The Berlin Patient

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Anonymous
Born Germany
Timothy Ray Brown
Born 1966
United States

The Berlin patient is a phrase that has been used on two distinct and unrelated occasions: in the first case, to describe a person who has exhibited prolonged "post treatment control" of HIV viral load after HIV treatments were interrupted, and in the second case to describe the one individual who is considered to have been cured of HIV infection. Both cases originated in Berlin, Germany.[1]

The first Berlin patient was described in 1998.[1] After receiving an experimental therapy, the patient, who has remained anonymous, has maintained low levels of HIV and has remained off antiretroviral therapy.[2][3]

The world-renowned "second" Berlin patient, Timothy Ray Brown, had a bone marrow transplant on February 7, 2007 to cure his leukemia, and hopefully his HIV. The results of the procedure were presented by Dr. Gero Hütter at the CROI 2008 Conference in Boston.[4] He received a stem cell transplant from a donor naturally immune to HIV and has remained off antiretroviral therapy since the first day of his stem cell transplant.[5]

Their stories were chronicled in the 2014 book, Cured: The People who Defeated HIV (2015) by Nathalia Holt.[6] However, the book is misleading because it describes the first Berlin patient as cured when that is not the case; rather, he has been able to maintain a low level of HIV viral load for many years without ongoing treatment - this does not guarantee that disease will not occur. The Visconti Cohort, a group of fourteen patients who received early therapy for the virus (described in a scientific paper published in 2013[7]), were considered to be in "long-term virological remission," meaning that they still harbor the virus within their bodies but HIV viral loads are low or undetectable despite being off antiretroviral therapy.[8] At least two Visconti cohort members have since restarted antiretroviral therapy; in one case due to increasing viral load and CD4 T cell count decline, and in another case due to a cancer diagnosis. Another cohort member is displaying clear evidence of declining CD4 T cell counts over time. This information was revealed in the last two slides of a presentation given by Asier Sáez-Cirión at the International AIDS Society's Towards an HIV Cure Symposium in 2015.[9] Timothy Ray Brown is the only individual who is considered to have a sterilizing cure, meaning there is strong evidence that he no longer harbors infectious HIV virus within his body.

Anonymous: the 1998 Berlin patient[edit]

The first Berlin patient was a German man in his mid-twenties.[3] He was a patient of Dr. Heiko Jessen in Berlin, Germany.[1][3] He was diagnosed with acute HIV infection in 1995.[1] He was prescribed an unusual combination therapy: didanosine, indinavir and hydroxyurea.[3] Hydroxyurea was the most unusual of the three, as it is a cancer drug not approved by the J.A. Food and Drug Administration (FDA) for HIV treatment.[10] The combination was part of a small trial Dr. Jessen was testing in patients during acute HIV infection.[1] After several treatment interruptions, the patient went off the prescribed therapy completely.[3] The virus became almost undetectable.[3] The patient has remained off antiretroviral therapy.[3] In 2014 a follow-up report in NEJM concludes "a likely explanation for control of viral replication in this patient is genetic background, regardless of intervention," although this point is still under debate.[2] The NEJM update reports that the individual possesses the HLA-B*57 allele which has been associated with HIV control, and a large proportion of CD8 T cell responses targeting HIV are restricted by HLA-B*57.

Timothy Ray Brown: the 2008 cured Berlin patient[edit]

The most famous Berlin patient is Timothy Ray Brown. He is originally from Seattle, Washington.[11] He was diagnosed with HIV in 1995 and began antiretroviral therapy. In 2006, Timothy was diagnosed with acute myeloid leukemia (AML). His physician, Dr. Gero Hütter, at Charité Hospital in Berlin, arranged for him to receive a hematopoietic stem cell transplant from a donor with the "delta 32" mutation on the CCR5 receptor.[12] This mutation, found at relatively high frequencies in Northern Europeans (16%), results in a mutated CCR5 protein.[13] The majority of HIV cannot enter a human cell without a functional CCR5 gene. An exception to this is a small minority of viruses that use alternate receptors, such as CXCR4 or CCR2.[14] Those individuals who are homozygous for the CCR5 mutation are resistant to HIV and rarely progress to AIDS. Timothy received two stem cell transplants from one donor homozygous for the delta32 mutation: one in 2007 and one in 2008.[12] Timothy stopped taking his antiretroviral medication on the day of his first transplant. Three months after the first stem cell transplant, levels of HIV rapidly plummeted to undetectable levels while his CD4 T cell count increased. In addition, blood and tissue samples from areas of the body where HIV is known to hide were tested. The results were published in the New England Journal of Medicine.[12] Today, Timothy still remains off antiretroviral therapy and is considered cured,[15][16][17] though some debate exists whether there is no trace of the virus in his body (a "sterilizing" cure) or whether he simply no longer needs treatment (a "functional" cure).[18]

See also[edit]

References[edit]

  1. ^ a b c d e Schoofs M (June 21, 1998). "The Berlin Patient". New York Times Magazine. 
  2. ^ a b Jessen H, Allen TM, Streeck H (February 2014). "How a single patient influenced HIV research--15-year follow-up". The New England Journal of Medicine. 370 (7): 682–3. doi:10.1056/NEJMc1308413. PMC 4264571Freely accessible. PMID 24521131. 
  3. ^ a b c d e f g Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, Siliciano R, Walker B, Lori F (May 1999). "Control of HIV despite the discontinuation of antiretroviral therapy". The New England Journal of Medicine. 340 (21): 1683–4. doi:10.1056/NEJM199905273402114. PMID 10348681. 
  4. ^ Schoofs M. "A Doctor, a Mutation and a Potential Cure for AIDS". Wall Street Journal. 
  5. ^ Cured: The People Who Defeated HIV. Penguin Publishing Group. 24 February 2015. ISBN 978-0-14-218184-3.  OCLC 937872774
  6. ^ Johnson G (May 9, 2014). "Patients and Fortitude 'Cured,' by Nathalia Holt". The New York Times. Retrieved 7 May 2018. 
  7. ^ Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. (March 2013). "Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study". PLoS Pathogens. 9 (3): e1003211. doi:10.1371/journal.ppat.1003211. PMC 3597518Freely accessible. PMID 23516360. 
  8. ^ "Making Sense of the Three Types of HIV Cure: The Berlin Patient, the Mississippi Child, and the VISCONTI Cohort". Retrieved 23 May 2015. 
  9. ^ Sáez-Cirión A (July 19, 2015). "HIV-1 virological remission for more than 12 years after interruption of early initiated antiretroviral therapy in a perinatally-infected child" (PDF). International AIDS Society's Towards an HIV Cure Symposium. 
  10. ^ Gibbs MA, Sorensen SJ (January 2000). "Hydroxyurea in the treatment of HIV-1". The Annals of Pharmacotherapy. 34 (1): 89–93. doi:10.1345/aph.19004. PMID 10669190. 
  11. ^ Doughton S (July 17, 2013). "'I don't want to be only person cured of HIV'". Seattle Times. 
  12. ^ a b c Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E (February 2009). "Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation". The New England Journal of Medicine. 360 (7): 692–8. doi:10.1056/NEJMoa0802905. PMID 19213682. 
  13. ^ Novembre J, Galvani AP, Slatkin M (November 2005). "The geographic spread of the CCR5 Delta32 HIV-resistance allele". PLoS Biology. 3 (11): e339. doi:10.1371/journal.pbio.0030339. PMC 1255740Freely accessible. PMID 16216086.  open access publication – free to read
  14. ^ Alkhatib G (March 2009). "The biology of CCR5 and CXCR4". Current Opinion in HIV and AIDS. 4 (2): 96–103. doi:10.1097/COH.0b013e328324bbec. PMC 2718543Freely accessible. PMID 19339947. 
  15. ^ Rosenberg T (May 29, 2011). "The Man Who Had HIV and Now Does Not". New York Magazine. 
  16. ^ Pollack A (November 28, 2011). "New Hope of a Cure for H.I.V." 
  17. ^ Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T (March 2011). "Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation". Blood. 117 (10): 2791–9. doi:10.1182/blood-2010-09-309591. PMID 21148083. 
  18. ^ Knox R (June 13, 2012). "Traces Of Virus In Man Cured Of HIV Trigger Scientific Debate". NPR News. Retrieved December 1, 2016.