Skip to main content
SpringerLink
Log in

The ABC of HIV Clinical Trials

  • Review Article
  • Published:
Pharmaceutical Medicine Aims and scope Submit manuscript

Abstract

There are many different types of HIV clinical trials. For new antiretrovirals, efficacy is established from phase III regulatory trials, which normally include 150–400 patients per treatment arm, studied for 96 weeks. Antiretrovirals used for first-line treatment are usually combined with approved antiretrovirals in triple combinations and compared with a control arm of standard triple antiretroviral drug treatment. Doubleblinded trials are preferable, but several antiretrovirals have been approved from open-label trials. Most regulatory clinical trials are designed to show the non-inferiority of the new antiretroviral versus standardof- care. The primary efficacy parameter is normally HIVRNAsuppression below 50 copies/mL by week 48, using a standardized efficacy endpoint (time to loss of virological response or confirmed virological response). If non-inferior efficacy is shown for the new antiretroviral, secondary analyses may then show other benefits, in terms of safety, convenience or drug resistance profiles. The antiretrovirals used in highly treatment-experienced patients are normally combined with a ‘background regimen’ of antiretrovirals, selected on the basis of drug resistance assays and treatment history. The results from trials in treatment-experienced patients are strongly dependent on baseline resistance profiles and the activity of the antiretrovirals used in the background regimen. The analysis of safety is well standardized, with toxicity grading systems for clinical and laboratory adverse events. Drug resistance at treatment failure could affect responses to second-line treatments. Where possible, patients should be followed-up after the failure of randomized medication, to assess longer term efficacy and safety outcomes on subsequent treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV
Table V
Table VI
Table VII
Table VIII

Similar content being viewed by others

References

  1. Mellors J, Rinaldo C, Gupta P, et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996 May 24; 272: 1167–70

    Article  PubMed  CAS  Google Scholar 

  2. O’Brien W, Hartigan P, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 1996; 334: 426–31

    Article  PubMed  Google Scholar 

  3. Hammer S, Eron J, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society — USA panel. JAMA 2008; 300 (5): 555–70

    Article  PubMed  CAS  Google Scholar 

  4. European AIDS Clinical Society (EACS). Guidelines for the clinical management and treatment of HIV infected adults in Europe [online]. Available from URL: http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf [Accessed 2009 Aug 24]

    Google Scholar 

  5. Gallant J, DeJesus E, Arribas J, et al. Tenofovir DF, emtricitabine and efavirenz versus zidovudine, lamivudine and efavirenz for HIV. N Engl J Med 2006; 354: 251–60

    Article  PubMed  CAS  Google Scholar 

  6. Ortiz R, DeJesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ ritonavir versus lopinavir-ritonavir in treatment naïve HIV-1 infected patients at week 48. AIDS 2008; 22: 1389–97

    Article  PubMed  CAS  Google Scholar 

  7. Haubrich R, Cahn P, Grinsztejn B, et al. DUET-1: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 612 treatment-experienced HIV-1-infected patients [abstract no. 790]. 15th Conference on Retroviruses and Opportunistic Infections; 2008 Feb 3–6; Boston (MA)

    Google Scholar 

  8. Clumeck N, Clotet C, Johnson M, et al. Virological response with fully active etravirine after 48 weeks of treatment: pooled results from the DUET-1 and DUET-2 trials [abstract no. P023]. 9th International Congress on Drug Therapy in HIV infection (HIV9); 2008 Nov 9–13; Glasgow

    Google Scholar 

  9. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008 Jul 24; 359 (4): 339–54

    Article  PubMed  Google Scholar 

  10. Cooper D, Gatell J, Rockstroh J, et al. 48-Week results from BENCHMRK-1, a phase III study of raltegravir in patients failing antiretroviral therapy with triple class resistant HIV-1 [abstract no. 788]. 15th Conference on Retroviruses and Opportunistic Infections; 2008 Feb 3–6; Boston (MA)

    Google Scholar 

  11. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008 Oct 2; 359 (14): 1429–41

    Article  PubMed  CAS  Google Scholar 

  12. Nozza S, Visco F, Soria A, et al. Excellent short-term CD4 recovery with a PI- and NRTI-sparing regimen in triple-class failure HIV-infected patients: raltegravir, maraviroc, etravirine [abstract no. P045]. 9th International Congress on Drug Therapy in HIV infection (HIV9); 2008 Nov 9–13; Glasgow

    Google Scholar 

  13. Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of virologic success with raltegravir plus etravirine and darunavir/ritonavir in treatmentexperienced patients with multidrug-resistant virus: results of the ANRS 139 TRIO trial [abstract]. 11th International AIDS Conference; 2008 Jul 3–8; Mexico City

    Google Scholar 

  14. Hill A, Sabin C. Designing and interpreting HIV noninferiority trials in naï ve and experienced patients. AIDS 2008; 22: 913–21

    Article  PubMed  Google Scholar 

  15. 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 [online]. Available from URL: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm070968.pdf [Accessed 2009 Aug 24]

    Google Scholar 

  16. Lennox J, Dejesus E, Lazzarin A, et al. STARTMRK, a phase III study of the safety & efficacy of raltegravir (RAL)-based versus efavirenz (EFV)-based combination therapy in treatment-naive HIV-infected patients [abstract no. H-896a]. 48th Annual ICAAC/IDSA 46th Annual Meeting; 2008 Oct 25–28; Washington, DC

    Google Scholar 

  17. US FDA. Prezista™ (Tibotec, Inc.) (darunavir): prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021976s003s004lbl.pdf [Accessed 2009 Sep 15]

    Google Scholar 

  18. Molina J, Andrade-Villanueva J, Echevarria J, et al. Atazanavir/ritonavir vs lopinavir-ritonavir in antiretroviral naï ve HIV-1 infected patients: CASTLE 96 week efficacy and safety [abstract no. H-1250d]. 48th Annual ICAAC/IDSA 46th Annual Meeting; 2008 Oct 25–28; Washington, DC

    Google Scholar 

  19. Roche Diagnostics GmbH, Manhheim, Germany. COBAS amplicor HIV-1 MONITOR test, version 1.5 [package insert; online]. Available from URL: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/Infectious Disease/ucm093531.pdf [Accessed 2009 Aug 24]

    Google Scholar 

  20. Lima V, Harrigan R, Montaner J. Increased reporting of detectable plasma HIV-1 RNA levels at the critical threshold of 50 copies per milliliter with the Taqman assay in comparison to the Amplicor assay. J Acquir Immune Defic Syndr 2009 May 1; 51 (1): 3–6

    Article  PubMed  CAS  Google Scholar 

  21. Ribaudo H, Lennox J, Currier J, et al. Virologic failure endpoint definition in clinical trials: is using HIV-1 RNA threshold <200 copies/mL better than <50 copies/mL? An analysis of ACTG studies [abstract no. 580]. 16th Conference on Retroviruses and Opportunistic Infections; 2009 Feb 8–11; Montreal (QC)

    Google Scholar 

  22. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004 Apr 29; 350 (18): 1850–61

    Article  PubMed  CAS  Google Scholar 

  23. Riddler S, Haubrich R, DiRienzo A, et al., ACTG Study 5142 Team. Classsparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008 May 15; 358 (20): 2095–106

    Article  PubMed  CAS  Google Scholar 

  24. Sax P, Tierney C, Collier A, et al. ACTG 5202: shorter time to virologic failure (VF) with abacavir/lamivudine (ABC/3TC) than tenofovir/emtricitabine (TDF/FTC) as part of combination therapy in treatment-naï ve subjects with screening HIV RNA 100,000 c/mL [abstract no. THAB0303]. AIDS 2008- XVII International AIDS Conference; 2008 Aug 3–8; Mexico City

    Google Scholar 

  25. Hill A, DeMasi R. Discordant conclusions from HIV efficacy trials: an evaluation of efficacy endpoints. Antivir Ther 2005; 10: 367–74

    PubMed  CAS  Google Scholar 

  26. Saag M, Ive P, Heera J, 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 naï ve patients infected with R5 HIV1: week 48 results of the MERIT study [abstract no. WESS104]. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 2007 Jul 22–25; Sydney (NSW)

    Google Scholar 

  27. Hill A, Hirschel B, Katlama C. The Monark trial: where now for boosted protease inhibitor monotherapy? AIDS 2008; 22 (6): 777–9

    Article  PubMed  Google Scholar 

  28. Cameron W, da Silva B, Arribas J, 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) [abstract no. THLB0201]. XVI International AIDS Conference; 2006 Aug 13–18; Toronto (ON)

    Google Scholar 

  29. Arribas J, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV-viral suppression: forty eight week results of a randomized, controlled, open label, clinical trial (OK04 study) [abstract no. THLB0203]. XVI International AIDS Conference; 2006 Aug 13–18; Toronto (ON)

    Google Scholar 

  30. Nunes EP, Oliveira MS, Almeida MMTB, et al. 48-Week efficacy and safety results of simplification to single agent lopinavir/ritonavir (LPV/r) regimen in patients suppressed below 80 copies/mL on HAART: the KalMo study [abstract no. TUAB0103]. XVI InternationalAIDS Conference; 2006 Aug 13–18; Toronto (ON)

    Google Scholar 

  31. Phillips AN, Walker S. Drug switching and virologic based endpoints in trials of antiretroviral drugs for HIV infection [editorial]. AIDS 2004; 18: 365–70

    Article  PubMed  Google Scholar 

  32. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355: 2283–96

    Article  Google Scholar 

  33. Levy Y, and the SILCAAT Scientific Committee. Effect of interleukin-2 on clinical outcomes in patients with CD4+ cells count 50 to 299/mm3: primary results of the SILCAAT study [abstract no. 90bLB]. 16th Conference on Retroviruses and Opportunistic Infections; 2009 Feb 8–11; Montreal (QC)

    Google Scholar 

  34. Haubrich R, Eron J, Thompson M, et al. Reduction in AIDS-defining events/deaths with etravirine compared to placebo: pooled DUET 48-week results [abstract no. P027]. 9th International Congress on Drug Therapy in HIV infection (HIV9); 2008 Nov 9–13; Glasgow

    Google Scholar 

  35. Hirsch M, Gunthard H, Schapiro J, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society — USA Panel. Clin Inf Dis 2008; 47: 266–85

    Article  Google Scholar 

  36. Gupta R, Hill A, Sawyer A, et al. Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials. Clin Infect Dis 2008; 47: 712–22

    Article  PubMed  Google Scholar 

  37. Hill A, Ruxrungtham K, Hanvanich M, et al. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Expert Opin Pharmacother 2007; 8 (5): 1–10

    Article  Google Scholar 

  38. Sabin C, Worm S, Weber R, et al. Recent use of abacavir and didanosine, but not thymidine analogues, is associated with risk of myocardial infarction [abstract no. 957c]. 15th Conference on Retroviruses and Opportunistic Infections; 2008 Feb 3–6; Boston (MA)

    Google Scholar 

  39. Division of AIDS table for grading the severity of adult and pediatric adverse events [online]. Available from URL: http://rcc.tech-res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GradingTable_Clarification_August2009_Final.pdf [Accessed 2009 Oct 30]

  40. Hill A, Balkin A. Risk factors for gastrointestinal adverse events in HIV treated and untreated patients. AIDS Rev 2009 Jan–Mar; 11 (1): 30–8

    PubMed  Google Scholar 

  41. Eron J, Yeni P, Gathe J, et al. 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 non-inferiority trial. Lancet 2006; 368: 476–82

    Article  PubMed  CAS  Google Scholar 

  42. Cooper D, Zajdenverg R, Ruxrungtham K, et al. Efficacy and safety of two doses of tipranavir/ritonavir versus lopinavir/ritonavir-based therapy in antiretroviral-naï ve patients: results of BI 1182.33 [abstract no. PL13.4]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12–16; Glasgow

    Google Scholar 

  43. Malan N, Krantz E, Neal D, et al. Efficacy and safety of atazanavir with and without ritonavir in antiretroviral-naïve subjects. BMS089: 48-week results [abstract no. 89]. 13th Conference on Retroviruses and Opportunistic Infections; 2006 Feb 5–8; Denver (CO)

    Google Scholar 

  44. Squires K, Lazzarin A, Gatell 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: 1011–9

    Article  PubMed  CAS  Google Scholar 

  45. Piaggio G, Elbourne D, Altman D, et al. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 2006; 295: 1152–60

    Article  PubMed  CAS  Google Scholar 

  46. Parienti JJ, Verdon R, Massari V. Methodological standards in non-inferiority AIDS trials: moving from adherence to compliance. BMC Med Res Methodol 2006; 6: 46–55

    Article  PubMed  Google Scholar 

  47. De Jesus E, McCarty D, Farthing CF, 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 2004 Aug; 39 (3): 411–8

    Article  Google Scholar 

  48. Moyle G, De Jesus E, Cahn P, 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: 417–25

    Article  PubMed  CAS  Google Scholar 

  49. Gathe J, DaSilva B, Loufty M, et al. Study M05-730 primary efficacy results at week 48: phase 3, randomized, open-label study of lopinavir-ritonavir (LPV/r) tablets once-daily (OD) versus twice-daily (BID), coadministered with tenofovir (TDF)+emtricitabine (FTC) in antiretroviral naive (ARV) HIV-1 infected subjects [abstract no. 775]. 15th Conference on Retroviruses and Opportunistic Infections; 2008 Feb 3–6; Boston (MA)

    Google Scholar 

  50. Martinez E, Arranz J, Podzdamczer D, 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 [abstract no. WESS101]. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 2007 Jul 22–25; Sydney (NSW)

    Google Scholar 

  51. Cooper D, Bloch M, Humphries A, et al. Simplifcation with fixed-dose tenofovir-emticitabine or abacavir-lamivudine in adults with suppressed HIV replication (the STEAL study): a randomized, open-label, 96 week, non-inferiority trial [abstract no. 576]. 16th Conference on Retroviruses and Opportunistic Infections; 2009 Feb 8–11; Montreal (QC)

    Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this review. The author has received consultancy payments from TIBOTEC, which developed darunavir, etravirine and rilpivirine.

Author information

Authors and Affiliations

  1. Pharmacology Research Laboratories, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK

    Andrew Hill (Senior Visiting Research Fellow)

Authors
  1. Andrew Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew Hill.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hill, A. The ABC of HIV Clinical Trials. Pharm Med 23, 201–211 (2009). https://doi.org/10.1007/BF03256771

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256771

Keywords

Search

Navigation