial  was powered to show noninferiority of fosamprenavir/ritonavir versus a control arm of nelfinavir, which is no longer recommended for first-line treatment. When trials are designed, it is difficult to predict the future standard of care at the time the results will be presented. In situations like this, it may be necessary to conduct follow-up trials, to re-evaluate drugs against new standards of care. The KLEAN trial  re-assessed the efficacy of fosamprenavir/ritonavir against a more reliable control, lopinavir/ritonavir, after the results of the SOLO trial were assessed.
The TITAN trial was a comparison of darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir in treatment-experienced patients . Figure 2 shows a systematic review of reference trials to show that the control arm of the TITAN trial, lopinavir/ritonavir, performed in a similar way to reference trials in experienced patients. This approach can be used to show the validity of the efficacy in the control arm. Lopinavir/ritonavir showed significantly higher efficacy than nelfinavir for naive patients in the Abbott 863 trial , and significantly higher efficacy than control protease inhibitors for experienced patients in the Abbott 888 trial . The efficacy of the lopinavir/ritonavir arm of the TITAN trial appears similar to the efficacy of lopinavir/ritonavir in other trials of experienced patients [15–17,37,38], which supports the noninferiority conclusion for darunavir/ritonavir in the TITAN trial.
The standard design for trials in highly experienced patients has been to use an ‘optimized background’ arm for all patients and then to randomize to use or not use a new experimental drug. These trials have been designed to show an efficacy benefit for the new treatment. This model was used for the TORO trials of enfuvirtide , the MOTIVATE trials of maraviroc [39,40], the BENCHMRK trials of raltegravir [5,41] and the DUET trials of etravirine [31,32]. The POWER and RESIST trials of darunavir and tipranavir included investigator-selected protease inhibitors in the control arms, but baseline resistance testing predicted marginal efficacy for the control PIs chosen [33,42].
These trial designs have recently been criticized, given the excess risk of virological failure in the control arm, and the subsequent risk of developing drug resistance, which could compromise future treatment options [43,44].
Combinations of new antiretrovirals with a low potential for cross-resistance are likely to lead to full suppression of HIV RNA in the majority of treatment-experienced patients. For example, 16-week data from the BENCHMRK trials of the integrase inhibitor raltegravir, showed at least 90% of patients with HIV RNA < 400 copies/ml when raltegravir was initiated either with enfuvirtide, darunavir or both drugs . Given these new developments, there may be ethical issues in conducting new clinical trials in which a control arm is expected to underperform virologically, except in the most treatment-experienced patients.
In future noninferiority trials could be used to identify drug combinations which achieve a consistently high efficacy rate in treatment-experienced patients, but with a lower pill burden, lower numbers of drugs required and fewer adverse events. For example, patients with current suppression on more complex combinations (such as multiple nucleoside reverse transcriptase inhibitors, dual boosted protease inhibitors, enfuvirtide) could be randomized either to continue their current treatment, or to transfer onto a more simple combination of new drugs. Alternatively, patients could be transferred onto combinations of new drugs, and randomized to either continue or stop parts of their optimized background regimen (such as nucleoside reverse transcriptase inhibitors). These noninferiority trial designs are less likely to lead to excess virological failures in control arms, and could allow access to new treatments for the majority of trial participants. If the efficacy of single drugs is compared in experienced patients also given an optimized background of other active drugs, it is important to assess the extent to which the optimized background used would dominate the efficacy profile, and to what extent the randomized treatment component is contributing to the overall efficacy profile.
1. Bartlett J, Fath M, DeMasi R, Hermes A, Quinn J, Mondou E. An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults. AIDS 2006; 20:2051–2064.
2. Gallant J, DeJesus E, Arribas J, Pozniak A, et al
. Tenofovir DF, emtricitabine and efavirenz vs zidovudine, lamivudine and efavirenz for HIV. N Engl J Med 2006; 354:251–260.
3. DeJesus E, Ortiz R, Khanlou H, Voronin E, van Lunzen J, Andrade-Villanueva J, et al.
Efficacy and safety of darunavir/ritonavir versus lopinavir/ritonavir in ARV treatment naive HIV-1 infected patients at Week 48: ARTEMIS. Proceedings of ICAAC
, Chicago, USA, September 2007 [abstract H-718b].
4. Lampe FC, Smith CJ, Madge S, Kinloch-de Loes S, Tyrer M, Sabin CA, et al
. Success of clinical care for human immunodeficiency virus infection according to demographic group among sexually infected patients in a routine clinic population, 1999 to 2004. Arch Intern Med 2007; 167:692–700.
5. Cooper D, Gatell J, Rockstroh J, Katlama C, Yeni P, Lazzarin A, et al.
Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Proceedings of the 14th Conference on Retroviruses and Opportunistic Infections
, Los Angeles, USA, February 2007 [abstract 105aLB].
6. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA 3rd, et al
. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004; 350:1850–1861.
7. Parienti J, Verdon R, Massari W. Methodological standards in noninferiority AIDS trials: moving from adherence to compliance. BMC Med Res Methodol 2006; 6:46–55.
8. European Medicines Agency. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use: statistical principles for clinical trials (E9). http://www.emea.eu.int/pdfs/human/ich/036396en.pdf
. Accessed 15 August 2007.
9. US Department of Health and Human Services, Food and Drug Administration and Center for Drug Evaluation and Research. Guidance for industry: antiretroviral drugs using plasma HIV RNA measurements—clinical considerations for accelerated and traditional approval. http://www.fda.gov/CDER/GUIDANCE/3647fnl.pdf
. Accessed 15 August 2007).
10. Staszewski S, Keiser P, Montaner J, Raffi F, Gathe J, Brotas V, et al
. Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zuidovudine in antiretroviral-naive HIV-infected adults. A randomised equivalence trial. JAMA 2001; 285:1155–1163.
11. Benson C, van der Horst C, LaMarca A, Haas D, McDonald C, Steinhart C, et al
. A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV. AIDS 2004; 18:2269–2276.
12. Madruga J, Berger D, McMurchie M, Suter F, Banhegyi D, Ruxrungtham K, et al
. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomized, controlled Phase III trial. Lancet 2007; 370:49–58.
13. Martinez E, Arranz J, Podzdamczer D, Ribera E, Knobel H, Roca V, et al.
Efficacy and safety of NRTI's switch to tenofovir plus emtricitabine versus abacavir plus lamivudine in patients with virologic suppression receiving a lamivudine containing HAART: the BICOMBO study. Proceedings of the Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention
, Sydney, Australia, July 2007 [abstract WESS101].
14. Squires K, Lazzarin A, Gatell J, Powderly W, Pokrovskiy V, Delfraissy J, et al
. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 2004; 36:1011–1019.
15. Anon. fosAmprenavir (Lexiva) US prescribing information
. GlaxoSmithKilne/Vertex, May 2004 (www.lexiva.com
16. Cohen C, Nieto-Cisneros L, Zala C, Fessel W, Gonzalez-Garcia J, Gladysz A, et al
. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomised multinational trial. Curr Med Res Opin 2005; 21:1683–1692.
17. Johnson M, Grinsztejn B, Rodriguez C, Coco J, DeJesus E, Lazzarin A, et al
. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 2005; 19:685–694.
18. Rodriguez-French A, Boghossian J, Gray G, Nadler J, Quinones A, Sepulveda G, et al
. The NEAT Study: a 48 week open-label study to compare the antiviral efficacy of GW433908 versus nelfinavir in antiretroviral naïve patients. J Acquir Immune Defic Syndr 2004; 35:22–32.
19. Lange S, Freitag G. Therapeutic equivalence – clinical issues and statistical methodology in noninferiority trials. Choice of delta: requirements and reality – results of a systematic review. Biomet J 2005; 1:12–27.
20. Eron J, Yeni P, Gathe J, Estrada V, DeJesus E, Staszewski S. The KLEAN study of fosamprenavi-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, or initial treatment of HIV infection over 48 weeks: a randomised noninferiority trial. Lancet 2006; 368:476–482.
21. Cooper D, Zajdenverg R, Ruxrungtham K, Chavez L. Efficacy and safety of two doses of tipranavir/ritonavir versus lopinavir/ritonavir-based therapy in antiretroviral-naive patients: results of BI 1182.33. Proceedings of the Eighth International Congress on Drug Therapy in HIV Infection
, Glasgow, 2006 [abstract PL13.4].
22. Johnson MA, Gathe JC, Podzamczer D, Molina J, Naylor C, Chiu Y, et al
. A once-daily lopinavir/ritonavir based regimen provides noninferior antiviral activity compared with a twice-daily regimen. J Acquir Immune Defic Syndr 2006; 43:153–160.
24. Saag M, Ive P, Heera J, Tawadrous M, DeJesus E, Clumeck N, et al.
A multicentre, randomised, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine[3TC], for the treatment of antiretroviral naive patients infected with R5 HIV1; week 48 results of the MERIT Study. Proceedings of the Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention
, Sydney, Australia, July 2007 [abstract WESS104].
25. Hill A, DeMasi R. Discordant conclusions from HIV efficacy trials – an evaluation of efficacy endpoints. Antivir Ther 2005; 10:367–374.
26. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman J, Miller M, et al
. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292:191–201.
27. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al
. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet (England) 2004; 363:1253–1263.
29. Klein CE, Chiu YL, Awni W, Zhu T, Heuser RS, Doan T, et al
. The tablet formulation of lopinavir/ritonavir provides similar bioavailability to the soft-gelatin capsule formulation with less pharmacokinetic variability and diminished food effect. J Acquir Immune Defic Syndr 2007; 44:401–410.
30. Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, et al
. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002; 346:2039–2046.
31. Madruga J, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, et al
. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1 infected patients in DUET-1: 24-week results from a randomized, double-blind, placebo controlled trial. Lancet 2007; 370:29–38.
32. Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, et al
. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1 infected patients in DUET-2: 24-week results from a randomized, double-blind, placebo controlled trial. Lancet 2007; 370:39–48.
33. Clotet B, Bellos N, Molina J, Cooper D, Goffard J, Lazzarin A, et al
. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomized trials. Lancet 2007; 369:1169–1178.
34. Nelson M, Arastéh K, Clotet B, Cooper D, Henry K, Katlama C, et al
. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr 2005; 40:404–411.
35. Gathe J, Ive P, Wood R, Schurmann D, Bellos N, DeJesus E, et al
. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1 infected patients. AIDS 2004; 18:1529–1537.
36. Anon. Lopinavir/ritoanvir (Kaletra) US rrprescribing information. Abbott Laboratories, Abbott Park Illinois, USA, August 2004 (www.kaletra.com
). Accessed 2 January 2007.
37. Benson CA, Deeks SG, Brun SC, Gulick RM, Eron JJ, Kessler HA, et al
. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis 2002; 185:599–607.
38. Kempf DJ, Isaacson JD, King MS, Brun SC, Sylte J, Richards B, et al
. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antivir Ther 2002; 7:165–174.
39. Nelson M, Fatkenheuer G, Konourina I, Lazzarin A, Clumeck N, Horban A, et al.
Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. Proceedings of the 14 th Conference on Retroviruses and Opportunistic Infections
, Los Angeles, USA, February 2007 [abstract 104aLB].
40. Lalezari J, Goodrich J, DeJesus E, Lampris H, Gulick R, Saag M, et al.
Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 Study in the US and Canada. Proceedings of the 14 th Conference on Retroviruses and Opportunistic Infections
, Los Angeles, USA, February 2007 [abstract 104bLB].
41. Steigbegel R, Kumar P, Eron J, Schechter M, Markowitz M, Loufty M, et al.
Results of BENCHMRK-2, a Phase III Study Evaluating the Efficacy and Safety of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients with Triple-class Resistant Virus. Proceedings of the 14 th Conference on Retroviruses and Opportunistic Infections
, Los Angeles, USA, February 2007 [abstract 105bLB].
42. Hicks CB, Cahn P, Cooper DA, Walmsley SL, Katlama C, Clotet B, et al
. Durable efficacy of tipranavir–ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 2006; 368:466–475.
43. Lederman M, Miller V, Weller I, Deeks S. A new approach for ‘deep salvage’ trials in advanced HIV infection. AIDS 2007; 21:1503–1506.
44. De Gruttola V, Flexner C, Schapiro J, Hughes M, Van Der Laan M, Kuritzkes D, et al
. Drug development strategies for salvage therapy: conflicts and solutions. AIDS Res Hum Retrovirus 2006; 22:1106–1109.
45. Moyle G, DeJesus E, Cahn P, Castillo S, Zhao H, Gordon D, et al
. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral naive HIV-infected patients. J Acquir Immune Defic Syndr 2005; 38:417–425.
46. Walmsley S, Ruxrungtham K, Slim J, Ward D, Larson P, Raffi F. The Gemini Study Saquinavir/r (SQV/r) vs lopinavir/r (LPV/r) plus emtricitabine/tenofovir (FTC/TDF) as initial therapy in HIV-1 infected patients. Proceedings of the European AIDS Clinical Society Conference
, Madrid, Spain, October 2007 [abstract PS1/4].
47. De Jesus E, McCarty D, Farthing CF, Shortino D, Grinsztejn B, Thomas D, et al
. Once-daily versus twice-daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection: a randomized equivalence trial. Clin Infect Dis (United States) 2004; 39:411–418.
48. DeJesus E, Herrera G, Teofilo E, Gerstoft J, Buendia C, Brand J, et al
. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral naive HIV infected adults. Clin Infect Dis 2004; 39:1038–1046.
49. Malan N, Krantz E, Neal D, Kastango K, Frederick D, Mathew M. Efficacy and safety of atazanavir with and without ritonavir in antiretroviral-naive subjects. BMS089: 48-week results. Proceedings of the 13 th Conference on Retroviruses and Opportunistic Infections
, Denver, Colorado, February 2006 [abstract].