Clinical trial NCT02556333: Emtricitabine/Tenofovir Alafenamide as Salvage ART
Official title: Safety and Efficacy of Emtricitabine/Tenofovir Alafenamide as Part of Salvage Antiretroviral Regimens in Patients With Uncontrolled Viremia and Drug-Resistant HIV Infection
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HIV
Keywords: TAF
F/TAF
antiretroviral therapy
TDF
directly observed therapy
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2015-09-22
Enrollment: 1
Sex: ALL
Minimum age (years): 14
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: HIV RNA Change From Baseline to Day 10
timeFrame: 10 days
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Alice Pau, Pharm.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dombrowski JC, Kitahata MM, Van Rompaey SE, Crane HM, Mugavero MJ, Eron JJ, Boswell SL, Rodriguez B, Mathews WC, Martin JN, Moore RD, Golden MR. High levels of antiretroviral use and viral suppression among persons in HIV care in the United States, 2010. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):299-306. doi: 10.1097/QAI.0b013e3182945bc7.
citation: Deeks SG, Gange SJ, Kitahata MM, Saag MS, Justice AC, Hogg RS, Eron JJ, Brooks JT, Rourke SB, Gill MJ, Bosch RJ, Benson CA, Collier AC, Martin JN, Klein MB, Jacobson LP, Rodriguez B, Sterling TR, Kirk GD, Napravnik S, Rachlis AR, Calzavara LM, Horberg MA, Silverberg MJ, Gebo KA, Kushel MB, Goedert JJ, McKaig RG, Moore RD. Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America. Clin Infect Dis. 2009 Nov 15;49(10):1582-90. doi: 10.1086/644768.
citation: Ezinga M, Wetzels JF, Bosch ME, van der Ven AJ, Burger DM. Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration. Antivir Ther. 2014;19(8):765-71. doi: 10.3851/IMP2761. Epub 2014 Feb 28.