A new example of long-term post-treatment control of HIV viral load was reported this past Monday at the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) in Vancouver, attracting widespread media attention. Presented by Asier Sáez-Cirión from Institut Pasteur in France, the case involves a teenager who acquired HIV infection perinatally and was taken off ART at around the age of six, subsequently maintaining very strict control of viral load for over 12 years and counting (the slide presentation is now posted online). Sáez-Cirión is also the lead investigator for the well publicized VISCONTI cohort, a group of early-treated adults who are exhibiting long-term of HIV viral load after ART interruption (described in some detail in a paper in 2013, at which time the cohort had 14 members, and recently reported to now number 20 with an average time off ART of over nine years. Update 7/25/15: the status of several VISCONTI cohort participants has changed, see addendum below).
The new case was discovered as a result of an analysis of the French National Agency for AIDS Research (ANRS) pediatric cohort study, which has been following over 10,000 mother-child pairs sine 1986. A total of 100 infants were identified who had begun ART within six months of birth and, of those, 15 had interrupted treatment after an average of 33 months. Only two of the 15 showed evidence of control of viral load: one for around three years before viral load climbed above 500 copies, the other on an ongoing basis, making her the subject of further investigation.
Records showed that the mother had advanced disease at the time of birth, with a viral load of 4.63 million copies and a CD4 count of 81. The baby received six weeks of AZT monotherapy in an unsuccessful attempt to prevent infection, after which HIV viral load became detectable and rose to 2.17 million copies leading to the initiation of ART consisting of AZT, ddI, 3TC and ritonavir (the AZT was later dropped from the regimen due to side effects). Viral load was suppressed but briefly rebounded during two periods of nonadherence, to 75,190 and 97,000 copies, respectively.
In an echo of the Mississippi baby case, the child was lost to follow up between 5.8 and 6.8 years of age. On return to care, it was learned that ART had been stopped several months previously, but viral load remained below 50 copies. During continued follow up, viral load has stayed undetectable with the exception of two readings, one a little over 500 copies at age 11 and another of 48 copies at age 14 (close to the borderline of the more sensitive assay used at that time). Recently, ultrasensitive tests capable of detecting as few as 4 copies of HIV RNA per milliliter of blood have been employed, with no positive results recorded. The CD4 percentage is reportedly within the normal range for a comparable HIV-negative person. The individual is now 18.5 years old. The researchers have tested for the presence of ART in plasma samples to formally rule out any possibility of undisclosed usage, and these tests were all negative.
HIV reservoir measurements revealed that HIV DNA is present at around 125 - 316 copies per million CD4 T cells, and low levels of replication-competent virus were detected in samples of purified CD4 T cells after stimulation. HIV-specific CD8 T cells were detectable but were of a low magnitude, and no evidence of CD8 T cell-mediated suppression of HIV replication was observed in a laboratory assay. No data on HIV-specific CD4 T cell responses are available as yet—notably, a poster at IAS 2015 reported that VISCONTI cohort members have “robust” HIV-specific CD4 T cell responses, challenging the widely held view that anti-HIV immunity in these individuals is unusually weak (abstract appended below, an earlier version of the study was presented at CROI 2014)). No immune response genes known to be associated viral load control were present in the individual and they were homozygous for several HLA alleles, a phenomenon that has been associated with a greater risk of rapid progression in HIV in the absence of treatment. Analyses of inflammatory biomarkers have not been conducted yet (to the best of my knowledge, no data on inflammatory biomarkers in VISCONTI cohort members has been presented either).
As with the published paper on the VISCONTI cohort, Sáez-Cirión and colleagues were careful to use the term “virological remission” to describe the outcome in their IAS 2015 abstract describing the case. Although the distinction may seem subtle, this is not necessarily synonymous with just “remission” (the term used in most of the news reports), which is generally interpreted as meaning remission from any increased risk of disease. At the current time, it is not actually known for sure if the low levels of HIV present in these post-treatment controllers are associated with a long-term health prognosis that is similar to, better, or worse than a comparable HIV-positive individual whose virus is suppressed by ART. As covered in a recent blog post, there are some reasons to be concerned that the HIV suppression in at least some of these cases may not have equivalent health benefits to that achieved by ART.
The researchers have also stressed that post-treatment control is an extremely rare phenomenon and that ART should not be interrupted outside of clinical trials at this time. There have been many published studies of ART interruptions in children and adolescents, some including quite large numbers of participants, but examples of even short-term post-treatment control are few and far between. Examples in the scientific literature include a teenager who maintained undetectable viral load for over five years after stopping ART; however there was no documented history of high viral load prior to treatment and they were found to be heterozygous for the CCR5-Δ32 mutation. Another paper mentions one participant whose viral load stayed below 400 copies for one year after ART interruption, but no further details are provided. The majority of children in these studies experienced viral load rebound and CD4 T cell loss as a result of treatment cessation.
The new case adds to the evidence that early ART is beneficial and may, in rare instances, facilitate long-term control of viral load after treatment interruption. Ongoing and planned trials in both children and adults aim to carefully investigate the extent to which virologic remission might be achieved by this strategy. Researchers are also exploring early ART combined with additional interventions such as latency-reversing agents and immunotherapies with the aim of increasing the likelihood of virologic remission.
Addendum 7/25/15, VISCONTI cohort update: Asier Sáez-Cirión's slide presentation has now been posted on the International AIDS Society's Towards an HIV Cure Symposium website (along with the other materials from the meeting, which took place in Vancouver on July 18 & 19, immediately prior to IAS 2015). At the end, the slides include an important update on the current status of VISCONTI cohort participants. Of the 14 individuals described in the 2013 PLoS Pathogens paper, one has experienced a viral load rebound (reaching close to 100,000 copies) after six years off ART, necessitating reinstitution of treatment. Another has persistently detectable viral load (in the 100-1,000 copy range) and a declining CD4 T cell count that is now below 500 cells. A third is reported to have developed "ORL cancer" (which I believe refers to head and neck cancer), and resumed treatment. Lastly, a fourth member of the original 14 is lost to follow up, so a total of 10 continue to be followed with undetectable viral load.
The last slide of the presentation notes that six additional post-treatment controllers have been added to the VISCONTI cohort (explaining the reference to a total of 20 individuals in Sáez-Cirión's latest published review from earlier this year), but no details on their viral loads and CD4 T cell counts are provided. A graph is shown for one of the new additions who, like several of the initial cohort members, possesses the HLA B*35 allele; the viral load in this individual appears to be well-controlled off ART but the CD4 T count is below 400. Hopefully these updated findings will be fully disclosed and discussed soon.
8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015), Vancouver, Canada, July 19-22, 2015
MOAA0105LB Oral Abstract
HIV-1 virological remission for more than 11 years after interruption of early initiated antiretroviral therapy in a perinatally-infected child
P. Frange1,2,3, A. Faye4,5, V. Avettand-Fenoel1,2, E. Bellaton6, D. Deschamps7,8, M. Angin9, S. Caillat-Zucman10,11, G. Peytavin12,13, J. Le Chenadec14,15, J. Warszawski14,15, C. Rouzioux1,2, A. Saez-Cirion9, ANRS EPF-CO10 Pediatric Cohort
1Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Necker - Enfants malades, Laboratoire de Microbiologie clinique, Paris, France, 2EA7327, Université Paris Descartes, Paris, France, 3AP-HP, Hôpital Necker - Enfants malades, Unité d'Immunologie, Hématologie et Rhumatologie pédiatriques, Paris, France, 4AP-HP, Hôpital Robert Debré, Service de Pédiatrie générale, Paris, France, 5Université Paris 7 Denis Diderot, Paris, France, 6AP-HP, Hôpital Robert Debré, Service d'Hématologie pédiatrique, Paris, France, 7AP-HP, Hôpital Bichat - Claude Bernard, Laboratoire de Virologie, Paris, France, 8INSERM UMR1137 IAME Université Paris Diderot, Paris, France, 9Institut Pasteur, Unite de HIV inflammation et persistance, Paris, France, 10AP-HP, Hôpital Robert Debré, Laboratoire d'Immunologie, Paris, France, 11INSERM UMR1149, Université Paris Diderot, Paris, France, 12AP-HP, Hôpital Bichat, Laboratoire de Pharma-Toxicologie, Paris, France, 13IAME, INSERM UMR 1137, Université Paris Diderot, Paris, France, 14AP-HP, Hôpital Bicêtre, Service d'Epidémiologie et de Santé publique, Le Kremlin-Bicetre, France, 15INSERM U1018, Université Paris Sud, Le Kremlin-Bicetre, France
Background: Durable HIV-1 remission after interruption of combined antiretroviral therapy (cART) has been reported in some adults who started cART during primary HIV-1 infection. The in utero HIV-1-infected «Mississippi child», exhibited transient viral control after interrupting very early-initiated cART. However viremia rebounded 27 months later, leaving unclear the possibility of obtaining long-term post-treatment remission in vertically-infected children. Here we report the case of a perinatally-HIV-1-infected adolescent who shows unprecedented virological remission more than 11 years after cART discontinuation.
Methods: HIV-RNA and CD4+ T-cell counts have been monitored since birth. Ultrasensitive HIV-RNA, PBMC-associated HIV-DNA, flow-cytometry-assessed frequency of HIV-specific CD8+ T-cells, CD8+ T-cell mediated HIV-suppression, reactivation of the CD4+ T-cell reservoir were evaluated after 10 and 11 years of control off therapy. Plasma concentrations of antiretrovirals were determined by tandem mass spectrometry.
Results: One infant born from a woman with uncontrolled HIV-1 viremia received zidovudine-based prophylaxis during 6 weeks. HIV-RNA and DNA were not detected 3 and 14 days after birth. HIV-DNA was detected at 4 weeks of age. HIV-RNA reached a peak of 2.1x106 copies/ml at 3 months of age when cART (zidovudine, lamivudine, didanosine, ritonavir) was initiated. HIV-RNA was undetectable one month later and remained below assay-detection limits while on cART, except at 15 and 21 months of age. Between 5.8 and 6.8 years of age cART was discontinued by the family. HIV-RNA was undetectable at 6.8 years of age and cART was not resumed. HIV-RNA has remained < 50 copies/ml through 18.3 years of age, except for one blip (515 copies/ml). CD4+ T-cell counts remained stable. After 11 years of control off therapy (confirmed by undetectable plasma concentrations of antiretrovirals), HIV-RNA was below 4 copies/ml and HIV-DNA was 2.2 Log copies/106 PBMC. Low levels of HIV-RNA and p24 were detected upon activation of CD4+ T-cells with PHA. HLA genotype showed homozygosity at several loci (A*2301-;B*1503/4101;C*0210/0802;DRB1*1101-;DQB1*0602-). HIV-specific CD8+ T-cell responses and T-cell activation were very weak. HIV-1 western blot was positive with absence of antibodies against gp110 and p18.
Conclusions: This case provides first-time evidence that very long-term HIV-1 remission is possible in perinatally-infected-early-treated children, with similar characteristics as reported in adult post-treatment controllers.
TUPEA093 - Poster Exhibition
Robust HIV-specific T cells in post-treatment controllers from the VISCONTI cohort
A. Samri1, V. Avettand-Fenoel2,3, L. Hocqueloux4, C. Bacchus-Souffan5, A. Cheret6, A. Emarre7, B. Descours8, A. Saez-Cirion9, C. Rouzioux2,3, B. Autran10,11, VISCONTI Study Group
1Centre d'Immunologie et Maladies Infectieuses, UMR-S Inserm UPMCU 1135, Paris, France, 2Paris-Descartes University, Sorbonne Paris-Cité, Virology Laboratory, EA 3620, Paris, France, 3Necker Enfants-Malades Hospital, Virology Laboratory, Paris, France, 4Regional Hospital Center, Infectious and Tropical Diseases Department, Orléans, France, 5Université Pierre et Marie Curie, Sorbonne Universités, Centre d'Immunologie et Maladies Infectieuses, CIMI, UMR-S 1135, Paris, France, 6CHU Druon, Infectious Diseases Department, Tourcoing, France, 7Université Pierre et Marie Curie, Centre d'Immunologie et Maladies Infectieuses, CIMI, UMR-S 1135, Paris, France, 8Université Pierre et Marie Curie, Laboratoire Immunité et Infection UMR-S-945, Paris, France, 9Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France, 10Université Pierre et Marie Curie, Sorbonne Universités, Centre d'Immunologie et Maladies Infectieuses, CIMI, Paris, France, 11Pitié-Salpétrière, C. Foix University Hospital, AP-HP, Immunology Department, Paris, France
Background: Post-Treatment-Controllers (PTCs) represent models of functional HIV remission with an exceptional HIV control years after interruption of an early-initiated antiretroviral therapy. The enrichment in the HLA-B35 allele, associated with symptomatic primary-infection and poor prognosis, instead of the protective HLA alleles reported in Elite Controllers (ECs) questions the role mechanism of this HIV control and the role of anti-HIV T cell responses, particularly those driven by HLA-B35. We therefore compared the PTCs HIV-specific CD4 and CD8 T cells to those from continuously early-treated patients (CETs) and ECs.
Methods: We included 12 PTCs from the VISCONTI study*, half HLA-B35+, 10 CETs under a cART initiated within 10 weeks post-infection and 8 ECs from the ANRS-Co15 cohort. Multiparametric flow-cytometry assessed HIV-specific IFNg, IL2, TNFα, MIP1β or CD40L producing CD4 and CD8 T cell stimulated with HIV-p24 protein and peptides. The cell-associated HIV-DNA was measured in PBMCs and naïve and memory sorted resting CD4 T cell subsets.
Results: High frequencies of HIV-p24 specific CD4+ cellswere observed in PTCs and did not differ from the ECs or CETs ones. A third of these PTCs HIV-p24 specific CD4 cells were highly polyfunctional producing 2, 3 and 4 functions, similarly to from CETs and ECs. HLA-B35 did not influence these results. In contrast frequencies of PTCs CD8+ cells producing against HIV-p24 peptides IFNg (p=0.015) or MIP1b (p=0.001) were lower than ECs but equivalent to CETs ones, without differences in poly-functionality between the 3 groups. Among the functions tested here-in there were 20-fold less IFN-g producing HLA-B35+ CD8 T cells than HLA-B35- ones (0.006% versus 0.130%, p=0.041) against HIV-p24 peptides.
Conclusions: The model of HIV remission represented by VISCONTI PTCs is characterized by robust polyfunctional HIV-specific CD4+ T cells similar to those from Elite Controllers and from continuously early-treated patients, independently from the HLA-B35 allele which negatively impacts IFN-g producing CD8 T cells. These results illustrate differences between ECs and PTCs linked to HLA background and suggest early initiation of treatment allows maintenance of robust HIV-p24 specific CD4 T cells in PTCs.