Through control of viral replication antiretroviral therapy (ART) has revolutionized the course of HIV disease and HIV prevention . However, ART has no effect on HIV reservoir and therefore has to be administered life-long in order to maintain the virological suppression needed for an optimal clinical course and the prevention of transmission . Despite better tolerability and greater simplicity of recent ART, long-term exposure is associated with toxicity and comorbidities [3,4]. Furthermore, access, sustainability and cost of ART raise major concerns worldwide, particularly in the context of forthcoming universal anti-HIV therapy once diagnosis is made.
Whether ART-free HIV remission is achievable is one of the biggest current challenges in HIV research . In the 2000 era, several studies mostly in chronically infected patients, performed mainly to minimize treatment exposure and toxicity, investigating ART interruption have shown that treatment interruption was detrimental in terms of viral rebound, clinical events and mortality [6–9].
However, drug-free control of viral replication occurs in few patient populations. Elite controllers are defined as patients in whom 90% of plasma HIV RNA values during follow-up are below 500 copies/ml  without ever being treated, but represent less than 1% of the infected population . More recently reported posttreatment controllers (PTC) are patients capable of controlling HIV viremia off-ART, after treatment was initiated at the time of HIV primary infection . Furthermore, early treated infants, such as the ’Mississipi baby’ [13–15] or bone-marrow transplant recipients , have been reported to show transient viral remission. Finally, few chronically HIV-infected patients from the SALTO study  who achieved HIV remission for several months while off-ART had joined the PTC population. Although these situations are heterogeneous and no clues exist yet on the best markers to predict remission, a common characteristic of these individuals controlling their viral replication was a low total HIV DNA reservoir and an excellent immune status. Furthermore, the current target of investigational HIV cure strategies that use antilatency agents aimed at DNA reactivation into RNA, is the decrease of the HIV DNA reservoir pool, again with the ultimate goal of remission off-therapy.
Therefore, in the ULTRASTOP study, we asked whether patients selected with low reservoir under ART and excellent immune status mimicking characteristics of HIV PTC could achieve a remission while off-ART.
ULTRASTOP is a proof-of-concept study designed to evaluate whether a drug-free remission state is achievable following analytic treatment interruption (ATI) in HIV-1-infected patients treated at early chronic phase of HIV infection with an excellent immunological status defined as CD4+ higher than 500 cells/μl and normal CD4+/CD8+ ratio in addition to a low reservoir defined as HIV DNA below level of detection. The primary end point was the proportion of patients in remission at W24 defined as maintaining HIV-1 RNA (plasma viral load, pVL) less than 400 copies/ml, with a CD4+ cell count above 400 cells/μl in the absence of any Center for Disease Control and Prevention (CDC) grade B or C clinical event after 24 weeks off-ART. All HIV RNA rebound or CD4+ decline had to be confirmed at 2–4 weeks interval.
Based on a 33% estimated success rate in patients with HIV-1 DNA not more than 70/106 peripheral blood mononuclear cells (PBMCs) in a treatment interruption study in chronically infected early treated patients , by including 15 individuals, we had a 95% probability to discard a strategy for which the success rate was smaller than 10% and a 80% power to select a strategy for which the success rate was above or equal to 33%.
In order to limit the number of patients exposed to this monitored treatment interruption, the 15 individuals were planned to be enrolled in three consecutive cohorts of five. Enrolment in cohort 2 started, if at least one of five patient from cohort 1 remained in success at W8, and in cohort 3 if at least two of ten of patients of cohorts 1 and 2 remained in success by W8 of the last enrolled patients. Patients resuming treatment without reaching the primary endpoint were replaced.
The study protocol (NCT01876862, EudraCT No. 2013-A00276-39) was approved by the Investigational Review Board of Hôpital Pitié-Salpétrière (CPP Ile de France VI) and by IRBs/IECs at each study site. A written informed consent was obtained from all study participants.
We included chronically HIV-1-infected patients, 18 to 70 years of age, with a pVL below 50 copies/ml for at least 2 years on combination antiretroviral therapy (cART), pVL below 50 copies/ml at screening, CD4+ cells count above 500 cells/μl, a CD4+/CD8+ ratio more than 0.9, a CD4+ nadir above 300 cells/μl, and a total HIV-DNA below 100 copies/106 PBMCs. Patients treated at primary infection, with prior AIDS-defining event or CDC B event, active hepatitis B virus or hepatitis C virus could not be included. To ascertain their psychological capacity to undergo a treatment interruption strategy, all patients were evaluated by a clinical psychologist prior to inclusion. Enrolled patients gave their consent to use double barrier contraceptive methods and refrain from unprotected intercourse.
Follow-up and biological assessments
All patients satisfying inclusion criteria interrupted ART at day 0 except for patients with a baseline non-nucleoside reverse-transcriptase inhibitor (NNRTI) containing ART regimen in whom NNRTI was discontinued 2 weeks before the nucleoside reverse-transcriptase inhibitor (NRTI) backbone maintained up to day 0. Clinical and biological monitoring was performed at week 2, 4 and every 4 weeks off-ART until week 48. Plasma drug concentration monitoring was performed at each visit.
Any confirmed plasma viral load above 400 copies/ml was followed by immediate ART resumption with then a follow-up at weeks 4, 12 and 24 post resumption.
Plasma viral load (pVL) was quantified using the Amplicor monitors assay (Cobas Taqman 2.0; Roche Diagnostics, Basel Switzerland). Below the standard cutoff, the assay indicates the quantitative detection of HIV-1 RNA in the range of 1 to 20 copies/ml . Total cell HIV DNA was quantified in PBMCs by triplicate ultrasensitive real-time polymerase chain reaction as previously described . Total DNA was extracted with Magnapur total nucleic assay (Roche), and amplified in long terminal repeat gene. To determine resistance profile, bulk sequences of the reverse transcriptase, protease and integrase genes on RNA were determined using the ANRS consensus technique primer sequences described at http://www.hivfrenchresistance.org.
Analyses were performed on whole blood. A cocktail of antibodies CD45-FITC (BC), CD4-APC (BD), CD3-Percep-cy5,5 (BD), CD8-APC-H7 (BD), CD38-PE (BD) and HLA-DR-PE-Cy7 (BD) were added to 100 μl of blood, after 15 min of incubation, red blood cells were lysed with FACS lysing solution (BD Biosciences, San Jose, California, USA). Cells were washed with PBS and resuspended in CellFIX before acquisition on Canto analyser.
Human leukocyte antigen typing
The participants were serologically human leukocyte antigen (HLA)-typed using complement-mediated lymphocytotoxicity testing (InGen One Lambda; Chilly Mazarin, Palaiseau, France). High-definition genotyping of the HLA-B*35 alleles was conducted by direct exon sequencing.
Endpoints and statistical analysis
The primary endpoint was the proportion of patients in drug-free remission defined as pVL below 400 copies/ml and CD4+ above 400 cells/μl and no CDC grade B or C clinical event after 24 weeks following ATI. Secondary endpoints included the following: remission rate at W48, time to viral rebound, kinetics of HIV RNA and DNA, changes in CD4+ and CD8+ cell counts, changes in HLA-DR, CD38 activation markers, resistance profile of viruses, time to plasma viral suppression after ART resumption.
Categorical and continuous variables were described as number with percentage and median with minimum and maximum, respectively. The Wilcoxon paired test was used to compare changes in continuous variables and McNemar test to compare changes in categorical variables between baseline and key study time points. Analyses were performed using the SAS software package (version 9.4 for Windows). All reported P values are two sided with a significant level of 0.05.
Twenty patients were screened between December 2013 and April 2014. Nine patients were excluded for HIV DNA above 100 copies/106 PBMCs (n = 7), pVL above 20 copies/ml (n = 1) and CD4+/CD8+ below 0.9 (n = 1). Eleven patients were included: five patients in cohort 1, six patients in cohort 2. One patient from cohort 2 discontinued study protocol with ART resumption without failure at week 8 (pVL 365 copies/ml) and was not analyzed. As only one patient from the two cohorts maintained suppressed viremia at week 8 after enrollment of the last patient from cohort 2, enrollment in cohort 3 did not start, according to protocol.
The 10 patients analyzed were chronically HIV-infected patients with a median CD4+ cell count of 1118 cells/μl (608–1494), CD4+/CD8+ ratio of 2.1 (1.4–2.6) and a total HIV-DNA below 66 copies/106 PBMCs (<66–66) at screening. They had been on ART for a median duration over 5 years with nearly 5 years of viral suppression (Table 1). They had initiated therapy early in the chronic phase of HIV infection with a median pre-ART pVL of 4 log10 copies/ml (range 2.3–5.0), and a CD4+ nadir of 495 cells/μl (330–739). Baseline ART regimens are indicated in Table 2. Five patients were either HLA B27 or HLA B57*01 with no difference in other baseline characteristics from the other patients.
All patients underwent ATI. Individual data are shown in Table 2. One patient (pt#6) reached the primary end point of drug-free remission at week 24 and remained so up to week 48 leading to a drug-free remission rate of 10.0%, (95% exact confidence interval (CI): 0.3–44.5) at both W24 and W48. Nine patients experienced viral rebound at week 2 (two patients), week 4 (six patients) and week 12 (one patient). The median (range) delay to rebound was 4 weeks (2–12). The median pVL at first rebound was 2125 copies/ml (496–176 548 copies/ml) and 7213 (3445–258 029 copies/ml) at the second evaluation within 1 to 2 weeks. Parallel to the dynamics of HIV RNA, HIV DNA increased at first rebound at a median level of 106 copies/106 PBMCs (range: <66 to 424), P = 0.016 compared with baseline (Figs 1 and 2). In the nine rebounding patients, treatment interruption led to a median (range) decrease in CD4+ cells of –124 cells/μl (–690; +127) (P = 0.098); CD8+ cell counts did not change significantly with –21 CD8+ cells/μl (–297; +1014) (P = 0.820), whereas CD4+/CD8+ ratio decreased by –0.2 (–1.6; +0.3) (P = 0.055). Loss of viral control was accompanied by an increase in T-cells activation with an increase in the percentage of CD38+ cells (+10.8%, P = 0.01) and CD38+HLA-DR (+5.1%, P = 0.01) expression on CD8+ T-cell surface (Fig. 3).
Characteristics of the posttreatment controller
The PTC maintained a pVL below 400 copies/ml for 56 weeks and remains in follow-up off-ART to this date. At week 48 off-ART, his pVL was of 282 copies/ml. He had a total number of 12 pVL evaluations between his enrollment in April 2014 and June 2015 with six values of pVL below 50 copies/ml and six values comprised between 70 and 282 copies/ml. He had a pretherapeutic pVL of 187 copies/ml, a known zenith viral load of 3063 copies/ml, a CD4+ nadir of 566 cells/μl and had pVL less than 20 copies/ml under cART during 3.3 years prior to ATI. He is infected with a wild-type R5, B subtype HIV virus and is positive for HLA B*27 : 03, negative for B*57 : 01 and also positive B*40 : 01. He does not present a delta 32 mutation. His CD4+ cell counts declined relatively slowly from 915 cells/μl at ATI to 727 cells/μl at week 48 off-ART. Activation level was low and stable during follow-up with a modest increase on percentage of CD8+CD38+ (36.4%) at week 48 off-ART compared with baseline levels (21.4%). All plasma drug concentrations remained undetectable.
Safety and resistance
During treatment interruption no grade 3 or 4 adverse event was noted and a total of 25 grade 1 or 2 events were recorded in seven patients. The most common adverse events were headaches (n = 4), muscular soreness (n = 2), diarrhea (n = 2), myalgia (n = 2), and adenopathy (n = 2). After treatment resumption 17 adverse events were reported in eight patients with two grade 4 events in the same patient, considered not be related to study intervention (hospitalization for self-induced drug overdose and then for fibromyalgia). No HIV transmission was reported in patients’ partners during the study period.
Genotypic testing performed in the nine rebounders revealed no new resistance mutations. Furthermore, all patients presented a wild genotypic test of resistance except three of them [pt#3 with a K101E mutation, pt#8 with a M184 V mutation and pt#9 with thymidine analogues mutations (TAMs) and K103N and K138A].
Nine patients resumed ART with their initial drug regimen, except pt#3 and pt#9 who re-initiated with a triple-drug regimen given the high viral loads at time of rebound.
Plasma viral load rapidly decreased with viral suppression (<50 copies/ml) achieved by week 4 in 8/9 patients and by week 12 for the last one. At week 24 post treatment resumption, all patients except one had a pVL less than 1 copies/ml (Table 2) with a return to median baseline HIV DNA value less than 66 copies/106 PBMCs (<66–164), (P = 0.125 compared with baseline). Median CD4+ cell count at W24 post RxR was 823 cells/μl (641–1452) with a decrease of –98 cells compared with baseline (–445 to 123), (P = 0.039), there was no change in CD8+ levels +21 (–161 to 271) (P = 0.594) and the CD4+/CD8+ ratio decreased by –0.4 (–0.8 to 0.1) (P = 0.020), reaching a median of 1.4 (1.2–2.1).
We identified one patient who maintained a pVL below 400 copies/ml at 24 weeks, and up to 48 weeks after ATI, thus qualifying for the PTC definition. Overall, in this highly selected population of 10 patients having an ultralow reservoir with DNA values below 100 copies/106 PBMC, the remission rate up to 48 weeks after ATI was 10% (95% CI: 0.3–44.5). Despite an excellent immunological and virological status, nine patients rapidly lost viral control within 1 month.
Indeed, even though the number of studied patients was limited, the drug-free remission rate observed herein appears to be similar to the one reported in the observational SALTO study investigating ATI in chronically infected patients with preART values combining CD4+ above 350 cells/μl and pVL below 50.000 cp /ml, in whom 7.5% (95% CI: 3.7–14.6) had drug-free remission within a 1-year period . In the SALTO study the only predictive factor associated with viral control off-ART in multivariable analysis was a low DNA . Similarly, our remission rate does not seem to differ from the 12% rate estimated for the VISCONTI PTCs . Again, in this latter group, the 89 months-long post treatment interruption viral control had also been associated with the low levels of HIV reservoirs, facilitated by an early treatment initiated within 10 weeks after primary infection, and prolonged for a median of 36 months .
Stopping ART, even in patients with long-term suppressed viremia, excellent immune status and low viral production, is highly challenging nowadays, given the known benefits of treatment, including the minimized risk of transmission. Therefore the study was designed as to limit the number of patients exposed to this ATI strategy, with an enrollment in successive cohorts. Based on the results from the SALTO study , we hypothesized that three cohorts of five patients each, would provide the statistical power needed to detect a remission rate significantly higher than 10%, and although this goal was not reached, we found that one in 10 patients had an ART-free remission, showing that this may occur event when treatment had not been initiated at time of primary infection.
Most importantly, in order to meet known potential predictors of drug-free remission, patients had been selected with a very low value of total DNA – a rare event – of less than 100 copies/106 PBMC. In addition, we selected patients who could have the best chances to experience a delay in viral rebound. Indeed, they had been treated at early stages of infection given the CD4+ nadir of 495 cells/μl (330–739) and the limited pre-HAART pVL of 4 log10 copies/ml (2.3–5.0).
Despite this excellent profile, patients rapidly relapsed following ATI with a median time to viral rebound of 1 month with substantial viremia [median min–max pVL at first rebound of 2125 copies/ml (496–176 548 copies/ml), confirmed at 7213 (3445–258 029 copies/ml) within 2 weeks]. Indeed, whereas we hypothesized that viral rebound could be delayed, the delays of viral rebound observed in the ULTRASTOP study did not differ from previous mid-2000s ATI studies performed in short-term treated chronically infected patients [6,8,9].
We could not identify any specific reason why the patient #6 remained in drug-free remission after 14 months of ATI. Low HIV DNA levels at time of treatment interruption have been suggested to be more predictive of disease progression than pVL and to be associated with time to plasma virus rebound to 400 copies/ml  and plasma viral set-point after treatment interruption . In more ancient studies, low HIV-1 DNA levels had already been associated with a longer time to clinical progression, a lower viral set-point and reduced chance of virological failure on ART re-initiation [22,23]. These data had suggested that HIV DNA could be a predictive marker to guide treatment interruption strategies. In our study however, the strict inclusion criterion of low HIV-DNA levels seemed to have no effect either on the time to rebound, or on the magnitude of pVL relapse. The rapid rebound observed within 4–12 weeks questions whether this virus arose from some tissular compartment. Second, as the threshold of the DNA assay is of less than 66 HIV-DNA copies/million PBMCs and we cannot eliminate some residual circulating reservoir, we are currently investigating whether some blood CD4+ subsets, particularly the central- or transitional-memory CD4+ T cells, still harbor HIV reservoirs in these patients.
Interestingly, although our study had no specific HLA inclusion criteria, half of the patients harbored a favorable genetic profile with either HLA-B*27 or B*57, known to be associated with spontaneous viral control in elite or HIV-controllers and long term non-progressors [24–26]. Indeed, the high proportion of patients with these rare HLA alleles in our population reflects very likely the fact that such profiles are associated with low HIV reservoirs. However, although the unique PTC was HLA-B*27+, these HLA alleles combined to the low HIV-DNA levels, were insufficient to delay the rapid rebound seen in the four other HLA-B*27 or B*57+ patients. Similarly these protective HLA alleles do not contribute to the VISCONTI posttreatment control in which conversely HLA-B*35 alleles, usually associated with poor prognosis, are enriched .
Indeed, we did not find any difference within baseline characteristics in our ULTRASTOP PTC and other patients with a similar HIV DNA levels or pre-ART CD4+ cell count, although he was the patient with the lowest pretherapeutic pVL starting ART 1 year after primary infection. Therefore we cannot exclude that this patient was an elite controller or shares VISCONTI characteristics.
Reseeding HIV reservoirs after ATI was an important concern especially in a population with maximal viral control and low reservoir. The kinetic of reservoirs’ changes were supposed to be slow as suggested by studies showing that HIV reservoirs do not significantly increase over at least 12 weeks in PHI patients though restored to before treatment interruption levels after re-initiation of ART . In contrast, we found that HIV DNA values increased very rapidly after treatment interruption, paralleling viral rebound, and even more importantly rapidly returned to baseline values after treatment resumption.
Overall, ULTRASTOP clearly demonstrates that in a highly motivated towards clinical research and carefully monitored population, suppressive therapy can be safely interrupted with rapid return to preinterruption values and no relevant clinical or virological damage and no increase in cell–blood reservoir. No mutation of resistance was acquired and no case of HIV transmission was noted in patient partners, suggesting that this study design was safe and that close patient monitoring and rapid treatment resumption were key to a minimal risk treatment interruption strategy, thus re-enforcing the feasibility of ATI in proof-of-concept studies towards a cure.
Our study has several limitations, including most importantly its small number of patients, given the drastic selection criteria with a cell-associated DNA below level of detection and the strict enrollment rule of the third cohort based on the success rate of the two previous cohorts in order to expose a minimum of patients to ATI, as well as the psychological criteria needed for such treatment interruption studies.
In conclusion, in chronically infected patients with ultralow reservoir and excellent immune profile treatment interruption, drug-free remission was achieved for more than 1 year in one out of 10 patients, whereas the other nine rapidly rebounded. However study intervention was safe and our study design could be reproduced in future studies investigating cure strategies.
This study was conducted with the financial support of the Shueller-Bettencourt Foundation. We would like to thank Gilles Brücker for his major role in the realization of this study.
ULTRASTOP Study Group: Ruxandra Calin, Roland Tubiana, Marc-Antoine Valantin, Luminita Schneider, Fabienne Caby, Yasmine Dudoit, Christine Katlama, Pitié-Salpêtrière Hospital, Infectious Diseases Department, Paris, France; Sidonie Lambert-Niclot, Cathia Soulie, Anne-Genevieve Marcelain, Vincent Calvez, Pitié-Salpêtrière Hospital, Virology Department, Paris, France; Chiraz Hamimi, Guislaine Carcelain, Brigitte Autran, Pitié-Salpêtrière Hospital, Immunology Department, Paris, France; Jonathan Bellet, Lambert Assoumou, Dominique Costagliola, Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique, Paris, France; Katia Bourdic, Olivier Lambotte, Kremlin-Bicêtre Hospital, Infectious Diseases Department, Le Kremlin-Bicêtre, France; Diane Bolens, Julie Bottero, Manuela Sebire, Pierre-Marie Girard, Saint-Antoine Hospital, Infectious Diseases Department Paris, France.
Conflicts of interest
There are no conflicts of interest.
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