The Late Presenter Treatment Optimisation Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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HIV/AIDS

Intervention / Treatment
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* Drug: Biktarvy
* Drug: Symtuza


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The ability to understand and sign a written informed consent form (ICF) and must be willing to comply with all study requirements. Male or non-pregnant, non-lactating females†. Age ≥ 18 years. Have documented, untreated HIV-1 infection with either: AIDS with any CD4 cell count (AIDS-defining conditions are listed within Appendix 3). Or Severe bacterial infection (BI)‡ and must have a CD4 cell count < 200/μl within 28 days prior to study entry§. Or 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 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. Have an entry HIV viral load > 1000 copies/mL Have the ability to take oral medications. 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: Any therapeutic ARV which commenced less than 2 weeks prior to screening and which was taken for more than 48 hours Systemic cancer chemotherapy within 30 days prior to study entry, or current treatment for cancer (with the exception of Kaposi's sarcoma) or lymphoma. 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). Known resistance to the components of study medications (see section 6.1.3 for more details). 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. Current drug or alcohol use that, in the opinion of the Investigator, would cause interference with the study. 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). History or presence of allergy to the study drugs or their components, or drugs of their class. Using any concomitant therapy disallowed as per the product labelling for the study drugs. Any investigational drug within 30 days prior to the study drug administration. Patients with severe (Child Pugh class C) hepatic impairment. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Biktarvy<br>Bictegravir is an inhibitor of HIV-1 integrase that is being evaluated for the treatment of HIV-1 infection. Biktarvy® received marketing authorisation valid throughout the European Union (EU) in June 2018. Biktarvy is a combination of bictegravir, emtricitabine, and tenofovir (B/F/TAF). Method of administration: One combined B 50mg/F 200mg/TAF 25mg tablet taken orally once daily for up to 48 weeks without regard to food. | Drug: Biktarvy<br>* Integrase inhibitor used to treat HIV-1 infection<br>|
| Experimental: Symtuza<br>Symtuza® is a boosted PI indicated for the treatment of HIV-1 infection. Symtuza® received marketing authorisation valid throughout the EU in September 2017. Symtuza is a combination of darunavir, cobicistat, emtricitabine and tenofovir alafenamide (D/C/F/TAF) Method of administration: One combined D 800mg/C 150mg/F 200mg/TAF 10mg tablet taken orally once daily for up to 48 weeks with the addition of food. | Drug: Symtuza<br>* Protease inhibitor used to treat HIV-1 infection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with HIV-RNA viral load <50 copies/mL |  | Week 24, 36 and 48 | 
| HIV-1 drug resistance confirmed |  | Through study completion, an average of 1 year | 
| Time to reach CD4 (cluster of differentiation 4) count >200/µL |  | Through study completion, an average of 1 year | 
| CD4/CD8 (cluster of differentiation 8) ratio |  | Week 4, 8, 12, 24, 36, 48 | 
| Incidence of Immune Reconstitution Inflammatory Syndrome |  | Week 48 | 
| 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 | 
| 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 | 
| 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 | 
| Health care resource use, including total inpatient days and emergency room visits |  | Week 48 | 
| 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 | 
| 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 |