A disease in remission? New hope in the quest to cure HIV
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For 10 years Timothy Ray Brown was a lone living legend among Aids activists. The “Berlin patient”, as he is generally called, was the only person known to have had HIV, the virus responsible for the disease, cleared permanently from his body.
This week Mr Brown was joined — at least provisionally — by a second man, the anonymous “London patient”. He has been free of HIV infection for 18 months after undergoing a bone-marrow transplant from a donor with a genetic mutation that makes him resistant to the virus.
A scientific team from several UK universities reported details of the case at the Conference on Retroviruses and Opportunistic Infections in Seattle, describing it as “long-term remission”, although they added that “it is too early to say with certainty that he has been cured of HIV.”
Even a decade ago, there would have been a flurry of excitement about the announcement of a potential cure for a disease that is normally present for life — and which once inspired unique fear because of the death toll it left behind, among largely gay communities in western countries and across big swaths of sub-Saharan Africa.
The disease remains a potent threat. According to the most recent figures from UNAids, 36.9m people worldwide were living with HIV in 2017; 1.8m were newly infected with the virus and almost 1m died of Aids-related illnesses.
Yet the relatively muted response to this week’s news about the London patient speaks volumes about the course of the disease over the past decade — both false dawns about potential cures but also spectacular successes in treating HIV. Once considered a death sentence, the reality is that most patients with access to Aids drugs are now able to live almost symptom-free.
“Yes there are people seeking a cure but we have to do this in a responsible scientific manner — and not rush out to give people false hope, as some journalists have done,” says Carl Dieffenbach, director of the Aids division of the US National Institute of Allergy and Infectious Diseases. “The [London patient] is important but not the game-changer.”
Although the news about the London patient has raised hopes about the potential for a cure, experts have been careful to give several reasons for caution. One is that drastic radiotherapy or chemotherapy is required to wipe out the patient’s own immune system, killing all white blood cells, before rebuilding it with transplants from a donor with a rare protein variant called CCR5. HIV uses CCR5 as a gateway into cells, which is closed in a small minority of people who are naturally resistant to Aids.
The procedure has been carried out only on people with HIV who need bone marrow transplants because they are suffering from cancer (leukaemia in the Berlin patient and Hodgkin’s lymphoma in the London patient), and the proportion of successful outcomes is low.
“There are two people now who appear to be in virological remission,” says Dr Dieffenbach. “As far as we can tell the number in whom this procedure has been attempted is in the order of 20 or more.”
The Berlin patient does appear to be permanently rid of HIV, but it is too soon to be certain about his London counterpart. Aids researchers remember past cases in which cures were claimed but turned out not to be durable. Celebrated disappointments include two “Boston patients” and the “Mississippi baby”, in whom infection returned after apparently disappearing for long periods.
At the same time, some of the urgency that once surrounded the search for a cure for Aids has been muted by striking achievements in treating the disease. Clinicians point to the remarkable success of antiretroviral therapy, or ART — conventional drugs taken by mouth once a day — in suppressing HIV to levels that are undetectable by normal clinical testing and have no effect on the patient’s health.
According to UNAids, 21.7m people worldwide receive ART. The global market for HIV medicines is worth about $28bn a year; Gilead Sciences of the US has the largest share, followed by GlaxoSmithKline of the UK. The medicines are so safe and effective that increasing numbers of people who are at high risk of HIV exposure but not infected are taking them, a procedure known as pre-exposure prophylaxis, or PrEP.
“An HIV vaccine is still a long way away and cure strategies are pretty brutal at the moment, yet antiretroviral therapy today allows you to live a normal, healthy life,” says Chloe Orkin, an Aids specialist at Queen Mary University of London.
Prof Orkin and Susan Swindells of the University of Nebraska Medical Centre presented two clinical studies on Thursday at the Seattle conference, showing that a long-acting antiviral injection once a month suppresses HIV as effectively as daily tablets.
The trials compared an injectable combination of two drugs — developed by ViiV Healthcare, GSK’s HIV division, with Johnson & Johnson of the US — with a standard daily oral treatment combining three different drugs. A vast majority of participants preferred monthly injections to daily tablets.
“The positive safety and efficacy results reinforce the potential of [this] first long-acting, injectable option for people living with HIV,” says Prof Swindells. “This novel approach may help alleviate the burden often associated with daily oral treatment regimens and contribute to making HIV a smaller part of peoples’ lives.”
Following the success of the trials, Viiv expects to apply for regulatory approval to market the monthly injectable combination this year. A further clinical study is evaluating a longer-acting version of the therapy injected every two months.
“In terms of treatment, HIV is easier to control than diabetes,” says Prof Orkin, who chairs the British HIV Association. She makes the further point that more than 98 per cent of people on antiretroviral therapy have no detectable virus in their blood — and “evidence over the past few years makes it absolutely clear that a person with sustained, undetectable levels of HIV in their blood cannot transmit HIV to their sexual partners”. Hence a slogan heard increasingly in the Aids field: U=U, meaning undetectable equals untransmittable.
Making antiretroviral therapy available to everyone who needs it is therefore a worldwide public health priority. Aids campaigners at the Seattle conference were encouraged to hear the results of a study covering a million people in South Africa and Zambia — the world’s most extensive HIV prevention trial — which showed a 30 per cent decline in new infections through a combination of counselling, testing and then referral to care and treatment for those who were HIV-positive.
“This important study clearly demonstrates the critical impact of community-based HIV prevention, testing and linkage to treatment,” says Michel Sidibé, executive director of UNAids. “It reinforces UNAids’ call for more community healthcare workers across Africa and the need for increased investment in HIV prevention and treatment, including new and better tools and systems to deliver them.”
Even so, the excitement felt by many people about this week’s news of the London patient reflects a yearning for a cure that would reliably eradicate HIV from its hiding places deep inside the immune system and avoid the need for life-long medication, whether taken as pills or injections.
The London team accepts that the complexity of its procedure and the toxicity of chemotherapy mean that it cannot become a standard HIV treatment. But it offers hope for developing simpler and gentler strategies that might eliminate HIV by targeting the CCR5 “receptor” on which the virus depends.
“Continuing our research, we need to understand if we could knock out this receptor in people with HIV, which may be possible with gene therapy,” says Ravindra Gupta, a professor at University College London, the project leader.
Coincidentally the HIV-resistant CCR5 mutation introduced to the London patient through his bone marrow transplant is the same one targeted by He Jiankui, the controversial Chinese scientist who made the world’s first genetically modified babies last year. Dr He drew worldwide condemnation on ethical and safety grounds when he revealed the birth of twins whose CCR5 genes had been altered with the editing technique known as Crispr.
No one is suggesting that HIV-proofing of future generations justifies the risky and unethical procedure carried out by Dr He, but research is already under way to investigate the potential of Crispr as gene therapy for Aids.
For instance, the Seattle conference heard about studies on monkeys where scientists are investigating Crispr to edit HIV genes out of infected cells. Dr Dieffenbach calls it “the first really profound experiment that has been reported using Crispr” in Aids research.
“The group at Temple University [in Philadelphia] put a Crispr system into non-human primates . . . and it was surprisingly effective,” he says. “That gives us hope that down the road Crispr could be used in people in a similar way but, again, it’s early days.”
Even those who are preoccupied with more immediate issues such as HIV testing and access to medicines in the developing world are fascinated by the scientific promise.
“To find a cure for HIV is the ultimate dream,” says Dr Sidibé. “Although the [London patient] breakthrough is complicated and much more work is needed, it gives us great hope that we could potentially end Aids with science, through a vaccine or a cure.”
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