Is it time to give up on a cure for HIV?

If Hannah Gay had wanted to be a world-famous scientist, she would probably not have chosen to make a career at the Blair E Batson Hospital for Children in Jackson, Mississippi, but with her desire to help the underprivileged sick, underpinned by a strong Christian faith, that is where she was working in the summer of 2010. It says much about the many problems that HIV (or human immunodeficiency virus) has caused researchers over some decades that a single decision taken by Gay when confronted with a possibly infected newborn baby propelled her into a limelight she had never sought. For 27 months, she was the HIV paediatrician who might have stumbled across the cure for Aids (acquired immune deficiency syndrome—the disease caused by HIV).

Gay, an associate professor of paediatrics and an HIV specialist at the University of Mississippi Medical Center, of which Batson is part, was called to see a baby brought in from a rural hospital because the mother had tested positive for HIV in labour. It is not a situation that so often occurs anymore in the United States or Europe. If antenatal tests pick up the virus, a pregnant woman is put on drugs that suppress it to very low levels in her blood, safeguarding the baby from infection at birth. Relatively few babies are now born with HIV in affluent countries. But this mother had not attended an antenatal clinic. She did not know she had HIV.

It can take weeks or months of testing and re-testing to confirm that a baby has the virus. Knowing early treatment is best, Gay decided not to wait. Within 30 hours of her birth, the Mississippi baby, as she became known, was on not one or two antiretroviral drugs, as would be more usual in these circumstances, but the full three-drug cocktail. And so she would have remained, had not mother and child disappeared, 18 months later.

When they made contact with the hospital again, after a five-month absence, tests showed no trace of the virus. When the news got out, the HIV research world erupted. Could this be the longed-for cure? In 2013, Gay, with two other women scientists who co-authored a paper on the case, was named one of Time magazine’s 100 most influential people in the world.

But on 10th July, after more than two years without drug treatment, it was announced by the US National Institutes of Health that the tests carried out on the child every six or eight weeks showed the virus had finally rebounded. It was less than a fortnight before the start of the International Aids Conference in Melbourne, Australia. The hope and excitement generated by the Mississippi baby case evaporated, to be replaced by real disappointment, albeit stoically expressed.

Yet no scientist who has worked on HIV would be entirely surprised at the turn of events. The virus is one of the most formidable foes researchers have ever encountered. Whenever HIV has apparently been eradicated from a patient, it has turned out that it was only hiding somewhere where the tests we have at the moment cannot find it.

It was 33 years ago that doctors in the US began to see unexpected clusters of fatal illness in gay men. In New York, the killer was a cancer called Karposi’s sarcoma. In Los Angeles, victims succumbed to a rare form of pneumonia. Before long, scientists realised that these were infections picked up by people whose immune systems had been damaged by a virus—but checking its spread still defeats them. There are now around 35m people living with HIV globally, with the largest concentrations in sub-Saharan Africa. Although the numbers of new infections are dropping, there were more than two million in 2012 and, in spite of growing access to treatment which keeps the virus at a harmlessly low level in the blood, more than 1.5m deaths. Increasingly, as drug therapy reaches the better-off, Aids is becoming a condition seen in marginalised communities that are harder to reach, from the drug users of eastern Europe to gay men in countries that oppose homosexuality, and sex workers everywhere. In the US, there are 1.1m people with HIV and nearly 50,000 new infections every year, most commonly in impoverished black communities. In the UK, although less than 100,000 people have HIV, the infection rate is rising, particularly among gay and bisexual men. Drug treatment has bought time, but with the costs and the continuing spread of HIV, a cure for Aids is badly needed.

The scientific community insists that it is unbowed by the latest setback. The glass is half-full. Hannah Gay may not get a Nobel Prize, but she has made a great contribution to the pool of knowledge about HIV. The Mississippi baby was off drugs and had an undetectable virus for 27 months, which is longer than has ever been achieved before. The child, now four, is still of enormous interest to researchers, who want to know whether it was the early initiation of treatment, the particular drug cocktail, something about the baby’s genetic make-up or a combination of all of those things that gave her such a lengthy remission.

There is just one man who appears to have beaten HIV. Timothy Ray Brown, the so-called “Berlin patient” after the city where he was treated, had two bone marrow stem cell transplants in 2007 and 2008 for acute myeloid leukaemia. His consultant managed to find a donor who had genetic resistance to HIV. The levels of virus in Brown’s blood dropped as the resistant stem cells replaced his own and replicated. Brown has now been free of HIV for six years.

But it appears his experience will probably be unique. A stem cell transplant can never be done lightly. It carries serious risks. The biggest achievement—and a very considerable one—of HIV research has been to develop the antiretroviral drugs that suppress the virus in the body to the point where people can live normal, healthy lives. It would be ethically questionable to attempt a stem cell transplant in somebody for treatable HIV. Two other men with HIV have undergone the operations for cancer. There were high hopes for the “Boston patients” as they are known, but as with the Mississippi baby, they were dashed and relatively quickly. The Boston pair did not have a donor with genetic resistance to HIV and the virus returned, in one case within 12 weeks and in the other within 32 weeks of stopping medication.

What scientists take from the Boston and Mississippi patients is that although it is possible to knock out HIV, the victory is only temporary. The tests they currently have to detect it are not good enough. The truth is that the virus never went away.

“The data is confirming that the assays we have in hand are not sufficient to detect latently infected cells in different compartments of the body,” says Françoise Barré-Sinoussi, a virologist and Director of the Regulation of Retroviral Infections Division at the Institut Pasteur in Paris. Barré-Sinoussi won the Nobel Prize in physiology or medicine in 2008 with Luc Montagnier for the discovery that the human immunodeficiency virus caused Aids.

Better tests are now one of the major research priorities. HIV invades the CD4 cells, part of the immune system, and appears to linger there in a dormant form even when drugs have suppressed its malign activity. The body’s defensive T-cells, which fight infection, do not recognise it in its inactive state. Several groups of scientists in a number of countries are now focused on finding the latent HIV virus and “waking it up” with drugs. In a two-stage strategy that has been dubbed “kick and kill,” they hope to prompt the immune system to recognise the virus and attack it. At first, it was thought that just flushing out the virus would be enough to set the immune system to work killing infected cells, but studies in 2012 suggested that did not happen.

In Melbourne in July, a group of Danish scientists from Aarhus University was the latest to report success in shaking HIV out of its latent state, using an anti-cancer drug called romidepsin. In a tiny pilot trial, five out of six patients with previously undetectable HIV had measurable amounts of virus in their blood after taking the drug, but the group could not show any evidence that infected cells had been killed off as a result. “The immune system’s reaction to the exposed HIV-infected cells may not itself be strong enough to clear the cells from the body. But the mechanism to activate and expose the virus may potentially one day be part of a combination of drugs which together can eradicate HIV infection,” said Ole Schmeltz Søgaard, the senior researcher.

Scientists are now looking to boost the immune system with a therapeutic vaccine, designed to help it home in on HIV. A team at Imperial College London is preparing for a trial they hope will start next year, using an anti-cancer drug to wake up the dormant HIV followed by a therapeutic vaccine developed at Oxford University. Five British universities are involved; there is a high degree of collaboration among researchers across the world, who understand that no single team is going to defeat HIV alone.

Talk of a “cure” for HIV, in the light of recent developments, appears hugely optimistic. Yet the word was used by the International Aids Society, the professional body of HIV scientists which runs conferences every two years, to headline a new strategy in 2011.  Barré-Sinoussi, then IAS president, fought against it. “I did not want to call it ‘cure,’” she said. “I said no way. So they said OK, but we have to use the word ‘cure.’ After a lot of discussion, we called it ‘Towards an HIV Cure.’” The HIV field is unusual in that scientists, social scientists, activists and patients work very closely together and are all heavily involved in political campaigning. At a time when the interest in HIV/Aids of politicians and donors appeared to be in danger of waning, as drugs were distributed in sub-Saharan Africa and the death toll dropped, and when other global health issues such as the deaths of newborns and women in pregnancy were starting to take precedence at United Nations meetings, it was clearly savvy to set a cure as the goal.

Even in 2011, many scientists were explaining that they meant a “functional cure,” rather than what most people understand by the word. Remission is the real aim. Scientific ambition has been tempered by knowledge hard-won over the last decades. Researchers want to fight HIV to a standstill. Many think it is the best result they can hope for.

Drug treatment has shown that HIV can be held at bay. Early drug treatment, as soon as possible after infection, looks very promising. It is not just the Mississippi baby case that suggests so. There is also the Visconti cohort, a group of people in France who started on drug therapy within 10 weeks of their infection with HIV, which is unusually early. Most people have no symptoms for months or even years. These patients agreed to stop the drugs after an average of three years. The virus is still there, but the levels are not increasing and the patients are fine.

“There are 20 patients now. For some of them it is 10 years ago that they went off treatment and they are still controlling it [the virus] really well,” said Barré-Sinoussi, who calls them “very interesting patients.” They are not people with genetic resistance to HIV—the so-called “elite controllers.” Indeed, they got early treatment because the virus hit them exceptionally hard when they became infected, depleting their immune systems, so they became ill and were picked up by doctors. Nobody knows if this is a permanent state of affairs, but they provide some of the best evidence that a “functional cure” may be possible. Data from these and others like the Mississippi baby and Boston patients “clearly indicates we should be able to induce what we call permanent remission of treatment,” said Barré-Sinoussi.

Steven Deeks, professor of medicine at the University of California, San Francisco, has been involved in HIV research since 1993 and is another lead player in the IAS’s Towards a Cure initiative. He also has an upbeat take on things. “There have been a number of recent setbacks with the Boston cases and the baby in Mississippi which are disappointing but, to be honest, are scientifically fascinating because they really point out what the bar is going to be for a cure,” he said. “It will only take one virus sitting in one cell living in some part of the body that can rest there for years to start the whole process, to ignite the fire. So as we move forward and try to come up with curative interventions we have to do two things: one, we have to get rid of as much of the virus as we can; and two, we have to have a way to clean up what little virus is left, which is where the vaccine work comes into play.”

Classical vaccines, like those against measles, teach the immune system to recognise the virus and keep it out. But therapeutic vaccines are used to help the immune systems of people who already have a virus to recognise the enemy within and fight it. In the early years of HIV research, there were bold pronouncements about the imminence of a preventive vaccine. In 1984, when the virus was identified, Margaret Heckler, Ronald Reagan’s head of health and human services, predicted a vaccine within two years. Others later said it would take 10. Thirty years and many candidate vaccines on, we are nowhere near. One large trial in humans in Thailand came up with a modest benefit, but it was not enough for scientists to want to take it any further.

More recently, it has been back to animal studies. Last September, scientists from the Oregon Health and Science University said they had managed to protect nine out of 16 rhesus monkeys from infection with a vaccine against simian immunodeficiency virus—their version of HIV. The vaccinated monkeys became infected when exposed to the virus, but scientists said it was completely cleared from the animals’ bodies over time. That is promising, but still a million miles from an immunisation programme for humans. It is still not possible to be sure that hidden virus does not linger on. SIV is not exactly the same as HIV. Other primate studies have also shown good results. We have been here before.

But the vaccine work is now taking on a new relevance. The Imperial College study will use a vaccine originally designed to prevent infection. It did not stop the entry of HIV into human cells, but it may be able coach the immune system to recognise and fight a virus that is already there. “Cure has been all about getting rid of the virus and vaccine has been all about making the immune system strong enough to prevent infection,” said Deeks. “But it’s quite clear that the work in the vaccine world which is all about enhancing the capacity of the immune system to control virus, will have huge implications for the cure.”

HIV research has been littered with dashed hopes and heroic failures. In spite of many attempts, there has yet to be a successful microbicide—a virus-killing cream or gel that women in low-income countries could use to protect themselves during sex with HIV-infected men. Other preventive measures may help certain at-risk groups, but not everyone. They include circumcision and the use of antiretroviral drugs as prophylactics. Research has shown the drugs are protective against infection, but only the really determined are going to want to take medication with side effects every day and the cost means this may only be an option in richer countries anyway.

Given that treatment—the real success story—keeps people alive and well, working and bringing up their families, there could be an argument for investing most of the money and effort in just that. HIV infection becomes a chronic but not so troublesome disease. Deaths drop. But the truth is that this virus will not be so easily contained. People with HIV in the UK or US go through one cocktail of drugs after another. The virus mutates, first-line drugs and then second-line and third-line and fourth-line no longer work. The pharmaceutical companies are developing new versions all the time, and they are exorbitantly expensive. Those new drugs are unaffordable in Africa. Donor nations, all experiencing economic malaise, will not foot the bill if resistance in low-income countries eventually follows the pattern in the west. There is a real need for a preventive vaccine or a cure, functional or otherwise. And that, in spite of setbacks, is what drives the researchers on.