Emtricitabine/Tenofovir Alafenamide as Salvage ART

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.

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.