The Late Presenter Treatment Optimisation Study

HIV/AIDS Clinical Trial

— LAPTOP  

Official title:

An Open-Label, Multi-Centre, Randomised Study to Investigate Integrase Inhibitor Versus Boosted Protease Inhibitor Antiretroviral Therapy for Patients With Advanced HIV Disease

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03696160
• Other study ID #: NEAT44
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 5, 2019
• Est. completion date: June 2024

Study information

• Verified date: September 2023
• Source: NEAT ID Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main purpose of this study is to compare two different types of HIV treatments, in terms of effectiveness and improvement of side effects, for patients who are diagnosed with a more advanced HIV infection. Patients with advanced HIV infections are otherwise known as 'late presenters'.

There are many effective treatments for HIV available; however, for late presenting patients the investigators do not know which type of treatment performs best. This is the first large study to compare treatments for patients in this situation, and the investigators hope that the results of this study will help doctors decide which treatments to use in the future.

The two different types of treatment the investigators are comparing both contain a mixture of drugs that work together to combat HIV:

The Boosted Protease Inhibitor combination (PI) which is a combination tablet containing:

darunavir, cobicistat, emtricitabine and tenofovir alafenamide. It was approved for use in Europe under the brand name Symtuza®.

The Integrase Inhibitor combination (INI). Which is a combination tablet containing:

bictegravir, emtricitabine and tenofovir alafenamide. This is a a newer combination which was approved for use in Europe in June 2018 under the brand name of Biktarvy®.

The main difference between the two treatments is how each one fights a HIV infection. They both stop a part of the virus from working (i.e. inhibit it), to prevent it from making copies of itself. The PI treatment contains drugs to stop the protease part of the virus, whereas the INI treatment contains drugs to stop the integrase part.

In recent studies, it appears that treatments containing integrase inhibitors may be better for late presenting patients. They have been shown to quickly bring down the amount of virus in the body, and the side effects may be more acceptable to late presenters.

To compare the two treatments, half of the participants on this study will be given the PI treatment, and the other half will be given the INI treatment.

Description:

The effectiveness of HIV antiretroviral therapy (ART) has consistently improved over the years. This is largely due to newer drugs having improved antiviral effectiveness and more tolerable side effect profiles; resulting in better viral suppression and improved treatment adherence. On the other hand, most recent clinical trials look at the effectiveness of ART in patients with less advanced disease. These patients usually suffer from less related diseases, drug-drug interactions, and other risks for treatment failure. Outside of these trials, the number of patients who present to clinic with a more developed advanced HIV infection, known as 'late presenters', remains high across Europe. Trials for these patients have tended to focus on the time of starting treatment and the management of infections.

Much less is known about which ART treatments perform best for these late presenting patients; particularly in terms of virus suppression, immune system recovery, side effects and improvement of AIDs related diseases. No specific drug combinations have been compared in appropriate clinical trials before, and the international guidelines for first line treatment judge all therapies as equal standard of care for these patients.

The investigators anticipate that Integrase inhibitor containing regimes may be better suited to patients with advanced disease, due to their beneficial side-effect profile and ability to rapidly decrease viral load levels. Therefore the investigators are conducting this clinical trial to compare an integrase inhibitor regime, against a protease inhibitor regime in patients with advanced HIV infection. The aim of the study is to demonstrate the non-inferiority of Biktarvy® against Symtuza®.

Patients will be recruited from sites across Europe, and randomized onto either arm of the study. After randomisation onto either treatment regime, patients will attend approximately 9 follow-up visits over the course of a year. During these visits, patients will be asked to complete two questionnaires, to assess their quality of life and HIV symptoms. They will also be asked to provide a number of blood samples. These samples are to ensure that the patient is not resistant to the study drug and that their disease is not worsening. Samples to test for study drug resistance will be shipped to a laboratory for analysis in the even that the patient experiences virological failure.

Biktarvy® will be supplied from Gilead and Symtuza® will be provided by Janssen Pharmaceuticals.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 447
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. The ability to understand and sign a written informed consent form (ICF) and must be willing to comply with all study requirements.

2. Male or non-pregnant, non-lactating females†.

3. Age = 18 years.

4. Have documented, untreated HIV-1 infection with either:

1. AIDS with any CD4 cell count (AIDS-defining conditions are listed within Appendix 3).

Or

2. Severe bacterial infection (BI)‡ and must have a CD4 cell count < 200/µl within 28 days prior to study entry§.

Or

3. Any symptoms or no symptoms and must have a CD4 cell count < 100/µL within 28 days prior to study entry and must have an entry HIV viral load > 1000 copies/mL.

Or

4. Currently receiving treatment for OI**. i. Subjects with other serious OIs, including other AIDS-defining and AIDS-related OIs for which appropriate therapy other than ART exists are eligible, but Investigator approval must be obtained. ii. Current OI treatment can have been discontinued prior to start of ART.

5. Have an entry HIV viral load > 1000 copies/mL

6. Have the ability to take oral medications.

7. Females of childbearing potential and heterosexually active males must be willing to use a highly effective method of contraception and be willing to continue practising these birth control methods during the trial and for at least 30 days after the last dose of study medication. See Appendix 7 for further details.

Such methods include:

• True abstinence from penile-vaginal intercourse, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), and withdrawal are not acceptable methods of contraception).

• Non-hormonal Intrauterine device or non-hormonal intrauterine system that meets the effectiveness criteria as stated in the product label.

• Male partner sterilization prior to the female subject's entry into the study, and this male is the sole partner for that subject.

• Combined (oestrogen and progesterone containing) hormonal contraception associated with the inhibition of ovulation*:

• Oral

• Intravaginal

• Transdermal

• Bilateral tubal occlusion

Exclusion Criteria:

1. Any therapeutic ARV which commenced less than 2 weeks prior to screening and which was taken for more than 48 hours

2. Systemic cancer chemotherapy within 30 days prior to study entry, or current treatment for cancer (with the exception of Kaposi's sarcoma) or lymphoma.

3. Current or anticipated use of contraindicated medications (see Summary of Product Characteristics (SmPC) for Symtuza® and Biktarvy®) or anticipated systemic chemotherapy during study enrolment (administration of any contraindicated medication must be discontinued at least 30 days prior to the baseline visit and for the duration of the study).

4. Known resistance to the components of study medications (see section 6.1.3 for more details).

5. History or symptoms of advanced renal and/or hepatic impairment. Such as, kidney failure requiring dialysis; eGFR <30 mL/min; hepatic transaminases (AST and ALT) > 5 x upper limit of normal (ULN); or, platelet count <50,000.

6. Current drug or alcohol use that, in the opinion of the Investigator, would cause interference with the study.

7. Cryptococcal meningitis or active TB, or current or expected treatment requiring Rifampicin or Rifabutin (patients with expected latent TB will have a TB test (IGRAs e.g. ELISPOT, QuantiFERON etc.) at their screening visit).

8. History or presence of allergy to the study drugs or their components, or drugs of their class.

9. Using any concomitant therapy disallowed as per the product labelling for the study drugs.

10. Any investigational drug within 30 days prior to the study drug administration.

11. Patients with severe (Child Pugh class C) hepatic impairment.

12. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the study.

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• HIV/AIDS

Intervention

Drug:
• Biktarvy
Integrase inhibitor used to treat HIV-1 infection
• Symtuza
Protease inhibitor used to treat HIV-1 infection

Locations

Country	Name	City	State
Belgium	Institute of Tropical Medicine	Antwerp
Belgium	CHU Saint-Pierre	Brussels
Belgium	University Hospital Ghent	Gent
France	Hopital Europeen Marseille	Marseille
France	Groupe Hospitalier Sud Ile-de-France (Melun)	Melun
France	Hôpital Gui de Chauliac	Montpellier
France	CHU de Nantes	Nantes
France	Hopital Lariboisiere	Paris
France	Hôpital Saint Antoine	Paris
France	Hopital Saint-Louis	Paris
France	Pitié-Salpêtrière Hospital	Paris
Germany	Medizinische Klinik und Poliklinik Universitätsklinikum Bonn	Bonn
Germany	Goethe University Hospital Frankfurt	Frankfurt
Germany	ICH Study Center Gmbh & Co. KG	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Klinikum rechts der Isar der Technischen Universität München	Munich
Germany	University Hospital Klinikum rechts der Isar der TUM	Munich
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	St Vincent's University Hospital	Dublin
Italy	Luigi Sacco Hospital	Milan
Italy	Ospedale San Raffaele	Milan
Italy	ASST Santi Paolo	Milano
Italy	Clinica of Infectious Diseases	Modena
Italy	INMI Lazzaro Spallanzani, Rome	Rome
Spain	Hospital General Universatario Alicante	Alicante
Spain	Hospital Clinic (Helios Building)	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari Vall d'Herbon	Barcelona
Spain	Hospital General Universitatrio de Elche	Elche
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Universitatrio La Paz	Madrid
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Southmead Hospital	Bristol
United Kingdom	Leeds Teaching Hospital	Leeds
United Kingdom	Barts Health	London
United Kingdom	Chelsea and Westminister	London
United Kingdom	Guy's Hospital	London
United Kingdom	Homerton University Hospital	London
United Kingdom	Imperial College Healthcare Trust	London
United Kingdom	Kings College London	London
United Kingdom	Mortimer Market Centre	London
United Kingdom	Royal Free Hospital	London
United Kingdom	St George's Hospital	London
United Kingdom	University Hospital Lewisham	London
United Kingdom	North Manchester General Hospital	Manchester
United Kingdom	Sheffield Teaching Hospital	Sheffield

Sponsors (3)

Lead Sponsor	Collaborator
NEAT ID Foundation	Gilead Sciences, Janssen Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Ireland,  Italy,  Spain,  United Kingdom, 

References & Publications (23)

Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, Gengiah T, Gengiah S, Naidoo A, Jithoo N, Nair G, El-Sadr WM, Friedland G, Abdool Karim Q. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011 Oct 20;365(16):1492-501. doi: 10.1056/NEJMoa1014181. — View Citation

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Demarest J, Underwood M, St Clair M, Dorey D, Brown D, Zolopa A. Short Communication: Dolutegravir-Based Regimens Are Active in Integrase Strand Transfer Inhibitor-Naive Patients with Nucleoside Reverse Transcriptase Inhibitor Resistance. AIDS Res Hum Retroviruses. 2018 Apr;34(4):343-346. doi: 10.1089/AID.2017.0184. Epub 2018 Mar 22. — View Citation

Dutertre M et al. Initiation of ART Based on Integrase Inhibitors Increases the Risk of IRIS. Conference on Retroviruses and Opportunistic Infections. February 2017. Seattle, WA, USA. Abstract 732.

Gallant et al. A phase 3 randomized controlled clinical trial of bictegravir in a fixed dose combination, B/F/TAF, vs ABC/DTG/3TC in treatment-naïve adults at week 48. 9th IAS Conference on HIV Science; Paris, France; July 23-26, 2017. MOAB0105LB

Hill AM, Mitchell N, Hughes S, Pozniak AL. Risks of cardiovascular or central nervous system adverse events and immune reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta-analysis of randomized trials. Curr Opin HIV AIDS. 2018 Mar;13(2):102-111. doi: 10.1097/COH.0000000000000445. — View Citation

Late presenters working group in COHERE in EuroCoord; Mocroft A, Lundgren J, Antinori A, Monforte Ad, Brannstrom J, Bonnet F, Brockmeyer N, Casabona J, Castagna A, Costagliola D, De Wit S, Fatkenheuer G, Furrer H, Jadand C, Johnson A, Lazanas M, Leport C, Moreno S, Mussini C, Obel N, Post F, Reiss P, Sabin C, Skaletz-Rorowski A, Suarez-Loano I, Torti C, Warszawski J, Wittkop L, Zangerle R, Chene G, Raben D, Kirk O. Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013. Euro Surveill. 2015;20(47). doi: 10.2807/1560-7917.ES.2015.20.47.30070. — View Citation

Levy et al. ANRS 146 - GeSIDA 7211 OPTIMAL phase III trial: maraviroc plus cART in advanced HIV-1-infected individuals. Journal Of The International Aids Society (Vol. 20, Pp. 6-7)

Montlahuc C, Guiguet M, Abgrall S, Daneluzzi V, de Salvador F, Launay O, Martinez V, Partisani M, Pradier C, Rouveix E, Valin N, Grabar S, Costagliola D; French Hospital Database ANRS CO4 cohort. Impact of late presentation on the risk of death among HIV-infected people in France (2003-2009). J Acquir Immune Defic Syndr. 2013 Oct 1;64(2):197-203. doi: 10.1097/QAI.0b013e31829cfbfa. — View Citation

Mussini C, Manzardo C, Johnson M, Monforte Ad, Uberti-Foppa C, Antinori A, Gill MJ, Sighinolfi L, Borghi V, Lazzarin A, Miro JM, Sabin C; Late Presenter Investigators. Patients presenting with AIDS in the HAART era: a collaborative cohort analysis. AIDS. 2008 Nov 30;22(18):2461-9. doi: 10.1097/QAD.0b013e328314b5f1. — View Citation

Paredes R, Tzou PL, van Zyl G, Barrow G, Camacho R, Carmona S, Grant PM, Gupta RK, Hamers RL, Harrigan PR, Jordan MR, Kantor R, Katzenstein DA, Kuritzkes DR, Maldarelli F, Otelea D, Wallis CL, Schapiro JM, Shafer RW. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation. PLoS One. 2017 Jul 28;12(7):e0181357. doi: 10.1371/journal.pone.0181357. eCollection 2017. — View Citation

Psichogiou M, Basoulis D, Tsikala-Vafea M, Vlachos S, Kapelios CJ, Daikos GL. Integrase Strand Transfer Inhibitors and the Emergence of Immune Reconstitution Inflammatory Syndrome (IRIS). Curr HIV Res. 2017;15(6):405-410. doi: 10.2174/1570162X15666171122155708. — View Citation

Raffetti E, Postorino MC, Castelli F, Casari S, Castelnuovo F, Maggiolo F, Di Filippo E, D'Avino A, Gori A, Ladisa N, Di Pietro M, Sighinolfi L, Zacchi F, Torti C. The risk of late or advanced presentation of HIV infected patients is still high, associated factors evolve but impact on overall mortality is vanishing over calendar years: results from the Italian MASTER Cohort. BMC Public Health. 2016 Aug 25;16(1):878. doi: 10.1186/s12889-016-3477-z. — View Citation

Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, Bloch M, Podzamczer D, Pokrovsky V, Pulido F, Almond S, Margolis D, Brennan C, Min S; SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013 Mar 2;381(9868):735-43. doi: 10.1016/S0140-6736(12)61853-4. Epub 2013 Jan 8. — View Citation

Sax et al. Phase 3 Randomized, Controlled, Clinical Trial of Bictegravir Coformulated With FTC/TAF in a Fixed-Dose Combination vs Dolutegravir + FTC/TAF in Treatment-Naïve HIV-1-Positive Adults: Week 48 Results. 9th IAS Conference on HIV Science; Paris, France; July 23-26, 2017

Slama L, Landman R, Assoumou L, Benalycherif A, Samri A, Joly V, Pialoux G, Valin N, Cabie A, Duvivier C, Lambert-Niclot S, Marcelin AG, Peytavin G, Costagliola D, Girard PM; IMEA 040 DATA Study Group. Efficacy and safety of once-daily ritonavir-boosted atazanavir or darunavir in combination with a dual nucleos(t)ide analogue backbone in HIV-1-infected combined ART (cART)-naive patients with severe immunosuppression: a 48 week, non-comparative, randomized, multicentre trial (IMEA 040 DATA trial). J Antimicrob Chemother. 2016 Aug;71(8):2252-61. doi: 10.1093/jac/dkw103. Epub 2016 Apr 10. — View Citation

Sobrino-Vegas P, Rodriguez-Urrego J, Berenguer J, Caro-Murillo AM, Blanco JR, Viciana P, Moreno S, Bernardino I, del Amo J; CoRIS. Educational gradient in HIV diagnosis delay, mortality, antiretroviral treatment initiation and response in a country with universal health care. Antivir Ther. 2012;17(1):1-8. doi: 10.3851/IMP1939. — View Citation

Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C, Pappa K, Wynne B, Min S, Nichols G; SINGLE Investigators. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013 Nov 7;369(19):1807-18. doi: 10.1056/NEJMoa1215541. — View Citation

Wijting I et al. Integrase Inhibitors are an Independent Risk Factor for IRIS: An ATHENA Cohort Study. Conference on Retroviruses and Opportunistic Infections. February 2017. Seattle, WA, USA. Abstract 731.

Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575. doi: 10.1371/journal.pone.0005575. Epub 2009 May 18. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mutations detected by deep sequencing compared with those detected by population sequencing	The resistance associated mutations in genes encoding the reverse transcriptase, protease and integrase of HIV as detected by ultra-deep sequencing and sanger sequencing.	Week 48
Other	Proportion of patients with HIV-RNA viral load < 50 copies/mL		Week 4, 8, 12
Primary	Time to treatment failure	Composite outcome: time to treatment failure due to either virological or clinical reasons. Virological reasons can either be insufficient virological response or viral rebound. Clinical reasons can be death related to HIV/AIDS/opportunistic infection or severe bacterial infection, new or recurrent AIDS defining event, any serious non-AIDS defining event or clinically relevant adverse events of any grade or immune reconstitution inflammatory syndrome requiring treatment	Earliest at 12 weeks, latest 48 weeks
Secondary	Proportion of patients with HIV-RNA viral load <50 copies/mL		Week 24, 36 and 48
Secondary	HIV-1 drug resistance confirmed		Through study completion, an average of 1 year
Secondary	Time to reach CD4 (cluster of differentiation 4) count >200/µL		Through study completion, an average of 1 year
Secondary	CD4/CD8 (cluster of differentiation 8) ratio		Week 4, 8, 12, 24, 36, 48
Secondary	Incidence of Immune Reconstitution Inflammatory Syndrome		Week 48
Secondary	Incidence and duration of hospitalisation or rate of relapse of specific opportunistic or bacterial infection	Start/Stop of hospitalization for any reason Start/Stop of opportunistic infections as listed within Appendix 3 (AIDS defining events according to https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2.htm) Start/Stop of severe BI, which consists of any of bacterial pneumonia, invasive bacterial infection (IBI) or any bacterial infectious disorder with grade 3 severity or requiring unscheduled hospital admission. An IBI is defined as the isolation of a bacterial organism from a normally sterile body site, or for bacterial nucleic acid to be detected at a normally sterile body site. Sterile body sites include blood, cerebrospinal fluid, pleural fluid, pericardial fluid, peritoneal fluid, joint fluid, bone aspirate, or a deep tissue abscess.	Week 48
Secondary	Number of participants with treatment-related adverse events as assessed by Division of AIDS Adverse Event (AE) Grading Table Corrected Version 2.1-July 2017		Week 48
Secondary	Antiretroviral therapy and opportunistic or bacterial infection treatment changes and dose modifications due to toxicities and drug-drug interaction with antiretroviral therapy, and Immune Reconstitution Inflammatory Syndrome		Week 48
Secondary	Health care resource use, including total inpatient days and emergency room visits		Week 48
Secondary	Quality of life questionnaire outcomes	EQ-5D-3L (European Quality of life - 5 Dimensions - 3 Levels) questionnaires will be completed by patients throughout the study to assess any change throughout their treatment	Week 48
Secondary	Discontinuation or modification of study medication due to insufficient virological response or resistance mutation development	Discontinuation or modification of the single tablet regimen due virological reasons defined as a) Insufficient virological response, either: HIV-1 RNA reduction < 1 log 10 copies/mL at week 12, or; Viral load > 50 HIV-1 RNA copies/mL at week 48 b) Viral rebound, which is subsequently confirmed at the following scheduled or unscheduled visit, defined as either: a. Rebound of HIV-1 RNA to >200 copies/mL after having achieved HIV-1 RNA <50 copies/mL b. Rebound of HIV RNA by >1 log 10 copies/mL from nadir value, for patients whose viral load has never been suppressed below 50 copies/mL	Week 48