What is the state of play as the world returns to Durban 16 years after the historic 2000 AIDS conference? It is simple: less than half of people who need HIV treatment have access to it.
Around 17 million people living with HIV are receiving antiretroviral therapy, 20 million are not. We now know that 20 million people are at increased risk of developing tuberculosis and cancers – even if some of them still have high CD4 counts. We also know that providing those 20 million people with treatment will help prevent many new HIV infections.
It is clear what we need to do – we need to make sure an additional 20 million people have access to treatment. On this score most of the researchers, doctors, diplomats, policy-makers and activists gathering in Durban will agree. We have all the slogans and all the right rhetoric. We all agree that 90-90-90 is the way to go.
But 20 million? Twenty million when all we’ve achieved so far is 17 million – and that 17 million only through years of struggle, sweat and tears, with years of donor assistance, and unprecedented political will. Is it not madness to think we can get another 20 million on treatment? Is a reality check overdue?
If we are ever to get near an additional 20 million, then Durban has to be a turning point. It has to be the moment where we once again get serious about the HIV epidemic.
What should we be getting serious about? Firstly, we must get serious about where we will find the healthcare workers to support an extra 20 million people on treatment. Secondly, we have to stop pretending we can end AIDS without dealing with the widespread dysfunction in our healthcare systems. Thirdly, we have to get serious about how we are going to produce and pay for the medicines needed to treat an extra 20 million people. Lastly, we need detailed, fully funded plans that will make treatment for all a reality.
Getting serious also means an unwavering commitment to the evidence in all aspects of our AIDS response. It means being guided by the scientific evidence rather than by what sounds good or by what “sells on the hill”. It means never again wasting money in the way money was wasted on, for example, abstinence-only programmes. It means standing up to the moral Mother Grundys and providing young people with proper sex education and access to condoms. It means asking “Why are we so quick to stigmatise ‘sugar daddies’? but so slow to ensure young people have easy access to condoms?”
Getting serious means addressing the political obstacles to fixing our healthcare systems. It means dealing with corruption, mismanagement and patronage in our healthcare systems. It means not turning a blind eye when healthcare systems are wrecked by people who are politically well-connected – as is happening in the Free State province here in South Africa. It also means acknowledging that while PEPFAR giveth, the United States Trade Representative taketh away – the latter by bullying poor countries into trade deals that compromise access to medicines.
Getting serious also means not tiptoeing around cruel and inhumane legislation such as the anti-gay laws in place in many countries. At a conference like the International AIDS Conference IAC, we must say loudly and clearly that what countries like Nigeria and Uganda are doing is unacceptable and an affront to our common humanity.
Getting serious means an end to empty rhetoric and spin. It means that UNAIDS must stop talking about an end to AIDS while there are 20 million people who still need treatment. We cannot spread complacency just because we want to tell a positive story. Our lives are not an advertising campaign.
At this point in the AIDS response, complacency is our greatest enemy.
Even though a staggering 20 million people still need treatment, we have allowed the spotlight to shift. We have allowed the world to think AIDS is no longer a crisis. To the extent that we have allowed this to happen, we have betrayed the 20 million people needing treatment today. We have no choice. We are morally obliged to change this in Durban.
Getting an extra 20 million people on treatment will not be easy. If we are serious about things like 90-90-90 then we are going to have to rock the boat. I know that most of us want to be polite and not offend anyone. But our moral obligation is not to ourselves, or our own comfort, but to the 20 million people who still need treatment. We have to say to the governments of high burden countries: “You have to invest more. You have to do better.” We have to say to rich countries that they have a moral responsibility to the people still dying of AIDS and their families. And if governments don’t do their part we must name and shame them and stop the quiet diplomacy.
We don’t have to go hat-in-hand to Geneva or New York. We don’t have to accept ‘no’ for an answer. If a house is burning with people inside, then we help. That is what it means to be human.
If we are truly serious about things like 90-90-90, then we have to once again turn our crisis into a crisis for our political leaders. Together we must demand that HIV and TB is on the top of the agenda when the G7 or G20 meet. We must demand that more money is invested in TB research. We must say ‘no’ to a world where the United States government spends US$600-billion a year on its military, but the entire world can only find US$700-million per year for TB research.
We have the moral authority to demand a second wave in the AIDS response. We have no choice but to use it.
Welcome to Durban 2016, let’s roll up our sleeves and get serious. We have 20 million more people to treat.
Anele Yawa is the General Secretary of the Treatment Action Campaign.
It is strange to think of the progress we have made as a country since 2004, when the South African antiretroviral (ARV) programme rollout was started.
The success of the programme has been beyond some of our wildest dreams. A situation, where almost half a million people were dying every year, has been transformed. Over three million people are on safe treatment, life expectancy is up across the country (life expectancy is normal for people starting ARVs with CD4 counts above 350), and mother-to-child transmission has plummeted. The steps to accomplish this have been astounding, when you think about it – rolling out HIV testing, getting people ‘’staged’’ with CD4 counts, transitioning them to adherence interventions to get them started on ARVs, and keeping them in care, while reliably supplying the drugs and laboratory monitoring services.
The government has received much applause, both locally and internationally, for sustained political and financial support to the HIV programme since 2008, making it one of the few non-donor dependent programmes in Africa. The UNAIDS 90-90-90 targets have been embraced by the Department of Health as aspirational targets, and seem tantalisingly close. Data from the Africa Centre shows clear correlation with ARV coverage, and a decrease in new HIV infections. For the first time in decades, we have seen a decrease in TB numbers, almost certainly due to increased coverage of ARVs. All this, in a health system that can charitably be called less than optimal.
There are brave government officials who stood up during the denialist Mbeki administration period, who fought hard for a scientific approach, where cabinet did little to challenge their irrational President and his obdurate Minister of Health. Many of these same officials stayed on, and have supported the Zuma administration and current Health Minister Aaron Motsoeledi in giving us the world’s largest ARV programme. There are many unsung heroes in the struggle against AIDS denialism, and hopefully one day their story will be told.
However, to quote an old revolutionary: “Tell no lies…. Claim no easy victories”. We face huge challenges with sustaining the HIV response in South Africa, and we should not kid ourselves that the road to getting on top of the epidemic is even half-done. The rhetoric of agencies, suggesting the end of AIDS is around the corner, is grossly premature and very dangerous.
Two critical and vastly different factors have played a part in making our HIV response so effective:
Unprecedented community and civil society mobilisation. Led by the TAC, and quietly supported by many in government, the clashes with the state and the pharmaceutical industry kept the fight for better treatment front and centre of the AIDS response since 2000. Aided by researchers, clinicians, donors and a critical media, apathy on the part of the public was transformed into outrage at government’s initial denialism and subsequent anaemic support under Mbeki. Less acknowledged was the huge amount of community treatment literacy that was undertaken by civil society that prepared patients at a local and clinic level for taking treatment.
Resilience of ARVs. The spectre of mass ARV resistance and poor adherence never materialised. While ARV resistance is devastating at an individual level, and there may be a signal that certain drug classes now may have slightly reduced efficacy, the doomsayers have been proved wrong. Even the older regimens, associated with substantial irreversible toxicity, had people taking their treatment for years, a testament to the power of the medication and community support. Twelve years in, only a small percentage of people are on second and third line regimens.
These two factors allow us to look to the signals of where the HIV programme has challenges, and how we may start addressing these practically.
The UNAIDS 90-90-90 targets (ensure that 90% know their HIV status, 90% get ARVs and 90% are virally suppressed) provide a useful way to view these challenges. Here are a few of the major issues we need to address and some potential solutions, in no particular order, which may need to be tested by the current and next NSP.
While HIV testing is reaching a substantial number of people, the 90% knowing they are positive target is the biggest gap in the UNAIDS targets, and the NSP target of testing everyone annually will never be a reality with current testing models. Testing remains stuck in overloaded state facilities or in bureaucratic systems in the private sector.
New testing strategies have not been evident since the dawn of rapid testing over a decade ago, other than the Minister’s major push to test 15 million in 2010. There are lessons in this push, which got huge numbers of people tested and contributed to a surge of people accessing treatment (and a welcome rise in the average CD4 count at ARV initiation). The surge was largely driven by civil society, commercial pharmacies and donor programmes, often supported with the Department of Health (DoH) test kits; facility testing in traditional DoH clinics did not rise substantially.
It is probably not realistic to expect much more at traditional health facilities. Short of a major restructure and improved management of health staff, coupled with more resources, the burden of testing on these facilities will be significant.
Get everyone else involved in testing
The target setting in 2010 focused many minds outside of traditional facilities. It seems possible to set the first 90 as a target outside of clinics and hospitals – a similar campaign, but one that does not focus on the DoH clinics, but rather on workplaces, churches, schools, unions, sports clubs and others. There is nothing stopping the Minister from issuing this challenge, and insisting that the country’s sectors cooperate. How each sector gets people tested (in a way that respects human rights and legal requirements), and links them to care, could rest with the respective sector. A good start would be directing this challenge at the country’s biggest employer, the government. The Minister, as well as his officials have long and justifiably complained that other departments and parliament mouth rhetoric around HIV with no substance, leaving it a DoH issue. Imagine the Departments of Basic and Higher Education having to ensure all their teachers and students are tested, or the Department of Labour working with unions to get their members through the HIV pre and post-test counselling process, with DoH providing test kits.
Expand community and self-testing
There are some innovative testing models out there to be tried. Initial enthusiasm has been for community home testing, and this has been effective in finding undiagnosed HIV. However, subsequent waves of home testing by MSF in Africa, have demonstrated very low subsequent case finding, suggesting that these interventions are probably worth doing as a once off, but subsequent waves can be delayed. Self-testing is an innovative approach that has been shown to be safe and acceptable in several environments, including in a large study in Malawi. The World Health Organisation (WHO) is currently developing guidelines on self-testing, with several products on their way to commercial market. This may assist a lot in getting routine testing away from facilities, allowing pressured healthcare staff to play a role in confirming the diagnosis and starting ART, rather than testing healthy negatives.
Fix HIV testing quality assurance problems
Finally, an unpleasant elephant in the room is what WHO terms ‘’misdiagnosis’’, where incorrect HIV results are given to patients, undermining both testing and treatment programmes. While some high-profile cases have been due to the tests themselves, it is clear that most problems are seen with the health workers performing the test. The full extent of the problem is not known, although a simple enzyme-linked immunosorbent assay (ELISA) screening of new CD4 counts received by the National Health Laboratory Systems (NHLS) would solve the problem in a flash. Quality assurance programmes are needed at a facility level, to identify problem staff practices, with training and monitoring interventions triggered as needed. Again, this could be delegated to the NHLS as the monitor, if resourced adequately.
The budget for the HIV response is huge in absolute terms. While certainly appropriate considering the burden of disease, and the effectiveness of ARVs, the fact that the National Treasury largely finances the programme makes it vulnerable to economic downturns, currency fluctuations and political distractions, means that trying to find cost savings is important. The national ARV bill will be over R10 billion by 2018; removing CD4 counts as an initiation criteria and testing everyone will drive it higher.
Get new drugs to decrease costs
Thankfully, new drugs that are safer, cheaper, and more robust are in the offing, and will hopefully substantially reduce the drug bill, while limiting transition to second and subsequent line therapy. With the right studies, these may be available by 2019 in the South African state sector.
But don’t forget the kids…
These new drugs are being tested on children, and harmonisation with adult regimens guards them from stock outs. The paediatricians need to ask what evidence will ensure maximum harmonisation with adult regimens, and what research needs to be done to give firm recommendations.
Missing in action 1: Men
If the treatment programme is disaggregated by 90-90-90 gender data, South African women are pretty much there, due partly to high testing rates in PMTCT programmes, and familiarity with clinics through contraception and childcare. Men, however, are under-tested and access ART far less than women. UNAIDS released data showing that South Africa has the worst gender imbalance in terms of access to ART in the world. Men present later and at a lower CD4 count, with poorer outcomes, and have poorer adherence in some studies. The rhetoric around young women’s vulnerability to HIV (which is real) obscures the fact that male lifetime risk of HIV approximates women’s – it just occurs over a longer life period. Unfortunately, precious little creative thought is apparent around improving male access to care.
Get to the workplace and get creative
Some quick wins seem possible – as male representation in the workplace far exceeds women’s, this is an easy place to start, perhaps with the HIV testing programmes discussed above. In addition, expanding clinic times to accommodate working people seems sensible. However, this does not reach unemployed men, a huge number of people. Self-testing has been shown to be very acceptable to men, but finding acceptable and validated tests will probably only occur next year, and may take time to enter the state sector. New and creative ways to access men are desperately needed, if any of the 90s are to be attained.
Linkage to care
The previous NSP called for the implementation of a single-patient identifier (SPI) for health databases, a concept ratified by the national DoH using the national ID number, but very poorly implemented so far. The previous call was on the back of multiple concerns about poor monitoring and evaluation of the programme, and the unknown number of people ‘’lost’’ to the programme (either through default, death or simply getting their treatment elsewhere). Interpretation of data is therefore almost completely speculative – terms like ‘’lost-to-follow-up”, which often come with implicit stigmatising judgements on patients in systems, are probably more accurately titled ‘’lost from our (very poor) systems of monitoring”. Commonly cited numbers like 30% lost at two years from programmes, seem implausible looking at the remarkable increase in life expectancy. While some patients indeed may fall off the system and die, it seems more likely that most simply migrate between clinics that have non-existent referral systems.
Decree the SPI
As a single, decisive implementation priority, it is hard to see one with more profound implications than the single-patient identifier. It already exists in the private sector through pharmacies, where medical aid information is pooled. Some provinces have resisted the call for a single identifier, citing confidentiality issues or the fact that a small number of people don’t have ID books. While these concerns are real, they are easily remedied with international standards around accessing relatively confidential data, and ensuring a ‘’plan B’’ is available for people without ID numbers that allows testing. There is huge loss in terms of programme monitoring, as well as individual patient harm where referral is not done and health care workers have to guess at optimal treatments, harms patients every day. Starting with the NHLS, a national directive that all laboratory tests have to have to be submitted with the ID number should be implemented, with a national programme telling facility health staff that a date has been set, and specimens will be discarded without the number. This is already done for some facilities, for other information like health worker contact details, so there is precedent. Facilities then should transfer their file numbering system to one using the single patient identifier, with future promise that some of these records will make their way to an electronic centralised system that is centrally accessible. Until this is done, arguing about the extent of linkage to care problems and possible solutions seems pointless.
Support the NHLS
South Africans may not appreciate what a huge resource a National Health Laboratory Service is (there are few of them anywhere in the world), and how it may assist us in understanding health issues way beyond just HIV. However, the poor support, especially from provinces, that the NHLS has had over the last few years, has severely undermined it. Brave people still work there, and we need it to function efficiently and cost effectively, to get HIV and broader health programmes the lab support they need.
SMS (or WhatsApp) the nation
Innovative cell-phone based approaches also look promising in linking patients to care, but implementation at a mass scale has yet to be implemented. In other fields, such as Home Affairs, there is constant information fed to the public after applications for documents like passports or ID books. Everyone is reminded about their dentist, their car service, or their unpaid Metro bills and traffic fines, and there seems no reason this couldn’t be extended to the public health system to alert patients to appointments, drug shortages, or changing clinic times.
It is hard not to be cynical about support to community organisations. Governments, donors and agencies trumpet at almost every opportunity about how important civil society and community organisations. However, when expenditure is analysed, precious little trickles down to these organisations. As an example, the TAC almost had to close its doors, due to lack of funding, and still battles to find adequate financial support. Communities are tasked with all manner of support to HIV programmes, from education on adherence to palliative care, almost all of it unpaid. Reports of government funding ‘’sweetheart’’ organisations that do not rock the boat or who are unaccountable, abound. Donors who have supported programmes that publicly criticise or embarrass government, often with good cause, have been berated at times by politicians and officials.
Set targets for budget allocations
Treatment literacy and community support are acknowledged to be important. In the same way as many budgets have ‘’X percent’’ allocated to issues such as HIV prevention, a percentage should be allocated for civil society and community support, and monitored as a performance indicator. Those funded should be held to reporting standards seen with other organisations, to ensure accountability.
Novel models of care
MSF have revolutionised delivery of drugs, with their (inadvertently misleadingly-titled) ‘’adherence clubs’’, centralised dispensing points for chronic medications with a strong focus on HIV. However, scale-up of this model has remained challenging, and provincial level buy-in is very variable. In addition, the national DoH have been experimenting with home delivery of chronic medications, although uptake is apparently slow. In Gauteng, vending machines are available on a pilot basis in a limited number of facilities, through a donor programme. The DoH has signalled the urgent need for ‘’decanting’’ of patients out of busy facilities.
Get innovative chronic disease dispensing to scale
It is heartening to see these new approaches, that both try to decongest facilities, as well as make access more convenient to patients. However, they need to go to scale, as only a small minority of the population currently enjoy access to these new models of care.
Don’t discount verticalised services
These are loathed by many health managers, who prefer the simplicity one-size-fits-all model of primary care. Unfortunately, it seems that for certain marginalised or smaller groups, this may be the most effective way to address health needs, especially HIV care. Experience with groups like MSM, sex workers and adolescents, as well as pregnant women, suggest that tailored approaches work, and future priority groups like transgender populations are likely to need them too.
Civil society, in partnership with government, has been conducting a regular drug stock-out survey, in conjunction with a problem solving aspect, where reports of stock-outs are rapidly escalated and resolved, often within hours. Despite a rocky start to the relationship, the programme has yielded much information and fruitful collaboration, and two critical lessons:
Fixed-dose combination tablets very rarely stock out
This was seen across the country, where stock-outs of adult first-line ARVs and TB treatment, both fixed-dose combination, were almost non-existent. Other drugs regularly stocked out, and despite (often heroic) problem solving by health care staff to get these medications, stock-outs of ARVs in alternative regimens and for children were common. This needs careful consideration by guideline committees, when considering regimens, especially for children, where alignment with the adult FDC would protect them from individual stock-outs.
Call centres work
Having a call centre that knows who to look up with information, and rapidly resolve issues, is feasible on a tight budget and a small number of staff. The ability of staff to resolve facility-level stock-outs (national DoH has made substantial progress with depot-level shortages) is remarkable. It does suggest that perhaps testing this with other facility headaches – staffing, waiting times, other stock problems – is an interesting and constructive model for improving staff and patient lives.
It’s difficult to overstate the catastrophe that remains South Africa’s biggest killer. Despite some evidence of decreased new cases, the numbers remain staggering, with an additional burden of multi-drug resistant TB (MDR-TB), and nowhere near the resources to control either. MDR-TB has a higher mortality than Ebola, but the amount of programmatic and political attention pales against a disease not seen in South Africa since 1995, but which commands resources and focus across the country. In the diagnosis and treatment of TB, South Africa leads the world in many aspects. The introduction of the new diagnostic, the GeneXpert in 2012 was an ambitious undertaking but its early trials showed that the GeneXpert did not result in a reduction of mortality from TB. This suggests health-systems weaknesses. While South Africa is leading the world in the implementation of new drugs for the treatment of MDR-TB, including bedaquiline, the implementation of decentralised care with adequate M&E for MDR-TB is patchy in many areas. The solution lies somewhere between using the latest advances in technology with improvement in the basic principles of TB control: find, test and cure.
Give TB more budget and proper support
While there is evidence of some movement in the TB world, partly on the back of the Minister’s own “TB 90-90-90”, the TB department needs the sort of energy, creativity and, most importantly, budget that HIV world has enjoyed for over a decade.
Deal with facility infection control
Worrying studies recently have shown health care workers at very high risk of TB, as well as data suggesting many MDR infections happen in hospitals and clinics. The lack of South African Medical Association (SAMA) and nursing union outrage at what is clearly an occupational disaster, is disturbing. Facility rebuilding is expensive, but needs to be adequately planned for. In the meantime, the various interventions around administrative and personal protections around TB really need more priority.
Get us better drugs and diagnostics
We are seeing the first hint of this, and the research community needs to get fully behind these studies, while demanding the resources to execute them quickly.
Missing in action 2: Young women, men who have sex with men (MSM) and sex workers
Politicians don’t like talking about sex. It’s a vote killer, especially in a conservative country such as South Africa. Unfortunately, young women remain at catastrophic risk of HIV, for reasons we don’t understand, but are likely to be a complex intersection of behaviour, social ills like gender-based violence, and biology. Interventions that work (condoms, proper sex education that includes access to contraception, and pre-exposure prophylaxis) are not available at schools, despite objective evidence that this is when the vast majority become sexually active, and where substantial HIV and other sexually transmitted disease occurs. Brave moves by the DoH to start extending PrEP services to sex workers and perhaps to MSM, as an HIV-prevention plan, are to be applauded, but the same bravery is needed for a much larger segment of society.
DBE needs courage
The Department of Basic Education needs to change its policy, and immediately allow meaningful reproductive education, contraception and condoms into schools. Parent, teacher and politician sensitivities need to be seen in the context of incidence rates of up to 8% at some of the KwaZulu-Natal sites.
Politicians need to change laws
In tandem, the excellent progress made by a partnership of the DoH and a wide slew of civil society organisations to address the health needs of sex workers in the new plan, which includes a focus on HIV prevention with immediate treatment and PrEP, is undermined by the continued criminalisation of sex work, with harassment by the police a daily reality. Again, it will take brave leadership to address this, but it is necessary.
Missing in action 3: Civil society and business
The Mbeki era controversy distracted us, and let a huge portion of our society off the hook on the AIDS response. Beyond a few public statements by leaders from the churches, unions and within business, precious little of substance has come from these groups (with the exception of some home-based church groups, and some work-based treatment programmes).
Set them a challenge
Challenges need to be issued across all these groups, to support the HIV response. Again, a national HIV testing programme would be a tangible expression of this, linked to accountable targets.
It’s important to focus on what is important within the HIV programme. Much airtime has been given to the so-called ‘’non-communicable disease’’, both within the general health system and within HIV programmes. These conditions are often based on observational data from developed country populations, with increasingly questioned interventions. Well-meaning but evidence-free interventions, ranging from meaningless nutritional and exercise advice to mobile mammogram screening, have been adopted by various programme managers, and advocated by senior DoH staff. This despite the fact that TB remains the number one killer in the country, followed by other diseases of poverty.
Carefully evaluate screening programmes
It is remarkable to reflect on a statistic released in the last few years – that poorer Americans have witnessed a reduction in life expectancy in the last 30 years, and that this correlates clearly with increasing poverty. South Africans continue to die from under-nutrition and other diseases of poverty. Expensive screening programmes that use up the precious time healthcare staff need careful thought before being applied. In addition, health workers and the DoH need to understand that poverty reduction is probably going to make a far greater impact on health, especially when screening tests involve convoluted referral steps, invasive confirmation and relatively untested treatments. In addition, existing, evidence-based screening for TB is poorly done, and adding further layers of complexity to this seems a poor choice. Public health experts need to be better cheerleaders in this regard, and temper the disease-specific advocacy that has arisen within medicine. A basic income grant for poor people is likely to have a much greater impact on their health than a cholesterol screen or BMI check.
Finally, but just as importantly – despite evidence of a downturn in infections in some surveys – HIV new infections continue to be around 1 000 a day. As mentioned above, some brave choices are needed in schools to address the epidemic among young women, and legal challenges to sex worker legislation are required. However, other interventions would help.
Pre-exposure prophylaxis is complex, but it works. The current push is appropriate, but the group who most needs it, young women, will almost certainly not receive it using current models of care. Integrating PrEP into contraceptive, HIV testing and other programmes will require drive and creativity.
Support vaccine development
This is a long-term solution, but is looking more promising than a few years ago.
Stop getting distracted
Politicians are obsessed with people’s sex lives, disregarding home-grown evidence and insisting on supporting poorly thought-through programmes around concurrency and sugar daddies. We need focus on better relationships, gender violence and attention to condom provision and reproductive health, not billboards trumpeting often meaningless messages about who we have sex with.
Amílcar Cabral was a Guinea-Bissauan and Cape Verdean agricultural engineer, writer, and a nationalist thinker and political leader. He was also one of Africa’s foremost anti-colonial leaders (Wikipedia).
The full revolutionary quote by Cabral I referred to earlier in this article is: “Hide nothing from the masses of our people. Tell no lies. Expose lies whenever they are told. Mask no difficulties, mistakes, failures. Claim no easy victories…”
We can’t get complacent, with the empty promise from agencies of an ‘’AIDS-free generation” when our victories (in some cases) have been relatively easy, and many mistakes were dismissed.
Many of these problems (and solutions) are not specific to HIV. But HIV has allowed the whole area of health to be ambitious again, reconnecting with the energy that briefly arose after the Alma Alta Declaration on primary health care, but perhaps with more critical reflection (and resources to support it). It is an exciting time to be in the health field, especially in HIV, and people in South Africa rely on us to get it right.
Professor Francois Venter is the Deputy Executive at Wits Reproductive Health & HIV Institute, Professor in the Department of Medicine at the University of the Witwatersrand.
Conflict of interest declaration
Prof Venter receives support to both his salary and programmes from a large number of donors, as well as from the pharmaceutical industry (including drug donations to research projects) and managed care organisations. He currently runs a large sex worker health programme, an HIV-self testing programme, and is working on research studies on the new drugs detailed above, as well as a programme looking at non-communicable diseases. The views expressed here are not necessarily of his organisation.
By – Professor Lynn Morris, Professor Carolyn Williamson & Dr Kathy Mngadi
We are at a pivotal point in the pursuit of a vaccine against HIV. Two large efficacy trials will begin in 2016, both aimed at testing whether antibodies can protect against HIV infection.
The first is a classical vaccine approach based on active immunization while the second will test a passively administered broadly neutralizing antibody. Results from these trials are expected in 3-4 years’ time at the earliest.
There have also been significant advances in the laboratory that are delivering new vaccine concepts which are being fast-tracked for testing. On the eve of AIDS 2016 we reflect on the progress we have made, since we last met in Durban in 2000, towards the development of the ultimate game-changer for the HIV epidemic: an HIV vaccine.
New vaccine trials in populations at risk of HIV infection
A major global effort has focused on building on the success of the first partially effective vaccine that was tested in Thailand in 2009, which protected 31% of people from HIV infection. Although protection has been linked to the presence of antibodies that bind to a part of the viral envelope (known as variable loop 2 or V2), the reason why this vaccine worked is still under investigation. HIV is a highly diverse virus and so the Thai vaccine was redesigned to target clade C viruses that are dominant in southern Africa.
The trial will recruit 5 400 people in South Africa at risk of HIV infection, who will receive a total of five vaccinations over a year. The vaccine is comprised of two parts, a canarypox vector prime (ALVAC) and a protein boost, both of which contain fragments of HIV that stimulate the body to mount an immune response to HIV.
If, after 3 years, at least 50% of people are protected, the vaccine will be considered successful and rolled out for general use. Even at this level of protection, this vaccine could have a significant impact on the epidemic. The decision to move forward with this vaccine was dependent on results from a smaller trial showing that it is safe and able to stimulate the right kinds of immune responses. As all criteria were met, the large vaccine trial known as HVTN 702 was given the green light in April 2016 and will start in November of this year.
It has taken seven years of planning and the formation of the Pox-Protein Public-Private Partnership (P5) to get to this point. P5 comprises the South African Medical Research Council, the National Institute of Allergy and Infectious Diseases (NIAID), the HIV Vaccines Trial Network (HVTN), the Bill and Melinda Gates Foundation, the US Military HIV Research Program and vaccine manufacturers (Sanofi Pasteur and GSK). A similar plan to test this vaccine in large efficacy trials is also planned for Thailand using the original vaccine that is based on circulating strains in that country.
Another vaccine, developed by Janssen Pharmaceuticals and which showed encouraging results in animal studies, is also on track for large scale testing in humans (possibly in 2017). This vaccine will also use a prime boost approach, however, in this case, it will comprise an Adenovirus 26 (Ad26) vector and a protein boost. The vaccine contains mosaic HIV genes that are designed to target viruses from around the world and will be evaluated in southern and east Africa, as well as in Asia.
Other promising vaccines that are still in the animal phase of testing include a cytomegalovirus-based vector, which persists for a long time following vaccination and induces an extraordinarily large number of cellular immune responses. An HIV vaccine based on VSV that was used to make the successful Ebola vaccine is also under development.
Ramping up to AMP
Probably the most remarkable development in the vaccine space has been the advent of passive immunization for HIV prevention.
This new approach was made possible as a result of the discovery of broadly neutralizing antibodies that have the ability to kill a large number of HIV viruses from different clades. A vaccine with high efficacy is likely to require antibodies with this kind of activity, but to date no vaccine has managed to do this. However, the isolation of these antibodies from infected people, and the ability to make them in large quantities in the laboratory, has allowed us to directly test this.
This is the concept behind the ‘AMP’ (antibody mediated protection) study, which started in the Americas and Africa in 2016 and will enrol a total of 4 200 people at risk of HIV infection. This trial is being done as a collaboration between the HVTN and the HIV Prevention Trials Network (HPTN). A monoclonal antibody, called VRC01, will be directly infused into the bloodstream of human volunteers to determine whether it can protect against HIV infection and what levels of antibody are needed. The antibodies will decay over time, and repeated infusions will be needed to keep the levels high enough to provide protection.
The use of antibodies as passive immunisation is a well-established approach to provide protection from other infectious diseases such Rabies and Respiratory Syncytial Virus. This monoclonal antibody, while providing invaluable information for vaccines, is not planned as an end-product as there is a pipeline of better, more potent antibodies which can be used alone, or in combination to increase the chances of killing more viruses.
Other modes of antibody delivery, including subcutaneous injections and gene therapy, are also being explored. It is important to remember that passive immunization provides temporary protection, unlike a vaccine which generally gives life-long protection.
How basic research is helping us make better vaccines
Until now, a major hurdle in the development of an HIV vaccine has been the inability to make proteins that look like those on the virus particle and are suitable for manufacture. The trimeric viral envelope spike which is the target of neutralizing antibodies is a highly complex protein that has eluded structural biologists for decades. With new technologies this puzzle has finally been solved and initial studies in animals have shown that these laboratory-generated envelope proteins do induce better neutralizing antibodies. There is a major push to test these proteins in small experimental trials to see if they can stimulate neutralizing antibodies in human volunteers.
How to elicit broad and potent neutralizing antibodies remains the biggest challenge in vaccine research. This is because HIV has devised cunning ways to avoid detection by the immune system. It has an extraordinary ability to mutate and in addition the HIV envelope cloaks itself with sugars (glycans) making it difficult for antibodies to reach vulnerable sites. This plasticity allows HIV to continually evade the neutralizing antibody response, like a perpetual game of cat and mouse.
Furthermore, only some HIV-infected people make broadly neutralizing antibodies after many years into the infection. This, together with the unusual features of HIV antibodies, highlights how difficult it is for the human immune system to make these types of protective antibodies.
Several landmark studies in the last few years by a number of research groups around the world have provided clues as to why and how some HIV infected people make broadly neutralizing antibodies. These studies were only possible because of HIV infected people enrolling into studies and continuing to participate in them for long periods of time.
Perhaps one of the most important clues is the need for the immune system to see and adapt to variation in the viral epitope that is the target of broadly neutralizing antibodies. What that means for vaccination strategies is that we may need to make and test a whole series of vaccines that vary slightly from each other and that drive the antibody response along the pathway towards neutralization breadth. In other words we need to mimic viral evolution by vaccination. This is unprecedented in the history of vaccination and would obviously make the manufacture and delivery of such a vaccination approach more complex.
The journey of vaccine discovery
Even though an HIV vaccine remains elusive, we have come a long way since Durban 2000. Unlike vaccines for Ebola (and possibly Zika), HIV presents a far bigger scientific challenge. That we still do not have an effective HIV vaccine despite tremendous efforts is testimony to the inherent difficulties in doing this. The next decade is likely to bring more significant advances and we await the outcome of the two large efficacy trials with anticipation. Successful products would, without doubt, bring about a major paradigm shift in the fight against the global AIDS epidemic.
* Professor Lynn Morris is the Head of HIV Research at the National Institute for Communicable Diseases.
*Professor Carolyn Williamson is the Head of the Division of Medical Virology at the Institute of Infectious Disease and Molecular Medicine, Professor at University of Cape Town.
*Dr Kathy Mngadi is Honorary Lecturer in the School of Laboratory Medicine and Medical Science at the University of KwaZulu-Natal
By – Dr Thomas A. Rasmussen & Professor Sharon R. Lewin
Antiretroviral therapy (ART) has revolutionised the lives of people living with HIV and in many countries, life expectancy for someone living with HIV is now almost the same as someone not living with HIV. But ART is not a cure.
When ART is stopped, the virus rebounds within a few weeks in almost all infected individuals, even after many years of suppressive therapy. Understanding where and how HIV persists on ART and using these insights to develop therapies, which will ultimately enable us to cure HIV infection, or allow people living with HIV to safely stop ART with the virus staying under control, remain key goals in HIV research.
Over the past decade, there has been a substantial increase in our understanding of where and how HIV persists when someone is on ART. It is now clear that integration of the HIV genome into long-lived resting cells is a major barrier to a cure. This state is called HIV latency. But virus can also persist on ART in other forms. In both monkey models of HIV and in HIV-infected individuals on ART, virus has been found in T follicular helper cells, which are found in a specialised compartment in the lymphoid tissue. These cells are found in a part of the lymph node where penetration of immune fighting cells, or cytotoxic T-cells is limited. In some tissues, penetration of ART may not be optimal, which could also contribute to persistence. Finally, there is also some evidence that, in at least some individuals and in some sites, the virus may still be replicating at very low levels.
To date, there has been just one case of a cure for HIV, which occurred in the context of haematopoietic stem cell transplantation (HSCT) for leukaemia with HIV-resistant donor cells. HSCT is clearly not a feasible curative strategy for HIV, but we have learnt here that complete eradication of HIV is theoretically possible. Similar approaches have been tried, but no others have yet been successful and all six individuals receiving a similar transplant died of infection or cancer relapse within 12 months of transplantation.
Other case reports have confirmed that HSCT, even from a regular stem cell donor, can drastically reduce the frequency of infected cells, but when ART was subsequently discontinued, virus still rebounded off ART, although it took months and not weeks to rebound. These cases demonstrate that although reducing the frequency of latently infected cells might delay time to viral rebound, there is a need for continued effective immune surveillance against HIV to keep whatever remains in check.
Using gene therapy to either make a cell resistant to HIV or to literally remove HIV from the cell is now being actively investigated. The initial target of gene therapy was CCR5 – the same gene that is missing in some rare individuals that are naturally resistant to HIV. Clinical trials of gene therapy to eliminate CCR5 and make cells resistant to HIV was safe, but there remains much work to be done to increase the numbers of gene-modified cells. Other work, which still is at the stage of test-tube experiments, uses gene scissors to target the virus itself. This approach might be trickier than targeting CCR5 as the virus can rapidly mutate and change its genetic code so that the gene scissors no longer work.
By starting ART very early – within days to weeks of infection – it is possible to substantially reduce the number of latently infected cells, and this also helps preserve immune function. Although not an option for the majority of HIV-infected individuals who are diagnosed too late, early diagnosis and treatment could be an effective strategy to maintain immune control for some patients. Several years ago, French investigators described that post-treatment control was possible in up to 15% of individuals treated within months of infection. These data remain a little controversial as in other cohorts, post-treatment control is far less common. We still don’t fully understand what factors are important for post treatment control, but it seems that the nature of the immune is critically important. Interestingly, post-treatment control may differ in different ethnic groups. A recent report from Africa suggested that post-treatment control could occur at far higher frequencies in African populations than in Caucasians.
Early treatment of HIV-infected children at birth may also present an opportunity to induce post- treatment control. In the highly publicised case of the Mississippi child, ART was started 30 hours after birth and following cessation of ART at age 18 months, this child had a period of 2 years of post-treatment control. Early treatment of infants may potentially shift virus from hiding in long-lived to short-lived T-cells. Therefore, understanding the differences in where virus persists in children and in adults could provide important insights into novel strategies to find a cure for HIV. We will hear a lot about these approaches in Durban.
The reality is that most people globally are diagnosed with HIV years and not days after infection. The main strategies being tested to achieve remission is to reduce the amount of persistent virus and also boost the immune response to allow for long term control.
Activating the expression of HIV proteins in latently infected cells by drugs called latency-reversing agents could drive elimination of virus-expressing cells through immune- or virus-mediated cell death. This approach is usually referred to as “shock and kill”. A substantial body of research has helped identify latency-reversing agents including histone deacetylase inhibitors and disulfiram, which have now been tested in experimental clinical trials. These studies demonstrated that although HIV expression can be induced in patients on suppressive ART, this did not reduce the frequency of infected cells. In other words, shock but no kill.
On-going studies are looking at ways to augment the killing of these cells by boosting the immune system, for example through vaccines or medications that trigger suicide of the infected cells. Cure research is likely to benefit from the very significant investment in vaccines that have been developed to protect people from getting infected, some of these vaccines could work in cure too – for example vaccines that potently stimulate cells that are programmed to kill infected cells or alternatively highly effective antibodies, called broadly neutralising antibodies, that can also trigger killing of an infected cell. These vaccines are now being investigated in the setting of clinical trials in infected individuals on ART.
There have been some spectacular recent advances in the treatment of some cancers using drugs that boost the immune response – called immune checkpoint blockers.
These drugs reinvigorate exhausted T-cells so they can move in to action – against cancer cells and in the same way, against HIV-infected cells. These drugs, one that blocks CTLA4 and another that blocks PD1 are now in clinical trial in HIV-infected patients being treated for different cancers. Another way to boost the immune system is to trigger a very primitive immune response designed to respond to infections. These drugs are called toll-like receptor (TLR) agonists. In monkeys, TLR-7 agonists, currently being developed by Gilead, stimulate latently infected cells and an effective immune response leading to a modest reduction in infected cells. Clinical trials are now underway in HIV-infected individuals on ART.
Now, four years after the launch of the 2012 International AIDS Society (IAS) Global Scientific Strategy Towards and HIV Cure, we have had some successes and failures. We now have a clearer idea of where virus persists on ART, but still much to learn about different T-cell subsets and what happens inside tissue. We need better ways to measure total virus, especially virus that can rebound. Some advances in X-Ray imaging might help here, which could give a total snap shot of where the virus is sitting in the body. We also now know that activating latent virus is not enough to kill the cells. Other interventions are needed. A successful strategy will likely need two components – reducing the amount of virus that persists on ART and improving long-term immune surveillance to target any residual virus. We need far more work to be done on HIV cure in low income settings to better understand the effects of different HIV strains, the effects of co-infection and the impact of host genetics. Lessons from other fields, particularly oncology, transplantation and fundamental immunology, are all relevant to inform the next advances we need in cure research. Finally, we have to ensure that any intervention leading to a cure must be cost effective and widely available.
The implementation of combination ART in the mid-1990s is still regarded one of the most remarkable achievements in modern medicine. Life-long ART remains the single best option for any person infected with HIV. Finding a cure for HIV remains a major scientific challenge but many believe it to be within the realms of possibility and it will hopefully play an important role in seeing an end to HIV.
*DR Thomas A. Rasmussen is a Clinical Research Fellow at the Doherty Institute
*Professor Sharon R Lewin is the Director of the Doherty Institute for Infection and Immunity and Professor at the University of Melboune
It has been 15 years since you exhaled for the last time, you would have turned 27 this year. I would imagine it was a relief…a long breath that spoke of having carried a heavy burden and responsibility in your much too short life.
You were the Hector Peterson of the HIV generation in the 80s and 90s, a reluctant hero and activist who smiled bravely when you first hit the headlines after your primary school were grappling with how to deal with your disease.
The rest, as they say, is history.
You spoke out often, your words speaking of an old soul that has experienced way too much, seen way too much with your big, beautiful eyes.
I recall the iconic image of you standing on that huge stage at Kings Park Stadium, the dark suit hanging onto your fragile and tiny frame. But your big heart was there for all to see. You had been rehearsing your speech for weeks, understanding and knowing that what you said would be important…I remember how excited and nervous you were at the thought that then President Mbeki would be in the audience, but I also remember your profound disappointment when you realized he had walked out before you had completed your speech. But Nkosi, you did not need for him to be there, thousands heard you, millions continue to repeat and hold onto those words that continue to reverberate around the world. Your speech touched so many:
Hi, my name is Nkosi Johnson. I live in Melville, Johannesburg, South Africa.
I am 11 years old and I have full-blown AIDS. I was born HIV-positive.
When I was two years old, I was living in a care centre for HIV / AIDS-infected people. My mommy was obviously also infected and could not afford to keep me because she was very scared that the community she lived in would find out that we were both infected and chase us away.
I know she loved me very much and would visit me when she could. And then the care centre had to close down because they didn’t have any funds. So my foster mother, Gail Johnson, who was a director of the care centre and had taken me home for weekends, said at a board meeting she would take me home. She took me home with her and I have been living with her for eight years now.
I know that my blood is only dangerous to other people if they also have an open wound and my blood goes into it. That is the only time that people need to be careful when touching me.
In 1997 mommy Gail went to the school, Melpark Primary, and she had to fill in a form for my admission and it said does your child suffer from anything so she said yes: AIDS.
My mommy Gail and I have always been open about me having AIDS. And then my mommy Gail was waiting to hear if I was admitted to school. Then she phoned the school, who said we will call you and then they had a meeting about me.
Of the parents and the teachers at the meeting 50% said yes and 50% said no. And then on the day of my big brother’s wedding, the media found out that there was a problem about me going to school. No-one seemed to know what to do with me because I am infected. The AIDS workshops were done at the school for parents and teachers to teach them not to be scared of a child with AIDS. I am very proud to say that there is now a policy for all HIV-infected children to be allowed to go into schools and not be discriminated against.
And in the same year, just before I started school, my mommy Daphne died. She went on holiday to Newcastle- she died in her sleep. And mommy Gail got a phone call and I answered and my aunty said please can I speak to Gail? Mommy Gail told me almost immediately my mommy had died and I burst into tears. My mommy Gail took me to my Mommy’s funeral. I saw my mommy in the coffin and I saw her eyes were closed and then I saw them lowering it into the ground and then they covered her up. My granny was very sad that her daughter had died.
I hate having AIDS because I get very sick and I get very sad when I think of all the other children and babies that are sick with AIDS. I just wish that the government can start giving AZT to pregnant HIV mothers to help stop the virus being passed on to their babies. Babies are dying very quickly and I know one little abandoned baby who came to stay with us and his name was Micky. He couldn’t breathe, he couldn’t eat and he was so sick and Mommy Gail had to phone welfare to have him admitted to a hospital and he died. But he was such a cute little baby and I think the government must start doing it because I don’t want babies to die.
Because I was separated from my mother at an early age, because we were both HIV positive, my mommy Gail and I have always wanted to start a care centre for HIV / AIDS mothers and their children. I am very happy and proud to say that the first Nkosi’s Haven was opened last year. And we look after 10 mommies and 15 children. My mommy Gail and I want to open five Nkosi’s Havens by the end of next year because I want more infected mothers to stay together with their children- they mustn’t be separated from their children so they can be together and live longer with the love that they need.
When I grow up, I want to lecture to more and more people about AIDS- and if mommy Gail will let me, around the whole country. I want people to understand about AIDS- to be careful and respect AIDS- you can’t get AIDS if you touch, hug, kiss, hold hands with someone who is infected.
Care for us and accept us- we are all human beings. We are normal. We have hands. We have feet. We can walk, we can talk, we have needs just like everyone else- don’t be afraid of us- we are all the same!”
(An extract from his speech delivered in July 2000).
I remember how excited you were at traveling to the United States to meet Robin Williams who you said made you laugh. You always loved jokes…you would tell the worst jokes and laugh the loudest. I think that is where my son got his crazy sense of humour from!
Do you remember when you once visited us in Cape Town. You were so sick already and I remember waiting for you at Cape Town International Airport and having to hide my shock at seeing how much you had deteriorated…the crust of thrush sitting thick around your lips, the windbreaker completely dwarfing your frame. You were so excited to be in Cape Town and immediately wanted to go and eat ribs – you ordered the biggest rack of ribs only to stare at it and asking if we could take it home. The thrush was so bad that it was impossible for you to eat most food. The diarrhoea became to severe that we rushed you to our doctor where she put you on a drip to tide you over even though you should have probably been in hospital.
You loved music so much, one of your favourites the soundtrack from The Commitments…You would listen to it over and over again and of course my CD went home with you!
Do you remember us going to the Carols by Candlelight at Kirstenbosch? You managed to get us a ride on the golf cart, all the way to the lawns where you lay in our laps, covered in thick blankets and singing each carol at the top of [your voice. Your look of amazement when you looked back and saw the sea of candles will always stay with me.
Nkosi, on 18 July we will all return to Durban. Some of us are returnees, others are newbies who joined the HIV activist bus along the way. I want to promise you that we will not go to Durban and accept empty rhetoric, lofty promises and articulate but empty political speeches. No, we will go to Durban expecting to live up to your dream where no child is born HIV-positive, no child needs to be separated from their mothers because of disease and poverty and stigma is just an ugly swear word.
This will be a conference where the South African government will hear your message, this we owe to you and to the many other children who faced the same fate.
Lala Kakuhle gentle, beautiful warrior, we will feel your presence in Durban we will carry you in our hearts and songs.
All our love, admiration and respect.
ANSO THOM is the Head of Communications at SECTION 27 and an editor of Spotlight.