Impact of Antiretroviral Treatment and Predictors in Subjects With Extremely Low HIV-1 Reservoir: Optimization of New Cure Strategies
Conditions: Hiv
Sponsor: IrsiCaixa

Low Viral Reservoir in Treated Subjects (LoViReT) - Phase II. 
Predictors of Extremely Low HIV-1 DNA Reservoir in Subjects Initiating cART during 
Chronic Infection. 
 
 
PROTOCOL SUMMARY 
1.  IDENTIFICATION OF THE PROTOCOL 
Sponsor protocol code: LoViReT II 
Version/Date: Version 5, 19/01/2017 
2.  TITLE OF THE STUDY 
Low Viral Reservoir in Treated Subjects (LoViReT) - Phase II: Predictors of Extremely 
Low HIV-1 DNA Reservoir in Subjects Initiating cART during Chronic Infection 
 
3.  IDENTIFICATION OF THE SPONSOR 
AIDS Research Institute IrsiCaixa 
Univ. Hospital ‘Germans Trias i Pujol’ 
Carretera de Canyet s/n 
08916 Badalona (Barcelona), Spain 
4.  PRINCIPAL INVESTIGADOR 
Dr. Javier Martínez Picado 
Univ. Hospital ‘Germans Trias i Pujol’ 
Carretera de Canyet s/n 
08916 Badalona (Barcelona) 
 
5.  RESEARCH ETHICS COMMITTEE WITH DRUGS 
The IRB at Univ. Hospital ‘Germans Trias i Pujol’. 
 
6.  CENTER WHERE THE STUDY WILL BE CARRIED OUT 
Univ. Hospital ‘Germans Trias i Pujol’ 
 
7.  JUSTIFICATION AND RELEVANCE OF THE STUDY 
Antiretroviral therapy (ART) for HIV-1 significantly reduces the morbidity and mortality 
associated with AIDS events. However, it fails to eliminate the virus that persists in the 
form of latent infection in the cell reservoirs, which implies a rapid rebound of viral load 
if the treatment is interrupted1. Currently, there is a wide variety of strategies that aim 
to reduce the viral reservoir, with the ultimate goal of reducing it to undetectable levels2- 
4. 
 
To date, only two strategies have been successful in meeting this goal: the early start 
of antiretroviral treatment and allogeneic stem cell transplantation in the Berlin patient. 
However, despite having an undetectable latent reservoir, patients suffer a viral rebound 
within a few months after stopping treatment (except in the Berlin patient)5-9. These 
results show that an undetectable reservoir of HIV-1 does not mean a cure for the virus. 
Therefore, there is a need to understand the nature of HIV reservoirs that must be 
eliminated to achieve a cure10. 
 
Thus, LoViReT patients11 are the perfect model to: I) discover the places where the virus 
persists in the body despite the apparent eradication of HIV in the blood; II) elucidate 

the mechanisms by which a patient can maintain extremely low levels of HIV-1 DNA 
despite having started ART during chronic HIV-1 infection; and III) develop a predictive 
technique that can anticipate viral rebound before discontinuation of antiretroviral 
therapy. 
 
 
References 
 
1. 
Finzi, D. et al. Latent infection of CD4+ T cells provides a mechanism for lifelong 
persistence of HIV-1, even in patients on effective combination therapy. Nat. 
Med.5, 512–517 (1999). 
2. 
Deeks, S. G. et al. Towards an HIV cure: a global scientific strategy. Nat. Rev. 
Immunol.12, 607–14 (2012). 
3. 
Katlama, C. et al. Barriers to a cure for HIV: new ways to target and eradicate 
HIV-1 reservoirs. Lancet381, 2109–17 (2013). 
4. 
Richman, D. D. et al. The challenge of finding a cure for HIV infection. Science323, 
1304–7 (2009). 
5. 
Persaud, D. et al. Absence of detectable HIV-1 viremia after treatment cessation 
in an infant. N Engl J Med369, 1828–1835 (2013). 
6. 
Henrich, T. J. et al. Long-term reduction in peripheral blood HIV type 1 reservoirs 
following reduced-intensity conditioning allogeneic stem cell transplantation. J 
Infect Dis207, 1694–1702 (2013). 
7. 
Hütter, G. et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell 
transplantation. N Engl J Med360, 692–698 (2009). 
8. 
Henrich, T. J. et al. Antiretroviral-Free HIV-1 Remission and Viral Rebound After 
Allogeneic Stem Cell Transplantation: Report of 2 Cases. Ann. Intern. Med. 1–10 
(2014). doi:10.7326/M14-1027 
9. 
Yukl, S. A. et al. Challenges in detecting HIV persistence during potentially 
curative interventions: a study of the Berlin patient. PLoS Pathog9, e1003347 
(2013). 
10. 
Deeks, S. G. et al. International AIDS Society global scientific strategy: towards 
an HIV cure 2016. Nat. Med.22, 839–850 (2016). 
11. 
Salgado M , Gálvez C, Dalmau J, Carrillo J, Urrea V, Clotet B, Blanco J, M.-P. J. 
Low Viral Reservoir Treated patients (LoViReT): clinical predictors of low HIV-1 
DNA (Abstract PP 3.10). Jounal Virus Erad. (Abstracts Seventh Int. Work. HIV 
Persistence Dur. Ther.1 suplem 1, 
 
 
 
8.  DESIGN 
Unicentric, case-control, observational clinical study. 
 
9.  PRINCIPAL OBJECTIVE 
The main objective of the LoViReT project is to identify and characterize the most 
relevant factors involved in maintaining an extremely low viral reservoir in an exceptional 
group of patients treated during the chronic phase of infection with antiretroviral 
therapy. Among these factors we would include both virological factors (viral tropism, 
complete genome, replicative capacity ...), immuno-genetic factors (HLA, CTL response, 
plasma neutralization capacity, phenotype of lymphocyte populations, cell activation, 
transcriptomics ...) and clinical factors (progression clinic, mode of transmission, age, 
therapeutic picture, sex ...). 

10.  EXPERIMENTAL DRUG AND CONTROL. DOSAGE, PHYSICAL FORM, ROUTE OF 
ADMINISTRATION, THERAPEUTIC GROUP 
Does not apply 
 
 
11.  PRIMARY ENDPOINT 
The primary endpoint is to study the cell-associated HIV DNA, the level of CD4 + T cells 
from both peripheral blood and associated lymphoid tissues (rectum and lymph node) 
plus clinical parameters, factors immuno-genetic and the virus itself. 
 
 
 
12.  STUDY POPULATION AND TOTAL NUMBER OF PATIENTS 
 
12.1. Selection criteria: 
 
Inclusion criteria 
• 
≥ 18 years of age; 
• 
voluntarily signed informed consent; 
• 
proven HIV-1 infection; 
• 
on stable cART regimen for at least 3 years; 
• 
HIV-RNA <50 copies/mL during the last 3 years prior to the study (blips under 
200 copies/ml are permitted in 5% of determinations during last 3 years); 
• 
proviral HIV-DNA <50 copies/million PBMCs by using the ultrasensitive BioRad 
residual ddPCR quantification platform. 
 
 
Exclusion criteria 
• 
In women, pregnancy or breastfeeding. 
• 
cART discontinuation since the moment of the previous screening to the date of 
Visit #1. 
• 
HIV-RNA above 200 copies/mL since the moment of the previous screening to 
the date of Visit #1 
 
12.2. Total number of participants: 
This study is expected to include a total of 86 HIV-infected patients of which 43 patients 
will come from the LoViReT I cohort, forming the experimental group and the other 43 
patients will be shortlisted to form the control group. 
 
The patients of the control group will be included according to the reason 1 control: 1 
experimental, in a paired way by age, sex and clinical profile. 
 
13.  STATISTICAL ANALYSIS 
The absence of previous data for the factors to be analyzed makes it impossible to make 
an accurate study of the statistical power and the required sample size. However, we 
can make a rough estimate of the power by reference to the use of non-parametric tests 
and the measurement of the Cohen effect size (d), defined as the difference between 
the means divided by the standard deviation of the data. 

Although the size of the feasible sample does not allow us to achieve enough power to 
observe small effects (d = 0.2), with a sample size of 40 patients per group (a total N 
of 80) we reach a power of about 60% to average effects D = 0.5) and more than 90% 
for large effects (d = 0.8). With a sample size of 20 patients per group (N = 40) we 
reach a power of 70% for large effects. The calculations have been made considering a 
significance level of 0.05 and two tails. 
 
 
 
14.  ETHICAL CONSIDERATIONS 
The study will be carried out in accordance with the principles contained in the 
Declaration of Helsinki and in accordance with the Law on Medical Research in Human 
Matters (WMO), Royal Decree 1090/2015, CREC and approval by the Director of the 
Institution. 
 
The researcher undertakes to comply with the norms established in the applicable clinical 
trial regulations: Medicines Law 29/2006 (Official State Gazette No. 178, 07-27-06) and 
Royal Decree 1090/2015. 
 
The protocol will be evaluated by, at a minimum, by a Research Ethics Committee with 
medications. 
 
The participation of researchers in this study is free, voluntary and independent. 
 
 
 
15.  TREATMENT DURATION 
Does not apply 
 
 
16.  TIMELINE AND EXPECTED FINALIZATION DATE 
The expected duration of this study from the writing of the protocol to the final report is 
1 year and 10 months (from January 2018 to November 2019). The estimated calendar 
is quoted below: 
 
Presentation to IRB: February 2017 
Inclusion and collection of samples: January 2018 - December 2018 
Laboratory analysis: January 2018 – November 2019 
Final report: November 2019