HIV-AIDS in retreat
Meera Senthilingam reports on a groundbreaking medical trial in South Africa.
Lush green farmland stretches as far as the eye can see – sugar cane, citrus trees, pecans. Welcome to Zululand in the KwaZulu-Natal province of South Africa. It may be a pastoral idyll but it has also provided fertile ground for the world’s deadliest viral infection.
In the nearby town of Pongola the peace is shattered by the motorway that bisects the town. It’s a hub for safari tourists and migrant workers alike. Frequent signposts along the motorway direct international travellers to game reserves and country lodges. The same motorway also sees hundreds of trucks arrive and depart each day carrying the local produce. The truck drivers are far from home and in search of comfort.
This migration of young men goes some way to explaining why KwaZulu-Natal boasts one of the world’s highest HIV infection rates – at 37% it is twice the national average. And it’s not only the men who are affected. In South Africa HIV affects men, women and children. Young women bear the greatest burden; their infection rate is more than three times that of young men – 13% compared to 4%.
The epidemic is spreading like wildfire and part of the reason lies in this tranquil rural setting. Peer beyond the postcard and it means poverty, poor literacy, gender inequality, alcoholism and parents forced to live away from home to find work.
That’s the reason the region has been chosen as the testing ground for a radical trial to end the spread of HIV.
"Central and east Africa was where the virus first started to propagate - but now southern Africa is by far the worst affected region in the whole world," explains the quietly spoken Richard Hayes, an epidemiologist at the London School of Hygiene and Tropical Medicine.
Since the first reports of acquired immune deficiency syndrome (AIDS) surfaced in the 1980s, Hayes has occupied a front-row seat watching the epidemic spread across the world.
“Treatment as prevention is a pretty new idea in terms of HIV control.”
Until now, the main message sent out to badly affected African populations has been “condom, condom, condom”. The message has certainly been heard. Even in remote settlements hidden within the rolling hills of Zululand, residents of solitary huts will tell you they should “condomise”. Of course, they don’t always follow this advice. HIV remains rampant.
So Hayes is leading a trial to test an approach that would have been unthinkable a few years before: treat all HIV-infected people with antiretroviral drugs. “Treatment as prevention is a pretty new idea in terms of HIV control,” says Hayes, who is leading the trial. Known as “PopART” – Population effects of Antiretroviral therapy to Reduce HIV Transmission – the study is the largest of its kind.
“We hope this will lead to a steep reduction in the number of new HIV infections,” he says. It will involve up to 1.2 million people spread across 21 communities in two countries, South Africa and Zambia. The trial, started in 2013 and expected to run until 2019, is co-funded by groups including the US President’s Emergency Plan for AIDS Relief and the Gates Foundation.
HIV-positive people are generally quite healthy for the first few years after infection even without drugs. The primary goal of PopART is not to improve their health – it is to stop them spreading the virus. This is a radical departure from the way these drugs have generally been used.
When antiretrovirals were first rolled out in southern Africa they were expensive. In some people they produced severe side effects including pancreatitis and kidney disease. So they were only prescribed to people who had been infected for several years, when the virus had decimated their immune system and they were on the threshold of developing AIDS.
The immune cells most affected by the HIV virus are CD4 T cells. At first treatment was given only when the CD4 cell count had fallen below 200 cells per millilitre of blood; the normal level is 500 to 1,500 cells per millilitre. As new, less toxic drugs were developed, the recommended threshold for beginning treatment was raised to 350 cells per millilitre.
It also helped that the drugs became cheaper. Today, 60% of those in need receive antiretrovirals. The 2013 UNAIDS report says South Africa has set an example by successfully negotiating with pharmaceutical companies to buy these drugs at the lowest prices in the world – $113 per person per year – allowing many more people to access treatment.
Despite this great step forward, interventions to stop the spread of HIV continue to fail. Too few men wear condoms. And although billions have been spent on research, a vaccine has proved elusive. According to UNAIDS (the joint United Nations program on HIV/AIDS), 2013 saw 1.5 million new HIV infections in sub-Saharan Africa alone.
In 2008 World Health Organisation modellers came up with a different strategy: using anti-retrovirals to prevent the spread of HIV. Their model, published in the journal The Lancet, showed that an untreated person infects about seven others before they die. A person treated when their CD4 count was down to 350 infects three others. But if they were treated immediately after they are infected, the infection rate would be reduced to less than one and the epidemic would die out in 14 years.
It took a real-life study to finally galvanise the international community. In 2011 Mike Cohen’s team at the University of North Carolina recruited 1,763 mostly heterosexual couples where only one partner was HIV-positive. The infected partner began taking antiretrovirals immediately. The incidence of transmitting HIV to the uninfected partner was slashed by 96%, as long as the drugs were taken as prescribed.
The finding was so staggering the trial was terminated early for the results to be made public as soon as possible.
HIV researchers glimpsed the potential to bring the epidemic to its knees. The idea of treating every patient as soon as they were infected was hatched, which also meant expanding HIV testing. “Our mathematical models show we could achieve reductions of 60% in the rate of new infections,” says Hayes. This steep decline is predicted to take only three years – the duration of the PopART trial.
Of course finding funding to treat all the infected people in South Africa is a tall order. More than six million South Africans are living with HIV, and the numbers are rising fast: the country had 340,000 new infections in 2013. But not treating them is more costly in the long term if it allows the virus to spread.
Mathematical models, such as the one developed independently by Jan Hontelez from Erasmus University Medical Centre in the Netherlands, supported the idea that the investment would bring many benefits. His model incorporated the complexities of the South African epidemic including multiple sexual partners, the blood levels of the virus at different stages of infection and the impact of other sexually transmitted diseases. For instance, people infected with genital herpes have open sores that increase the risk of HIV transmission.
Hontelez published his results in the journal PLoS Medicine in late 2013. His most comprehensive model predicted that introducing universal testing and treatment could virtually eliminate HIV in South Africa in the next 17 years. Combining universal testing of HIV with the current HIV guidelines to begin patients on antiretrovirals once they reached a certain CD4 count could also eliminate the disease, but would take an extra decade.
The winning strategy hinges on two crucial factors: that people would willingly have regular check-ups of their HIV status and that, if infected, they would regularly take their medication, even if they felt healthy.
“HIV is difficult because it’s about sex and sexuality.”
And there lies the wild card. Human nature is unpredictable. Even in the US, it’s estimated that only 14% of those infected with HIV know their status: people are not inclined to have regular blood tests. And would those who have tested positive and agreed to go on treatment actually take their drugs regularly? Unprompted by any sign of their illness, their motivation could easily wane. Hayes acknowledges this is a “real concern”. Many critics doubt whether universal testing and treatment would work.
“I’m not as optimistic as the modellers,” says Peter Piot, director of the London School of Hygiene and Tropical Medicine and founding executive director of UNAIDS. Piot co-discovered the Ebola virus and has no doubt as to which disease presents the greater challenge. “HIV is difficult because it’s about sex and sexuality. You don’t fix that with a few drugs,” he says.
Would the millions of dollars it would take to treat healthy people bring the hoped-for dividend? Or could there be unintended negative consequences? Possibly, if people didn’t take the drugs regularly. Incomplete treatment could lead to a false sense of security: people might pass on the infection believing they were no longer infectious and virus levels would climb.
Irregular drug taking is also a recipe for breeding viruses that are resistant to the drugs. “We will be keeping an eye on resistance”, says Hayes. It could be the end of the epidemic or it could be a costly gamble that could make the situation worse. In the view of the PopART funders the upside was worth giving the trial a try.
“It is an enormous study!” exclaims Nulda Beyers, the primary investigator of the trial in South Africa. Her vivacious character and passion for her research are evident as we walk through the Desmond Tutu TB centre at Stellenbosch University, where she is director. Beyers says she is “not entirely convinced” that using treatment as prevention will “be the answer”.
“Theoretically it should work, but we just don’t know what’s going to happen … this trial will give an indication which package of interventions does work.”
Twenty-one communities are participating in the trial, which will explore three separate strategies.
One is the status quo. Here a person is only eligible for treatment once their CD4 cell count plummets below 350 cells per millilitre. In this group people are encouraged to know their HIV status and are regularly given advice to use condoms.
The second group also restricts treatment to people with a CD4 count below 350. But it deploys the full gamut of preventive public health measures. Dedicated teams of health workers go door-to-door offering in-home HIV testing and counselling and suggesting measures to reduce the risk of transmission – including a limitless supply of condoms.
Circumcision is recommended for men (a 2006 trial in young African men found the procedure reduced their risk of contracting HIV by up to 60%). Pregnant and breastfeeding women are counselled to be tested so they can be treated to avoid passing the virus to their baby. The early use of antiretrovirals cuts that risk to less than 1%. Where necessary health workers also refer patients to clinics that treat other sexually transmitted diseases.
The third strategy provides all the above. But in addition, once a person has tested positive they are immediately put on to antiretrovirals regardless of their CD4 count. They’re then linked to local health services should they need further assistance or care.
The teams involved in the study are now one year into the trial. Community HIV workers have reached more than 85% of households in South Africa and more than 95% in Zambia.
So far the trial has posed many challenges for the health workers going door-to-door. The aim is to reach everyone in the population, “but not everyone is always home, men are often out”, says Hayes. So the teams are now seeking out men in the places where they tend to congregate – typically bars, sporting facilities and the community taxi rank.
A further logistical challenge is providing patients with timely treatment once they have been tested. So far it’s taking longer than the three months anticipated. “They are still at risk of transmitting infection,” says Hayes. Such transmission will affect the results of the trial. “We need to try harder to speed that up.”
But the villagers themselves have been willing. Hayes’ teams have reported that people are more willing to change their behaviour when personal contact is made. “We’re getting a good uptake of services.”
People will be sampled randomly from all 21 communities and tested over the three-year trial. A total of 52,500 people will be tested annually.
The first test took place in April 2015. The percentage of new HIV infections is being compared between communities to see which of the interventions has worked best compared to baseline measures from one year ago.
The challenge will be to find and follow up those tested each year. “We will have to work hard to get them back,” says Hayes. The team is expecting to lose up to 25% of the sample being tested over the three years of the trial as people migrate and move on. “That’s about normal.”
“There is a sense of triumph, commitment
and vindication that you are on the last gasp on the journey to ending AIDS.”
Some results should emerge this year. The hope is that the encouraging trend that is at last emerging in this epidemic will accelerate. In 2013 in sub-Saharan Africa 1.5 million new infections recorded. It was a staggeringly high figure – but it represented a 33% decline in the rate of infections since 2005.
After more than 20 years and 39 million deaths, the end to the raging epidemic may be in sight at last.
“There is a great sense of triumph, commitment and vindication that you are on the last gasp on the journey to ending AIDS,” said activist and musician Bob Geldof at last year’s AIDS conference in Melbourne. “The scandal underlying all of this is the preposterous reluctance to fund the last mile.”
Extraordinary as it may sound, many now believe the end of HIV is possible as long as funding can be found to treat all of those infected now. It will be up to PopART to show the world the path by which to end AIDS.