Baby with HIV functionally cured - Dhondy/CA/Texy etc. care to shed more light

[The Outsider]

http://www.nytimes.com/2013/03/04/health/for-first-time-baby-cured-of-hiv-doctors-say.html?_r=0 Basically, a higher dose of the anti virus very early on followed by an accidental stopping of the anti viral shots resulted in this. So, how significant is this? Do we understand the mechanics behind why all this happened? Is it any use for other cases in babies or adults?

Doctors announced on Sunday that a baby had been cured of an H.I.V. infection for the first time, a startling development that could change how infected newborns are treated and sharply reduce the number of children living with the virus that causes AIDS. The baby, born in rural Mississippi, was treated aggressively with antiretroviral drugs starting around 30 hours after birth, something that is not usually done. If further study shows this works in other babies, it will almost certainly be recommended globally. The United Nations estimates that 330,000 babies were newly infected in 2011, the most recent year for which there is data, and that more than three million children globally are living with H.I.V. If the report is confirmed, the child born in Mississippi would be only the second well-documented case of a cure in the world. That could give a lift to research aimed at a cure, something that only a few years ago was thought to be virtually impossible, though some experts said the findings in the baby would probably not be relevant to adults. The first person cured was Timothy Brown, known as the Berlin patient, a middle-aged man with leukemia who received a bone-marrow transplant from a donor genetically resistant to H.I.V. infection. ŧor pediatrics, this is our Timothy Brown, said Dr. Deborah Persaud, associate professor at the Johns Hopkins ChildrenÃÔ Center and lead author of the report on the baby. ŪtÃÔ proof of principle that we can cure H.I.V. infection if we can replicate this case. Dr. Persaud and other researchers spoke in advance of a presentation of the findings on Monday at the Conference on Retroviruses and Opportunistic Infections in Atlanta. The results have not yet been published in a peer-reviewed medical journal. Some outside experts, who have not yet heard all the details, said they needed convincing that the baby had truly been infected. If not, this would be a case of prevention, something already done for babies born to infected mothers. ŵhe one uncertainty is really definitive evidence that the child was indeed infected, said Dr. Daniel R. Kuritzkes, chief of infectious diseases at Brigham and WomenÃÔ Hospital in Boston. Dr. Persaud and some other outside scientists said they were certain the baby whose name and gender were not disclosed had been infected. There were five positive tests in the babyÃÔ first month of life four for viral RNA and one for DNA. And once the treatment started, the virus levels in the babyÃÔ blood declined in the pattern characteristic of infected patients. Dr. Persaud said there was also little doubt that the child experienced what she called a ÅÇunctional cure. Now 2 1/2, the child has been off drugs for a year with no sign of functioning virus. The mother arrived at a rural hospital in the fall of 2010 already in labor and gave birth prematurely. She had not seen a doctor during the pregnancy and did not know she had H.I.V. When a test showed the mother might be infected, the hospital transferred the baby to the University of Mississippi Medical Center, where it arrived at about 30 hours old. Dr. Hannah B. Gay, an associate professor of pediatrics, ordered two blood draws an hour apart to test for the presence of the virus RNA and DNA. The tests found a level of virus at about 20,000 copies per milliliter, fairly low for a baby. But since tests so early in life were positive, it suggests the infection occurred in the womb rather than during delivery, Dr. Gay said. Typically a newborn with an infected mother would be given one or two drugs as a prophylactic measure. But Dr. Gay said that based on her experience, she almost immediately used a three-drug regimen aimed at treatment, not prophylaxis, not even waiting for the test results confirming infection. Virus levels rapidly declined with treatment and were undetectable by the time the baby was a month old. That remained the case until the baby was 18 months old, after which the mother stopped coming to the hospital and stopped giving the drugs. When the mother and child returned five months later, Dr. Gay expected to see high viral loads in the baby. But the tests were negative. Suspecting a laboratory error, she ordered more tests. ŵo my greater surprise, all of these came back negative, Dr. Gay said. Dr. Gay contacted Dr. Katherine Luzuriaga, an immunologist at the University of Massachusetts, who was working with Dr. Persaud and others on a project to document possible pediatric cures. The researchers, sponsored by amfAR, the Foundation for AIDS Research, put the baby through a battery of sophisticated tests. They found tiny amounts of some viral genetic material but no virus able to replicate, even lying dormant in so-called reservoirs in the body. There have been scattered cases reported in the past, including one in The New England Journal of Medicine in 1995, of babies clearing the virus, even without treatment. Those reports were greeted skeptically, particularly since testing methods were not very sophisticated back then. But those reports and this new one could suggest there is something different about babies immune systems, said Dr. Joseph McCune of the University of California, San Francisco. One hypothesis is that the drugs killed off the virus before it could establish a hidden reservoir in the baby. One reason people cannot be cured now is that the virus hides in a dormant state, out of reach of existing drugs. When drug therapy is stopped, the virus can emerge from hiding. ŵhat goes along with the concept that, if you treat before the virus has had an opportunity to establish a large reservoir and before it can destroy the immune system, thereÃÔ a chance you can withdraw therapy and have no virus, said Dr. Anthony S. Fauci, the director of the National Institute for Allergy and Infectious Diseases. Adults, however, typically do not know they are infected right as it happens, he said. Dr. Steven Deeks, professor of medicine at the University of California, San Francisco, said if the reservoir never established itself, then he would not call it a true cure, though this was somewhat a matter of semantics. Ÿas there enough time for a latent reservoir, the true barrier to cure, to establish itself? he said. Still, he and others said, the results could lead to a new protocol for quickly testing and treating infants. In the United States, transmission from mother to child is rare several experts said there are only about 200 cases a year or even fewer because infected mothers are generally treated during their pregnancies. If the mother has been treated during pregnancy, babies are typically given six weeks of prophylactic treatment with one drug, AZT, while being tested for infection. In cases like the Mississippi one, where the mother was not treated during pregnancy, standards have been changing, but typically two drugs are used. But women in many developing countries are less likely to be treated during pregnancy. And in South Africa and other African countries that lack sophisticated testing, babies born to infected mothers are often not tested until after six weeks, said Dr. Yvonne Bryson, chief of global pediatric infectious disease at the University of California, Los Angeles. Dr. Bryson, who was not involved in the Mississippi work, said she was certain the baby had been infected and called the finding ÅÐne of the most exciting things IÃ×e heard in a long time. Studies are being planned to see if early testing and aggressive treatment can work for other babies. While the bone marrow transplant that cured Mr. Brown is an arduous and life-threatening procedure, the Mississippi treatment is not and could become a new standard of care. While it might be difficult for some poorer countries to do, treating for only a year or two would be cost effective, ÅÔparing the kid a lifetime of antiretroviral therapy, said Rowena Johnston, director of research at amfAR.

[Stuge]

WOW

[Brainfade]

While this is a very significant step, it doesn't appear that it is a game-changer for adult anti-HIV therapy. The key is to hit the virus before it can establish reservoirs, which appears to have happened in this case. A second big question is - can poor African countries afford to provide this intensive treatment for their newborns? And even if they did, would their babies be provided the kind of care and monitoring that this child received in the US when s/he was on an ARV/HAART regimen? Finally, I think a person has to be virus-free for 5 years before being declared "cured." Let's fervently hope for it to be the case with this baby and others who may receive such treatment! The Timothy Brown (aka the Berlin patient) case that they mention as the first case of "cured" HIV, may be a bigger deal for adult treatments. In brief, an HIV-infected leukemia patient received a full immune-system makeover in Germany and has been virus-free for nearly 5 years. Here is a Science podcast about the case. http://www.sciencemag.org/content/332/6031/865.2.full

[The Outsider]

Thanks for that Cricaddict. Sorry, I haven't been able to get the time to listen to the podcast till now, but is the Timothy Brown case the same one who received a bone marrow transplant from someone who is genetically immune to HIV? If that's the case won't it's potential impact on treatment be very limited given that there are going to be such few cases where you can make such a transplant? Or has the case any more fundamental implications which can be replicated in the general population? Also, regarding this particular case how sure are doctors and scientists that a similar treatment of an aggressive dose early on followed by a complete withdrawal is going to work on other babies? That's something I haven't found addressed in the articles I read.

[Brainfade]

Thanks for that Cricaddict. Sorry, I haven't been able to get the time to listen to the podcast till now, but is the Timothy Brown case the same one who received a bone marrow transplant from someone who is genetically immune to HIV? If that's the case won't it's potential impact on treatment be very limited given that there are going to be such few cases where you can make such a transplant? Or has the case any more fundamental implications which can be replicated in the general population? Also, regarding this particular case how sure are doctors and scientists that a similar treatment of an aggressive dose early on followed by a complete withdrawal is going to work on other babies? That's something I haven't found addressed in the articles I read.

Let me answer the 2nd question first. I don't think anyone is sure that the strategy will always work. It is, after all, an n = 1. But it is infinitely better than n = 0! In Brown's case, the German doctor did a transplant with bone marrow cells that lack an important receptor to which HIV attaches. Finding a marrow match is rare enough, but finding one that matches *and* has that beneficial mutation was indeed a miracle of sorts. However, it has provided a proof-of-concept. Now, imagine this: we can isolate autologous stem cells (e.g., your own bone marrow), induce a specific, targeted, beneficial mutation in them, zap the existing bone marrow in your body, and replace it with the newly created marrow cells - which will keep the virus at bay. Am getting goosebumps just typing this!

[Texy]

There have been several other cases of infants clearing HIV infections without the use of highly active antiretroviral therapy. If the antiretrovial therapy can help this process, it will be a change to the way we treat infants with HIV, but has no congruity to adults. Usually Lopinavir and Ritonavir are not given to premature babies. Also this is more of a functional "cure." It just means they can't find it. What I find unprecedented about this is that the child is suppressing to a sub-detectable level. Hope no viral DNA survived.

[The Outsider]

Let me answer the 2nd question first. I don't think anyone is sure that the strategy will always work. It is, after all, an n = 1. But it is infinitely better than n = 0!

That's true. However, my question was how should I put it "more fundamental". In the sense that do scientists and doctors understand why such a treatment worked from a fundamental level or is it still something that can be attributed to "chance". I am using words in a very lose manner here, but hope I am able to convey my point.

In Brown's case, the German doctor did a transplant with bone marrow cells that lack an important receptor to which HIV attaches. Finding a marrow match is rare enough, but finding one that matches *and* has that beneficial mutation was indeed a miracle of sorts. However, it has provided a proof-of-concept. Now, imagine this: we can isolate autologous stem cells (e.g., your own bone marrow), induce a specific, targeted, beneficial mutation in them, zap the existing bone marrow in your body, and replace it with the newly created marrow cells - which will keep the virus at bay. Am getting goosebumps just typing this!

These kind of things sound just so incredible and out of the realm of someone like me. The kind of process you've described in your last paragraph look so immensely complicated that even the design and implementation of something like the LHC, which I consider to be an engineering marvel, pale in complexity. Apologies to bug you with more questions, but can you give some layman reference to how the stem cells are isolated and then reintroduced in the body through the bone marrow? Or maybe, write a paragraph or two about it when you have the time. I imagine it would be incredibly difficult to ascertain that something introduced in the bone marrow will necessarily multiply and take over the functions.

There have been several other cases of infants clearing HIV infections without the use of highly active antiretroviral therapy. If the antiretrovial therapy can help this process, it will be a change to the way we treat infants with HIV, but has no congruity to adults. Usually Lopinavir and Ritonavir are not given to premature babies. Also this is more of a functional "cure." It just means they can't find it. What I find unprecedented about this is that the child is suppressing to a sub-detectable level. Hope no viral DNA survived.

Texy, can you refer me to the other cases you talked about. Do we understand why and how infants have been cleared of HIV in those scenarios? Regarding the bold part I heard on NPR yesterday that they have found traces of the virus in the child but are confident that it has lost it's structure to replicate and grow.

[punjabi_khota]

Let me answer the 2nd question first. I don't think anyone is sure that the strategy will always work. It is' date=' after all, an [b']n = 1. But it is infinitely better than n = 0!

btw, 0! is equal to 1. I am not sure I see your point. :hysterical: :P

[Brainfade]

btw' date=' 0! is equal to 1. I am not sure I see your point. :hysterical: :P[/quote'] Ha ... I see what you did there :-). OK, n = 1 is infinitely better than n = 0 followed by (Exclamation mark)! Ab khush ho, Bhaisaab?

[Number]

offtopic : is Dhondy(lives in London I guess) related to Farrukh Dhondy ?

[The Outsider]

offtopic : is Dhondy(lives in London I guess) related to Farrukh Dhondy ?

No, Dhondy is just his pen (forum) name.

[Brainfade]

http://www.newscientist.com/article/dn23276-more-hiv-cured-first-a-baby-now-14-adults.html

Two weeks after the revelation that a baby has been "cured" of HIV, reports suggest that a similar treatment can cure some adults too. Early treatment seems crucial, but does not guarantee success. Asier Sáez-Cirión of the Pasteur Institute's unit for regulation of retroviral infections in Paris analysed 70 people with HIV who had been treated with antiretroviral drugs (ARVs) between 35 days and 10 weeks after infection – much sooner than people are normally treated. All of the participants' drug regimes had been interrupted for one reason or another. For example, some people had made a personal choice to stop taking the drugs, others had been part of a trial of different drug protocols. Most of the 70 people relapsed when their treatment was interrupted, with the virus rebounding rapidly to pre-treatment levels. But 14 of them – four women and 10 men – were able to stay off of ARVs without relapsing, having taken the drugs for an average of three years. The 14 adults still have traces of HIV in their blood, but at such low levels that their body can naturally keep it in check without drugs. Drugless years On average, the 14 adults have been off medication for seven years. One has gone 10-and-a-half years without drugs. "It's not eradication, but they can clearly live without pills for a very long period of time," says Sáez-Cirión. Last week, a baby was reported to have been "functionally cured" of HIV after receiving a three-drug regime of ARVs almost immediately after birth. Sáez-Cirión warns that rapid treatment doesn't work for everyone, but the new study reinforces the conclusion that early intervention is important. "There are three benefits to early treatment," says Sáez-Cirión. "It limits the reservoir of HIV that can persist, limits the diversity of the virus and preserves the immune response to the virus that keeps it in check." Further analysis confirmed that the 14 adults were not "super-controllers" – the 1 per cent of the population that are naturally resistant to HIV – since they lack the necessary protective genes. Also, natural controllers rapidly suppress their infections, whereas these 14 mostly had severe symptoms which led to their early treatment. "Paradoxically, doing badly helped them do better later," says Sáez-Cirión. Rapid response The researchers are trying to identify additional factors that could explain why early intervention only works on some people, hopefully extending the scope for more functional cures. "This whole area is fascinating, and we've been looking very closely at issues of early initiation of treatment, and the potential for functional cures," says Andrew Ball, senior adviser on HIV/AIDS strategy at the World Health Organization in Geneva. "The big challenge is identifying people very early in their infection," says Ball, adding that many people resist testing because of the stigma and potential discrimination. "There's a good rationale for being tested early, and the latest results may give some encouragement to do that," he says. Journal reference: PLoS Pathogens, DOI: 10.1371/journal.ppat.1003211

[ganeshran]

Also this is more of a functional "cure." It just means they can't find it. What I find unprecedented about this is that the child is suppressing to a sub-detectable level. Hope no viral DNA survived.

though it's beside the point, isnt HIV a retrovirus so it doesnt have DNA :hmmmm:

[Texy]

though it's beside the point' date=' isnt HIV a retrovirus so it doesnt have DNA :hmmmm:[/quote'] The virus replicates by using reverse transcriptase, a molecule that converts RNA into DNA, and integrates DNA into a genome using another molecule called integrase. HIV virus has some RNA in its capsid that gets converted into DNA in the host, and then integrated into the host's genome using those two molecules. Once it's in the genome, it's impossible to tell what DNA is viral and what is host. I have to look up those cases but yes there are several documented ones. Treatment can suppress the virus for a long time, but treatment itself cannot cure virus...it's always there, dormant or not....hiding in your T cells.

[ganeshran]

This looks like a chance discovery to be honest. Now the problem with replicating this in the lab is that a group of babies would have to be given therapeutic doses of ART (currently they get preventive doses of the drug) to prevent vertical transmission of HIV. And then we are going to have to willingly stop the therapy to test if the HIV goes below detectable levels. That is an ethical problem. Can we actually put a human baby's life in danger to test out this scenario? In this case the woman stopped the treatment of the baby for around 7 months because of some unspecified personal problem, but to do this knowingly presents an ethical conundrum. In case of normal patients (one where the infection has already taken hold), such a stoppage is potentially lethal because the viral levels usually rise exponentially.

[ganeshran]

The virus replicates by using reverse transcriptase, a molecule that converts RNA into DNA, and integrates DNA into a genome using another molecule called integrase. HIV virus has some RNA in its capsid that gets converted into DNA in the host, and then integrated into the host's genome using those two molecules. Once it's in the genome, it's impossible to tell what DNA is viral and what is host.

Doesn't the DNA have an in-built proof reading mechanism? I remember studying that after replication, an enzyme goes through each strand to make sure the right amino acids were coded and fixes in case anything went wrong. Or are these Viral DNA strands not attached to the host DNA and replicate independently of the host?