Emtricitabine/Tenofovir Alafenamide as Salvage ART

Study Overview
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Brief Summary
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Background: HIV attacks the immune system. Antiretroviral therapy (ART) is a combination of drugs used for treating HIV infection. For some people, ART drugs stop working against their HIV. Researchers want to see if a different form of the drug tenofovir (an ART drug currently approved by the FDA), combined with another drug, may help people whose HIV is resistant to ART. This combination pill is called F/TAF Objective: To study the safety and efficacy of the drug F/TAF, when used with other ART, for people whose HIV infection has been hard to control with available medicines. Eligibility: People age 14 years and older who have HIV infection and are enrolled in the DOTCOM (14-I-0009) protocol. Design: Participants will be screened with physical exam, medical history, and blood and urine tests. Participants will stay in the hospital for at least 10 days. For the first 9 days, they will take F/TAF by mouth along with their usual ART drugs. In the hospital, they will repeat the screening tests. Participants will have a DEXA scan, an x-ray that measures calcium and other minerals in the bones. Participants will lie on a soft table while the scanner passes over the lower spine and hips. Participants will get a supply of F/TAF and some new ART drugs to take at home. Participants will have follow-up visits in 1, 2, 4, 8, and 12 weeks. After the 12-week visit, they will come back about every 3 months for about 1 year. At these visits, participants will repeat the screening tests. They will discuss any problems taking their ART drugs. They may have another DEXA scan.

Detailed Description
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Despite the success of antiretroviral therapy (ART), a subset of HIV-1-infected patients have uncontrolled viremia, multiple drug class resistance, and limited treatment options. Tenofovir disoproxil fumarate (TDF) forms part of most ART regimens, however its long-term use is associated with renal tubulopathy and reduced bone mineral density. Viral mutations (eg, K65R, multiple thymidine analog mutations (TAMs) can confer resistance or reduced susceptibility to TDF. Tenofovir alafenamide (TAF) is an investigational oral prodrug of tenofovir. When compared to TDF, TAF demonstrated lower plasma tenofovir concentrations and more potent antiviral activity at approximately one-tenth of the dose. TAF has the advantage of reduced tenofovir exposure to the renal tubules and bone, potentially resulting in fewer kidney and bone effects. As with TDF, TAF has potent activities against hepatitis B virus (HBV), and may be a treatment option for patients with HIV/HBV co-infections. Phase 2 trials have demonstrated the non-inferiority of TAF to TDF in treating HIV-1 infection in ART-naive patients. Smaller reductions in bone mineral density were measured with TAF than TDF. The most common adverse events were nausea and diarrhea. This single-arm, single-site, open-label trial will explore the safety and efficacy of TAF in a fixed combination with emtricitabine (FTC) (F/TAF, Gilead Sciences Inc.) as part of a salvage antiretroviral regimen for HIV-1-infected adults and adolescents (greater than or equal to 14 years) who experienced virologic failure. The study will recruit patients who have failed TDF-containing regimens or cannot take TDF (due to resistance mutations or risk of renal injury) and for whom abacavir/lamivudine (ABC/3TC) is not an optimal alternative. Eligible patients will begin 9 days of inpatient directly observed therapy (DOT) with F/TAF plus their pre-enrollment background regimen. On Day 10, patients will switch to F/TAF plus OBT while waiting for the results of Day 10 HIV RNA results. Patients with an HIV RNA decline of <0.5 log10 from Day 1 to Day 10 will discontinue F/TAF, end their study participation, and continue OBT (with TDF/FTC or ABC/3TC in place of F/TAF, as appropriate) under the 14-I-0009 protocol. Patients with a greater than or equal to 0.5 log10 decline in HIV RNA will continue on F/TAF + OBT for 48 weeks, with periodic outpatient assessments of adherence, safety, renal function, bone mineral density, HIV RNA, and CD4 T cell counts. Switching of one or more drugs in an ART regimen due to inadequate viral response will require inpatient DOT under 14-I-0009.

Official Title
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Safety and Efficacy of Emtricitabine/Tenofovir Alafenamide as Part of Salvage Antiretroviral Regimens in Patients With Uncontrolled Viremia and Drug-Resistant HIV Infection

Conditions
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HIV

Intervention / Treatment
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* Drug: FTC/TAF


Participation Criteria
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Eligibility Criteria
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INCLUSION Age greater than or equal to 14 years Documented HIV-1 infection (written documentation of positive standard ELISA or rapid HIV-1/HIV-2 antibody test with confirmatory Western Blot, or documentation of repeated HIV RNA of > 1,000 copies/mL) Concurrent enrollment in the DOTCOM (14-I-0009) protocol For females of childbearing potential, willingness to use effective contraception for the duration of the study Willingness to be hospitalized for 10-15 days (with potential for day passes) Willingness to have blood samples stored for future research that may include genetic testing Multiple ART failure as defined by at least one of the following criteria: HIV RNA > 1000 copies/mL and documented virologic failure on at least 1 prior ART regimen and at least 2 consecutive HIV RNA plasma measurements of > 1,000 copies/mL, including the last documented value, while on the currently prescribed ART regimen for at least 6 months; or Documented extensive resistance to at least 3 antiretroviral (ARV) drug classes, and persistent plasma viremia (HIV RNA > 1,000 copies/mL for > 6 months) despite multiple regimen changes. The patient may be enrolled even if they have been prescribed their current regimens for less than 6 months. Where neither TDF nor ABC are optimal NRTI options as defined by at least one of the following criteria: Presence of the M184V mutation plus TDF-associated resistance mutations based on genotypic/phenotypic testing, specifically K65R alone, or with TAMs (such as 41L, 67N, 70R, 210W, 215Y/F, or 219Q/E) with or without other NRTI-associated mutations; or FTC/TDF is not considered an option due to impaired renal function (eGFR by Cockroft-Gault equation [eGFR(CG)]=30-60 mL/min), or risk of renal impairment because of conditions such as uncontrolled hypertension, diabetes mellitus, or history of renal toxicity while receiving a TDF-based regimen; and where ABC/3TC is contraindicated (ie, presence of HLA B*5701 allele or history of hypersensitivity reaction to ABC), or is a suboptimal option (eg, presence of ABC-associated resistance mutation(s) or in patients with HBV co-infection). EXCLUSION Severe renal impairment (eGFR(CG) <30 mL/min) Acute medical illness stemming from a significant co-morbidity (eg, malignancy requiring chemotherapy, treatment of an acute opportunistic infection or acute renal failture). Enrollment may be deferred up to 3 months to allow a condition to resolve or stabilize. Pregnancy; however if a patient becomes pregnant while enrolled in the protocol, she may continue participation throughout her pregnancy. Breastfeeding Concomitant use of one of the following medications: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bisphosphonate, St. John s wort, echinacea, milk thistle, sho-saiko-to, and probenecid. Any illness or condition that, in the investigator's opinion, may substantially increase the risk of participation in the study, or compromise the scientific objectives.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 100 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FTC/TAF<br>Emtricitabine 200mg/tenofovir alafenamide 25mg (FTC/TAF) tablet to be given orally once daily to be added to a failing regimen for 10 days. If HIV RNA decline by >= 0.5 log copies/mL, patient will continue on FTC/TAF with a new antiretroviral regimen for 48 weeks. If < 0.5 log copies/mL decline, patient will be taken off FTC/TAF. | Drug: FTC/TAF<br>* Tenofovir alafenamide (TAF) is an investigational oral prodrug of tenofovir. This trial will explore the safety and efficacy of TAF in a fixed combination with emtricitabine (FTC) (F/TAF, Gilead Sciences Inc.) as part of a salvage antiretroviral regimen for HIV-1-infected adults and adolescents (greater than or equal to 14 years) who experienced virologic failure.<br>* Other names: Emtricitabine 200mg/tenofovir alafenamide 25 mg (F/TAF);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV RNA Change From Baseline to Day 10 | An HIV RNA decline of >=0.5 log by day 10 will be considered to be an adequate virologic response, to proceed to the second phase of the study. | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TAF, F/TAF, antiretroviral therapy, TDF, directly observed therapy