Clinical trial NCT03262441
Conditions: Human Immunodeficiency Virus I Infection
Keywords: HIV Antiretroviral treatment Mycophenolate mofetil Cure Latency Reservoir CD4 T cell Anti-proliferation
Sponsor: Fred Hutchinson Cancer Center
Start date: 2018-02-12; Completion date: 2019-08-31
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, randomized Phase II study to determine whether Mycophenolate mofetil (MMF) given over 22 months meaningfully decreases the size of participants' HIV reservoir.

In addition to primary safety endpoints, the following hypotheses regarding drug efficacy will be tested:

1. MMF will be well tolerated and will not decrease adherence to or antiviral efficacy of ART.
2. Peripheral CD4+ T-cell counts and percentages will not meaningfully decrease during treatment with MMF and ART.
3. There will be no excess risk of opportunistic infections in MMF-treated study participants.
4. MMF therapy will lead to a progressive decrease in reservoir size over 22 months of treatment.
5. MMF therapy will lead to a continual shift in HIV reservoir composition from primarily effector memory CD4+ T cells (TEM) and central memory CD4+ T cells (TCM), to primarily stem cell like memory (TSCM) and naïve (TN) CD4+ T cells.
6. MMF will eliminate detectable measures of the HIV reservoir, including by cell-associated DNA/mRNA and quantitative viral outgrowth.
7. MMF will not decrease the humoral immune response to routine annual influenza vaccination.

Detailed description:
This is an open-label, randomized pilot trial to determine whether MMF given over 22 months meaningfully decreases the size of the HIV reservoir.

At the University of Washington in Seattle, investigators will enroll 5 study participants who have been on ≥2 years of suppressive ART. Study participants will be followed closely for at least 22 months with safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and mRNA (ca-DNA \& ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral load (scVL)). A "go/no-go" decision will occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir measured with ca-DNA.

All participants will be offered enrollment in a sub-study in which an anoscopy with rectum biopsies is performed on 3 occasions to assess the reservoir in the gastrointestinal lymphatic tissue (GALT).

Investigators will vaccinate study participants with the annual influenza vaccine and analyze their humoral response to this vaccine approximately one month later with a routine blood draw done in conjunction with a safety labs blood draw.

Investigators hypothesize that low doses of MMF will be well tolerated among healthy HIV-infected study participants who have fully ART-suppressed HIV. Investigators hypothesize that the incidence of opportunistic infections will not exceed that of comparable larger cohorts of HIV-treated patients. Of note, certain opportunistic infections such as herpes zoster or HSV-2 recurrence continue to occur despite suppressive ART, while pneumocystis pneumonia, CMV end organ disease, cryptococcus and many other opportunistic infections are much less common in this context. Therefore, in the event of an infection, Investigators will confer with the data safety management (DSM) panel to discuss whether this event is directly attributable to MMF. Finally, investigators hypothesize that peripheral blood CD4+ and CD8+ T cell counts will remain unchanged throughout MMF therapy, and that HIV replication will remain controlled on ART with addition of MMF.

Investigators hypothesize at least a 0.25-log reduction in cell-associated HIV DNA at one-year intervals in study participants who have a demonstrated anti-proliferative response to MMF treatment. Investigators hypothesize that cell-associated HIV DNA will undergo a shift from predominant residence in TCM and TEM to predominant residence in TN and TSCM. In regards to our sub-study, investigators predict that reservoir depletion will occur with equivalent rates in blood and GALT.

Arms: arm 1: Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months
Interventions: intervention 1: Mycophenolate Mofetil 500Mg Tab
Intervention descriptions: intervention 1: 500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Protocol  
 
 
 
1
Mycophenolate mofetil therapy for reduction of the HIV reservoir 
 
 
 
Sponsored by:  
amfAR, The Foundation for AIDS Research 
 
 
 
 
Principal Investigator 
Joshua T. Schiffer, MD, MSc 
 
Co-Principal Investigator 
Florian Hladik, MD, PhD 
 
 
 
Version Number:  Version 6.0 
 
March 12, 2018 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards.  The contents of this document shall not be disclosed to others without written 
authorization. 


Clinical Protocol  
 
 
 
2
Table of Contents:  
 
 
 
 
 
Page 
 
Statement of Compliance  
 
 
 
 
3 
 
Statement of Compliance Signature Pages 
 
 
 
4-5 
 
Investigator Team Roster  
 
 
 
 
6-8 
 
List of Abbreviations 
 
 
 
 
 
 
9-10 
 
Protocol Summary  
 
 
 
 
 
11-12 
 
Study Schema 
 
 
 
 
 
 
 
13 
1.0 
Introduction  
 
 
 
 
 
16-18 
2.0 
Study Hypotheses and Objectives 
 
 
 
18-19 
3.0 
Study Design 
 
 
 
 
 
19-20 
4.0 
Selection and Enrollment of Subjects 
 
 
 
20-22 
5.0 
Study Treatment 
 
 
 
 
 
22-23 
6.0 
Participant Management 
 
 
 
 
23-30 
7.0 
Expedited Adverse Event Reporting 
 
 
 
30 
8.0 
Statistical Considerations  
 
 
 
30-31 
9.0 
Human Subjects 
 
 
 
 
 
33-35 
10.0 Publication of Research Results  
 
 
35 
11.0 Biohazard Containment 
 
 
 
 
35 
12.0 Schedule of Evaluations 
 
 
 
 
35 
13.0 References  
 
 
 
 
 
36-40 


Clinical Protocol  
 
 
 
3
Statement of Compliance 
The trial "Mycophenolate mofetil therapy for reduction of the HIV reservoir” will be conducted in 
compliance with the protocol, International Conference on Harmonization Good Clinical Practice 
(GCP) E6, the applicable regulatory requirements, including the U.S. Code of Federal 
Regulations applicable to clinical studies (45 CFR 46 concerning informed consent and IRB 
regulations), and by investigators who have completed Protection of Human Subjects Training.  
 


Clinical Protocol  
 
 
 
4
Signature Page 1 
Your signatures below constitute your approval of this protocol and the attachments, and provides the 
necessary assurances that you will conduct this trial according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable U.S. federal regulations and International Conference on Harmonization 
guidelines. 
 
The Lead Principal Investigator(s) should sign this page.  A copy of this Signature Page 1 should be 
filed with the holder of the Regulatory documents and a copy should be maintained at the site. 
 
Principal Investigator:  
 
 _______________________________________________ 
                                                                    Print/Type 
 
Signed:  
Date: 
 
 
Name/Title 
 
 
 
 
 
Co-Principal Investigator:  
 
 _______________________________________________ 
                                                                    Print/Type 
 
Signed:  
Date: 
 
 
Name/Title 
 
 
 
Signature Page 2 
The signature below constitutes the approval of this protocol and the attachments by the 
investigators, and provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to local 
legal and regulatory requirements and applicable U.S. federal regulations and International 
Conference on Harmonization guidelines. 
 
The Investigator(s) of Record from each participating clinical site should sign the Signature Page 2 as 
appropriate.  This Signature Page 2 should be maintained at each site. 
 
I, the Investigator of Record, agree to conduct this study in full accordance with the provisions of this 
protocol. I will comply with all requirements regarding the obligations of investigators as outlined in 
the Statement of Investigator which I have also signed. 
I have read and understand the information in the product insert including the potential risks and side 
effects of the product under investigation, and will ensure that all associates, colleagues, and 


Clinical Protocol  
 
 
 
5
employees assisting in the conduct of the study are informed about the obligations incurred by their 
contribution to the study. 
 
Investigator of Record: 
  ______________________________________________ 
                                                                         Print/Type 
Signed:  ______________________________________________ 
                                                                         Signature 
Date: _____________________________ 
 
Investigator of Record: 
  ______________________________________________ 
                                                                         Print/Type 
Signed:  ______________________________________________ 
                                                                         Signature 
Date: _____________________________


Clinical Protocol  
 
 
 
6
Team Roster 
 
Principal Investigators / Protocol Chairs 
Joshua T Schiffer, MD, MSc 
Associate Member, Vaccine & Infectious Disease Division 
Fred Hutchinson Cancer Research Center  
Associate Professor of Medicine 
University of Washington 
1100 Eastlake Ave, E4-100 
Seattle, WA 98109-1024 
Phone: 206-667-7359 
E-mail: jschiffe@fredhutch.org  
 
Florian Hladik, MD, PhD 
Research Professor in UW OB/GYN 
Member, Vaccine & Infectious Disease Division 
Fred Hutchinson Cancer Research Center  
1100 Fairview Avenue N 
PO 19024; D3-100 
Seattle, WA 98109-1024 
Phone: 206-667-6848 
E-mail: fhladik@fredhutch.org  
 
 
Co-Investigators 
 
Ann Collier, MD 
Professor of Medicine 
University of Washington 
Harborview Medical Center, Box 359929 
325 9th Avenue  
Seattle, WA 98104-2499 
Phone: (206) 744-3293 
E-mail: acollier@u.washington.edu 
 
Robert W. Coombs, MD, PhD 
Professor of Medicine 
University of Washington 
Harborview Research Building 
325 Ninth Avenue  
Seattle, WA 98104-2499 
Phone: 206-897-5202 
E-mail: bcoombs@u.washington.edu 
 
 


Clinical Protocol  
 
 
 
7
Robert D. Harrington, MD 
Professor of Medicine 
University of Washington 
Harborview Medical Center, Box 359929 
325 9th Avenue  
Seattle, WA 98104-2499 
Phone: (206) 744-3293 
E-mail: rdh&u.washington.edu 
 
Keith Jerome, MD, PhD 
Professor of Laboratory Medicine 
University of Washington 
Member, Vaccine & Infectious Disease Division 
Fred Hutchinson Cancer Research Center  
1100 Eastlake Ave, E5-110 
Seattle, WA 98109-1024 
Phone: 206-667-6793 
E-mail: kjerome@fhcrc.org   
 
Amalia Magaret, PhD 
Research Professor of Laboratory Medicine 
University of Washington 
Joint Associate Member, Vaccine & Infectious Disease Division 
Virology Research Clinic 
Harborview Medical Center 
Seattle, WA 98104-2499 
Phone: 206-520-4316 
E-mail: amag@uw.edu 
 
Jeannine S. McCune, PhD 
Professor of Pharmacy 
Department of Population Sciences 
City of Hope 
Beckman Research Institute 
1500 East Duarte Road 
Duarte, CA 91010-3000 
Phone: 626-218-3716 
Email: jmccune@coh.org  
 
 
 


Clinical Protocol  
 
 
 
8
List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
ART 
Antiretroviral Therapy 
ca-DNA 
Cell-associated HIV DNA 
ca-RNA 
Cell-associated HIV RNA 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus 
CRF 
Case Report Form 
dd-PCR 
Digital droplet PCR 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IND 
Investigational New Drug 
IEC 
Independent or Institutional Ethics Committee 
IMPDH 
Inosine Monophosphate Dehydrogenase Activity 
IRB 
Institutional Review Board 
IUPM 
Infectious Unit Per Million 
MMF 
Mycophenolate Mofetil 
N 
Number (typically refers to participants) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
PBMC 
Peripheral Blood Mononuclear Cells 
PI 
Protease Inhibitor 
PK 
Pharmacokinetics 
PO 
Per os (by mouth) 
QVOA 
Quantitative Viral Outgrowth Assay 
SAE 
Serious Adverse Event/Serious Adverse Experience 
scVL 
Single copy plasma viral load 
TAPT 
Total Anti-Proliferation Test 
TILDA 
Tat/rev-Induced Limiting Dilution Assay 
TREC 
T Cell Receptor Excision Circles 
VL 
Viral Load 
WHO 
World Health Organization 


Clinical Protocol  
 
 
 
9
Protocol Summary 
 
Table 1.  Summary of Protocol 
Full Title 
Mycophenolate mofetil therapy for reduction of the HIV reservoir  
Short Title 
MMF for HIV reservoir reduction 
Clinical Trial 
Phase 
Phase II study 
IND Sponsor 
(if applicable) 
Applied and confirmed “exempt” status with FDA 
Conducted 
By 
Fred Hutchinson Cancer Research Center 
University of Washington 
Principal 
Investigators 
Joshua T. Schiffer, MD, MSc and Florian Hladik, MD, PhD 
Sample Size 
Approximately 5 HIV-infected subjects 
Study 
Population 
HIV infected individuals on ≥2 years of suppressive ART who will specifically 
need to have demonstrated full viral suppression with at least four negative 
plasma viral loads with no more than one documented viral blip during this 
time. 
Study Site 
University of Washington AIDS Clinical Trials Unit (UW ACTU) at Harborview 
Medical Center in Seattle 
Study Design 
A prospective, open label trial 
Study 
Duration 
Accrual will require approximately 2 months. Each enrolled participant will be 
followed for 22 months  
Study Agent  
Mycophenolate mofetil or Myfortic© 
Treatment 
Duration 
22 months 
Primary 
Objective 
 
Establish the impact of prolonged anti-proliferative therapy on the HIV 
reservoir.  
We will test the following hypotheses:  
1. MMF or Myfortic© therapy will lead to a progressive decrease in 
reservoir size over 22 months of treatment.   
2. MMF or Myfortic© therapy will lead to a continual shift in HIV reservoir 
composition from primarily effector memory CD4+ T cells (Tem) and 
central memory CD4+ T cells (Tcm) to primarily stem cell like memory 
(Tscm) and naïve (Tn) CD4+ T cells. 
3. MMF or Myfortic© will eliminate detectable measures of the HIV 
reservoir, including by cell-associated DNA/mRNA and quantitative 
viral outgrowth.  
Secondary 
Objectives 
Establish the safety of prolonged MMF or Myfortic© therapy in 5 
chronically HIV-1 infected patients whose viral loads are fully 
suppressed by ART. 


Clinical Protocol  
 
 
 
10
We will test the following hypotheses:  
1. MMF or Myfortic© will be well-tolerated and will not decrease 
adherence to or antiviral efficacy of ART. 
2. Peripheral CD4+ T cell counts and percentages will not meaningfully 
decrease during treatment with MMF or Myfortic© and ART. 
3. There will be no excess risk of opportunistic infections in MMF or 
Myfortic© treated study participants. 
Endpoint 
The primary endpoint of the study is HIV reservoir size at the end of drug 
treatment. 
 
 


Clinical Protocol  
 
 
 
11
Figure 1: Study schema 
 
 
 
Enrollment
(n= 5)
Study
termination
Month 22
Month 0
Month 12
Go / no-go
decision
•
Interview / physical exam: -1, 0, 1, 2, 3, 4, 5, 6, 9, 12, 15, 18.5, 22 months
•
Safety labs: -1, 0, 1, 2, 3 weeks, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18.5, 22, 22.5 months
•
Urine HcG (point-of-care-test for female participants): with each safety labs
•
Anti-proliferative assays: 0 and 1 week (inclusion testing), 1, 6, 12, 22 months
•
MPA (mycophenolic acid) serum levels: 0, 1 week, 1, 2, 3, 6, 9, 12, 15, 18.5, 22 months
•
Peripheral blood T cell TREC levels:0, 1, 6, 12, 22 months
•
Blood for RNA sequencing: 0 and 1 week, 1, 3, 6, 9, 12, 15, 18.5, 22 months
•
Plasma scVL: 0, 1, 3, 6, 9, 12, 15, 18.5, 22 months
•
Reservoir assays (DNA ddPCR, mRNA ddPCR): 0, 1, 2, 3, 4, 6, 9, 12, 15, 18.5, 22 months
•
Reservoir qVOA: 0, 12, 22 months
•
Rectal biopsies for reservoir assays (optional): 0, 12 & 22 months
•
Influenza vaccine: 6-12 months (seasonal) with antigen assay 1 month later


Clinical Protocol  
 
 
 
12
Table 2. Schedule of study visits and blood draws 
 
 


Clinical Protocol  
 
 
 
13
 
 
The bottom row in red indicates rolling blood volumes over 8 weeks prior to and including each blood draw and should not 
be higher than a total of 450 mL as per University of Washington policy.  
 


Clinical Protocol  
 
 
 
14
1.0 
INTRODUCTION 
1.1 
Background 
The use of antiretroviral therapy (ART) in HIV-infected patients is a shining success in medicine. 
These medications allow millions of patients to survive for decades, whereas untreated infection is 
often fatal within ten years. Widespread implementation of ART has also decreased HIV transmission 
because aviremic infected persons have little to no transmission potential.1 Nevertheless, there is still 
an urgent need for an HIV cure that would eliminate all of the virus from the body. Complete HIV 
eradication, or at least a functional cure in which too little HIV remains for the virus to reactivate over 
the lifespan of the infected person, would allow infected persons to permanently stop taking anti-viral 
therapy. An immediate benefit of cure would be avoidance of possible ART-associated toxicities and 
drug interactions.1,2 A definitive cure of HIV would reduce the stigma felt by many infected persons.3 
Finally, the transformation of HIV care provision from a chronic model whereby ART is given over 
decades to a cure therapy given over a few years, would save the United States healthcare system 
massive healthcare expenditures.   
Strategies currently under consideration for HIV cure are contingent upon first controlling the virus 
with ART.  Therefore, in keeping with current treatment guidelines, the usefulness of a cure 
intervention will depend upon the engagement and retention of infected persons in clinical care.4 An 
optimistic assumption is that publicity associated with development of a safe and effective cure may 
drive more infected persons to seek early HIV testing and management. Widespread implementation 
of HIV cure would then decrease both HIV prevalence and incidence.4 The scalability of each HIV 
cure approach will depend on its effectiveness, but also on its tolerability and affordability. Notably, 
many current HIV cure ideas involve treatments that are not yet widely used in the clinic.5 “Off the 
shelf” medications that require no further research and development expenditure, and have well 
established toxicity profiles, are therefore attractive potential options for HIV cure. 
The major barrier to HIV eradication is the HIV reservoir. The reservoir consists predominately of 
memory CD4+ T cells, which harbor non-replicating HIV DNA that is integrated into chromosomal 
DNA. Complete elimination of these cells, or at least inactivation of the “silent” HIV within these cells, 
is required for cure. The total reservoir typically consists of approximately 1-10 million CD4+ T cells.6-8 
On a per cell basis, the rate of reactivation of HIV is extraordinarily low. Yet, antiretroviral treatment 
interruption (ATI) studies demonstrate that HIV will reactivate approximately once per week.9,10 Thus, 
to achieve a lifetime remission from HIV reactivation off ART, the vast majority of the reservoir must 
be eliminated.   
Two groups estimated that a one-year remission off ART would require a 100- to 1000-fold reduction 
in the number of latently infected cells.10,11 Given the low number of cells that would remain after such 
an intervention, a major challenge is to achieve reliable and rapid measurement of the HIV reservoir. 
Total cell-associated HIV DNA is a sensitive method to estimate reservoir size,12-15 but is misleading 
because most HIV DNA is not replication competent. The gold standard quantitative viral outgrowth 
assay (QVOA) is specific for replication competent HIV but is laborious, slow and requires a large 
number of CD4+ T cells, making it less feasible for repeat monitoring.16 Much of the reservoir exists 
within deep tissues such as lymphatic tissue in the gastrointestinal tract (GALT) and lymph nodes: 
this adds to the challenge of quantitating latently HIV infected cells.   
Numerous technologies are being evaluated to eradicate the HIV reservoir. A majority of potential 
interventions are in preclinical development. Examples include gene therapy delivery of HIV DNA 
editing enzymes, chimeric antigen T cell therapy (CAR T cells), therapeutic vaccines, delivery of HIV 


Clinical Protocol  
 
 
 
15
antibodies or anti-HIV synthetic peptides, and transplantation of HIV resistant cells.5 Several latency-
reversing agents (LRAs) are being actively tested in human study participants.17 LRAs are designed 
to reactivate HIV from its latent form with the hope of inducing two downstream effects. First, cells 
with replicating HIV will lyse due to HIV replication while ART prevents infectious spread to new cells. 
Second, presentation of HIV peptides on the cell surface will induce a cytolytic immune response that 
may be augmented by other interventions such as a vaccine or CAR T cells. Unfortunately, 
demonstration of a reservoir reduction following clinical LRA therapy is so far lacking.17 
1.2  
Study rationale 
Our research group designed a mathematical model with the initial goal of identifying the most 
important barriers to eradication of the reservoir. This analysis led to the conclusion that anti-
proliferative therapy provided over a sustained period of time is potentially a far more potent approach 
than one time use of LRAs.18  
Based on extensive existing phylogenetic data, we first assumed that after suppressive ART of >1 
year, ongoing HIV replication does not contribute to persistence of the HIV reservoir.19-26 We 
demonstrated that even in the context of partially effective ART, the survival of the latent reservoir 
can be decoupled from active viral replication. The latent pool of cells can then be characterized with 
an exponential clearance equation, which is analogous to the compound interest formula in finance 
and characterizes the slow clearance of the HIV reservoir over many decades. Two papers estimate 
the reservoir clearance half-life to be 44 months,6,7 which means that it would take over 60 years for 
the reservoir to be cleared with ART alone.   
On suppressive ART, the latent reservoir clearance rate consists of the sum of three latent cell 
processes: proliferation, death and reactivation to active viral replication. Importantly, observed per 
cell proliferation rates are several orders of magnitude higher than reactivation rates.27 We identified 
in the literature that cells composing the reservoir, including effector memory (TEM), central memory 
(TCM), naïve (TN) and stem cell like (TSCM) memory CD4+ T cells, proliferate at rates similar to 
comparable cells without HIV integration.26,28-30 For example, a TCM cell divides roughly once every 2 
months.31 On the other hand, ATI studies suggest that a single HIV-infected cell within the reservoir 
will reactivate at a rate of approximately once every 265 years.10  Thus, because the viral reactivation 
rate is negligible and the net clearance rate of the latent reservoir approaches zero,6,7 the proliferation 
and death rates must be approximately in equilibrium.  
Using our model, we demonstrate that a small but prolonged decrease in HIV reservoir clearance rate 
would have a greater impact on decreasing the size of the reservoir than a single larger decrease in 
reservoir size, as would occur with a single dose of effective LRA treatment. This result is analogous 
to compound interest whereby small changes are amplified when applied over a long duration. Our 
model predicts that decades of ART would be needed after a 10-fold one-time reduction in the 
reservoir to achieve cure. Yet, a continuous 10-fold reduction in clearance rate would induce a 
functional cure in under five years.  
We next examined the theoretical effects of continuous alterations of the component rates that 
determine the overall clearance rate. If we assume a medical intervention that has a continuous effect 
on HIV reactivation, this intervention would need to induce a 100-fold increase in the basal 
reactivation rate for three years in order to approach a functional cure. On the other hand, just a 3-
fold decrease in the proliferation of reservoir cells extended over three years of treatment may be 
enough for a functional cure. Therefore, continuous anti-proliferative therapy would be the most 
efficient method to induce a cure.  


Clinical Protocol  
 
 
 
16
Several pieces of data are consistent with the predictions of our mathematical model. Chapuis et al 
treated six study participants with MMF for 20 weeks.32 Half of these patients demonstrated a 
substantial reduction in reservoir size measured by QVOA, ranging from 1 to 2 orders of magnitude. 
In addition, treated patients had a decrease in T cell proliferation as measured by Ki67 staining. 
Garcia et al treated nine chronically infected and ART-suppressed study participants with low-dose 
MMF for 17 weeks in addition to their ART.33 The authors noted that serum obtained 12 hours post 
dosing demonstrated a pronounced anti-proliferative effect (>60% inhibition) on T cells in vitro in 6 of 
the 9 subjects on MMF. These 6 patients had a notable median 6-12 week delay in viral rebound and 
a lowering of viral load set point following ATI, compared to the untreated controls as well as to the 
three study participants on MMF whose serum did not have strong anti-proliferative activity. A delay 
of this magnitude is consistent with an approximately 10-fold decrease in reservoir size,34 which 
aligns with predictions from our model. Our model further suggests that had participants taken ART 
and MMF for three years as we propose, then long-term remission would have been possible.  
While MMF has been used in HIV+ patients receiving organ and blood transplants, findings under 
these conditions indicate multiple confounders in transplantation settings,35-38 rendering them 
unsuitable to evaluate the effect of MMF. 
1.3  
Study drug 
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid, which inhibits an enzyme required 
for proliferation of lymphocytes, including B and T cells. MMF is used to prevent organ rejection 
following lung, liver, heart and kidney organ transplantation. Moreover, MMF is commonly used as a 
steroid-sparing agent for autoimmune diseases.  
MMF safety in HIV-infected patients has been established in over 300 HIV+ solid organ transplant 
recipients and other clinical settings.39-59 Fewer than 10% of treated participants developed nausea. 
Renal toxicity, cytopenia, opportunistic infections or decrease in peripheral CD4+ T cell counts were 
not noted.39-45,49 Of note, we will use 500mg twice daily in our study, which is lower than the 2-3g/day 
to prevent organ rejection. We will increase to 750 mg twice daily if an adequate anti-proliferative 
effect is not noted on a lower dose. 
Myfortic© is an enteric coated version of the MMF which is associated with less nausea, vomiting and 
diarrhea.  Myfortic© will be used for participants who have refractory nausea, vomiting and / or 
diarrhea on MMF, and who wish to remain in the study. 
 
2.0 
STUDY HYPOTHESES AND OBJECTIVES 
2.1 
Hypotheses 
2.1a MMF or Myfortic© will be well tolerated and will not decrease adherence to or antiviral 
efficacy of ART.  
2.1b Peripheral CD4+ T-cell counts and percentages will not meaningfully decrease during 
treatment with MMF or Myfortic© and ART. 
2.1c 
There will be no excess risk of opportunistic infections in MMF or Myfortic© treated 
study participants.  
2.1d MMF or Myfortic©  therapy will lead to a progressive decrease in reservoir size over 22 
months of treatment. 


Clinical Protocol  
 
 
 
17
2.1e MMF or Myfortic©  therapy will lead to a continual shift in HIV reservoir composition 
from primarily effector memory CD4+ T-cells (Tem) and central memory CD4+ T-cells 
(Tcm), to primarily stem cell like memory (Tscm) and naïve (Tn) CD4+ T-cells. 
2.1f 
MMF or Myfortic© will eliminate detectable measures of the HIV reservoir, including cell-
associated DNA/mRNA, and quantitative viral outgrowth.   
2.1g MMF or Myfortic© will not decrease the humoral immune response to routine annual 
influenza vaccination. 
 
2.2 
Primary Outcomes 
2.2a Change in cell-associated HIV DNA (ca-DNA) reservoir size as measured by 
multiplexed digital droplet PCR in study participants on versus off MMF or Myfortic© 
(historical controls). 
2.2b Change in HIV replication by single copy viral load (scVL) in study participants on 
versus off MMF or Myfortic©  (historical controls).  
2.3c 
Change of viral reactivation by cell-associated HIV mRNA in study participants on 
versus off MMF or Myfortic©  (historical controls).  
2.3d Change of the inducible HIV reservoir size by quantitative viral outgrowth assay (QVOA) 
in study participants on versus off MMF or Myfortic©  (historical controls).  
2.3d Change of the cellular composition of the HIV DNA reservoir in study participants on 
versus off MMF or Myfortic©  (historical controls). 
 
2.3 
Secondary Outcomes 
2.3a CD4+ T cell numbers that recently emigrated from the thymus 
2.3b Blood CD4+ T cell count 
2.3c 
Complete blood cell count, comprehensive metabolic panel 
2.3d Incidence of opportunistic infection 
2.3e Antibody response to annual influenza vaccination 
 
3.0 
STUDY DESIGN 
This is an open-label, randomized Phase II trial to determine whether MMF given over 22 months 
meaningfully decreases the size of the HIV reservoir.  
At the University of Washington in Seattle, we will enroll 5 study participants who have been on ≥2 
years of suppressive ART. Study participants will be followed closely for at least 22 months with 
safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and 
mRNA (ca-DNA & ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral 


Clinical Protocol  
 
 
 
18
load (scVL)). A “go/no-go” decision will occur after 12 months based on pre-defined thresholds of 
reduction in the HIV reservoir measured with ca-DNA.  
All participants will be offered enrollment in a sub-study in which an anoscopy with rectum biopsies is 
performed on 3 occasions to assess the reservoir in the gastrointestinal lymphatic tissue (GALT 
We will vaccinate study participants with the annual influenza vaccine and analyze their humoral 
response to this vaccine approximately one month later with a routine blood draw done in conjunction 
with a safety labs blood draw. 
We hypothesize that low doses of MMF will be well tolerated among healthy HIV-infected study 
participants who have fully ART-suppressed HIV. We hypothesize that the incidence of opportunistic 
infections will not exceed that of comparable larger cohorts of HIV-treated patients. Of note, certain 
opportunistic infections such as herpes zoster or HSV-2 recurrence continue to occur despite 
suppressive ART, while pneumocystis pneumonia, CMV end organ disease, cryptococcus and many 
other opportunistic infections are much less common in this context. Therefore, in the event of an 
infection, we will confer with the data safety management (DSM) panel to discuss whether this event 
is directly attributable to MMF. Finally, we hypothesize that peripheral blood CD4+ and CD8+ T cell 
counts will remain unchanged throughout MMF therapy, and that HIV replication will remain controlled 
on ART with addition of MMF.   
We hypothesize at least a 0.25-log reduction in cell-associated HIV DNA at one-year intervals in 
study participants who have a demonstrated anti-proliferative response to MMF treatment. We 
hypothesize that cell-associated HIV DNA will undergo a shift from predominant residence in TCM and 
TEM to predominant residence in TN and TSCM.  In regards to our sub-study, we predict that reservoir 
depletion will occur with equivalent rates in blood and GALT.   
 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
4.1 
Inclusion Criteria  
a. 
Confirmed HIV infection, by two different positive antibody tests and/or 
detectable plasma HIV RNA on two different dates 
 
b. 
≥18 and ≤65 years of age 
c. 
Continuous ART during the last two years, with current ART preferably including 
an integrase inhibitor 
d. 
HIV RNA <40 copies / mL on four occasions during continuous ART of ≥ 2 years 
with no more than one blip of <1000 HIV RNA copies / mL 
e. 
CD4+ T cell count > 350/mm3 within the past 365 days  
f. 
Karnofsky score ≥80 
g. 
Plan to reside in area 2 years  
 
h. 
Consents to study 
i. 
“Step 1” lead-in phase: Tolerability of MMF during one week dose escalation of 
500 mg once daily (or Myfortic© 360 mg once daily) 


Clinical Protocol  
 
 
 
19
j. 
“Step 2a” lead-in phase: Demonstrated tolerability and anti-proliferative effect (>= 
80% anti-proliferative effect) of one week of MMF 500 mg twice daily (or 
Myfortic© 360 mg twice daily)  
k.  
“Step 2b” lead-in phase (only if necessary based on inadequate anti-proliferative 
effect on 500 mg bid): Demonstrated tolerability and anti-proliferative effect (>= 
80% anti-proliferative effect) of one week of MMF 750 mg twice daily (or 
Myfortic© 540 mg twice daily) 
 
4.2 
Exclusion Criteria  
a. 
Active malignancy including skin cancer, myelodysplastic syndrome, or 
myeloproliferative disease within 24 weeks prior to study entry 
b. 
Prior organ or bone marrow transplantation 
c. 
Diagnosed autoimmune disease 
d. 
Medical need for ongoing treatment with an immunosuppressive drug 
e. 
Diagnosis of AIDS (defined as any AIDS-defining opportunistic infection or 
cancer, or a history of blood CD4+ T cell count < 200/µL) 
f. 
Active opportunistic infection 
g. 
Using disallowed medications (see 4.3) 
h. 
Vomiting or diarrhea which prohibits consistent use of study drugs 
i. 
Pregnant, intention to become pregnant, or breastfeeding 
j. 
Woman of child bearing age who are NOT using two forms of birth control OR 
 
practicing complete abstinence 
k. 
Excessive ingestion of ethanol, determined by an AUDIT score of >8 
l. 
Substance abuse 
m. 
History of medical non-compliance 
n. 
Quantiferon TB positive 
o. 
The following laboratory values (<30 days before enrollment):  
• Hemoglobin < 8.5 mg/dL 
• Absolute neutrophil count < 1000 cells/mm3 
• ALT > 2 x upper limit of normal 
• Platelet count < 100,000/uL 
• Creatinine clearance < 60 mL/min 
 
4.3 
Disallowed Medications 
a. 
Proton pump inhibitors 


Clinical Protocol  
 
 
 
20
 
b. 
Rifampin 
 
c. 
Cholestyramine 
 
d. 
Colestipol 
 
e. 
Estrogen or progestin contraceptive 
 
f. 
Cyclosporine, tacrolimus or pimecrolimus 
 
g. 
Fingolimod 
 
h. 
Leflunomide 
 
i. 
Magnesium salts 
 
j. 
Metronidazole (oral) 
 
k. 
Monoclonal antibodies 
 
l. 
Tofacitinib 
 
m. 
Systemic corticosteroids 
 
4.4 
Eligibility and Enrollment 
Protocol enrollment is available to all interested qualified individuals willing to adhere to the study. 
Written informed consent for study participation must be obtained before any study-related 
procedures are performed. Participant enrollment evaluation follows the Schedule of Evaluations 
(Table 2 and Section 12.0).  
 
4.5 
Sub-Study Procedures 
Co-enrollment into observational studies is allowed if blood volumes permit. Co-enrollment into other 
interventional studies will be considered by the study team on a case-by-case basis, and will depend 
upon blood volumes, whether participation is likely to interfere with completion of this study or the 
outcome of this study. 
 
 
5.0 
STUDY TREATMENT 
5.1 
Drug Regimen, Administration and Duration 
• Both MMF and Myfortic© should be taken on an empty stomach, 1 hour before or 2 
hours after food intake 
• Entry / “Step 1” lead-in period:   
o Mycophenolate mofetil (MMF) 500 mg or Myfortic© 360 mg daily for one week as 
the “Step 1” lead-in phase 
• Week 1 visit / “Step 2a” lead-in period:     
o Tolerability check  
o Start MMF 500 mg or Myfortic© 360 mg twice daily for 2 weeks as the “Step 2a” 
lead-in phase 


Clinical Protocol  
 
 
 
21
• Week 2 visit:  
o Tolerability check 
o Anti-proliferative testing 
• Week 3 visit:   
o If week 2 test shows a desired anti-proliferative effect (>=80% reduction in T cell 
proliferation one-hour post dosing): continue study at MMF 500 mg or Myfortic© 
360 mg twice daily for 22 months (“Step 3” enrollment) 
o If week 2 test does not show a desired anti-proliferative effect (<80% reduction in 
T cell proliferation one-hour post dosing): dose escalation to MMF 750 mg or 
Myfortic© 540 mg twice daily for 2 weeks (“Step 2b” lead-in phase) 
• Week 4 visit (only if dose escalation to MMF 750 mg or Myfortic© 540 mg twice daily 
occurred at week 3 visit):  
o Tolerability check 
o Anti-proliferative testing 
• Week 5 visit (if dose escalation to MMF 750 mg or Myfortic© 540 mg twice daily 
occurred at week 3) 
o If week 4 test shows a desired anti-proliferative effect (>=80% reduction in T cell 
proliferation one-hour post dosing): continue study at MMF 750 mg or Myfortic© 
540 mg twice daily for 22 months (“Step 3” enrollment) 
o If week 4 test does not show a desired anti-proliferative effect (<80% reduction in 
T cell proliferation one-hour post dosing): discharge from study 
 
5.2 
Drug Formulation 
MMF tablets, 250 mg, 500 mg 
Myfortic© tablets, 180 mg, 360mg 
5.3 
Drug Supply 
• Drugs will be procured locally in Seattle and stored by the AIDS Clinical Trial Unit 
pharmacy at Harborview Medical Center. Only drugs approved by the US Food and 
Drug Administration (FDA) will be used.  
 
6.0 
PARTICIPANT MANAGEMENT 
6.1  
Procedures 
Participants in this study will take 500 mg MMF once per day for one week as a lead in to limit drug-
related side effects. Provided they are tolerating the drug at lower dose, they will then initiate 500 mg 
MMF twice a day for 22 months in addition to their regular anti-HIV treatment. MMF will be switched 
to Myfortic© in the event of poorly tolerated nausea, vomiting or diarrhea and participant agreement 
to remain in the study.  As described above, dose escalation to 750 mg MMF twice daily is possible in 
the event of an inadequate anti-proliferative effect. Participants will visit the clinic and provide 
samples (blood and optional rectal biopsies) several times during the course of the study. If feeling 
nausea or vomiting, participants will be offered ondansetron 4mg oral tablets.  The specific 
procedures for the study visits are outlined below.  
Eligibility Visit (approximately 2 hours) 


Clinical Protocol  
 
 
 
22
During this visit, we will do the following:  
1) Provide participants with general information about the 2 West Clinic 
2) Ask participants to sign the Study Consent Form, the Release of Medical Information Form, 
and HIPAA Authorization Form 
3) Document that participants have HIV by medical records and also determine if participants 
have a medical condition that would preclude them from entering the study. In the event that 
documentation is unavailable, we will ask participants to allow us to do these tests after 
counseling and obtaining their verbal consent 
4) Take a medical and medication history 
5) Assess substance use history, including alcohol, and sexual risk behavior 
6) Perform a general clinical exam (including vital signs: weight, height, blood pressure, pulse 
and temperature) 
7) Obtain a urine specimen for pregnancy testing in female participants 
8) Draw about 5 teaspoons of blood for routine blood tests (blood cell counts and signs of 
anemia, kidney or liver dysfunction) 
9) Perform blood testing for hepatitis B and C if results are not already available from within 12 
months prior to eligibility visit.  
 
Entry Visit (approximately 1 hour) / Step 1 Lead-in 
If the information obtained at the eligibility visit indicates that a participant is eligible to participate in 
the study, we will ask them to come to the clinic for an entry visit. The purpose of this visit will be to 
enroll the participant in the study and obtain additional blood samples. We will ask all participants to 
take MMF for one week following this visit.  
During this visit, we will do the following:  
1) Draw 211 mL (43 teaspoons) of blood 
2) Perform follow up urine pregnancy testing in female participants 
3) Provide the study drug (MMF 500 mg daily) and instructions on how to use it. 
4) Schedule follow-up visits 
5) Answer any questions  
6) Focused physical exam as needed 
One-Week Visit (approximately 30 minutes) / Step 2a Lead-in 
Six days after enrolling in the study, we will ask participants to make a follow-up visit to discuss 
tolerability of the drug. Participants will be seen in the morning of day 7. If they are tolerating the 
dose, then their dose will be increased to MMF 500 mg twice daily.  
 At this visit, we will:  
1) Draw a combined total of 10.5 mL of blood (about 2 teaspoons). 


Clinical Protocol  
 
 
 
23
2) Ask the participant how they are tolerating the study medication 
3) Answer any questions  
4) Focused physical exam as needed 
Two-Week Visit (approximately 30 minutes) 
Thirteen days after enrolling in the study, we will ask participants to make a follow-up visit to measure 
anti-proliferative effect at trough and peak MMF levels. Participants will be seen in the morning of day 
14, approximately 12 hours after the last evening MMF dose. We will draw a small blood sample, then 
administer the morning MMF dose, ask the participant to wait for 60 minutes, and then take another 
small sample. We will use the first sample to assess the anti-proliferative effect at trough MMF levels, 
and the second sample to assess the anti-proliferative effect at peak MMF levels. At this visit, we will:  
5) Draw a combined total of 46.5 mL of blood (about 9 teaspoons) on 2 occasions separated by 1 
hour.   
6) Ask the participant how they are tolerating the study medication 
7) Answer any questions  
8) Focused physical exam as needed 
 
Three-Week Visit (approximately 30 minutes) 
 
The purpose of this visit is to determine how the participant is responding to the study drug. Based on 
the results of the peak MMF time point studies done in the lab, we will determine whether the 
participant is eligible to continue participating in the study at the current dose for 22 months (Step 3 / 
Enrollment) or might require a dose escalation (Step 2b / lead-in).  
 
If a participant does not have the desired anti-proliferative effect to MMF 500 mg twice daily at the 
two-week visit, we will administer MMF 750 mg po twice daily (Step 2b / lead-in): this will occur at the 
three-week visit because it takes approximately one week for the anti-proliferative assay to be 
performed.  
 
No blood will be drawn at the three-week visit. 
 
Four-Week Visit (approximately 30 minutes) 
 
For participants on 500 mg bid and those who required dose escalation to 750 mg bid, we will 
recheck for an anti-proliferative effect at a week 4 visit.  Participants will be seen in the morning, 
approximately 12 hours after the last evening MMF dose. We will draw a small blood sample, then 
administer the morning MMF dose, ask the participant to wait for 60 minutes, and then take another 
small sample. We will use the first sample to assess the anti-proliferative effect at trough MMF levels, 
and the second sample to assess the anti-proliferative effect at peak MMF levels. At this visit, we will:  
1) Draw a combined total of 157.5 mL of blood (about 11 teaspoons) on 2 occasions separated 
by 1 hour.   
2) Ask the participant how they are tolerating the study medication 


Clinical Protocol  
 
 
 
24
3) Answer any questions  
4) Focused physical exam as needed 
 
Five-Week Visit (approximately 30 minutes): only for participants receiving 750 mg po bid 
 
The purpose of this visit is to determine how participants who required escalation to 750 mg bid are 
responding to the study drug. Based on the results of the peak MMF time point studies done in the 
lab on the week 4 visit, we will determine whether the participant is eligible to continue participating in 
the study at the current dose for 22 months (Step 3 / Enrollment).  
 
If participants do not have the desired anti-proliferative effect to MMF 750 mg twice daily, they will be 
discharged from the study at the week 5 visit.  
 
No blood will be drawn at the week 5 visit. 
 
Treatment Modification 
 
If a participant develops nausea or diarrhea anytime during the first week on MMF 500 mg daily, we 
will offer the participant a change from MMF 500 mg daily to Myfortic© 360 mg daily. Myfortic© is an 
enteric coated version of MMF which is associated with less nausea and diarrhea in certain patients. 
If the participant tolerates the first week of Myfortic© 360 mg daily, then we will switch to Myfortic© 
360 mg twice daily during the second week. If this is tolerated, then we will test for an anti-
proliferative effect per protocol.  
 
In the case of refractory nausea or diarrhea after week one, participants will be offered a change from 
MMF 500 mg twice daily to Myfortic© 360 mg twice daily. If a study participant is on MMF 750 mg 
twice daily, then we will switch to Myfortic© 540 mg twice daily.  Participants will always have the 
option of withdrawing their participation from the trial rather than switching to Myfortic©. 
 
Follow-up Visits (approximately 30 minutes) 
Over the course of the study, we will ask participants to come in 19 more times (Table 2). Starting at 
entry, for the first month, we will ask them to come in weekly, then every other week for two months, 
then every month for the rest of the first 12 months, then at month 15, month 18½, and a final visit at 
22 months. The purpose of these visits is to obtain samples to measure how the drug is affecting the 
HIV reservoir and to check safety labs.  
We will check to see if the amount of HIV infected cells is decreasing after one year and after two 
years. If not, then we will ask the participant to stop participating in the study as we wish to see an 
effect of the drug at that point in time. 
Influenza vaccination will occur at one follow-up visit unless study participants have already received 
this vaccine in the community.  
During these visits, we will do the following:  


Clinical Protocol  
 
 
 
25
1) Draw between 6.5 and 255 mL of blood depending on visit (Table 2).  
2) Draw 2 sets of blood separated by an hour to obtain peak and trough drug levels (weeks, 12, 
24, 48, 74 & 88). 
3) Perform follow up urine pregnancy testing in female participants (point-of-care-test in the clinic) 
4) Ask how the participant is tolerating the study medication 
5) Answer any questions  
6) Discuss continuation in the study 
7) Perform a focused physical exam as needed 
Optional Rectal Biopsy Visit (up to 2 hours) 
We will give all participants the option of providing rectal biopsy samples once before starting the 
study medication, once at 12 months, and once at 22 months. Volunteers will be asked to have a 
bowel movement at home or in the clinic before the procedure. No other preparation is required. An 
anoscope will be inserted, and small amounts of rectal tissue from up to six locations will be biopsied. 
Medications e.g Lidocaine cream may be offered to participants to provide comfort prior to the rectal 
biopsy procedure. To reduce the risks of the procedure, we will ask the participants not to have anal 
sex for 5 days afterwards. Before undergoing the first procedure, participants will have their 
prothrombin time (PT), partial thromboplastin time (PTT) and platelet counts evaluated.  
Storage of Data and Leftover Samples for Use in Future Research 
Participants will be asked for permission to keep data and any remaining samples for possible use in 
future research studies.  Residual samples will be stored indefinitely at the University of WA and/or 
Fred Hutch.  Before conducting additional research unrelated to the original research questions, the 
UW HSD will review the request.   
Specimens may be shared with other investigators at the UW, Fred Hutch or other institutions.  The 
samples may not be sold or used directly for production of any commercial product. Tests may 
include genetic research.  Each sample will be encoded (labeled) only with a barcode and a unique 
tracking number to protect participant’s confidentiality. 
There are no benefits to participants in the collection, storage, and subsequent research use of 
samples.  Reports about future research done with a participant’s samples will not be kept in their 
health records. A participant’s decision can change at any time up to the point the samples are 
released for research use by notifying the study doctors in writing.  However, if a participant consents 
to future use and some of their sample has already been used for research purposes, the information 
from that research may still be used. Participants may also withdraw their permission by asking the 
researchers to anonymize their samples.    
 
6. 2 
Toxicity 
The participants will undergo standardized clinical evaluations at each visit. The evaluations will 
include an interim medical history, symptom-directed exam, assessment of concomitant medications, 
and collection of data on adverse events. Women of childbearing potential will undergo urine 
pregnancy tests at eligibility, enrollment and at each safety visit. Since MMF is FDA pregnancy 
category D, women involved in activity that could result in pregnancy will be required to use two forms 
of contraception. If women become pregnant during the study and are on a study medication, they will 


Clinical Protocol  
 
 
 
26
discontinue the medication immediately, and have no additional anoscopies if enrolled in the sub-
study. Women will be asked, but will not be required, to allow the study staff to contact them after 
delivery to get information about their pregnancy outcome. Pregnant participants will be linked to care 
appropriate for pregnant women with HIV infection.  
Participants will be closely monitored in a standardized fashion for potential toxicities and adverse 
events. Safety labs, including complete blood count, comprehensive metabolic panel, plasma HIV 
RNA concentrations and CD4 T cell counts will be monitored frequently as indicated in Figure 1 and 
Table 2. 
The Division of AIDS Table for Grading the Severity of Adult Adverse Events (DAIDS AE Grading 
Table), Version 1.0, dated December 2004, Clarification August 2009, will be used for screening 
eligibility and for grading toxicities and is available at http://rsc.tech-
res.com/safetyandpharmacovigilance. Alternate explanations for clinical or laboratory abnormalities 
that may at first appear to be related to the study agent must be explored. 
Management of adverse experiences will be according to the best clinical practice and the judgment 
of the site investigator. Participants with Grade 3 and 4 laboratory abnormalities will be asked to 
return to the clinic to have the test that is abnormal repeated, preferably within 72 hours. Laboratory 
norms will be the institutional values of the lab performing the tests. Abnormal clinical and laboratory 
findings will be followed until resolution to < Grade 2 or baseline. 
• Grade 1 – Continue study drug; routine monitoring.  
Grade 2 – Continue study drug; monitor closely with more frequent visits when clinically 
indicated. 
Grade 3 – Continue study drug while awaiting confirmatory results unless the clinician believes 
that remaining on study drug would be unsafe. In this case, proceed as below. 
• Confirmed Grade 3 events – Study drug should be discontinued until resolution to  Grade 2, 
unless the site investigator has compelling evidence that the toxicity is definitely NOT related 
to study drug. The event must be discussed with Drs. Schiffer and Harrington and then must 
be reviewed weekly until the toxicity resolves to ≤ Grade 2. If the event is possibly, probably, or 
definitely related to study drug but resolves to ≤ Grade 2 in less than 7 days, study drug can be 
restarted. If the toxicity worsens over the next 7 days or does not resolve to ≤ Grade 2 within 
14 days, the study drug must be permanently discontinued. If the toxicity recurs or evolves to ≥ 
Grade 3, the study regimen must be permanently discontinued. 
• Grade 4 (even before confirming) – The study drug must be discontinued unless the site 
investigator has compelling evidence that the event is not due to study drug. Drs. Schiffer and 
Harrington, and the DSM panel, must be promptly notified of all Grade 4 events. Study drug 
will be permanently discontinued in the event of an adverse event ≥ Grade 4 that is possibly, 
probably, or definitely related to study drug. Subjects experiencing adverse events requiring 
permanent discontinuation of drugs should be followed at least weekly until resolution of the 
adverse event to ≤ Grade 2 or until stabilized and no longer in need of such frequent 
monitoring, as determined by the site investigator. 
 
6.3 
Reporting Requirements 


Clinical Protocol  
 
 
 
27
Grade 2 events should be recorded on CRFs at each visit and will be assessed for relationship to 
study drug.  
 
Grade 3 or 4 events 
• 
Subjects should have abnormal laboratory tests repeated as soon as possible, preferably 
within 72 hours (to determine if the result was spurious).  
• 
Dr. Harrington and Dr. Schiffer must be notified of confirmed ≥ Grade 3 adverse events within 
24 hours, if they are possibly, probably or definitely related to the study. 
• 
The sponsor (American Foundation for AIDS Research or amfAR) will be notified of ≥ Grade 3 
adverse events within one week, if they are possibly, probably or definitely related to the study.   
 
6.4 
Criteria for Treatment and Individual Study Participant Discontinuation 
• The subject requires treatment with disallowed medications  
• Pregnancy 
• Nausea, vomiting or diarrhea refractory to anti-emetic medications  
• Drug toxicity that requires permanent study drug discontinuation as defined in Section 6.2. 
• If a participant does not plan to continue with the study  
• Go / no-go criterion at month 12: participants must have at least a 0.25 log reduction from baseline at 
12 months to continue on MMF. If this criterion is not met, participants will continue to be followed off 
study drug.  
• Subject stops their antiretroviral therapy regimen for greater than 2 weeks 
• The subject refuses further treatment and/or follow-up evaluations and decides to discontinue 
participation in the study 
• The investigator determines that further participation would be detrimental to the subject’s 
health or well-being 
• The subject experiences virologic failure. Virologic failure will be managed according to local 
guidelines. In this study, virologic failure is defined as plasma HIV RNA ≥ 1,000 copies/mL 
(confirmed by repeating the assay on 2nd aliquot of the same specimen).  If a participant has a viral load 
between 500-1000 HIV RNA copies, then we will call the participants for an immediate recheck of their 
viral load as soon as possible and will continue to do so, until this value normalizes or meets criteria for 
virologic failure. Of note, viral load may be checked by the participant’s primary care provider outside of 
the study: these values will be available to the study PI and the criteria for virologic failure will be the 
same. 
• The subject fails to comply with the study requirements so as to cause harm to him/herself or 
seriously interfere with the validity of the study results 
 
6.5 
Criteria for Study Discontinuation 


Clinical Protocol  
 
 
 
28
• The study is cancelled at the discretion of the IRB, DSMB and / or study PIs. This decision will 
be based on several possible factors including mild-moderate adverse effects in multiple 
participants, a severe adverse reaction in a single participant, and / or lack of 1-year efficacy in 
all participants. 
 
6.6  
Protocol for Study Discontinuation 
Participants who withdraw from the study based on criteria described in sections 6.4 and 6.5 
will be asked to return for a clinic visit for laboratory and safety tests.  This procedure will 
continue until normalization of test results.   
 
6.7 
Replacement of Study Subjects 
• All participants are strongly encouraged to attend all study visit dates, however if a participant misses 
an appointment they will be contacted until they can re-schedule the appointment or request being 
discharged from the study. If a participant misses 3 consecutive visits, they will be considered “lost-to-
follow-up”. 
• Replacement of participants. Considerable effort will be invested in maintaining participants in the 
study. New enrollee replaces a participant when a participant: 
o discontinues during the first six months of the study  
o is lost to follow-up during the first three months of the study  
o is unable to tolerate either MMF or Myfortic© during the lead-in phase of the study 
(Steps 1, 2a & 2b) 
o does not develop an adequate anti-proliferative effect on MMF or Myfortic© during the 
lead-in phase (Steps 2a & 2b) 
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING 
Requirements, definitions and methods for expedited reporting of Adverse Events are outlined in 
Version 2.0 of the NIH DAIDS EAE Manual, which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
Since this is not an NIH-sponsored trial, ≥ Grade 3 adverse events will be reported to the sponsor, the 
American Foundation for AIDS Research (amfAR), within one week, if they are possibly, probably or 
definitely related to the study.   
 
8.0 
STATISTICAL CONSIDERATIONS 
 
8.1 
General Design Issues 
This study intends to evaluate the effects of the FDA-approved drug, mycophenolate mofetil to 
determine if it diminishes the size of the HIV reservoir in participants on chronic ART. The study is a 
single-site, prospective, open label, and observational trial. We aim to enroll 5 participants on MMF 
500 mg twice daily. Inclusion criteria are described above. In addition, we will screen each participant 
to ensure that they have a pharmacologic anti-proliferative response to MMF. The drug intervention 


Clinical Protocol  
 
 
 
29
will last a maximum of 22 months with possibility for study extension in participants tolerating drug 
who demonstrate continued reservoir reduction at 22 months but still have a detectable reservoir. 
Participants will be followed closely with serial safety lab measurements and clinical visits to ensure 
drug tolerability and safety. In addition, we will ensure that HIV viral load remains suppressed. 
Moreover, participants will have serial measurements of their HIV DNA reservoir using various 
assays. In order to remain enrolled in the MMF treatment arm of the study, participants will be 
required to show sequential 0.25 log reductions in the HIV reservoir at month 12. We will also include 
a sub-study in which participants undergo an anoscopy to measure the HIV reservoir in tissue rather 
than blood. 
8.2 
Statistical outcomes 
8.2.1 Main statistical outcome 
• Change in cell-associated HIV DNA (ca-DNA) reservoir size as measured by 
multiplexed digital droplet PCR in study participants on versus off MMF (historical 
controls). 
8.2.2 Secondary statistical outcomes 
• Change in HIV replication by single copy viral load (scVL) in study participants on 
versus off MMF (historical controls).  
• Change of viral reactivation by cell-associated HIV mRNA in study participants on 
versus off MMF (historical controls).  
• Change of the inducible HIV reservoir size by quantitative viral outgrowth assay (QVOA) 
in study participants on versus off MMF (historical controls).  
• Change of the cellular composition of the HIV DNA reservoir in study participants on 
versus off MMF (historical controls). 
• CD4+ T cell numbers that recently emigrated from the thymus 
• Blood CD4+ T cell count 
• Complete blood cell count, comprehensive metabolic panel 
• Incidence of opportunistic infection 
• Antibody response to annual influenza vaccination 
8.2.3 Rationales of using the main and secondary statistical outcomes for the study 
The primary and secondary outcomes were chosen to test our hypotheses that MMF plus ART will 
reduce the size of the HIV latent reservoir more rapidly than ART alone. Various reservoir assays are 
used for the secondary outcomes to highlight the fact that each assay has limitations in terms of 
sensitivity and specificity, as well as blood volume required for the assay. Safety labs and clinical 
measures such as CD4+ T cell count and HIV plasma RNA are included as secondary outcomes to 
allow us to assess the safety of the addition of MMF to ART.  
 
8.3 
Randomization 


Clinical Protocol  
 
 
 
30
We will enroll 5 study participants who have been on ≥ 2 years of suppressive ART. There is no 
control group in this Phase II study and no randomization. 
 
8.4 
Sample Size and Accrual 
8.4.1 Sample size calculation for the primary endpoint of reservoir reduction 
Adequate power is not a prerequisite for this study given that any intervention that substantially 
reduces the reservoir in even a small number of patients would be a major step forward for the HIV 
cure field, and that funding is not available to support a control group. Nevertheless, our proposed 
study design is adequately powered to demonstrate statistical significance if MMF performs in 
accordance with predictions from our mathematical model. The rate of reservoir reduction on 
suppressive ART (no MMF) in a study by Siliciano et al was 0.0068 log10 infectious units per million 
(IUPM) resting CD4+ T cells per month (95% CI for the mean rate: 0.0026 - 0.0110; standard 
deviation: 0.017; annualized standard deviation 0.2).6 Similarly, Crooks described a rate of reservoir 
reduction on ART of 0.0072 log10 IUPM per month (95% CI for the mean rate: 0.0031 - 0.0108).7 An 
annual decrease in log10 IUPM on ART alone would average 12*0.0068 = 0.082, or a 17% reduction.  
 
8.5 
Data Safety and Monitoring Plan 
A Data Safety and Monitoring (DSM) panel has been formed and includes two experts in HIV clinical 
care (Dr. Nina Kim, MD, MSC: Associate Professor UW Department of Medicine and Dr. Shireesha 
Dhanireddy, MD: Associate Professor UW Department of Medicine), an expert in the clinical use of 
MMF (Dr. Brenda Sandmaier, MD: Professor UW Department of Medicine and Member FHCRC 
Clinical Research Division) and a biostatistician with considerable experience with HIV trials (Dr. Jim 
Hughes PhD, Professor UW Department of Biostatistics).The DSMB will focus on the safety and 
tolerance of all interventions, including use of MMF, phlebotomy, anoscopies, collection of rectal 
biopsies, and any events that may be related to participation in the study.  DSMB meetings will 
generally be conducted by face-to-face meeting or a combination of face-to-face meeting and 
teleconference, consisting of an open session and a closed session.  The first DSMB meeting will be 
an organizational meeting to review the protocol and monitoring plan; this will occur before the 
enrollment of the first subject.  The second meeting will occur after five participants have completed 
week 8, and then at six months, 12 months and 22 months after study initiation.  Upon completion or 
termination of the study, the DSMB will hold a final meeting.  A summary of each review will be sent 
to the amFAR Program Officer if they do not participate in a DSMB meeting.  The IRB will also be 
sent a summary of the main decision of the DSMB (e.g. to continue the study, modify, or stop the 
study).   
In addition to the real-time Adverse Event review and the DSMB review, the PI Dr. Joshua Schiffer 
and co-investigator Dr. Robert Harrington will review accrual, visit completeness, data completeness, 
any study-related events less serious than Adverse Events, any Protocol Deviations and any “Other 
Problems” monthly and as appropriate, discuss any issues with the laboratory PI, Dr. Florian Hladik, 
and the full study team at the monthly protocol team meetings.  If the amFAR Medical Officer 
requests cumulative summary reports of AEs, they will be made available.  
The DSMB will periodically (as described above) review accumulating safety data by treatment group.  
Prior to each meeting, the statistician will provide the DSMB members with a confidential report of 
safety data by study arm.  Reports will show interval as well as cumulative data.  Reports will show 


Clinical Protocol  
 
 
 
31
the data by coded treatment group; however, upon request of the DSMB, the protocol statistician will 
provide the Board with the actual treatment group data.   
Based upon the reports, the DSMB will determine whether to recommend that the study be continued, 
modified, or stopped for safety reasons.   
Study modification rules:   
• If there are any bowel perforations from rectal biopsies, no further rectal biopsies will be 
performed for the study.   
• If enrollment is delayed by more than 2 months after the study has enrolled its first participant 
because of failure to identify eligible subjects, the cumulative reasons for failure to qualify for 
the study will be reviewed, and changes may be made to eligibility criteria if the changes would 
not put participants at risk. An example of such a change would be to decrease the CD4+ T cell 
criteria for enrollment to fewer than 350 cells/mm3.   
• If enrollment is delayed by more than 3 months after the study has started its first participant 
on MMF because too few subjects meet the pre-defined anti-proliferative activity of MMF by in 
vitro proliferation test after one week of initial MMF therapy, the MMF dose may be increased 
following a subsequent IRB approved protocol change. It is expected that this dose increase 
will lead to more subjects fulfilling the anti-proliferation efficacy criteria. This and any further 
dose increase will be discussed with the DSMB, the IRB and the amFAR program officer 
before implementing.   
Study stopping rules:   
• The study will be stopped if two participants have a confirmed > Grade 4 adverse events 
probably or definitely due to the study drug ingested at the prescribed amount.   
• The study will be stopped if > 2 participants have confirmed Grade 3 adverse events probably 
or definitely due to the study drug ingested at the prescribed amount.   
 
8.6 
Analyses 
Aim one anticipated results: We hypothesize at least 0.25 log reductions in the HIV reservoir at 
month 12 in study participants who have a demonstrated anti-proliferative response to MMF 
treatment. We hypothesize that cell-associated HIV DNA will undergo a shift from predominantly 
residing in TCM and TEM to predominantly residing in TN and TSCM. Further, we predict that reservoir 
depletion will occur with equivalent rates in blood, and GALT.  
We will compute the change in reservoir volume in two ways. First, descriptively, we will use 
individual linear regressions to compute a slope in log viral load (VL) for each participant using time 
as the only covariate; and then we will describe the mean and standard deviation of that slope. 
Secondly, we will use linear mixed effects models, as others have done,60,61 to estimate an average 
slope using all the data at once, and a random intercept and slope per person. Estimation of a fixed 
effect for the interaction of time with treatment arm will help us determine whether the reservoir 
decreases more quickly with ART+MMF than with ART only in historical controls. We will assess the 
changing composition of the reservoir using similar models and include the proportion of cells that are 
naive (TN) as the outcome in a generalized linear mixed model with a log link. An interaction of time 
by treatment arm will determine whether rate of change in composition differs by arm. 
 


Clinical Protocol  
 
 
 
32
 Aim two anticipated results. We hypothesize that low doses of MMF will be well tolerated among 
healthy HIV-infected study participants who have fully ART-suppressed HIV. We hypothesize that the 
incidence of opportunistic infections will not exceed that of comparable larger cohorts of HIV-treated 
patients. Of note, certain opportunistic infections such as herpes zoster or HSV-2 recurrence continue 
to occur despite suppressive ART, while pneumocystis pneumonia, CMV end organ disease, 
cryptococcus and many other opportunistic infections are much less common in this context. 
Therefore, in the event of an infection, we will confer with the DSM panel to discuss whether any 
event is directly attributable to MMF. Additionally, we hypothesize that peripheral blood CD4+ and 
CD8+ T cell counts will remain unchanged throughout MMF therapy, and that HIV replication will 
remain well controlled on ART with the addition of MMF.  
 
 
9.0 
HUMAN SUBJECTS 
 
Participant will be 5 adults and children ≥ 18 and ≤65 years of age. Participants will have received 
ART for at least 2 years with demonstration of full viral suppression during this time, documented by 
at least four negative plasma viral loads and no more than one plasma viral blip during this time.  
They will also have a current CD4+ T cell count of ≥ 350/μl.  The participants will receive 500mg MMF 
twice daily in addition to their ART regimen.  The planned MMF treatment duration is 22 months, but 
efficacy Go/no-Go algorithms at the end of month 12 may lead to earlier termination of MMF 
treatment in some or all study participants.   
All study participants must plan to reside in the Seattle area for the duration of the study.  We 
anticipate pre-screening 30 potential study participants by medical charts to identify 15 who will be 
approached by study staff to schedule an in-person eligibility visit; the first 5 available study 
candidates will enter the anti-proliferation test phase receiving MMF for one week. We conservatively 
estimate that 1 of these 5 individuals will fail to document adequate T cell anti-proliferation and not be 
enrolled in this study. We will continue to screen and test until we enroll 5 participants with a verified 
in vivo anti-proliferative effect of MMF, who will then continue to take MMF for 22 months. Participants 
who discontinue MMF treatment due to inadequate efficacy in reducing the latent HIV reservoir at the 
12 month Go/no-Go decision point, or due to treatment related side effects, will not be replaced.   
Potential Risks include:  
(1) Stress and anxiety could result from study participation.  These will be minimized by careful 
explanation of study procedures, and maintenance of an open, supportive attitude by study 
personnel.   
(2) Potential risks from participation in this study include those related to blood draws.  All personnel 
responsible for blood drawing will be experienced phlebotomists who will follow standard procedures.  
Blood draws can be uncomfortable and cause bruising.  Some temporary anemia could occur from 
study phlebotomy.  A record of all study phlebotomies and blood volume drawn will be maintained for 
each participant, and total blood collection for clinical care and the study will be monitored and IRB 
limits for study purposes will not be exceeded.  Specifically, individual blood draws will never be more 
than 270 mL and total volumes of blood drawn over an eight-week period will never be more than 450 
mL. 
(3) Insertion of an anoscope may be uncomfortable.  Rectal biopsies usually do not hurt.  However, it 
is possible subjects could feel some brief pain or discomfort.  In rare cases, these biopsies may 


Clinical Protocol  
 
 
 
33
cause a significant amount of bleeding or, rarely, an infection at the site that was sampled.  In 
extremely rare circumstances, rectal biopsies can result in rectal perforation.  Lidocaine cream may 
cause local numbness, redness, swelling or irritation.  Extremely rare side effects include irregular 
heartbeat, shortness of breath and seizure.  Precautions will be taken by the experienced study 
gastroenterologist at the time the biopsies are obtained to prevent perforation and to prevent or 
minimize bleeding and infection.  In addition, as a further precaution, participants will be asked not to 
have anal sex for 5 days after the biopsies to help prevent any possible increase in risk of infection or 
bleeding.     
(4) Answering questions about smoking, alcohol use, and sexual behaviors may make subjects feel 
uncomfortable.   
(5) There are also potential risks related to confidentiality.  All participating staff and faculty at the site 
will maintain the confidentiality of study subjects, and study materials that could expose identity will 
be kept in locked cabinets or in password-protected files, accessible only to the study personnel at 
the research clinic conducting the study with a need to know.   
(6) Reports of MMF adverse reactions are based on dosages of 2-3 grams daily (rather than 1g daily 
in this study).  A detailed description of all adverse effects and precautions is contained in the 
CellCept® Product Monograph, which is included in the Appendix to the Clinical Protocol.  (Of note, 
we will be using the generic version of MMF and not CellCept.) 
The principal adverse reactions associated with the oral administration of MMF include diarrhea, 
leukopenia, sepsis, and nausea and vomiting.  There also is evidence of a higher frequency of certain 
types of infections, e.g., cytomegalovirus viremia, JC virus-associated progressive multifocal 
leukoencephalopathy (PML) and polyomavirus-associated nephropathy (PVAN).  Patients receiving 
MMF alone or as part of an immunosuppressive regimen are at increased risk of developing 
lymphomas and other malignancies, particularly of the skin.  These risks appear to be related to the 
intensity and duration of immunosuppression rather than to the use of any specific agent.   
There are also a small number of patients who received solid organ transplants and experienced 
reversible falls in their red cell or white cell counts while receiving MMF. Additionally, cases of Pure 
Red Cell Aplasia (PRCA) have been reported in some patients receiving MMF. PRCA is a condition in 
which the bone marrow stops producing red blood cells. In some instances, PRCA can be reversed 
by reducing or stopping MMF.  
 
MMF has embryo-fetal toxicity, causing fetal harm when administered to a pregnant female.  Use of 
MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an 
increased risk of congenital malformations, especially external ear and other facial abnormalities 
including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney and nervous 
system.   
There will be adequate protection against risks including IRB approval at the study site, written 
informed consent, rapid reporting of adverse events and data safety monitoring as above. 
(8) Use of ondansetron is occasionally associated with diarrhea, headache, fever, lightheadedness, 
dizziness, weakness, fatigue, constipation, rash, blurred vision, urinary retention, and muscle spasm. 
(9) The most common adverse reactions (≥20%) for Myfortic© include anemia, leukopenia, 
constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, 


Clinical Protocol  
 
 
 
34
insomnia.  Rare more severe complications include pure red cell aplasia and Progressive multifocal 
leukoencephalopathy (PML). 
 
10.0 PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by NIH policies.   
 
 
11.0 BIOHAZARD CONTAINMENT 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and tissues, appropriate blood and secretion precautions will be 
employed by all personnel in the drawing of blood and shipping and handling of all specimens for this 
study, as currently recommended by the Centers for Disease Control and Prevention and the National 
Institutes of Health. 
 
 
 
 
 
 
 
12.0 SCHEDULE OF EVALUATIONS  
 
See Table 2. 


Protocol 
 
 
 
35
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