Update published on the first Berlin patient

24 March 2014. Related: Basic science and immunology.

Richard Jefferys, TAG

In the late 1990s, a single case report about an individual displaying control of HIV viral load for nearly two years after interrupting antiretroviral therapy (ART) drew a huge amount of publicity, including a lengthy story in the New York Times magazine by Mark Schoofs in June of 1998. [1]

The case report was ultimately published in the New England Journal of Medicine on May 27, 1999. [2]

The man was dubbed “the Berlin patient” long before the moniker was also applied to Timothy Brown, the only adult considered cured of HIV infection. This first Berlin patient was under the care of Dr. Heiko Jessen, and he was treated with the unusual combination of ddI (Videx), indinavir (Crixivan) and the cancer drug hydroxyurea (which at the time was sometimes used both to potentiate ddI and for possible immune-modulating activity). Treatment was started during acute infection and subsequently interrupted twice for short periods before being completely discontinued. During the second interruption and after discontinuation, HIV viral load levels remained undetectable based on the assay in use, which had a cut-off of 500 copies/ml. The individual was reported to have strong HIV-specific CD4 T cell and CD8 T cell responses, suggesting cellular immunity might be responsible for the salutary outcome.

The case was influential in generating the hypothesis that treatment of acute infection followed by structured treatment interruptions might boost HIV-specific CD4 T cell and CD8 T cell responses and lead to post treatment control of HIV replication. The hypothesis was tested by the research group of Bruce Walker at Massachusetts General Hospital but ­– after early indications of promise – the hoped for result of prolonged control of HIV after ART withdrawal was not achieved. [3, 4]

Since that time, the fate of the original Berlin patient has been somewhat mysterious, with some published papers suggesting he had been lost to follow up. [5] One of the last public updates given was by Bruce Walker at the 2003 IAS conference in Paris; Walker noted he had visited Jessen en route to the meeting, and learned that the individual was maintaining good control of viral load,  but also that it had turned out that he possessed the HLA B*57 allele that is strongly associated with elite control of HIV replication in the absence of treatment.

The New England Journal of Medicine recently published a letter from Heiko Jessen, Todd Allen and Hendrik Streeck that provides an update on the case. [6]

Titled “How a Single Patient Influenced HIV Research – 15-Year Follow-up, ” it reveals that the individual has mostly maintained a low viral load off ART in the intervening years, with a mean level of 2, 812 copies and only one blip to 25, 000 copies. CD4 T cell count has remained relatively stable with a mean of 729 cells although a figure accompanying the paper indicates there have been a couple of dips below 500 (one accompanying the viral load blip some time ago, and one quite recently). The letter also notes that the individual has the HLA B*57 allele and concludes: “Although the early initiation of treatment may have long-term benefits for certain patients, a likely explanation for control of viral replication in this patient is genetic background, regardless of intervention. Thus, this case represents a cautionary tale of drawing broad conclusions from a single patient.”,

Since not every HIV positive person with the HLA B*57 allele becomes an elite controller, this conclusion is perhaps debatable, but it is impossible to know whether or not this individual would have ultimately maintained a low viral load even without the short course of ART. What is certain is that he is not cured of HIV infection. Unfortunately, there may be some confusion about this because a forthcoming book is promoting the idea that, along with Timothy Brown, the original Berlin patient is, in fact, cured. [8]

Although there is some uncertainty about the appropriate application of the term “functional cure, ” there is no definition that allows for persistently detectable HIV viral load. The commonly used terminology for cases like that of the first Berlin patient (as has been applied to members of the VISCONTI cohort) is “post treatment controller” or “virological remission.” [9]

Extended follow up will be required to define to what extent individuals in this situation are protected from disease progression.

Source TAG Basic Science Blog. Update published on the first Berlin patient.  (13 February 2014).

http://tagbasicscienceproject.typepad.com

References

1. Schoofs M. The Berlin patient. New York Times. 21 June 1998.
   http://www.nytimes.com/1998/06/21/magazine/the-berlin-patient.html?pagewanted=all
2. Lisziewicz J et al. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999; 340:1683May 27, 1999DOI: 10.1056/NEJM199905273402114.
   http://www.nejm.org/doi/full/10.1056/NEJM199905273402114
3. Resenberg E et al. Immune control of HIV-1 after early treatment of acute infection. Nature 407, 523-526 (28 September 2000) | doi:10.1038/35035103.
   http://www.nature.com/nature/journal/v407/n6803/full/407523a0.html
4. Kaufmann DE. Limited Durability of Viral Control following Treated Acute HIV Infection. PLoS Medicine. 26 October 2004. DOI: 10.1371/journal.pmed.0010036.
5. Shytaj L and Savarino A. A cure for AIDS: a matter of timing? Retrovirology 2013, 10:145.
   http://www.retrovirology.com/content/10/1/145
   http://www.retrovirology.com/content/pdf/1742-4690-10-145.pdf (PDF)
6. Walker B et al. Prospects for immunotherapy of HIV infection: lessons from acute infection. 2nd IAS Conference on HIV Pathogenesis and Treatment. Abstract 12.
   http://www.iasociety.org/Default.aspx?pageId=11&abstractId=11004
7. Jessen H et al. How a Single Patient Influenced HIV Research – 15-Year Follow-up. N Engl J Med 2014; 370:682-683February 13, 2014DOI: 10.1056/NEJMc1308413.
   http://www.nejm.org/doi/full/10.1056/NEJMc1308413
8. Holt N. Cured: How the Berlin patients defeated HIV and forever changed medical science.
   http://www.nathaliaholt.com/Book.html
9. Saéz-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 Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211.
   http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003211