New case of remission in a perinatally infected teenager

1 August 2015. Related: Conference reports, Cure-related research, IAS 8th Vancouver 2015.

Richard Jefferys, TAG

A new example of long-term post-treatment control of HIV viral load was reported on the second day of the IAS 2015 conference in Vancouver, attracting widespread media attention. [1]

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. Sáez-Cirión is also the lead investigator for the well publicised 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 [2], and recently reported to now number 20 with an average time off ART of over nine years). [3]

The new case was discovered as a result of an analysis of the French National Agency for AIDS Research (ANRS) paediatric 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/mL, 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 4.6 million copies and a CD4 count of 81 cells/mm3. 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 2.1 million copies/mL 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/mL, 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/mL. During continued follow up, viral load has stayed undetectable with the exception of two readings, one a little over 500 copies/mL at age 11 and another of 48 copies/mL 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/mL 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 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 at low levels, 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 [4], challenging the widely held view that anti-HIV immunity in these individuals is unusually weak. An earlier version of the study was presented at CROI 2014. [5]

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. [6]

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 “virologic 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. [7]

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 [8]; however there was no documented history of high viral load prior to treatment and they were found to be heterozygous for the CCR5-delta-32 mutation.

Another paper mentions a participant whose viral load stayed below 400 copies/mL 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. [9]

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 (25 July 2015): 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 18-19 July, immediately before IAS 2015). [10]

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 [2], 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 to 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” (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. [12]

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 cells/mm3. Hopefully these updated findings will be fully disclosed and discussed soon.

References:

1. Frange P et al. HIV-1 virological remission for more than 11 years after interruption of early initiated antiretroviral therapy in a perinatally-infected child. 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015), 19 – 22 July 2015. Oral abstract MOAA0105LB.
2. Sáez-Cirión A et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathogens, 14 March 2013. DOI: 10.1371/journal.ppat.1003211.
   http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003211
3. Rouzioux C et al. Post treatment controllers: what do they tell us? Current Opinion in HIV & AIDS: January 2015 – Volume 10 – Issue 1 – p 29-34 doi: 10.1097/COH.0000000000000123.
   http://journals.lww.com/co-hivandaids/toc/2015/01000
4. Samri A et al. Robust HIV-specific T cells in post-treatment controllers from the VISCONTI cohort. 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015), 19 – 22 July 2015. Poster abstract TUPEA093.
5. Samri A et al. Characterisation of functional profile of HIV-specific CD4+ T cells in VISCONTI group of patients. CROI 2014, 3 – 6 March 2014, Boston. Poster abstract 302.
   http://www.croiconference.org/sessions/characterization-functional-profile-hiv-specific-cd4-t-cells-visconti-group-patients
6. Carrington M et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 12 March 1999: 283(5408): 1748-1752. DOI: 10.1126/science.283.5408.1748.
   http://www.sciencemag.org/content/283/5408/1748.abstract
7. Jefferys R. Perspectives on post-treatment control of HIV. TAG basic science blog. (22 May 2015).
   http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2015/05/perspectives-on-post-treatment-control-of-hiv.html
8. Feeney ME et al. Absence of detectable viremia in a perinatally HIV-1-infected teenager after discontinuation of antiretroviral therapy. Jour Allergy and Clin Immun, August 2006: 118(2); 324-330.
   http://www.jacionline.org/article/S0091-6749(06)01191-2/fulltext
9. Saitoh A et al. Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection. Pediatrics March 2008; 121:3 e513-e521.
   http://pediatrics.aappublications.org/content/121/3/e513.long
10. IAS Towards and HIV Cure workshop.
    http://www.iasociety.org/What-we-do/Towards-an-HIV-Cure/Events/2015-Symposium
11. Rouzioux C et al. Post Treatment Controllers: what do they tell us? Current Opinion in HIV & AIDS: January 2015 – Volume 10 – Issue 1 – p 29-34 doi: 10.1097/COH.0000000000000123
    http://journals.lww.com/co-hivandaids/Abstract/2015/01000/Posttreatment_controllers___what_do_they_tell_us_.6.aspx