In the early days of the AIDS epidemic, the high price of antiretroviral medicines meant many lives were unnecessarily lost. While the global AIDS movement managed to force lower prices for key ARVs, the wider battle has not yet been won. Today, many people with hepatitis C, various cancers, drug-resistant tuberculosis and other conditions still cannot get the medicines they need to survive. This article explains the how inequality extends to drug development.
There are two broad problems with the way society currently pays for medicines.
The first, the innovation problem, is that we are not investing enough money and energy into finding treatments for diseases mostly affecting poor people. This is why most of our tuberculosis (TB) treatments today are more than fifty years old and not very good.
The second, the price problem, is that many of the medicines that are developed are sold at such high prices that people cannot afford them. This is why many people with hepatitis C cannot afford the highly effective new hepatitis C cures on the market. For these people the new cures might as well not exist.
The innovation problem
Last year, tuberculosis killed more people than any other infectious disease on the planet, including HIV. At 1.5 million deaths, it far outstripped headline-making outbreaks like Ebola (11,315 deaths in 21 months). Yet, in 2014 humanity invested less than US$700 million in TB research – only about a third of the two billion a year that the World Health Organisation estimates is required to bring an end to TB. Of this US$700 million, less than US$100 million was invested by the pharmaceutical industry. In fact, a number of large pharmaceutical companies have stopped doing TB research altogether.
The first part of this problem is simple. Since most people needing TB treatment are poor, pharmaceutical companies see little potential profit in developing new TB treatments. Companies choose rather to invest in researching medicines that will sell in rich countries – medicines for diabetes, heart disease, or erectile dysfunction.
The second part of the problem is more puzzling: given that industry does not invest, one would expect governments to step in to fill the gap. However, with the exception of the United States, governments do not. While the BRICS countries (Brazil, Russia, India, China and South Africa) have over 40% of the global TB burden, they contribute less than 4% of global investment in TB research.
The price problem
When the patent system does deliver important new medicines, as it sometimes does, those medicines are often priced out of reach for many of the people who need it. So, for example, the breakthrough hepatitis C drug sofosbuvir is priced at US$84 000 for an 84-day course. Similarly, high prices mean that women in South Africa who need the breast cancer drug trastuzumab often can’t afford its R500 000 price tag.
Companies argue that they have to ask these high prices to recoup their investment in developing the drugs and to fund their investment in developing new medicines. In recent years this argument has begun to wear very thin.
A United States senate investigation in 2014 found that the pricing of sofosbuvir had nothing to do with how much it costs to develop the drug. Rather than basing prices on the investments made into a drug, companies are typically setting prices at levels that maximise profits – even if that means many people can’t access the drug in question.
At a more fundamental level, high prices charged by pharmaceutical companies have brought into question the basic social contract between the public and the pharmaceutical industry.
The thinking is that the people, through our governments, grant patent monopolies to companies in return for investment in new medicines. However, enforcement of this social contract is very one-sided. While companies almost always get and maintain their patent monopolies, there is no enforcement of the expectation on companies to invest in research. Typically, companies invest only between 8 and 18% of revenue in research and development (R&D), while they typically spend double on marketing and advertising. In addition, the way in which companies spend their R&D funds is completely non-transparent.
All the available evidence suggests that we are not getting much bang for our buck in the current system where there is no obligation on industry to reciprocate high prices with high investment in R&D.
We have other options
Various solutions to these problems have been under discussion at the World Health Organisation (WHO) over the last decade – with very little progress to show for it. In addition, in 2015 the Secretary General of the United Nations, Ban Ki-moon, convened a High Level Panel to look at exactly these problems. Even if the HLP comes up with strong recommendations, it will be up to governments to make those recommendations a reality.
Some possible solutions include:
An R&D agreement or treaty
Given that industry is failing to invest in diseases that have an impact on poor people, governments have a responsibility to step in and fill that investment gap. One solution is an R&D treaty or agreement. Countries would all contribute to a central fund. Money in this fund would then be used to fund research in neglected areas like TB. This is a simple and workable solution. The only thing that is lacking is political will. Even if rich countries like the United States and Germany oppose such a treaty or agreement, there is nothing preventing other countries from going ahead without them.
When governments invest in research, they often do so in a way that allows companies to patent the products of that research. In this way, governments end up paying twice – once through research grants and again when paying high prices for patented medicines. If governments invest in a delinked way, they will not allow this double-payment to happen. In such a case, governments will fund research through grants and prizes and then ensure that all the research is paid for up front and that the research cost is “delinked” from the sale price of the eventual product. The so-called 3P Project (see our previous issue) is an example of a delinked model.
Bring balance to the system
International law allows for steps to be taken to balance the worst excesses or exploitation of patent monopolies. These balancing measures are commonly referred to as TRIPS flexibilities (Trade-Related Aspects of Intellectual Property Rights) and they include allowances for: compulsory licenses (overriding patents); only granting patents for truly innovative products and not for reformulations or new uses of old drugs; and for the public to file oppositions to the granting of specific patents.
The problem is that due to trade pressure from the United States Trade Representative, many countries have not written these TRIPS flexibilities into their national law – and if they have, they are often afraid to use them.
Doing away with pharmaceutical patents altogether
One of the remarkable things about the history of patents and medicines is that there is no evidence that providing increased patent protection around the world has led to greater medical advances. In fact, in the golden age of medical discovery from the 1940s to 1970s, much of the world did not offer any patent protection on medicines. There was also no increase in innovation following the TRIPS agreement in 1995, which compelled all World Trade Organisation member countries to provide for at least 20 years of patent protection.
It would of course not make sense to simply remove the patent system and not replace it with anything else. The world, after all, is in desperate need of new medicines. Governments would have to redirect the money they would have spent on purchasing patented medicines to providing research grants and sponsoring prize funds for the development of new medicines. All indications are that such a transition would in fact see R&D spending increase dramatically – given how little industry currently spends on R&D as a percentage of revenue.
Lotti Rutter is a Senior Researcher for Treatment Action Campaign
Marcus Low is an editor of Spotlight
“You are aware of the exploding prevalence of cancer around the world and in our own country. We have just moved in a circle. Just as the price of ARVs were unaffordable then, cancer drugs are devilishly unaffordable today. If no drastic action is taken today, we are going to be counting body bags like we are at war.”
Dr Aaron Motsoaledi, Health Minister of South Africa, 2016 budget vote speech. “Rationing is the ultimate consequence of high drug prices. Unsurprisingly, this is unpopular and is causing a backlash. In a number of US states, politicians are seeking to pass legislation forcing drug companies to disclose more information about the cost of producing their high-priced remedies. There is even talk of capping prices. The industry argues that such caps would drive capital out of the industry, cutting innovation and ultimately harming patients. But that is a hard argument to sustain when companies such as Gilead and Vertex are earning gross margins of 90 per cent and share prices are sky high. Pharmaceutical innovation has been one of the great successes of the past century, improving the lives of people immeasurably round the globe. But if the current dispensation is to continue, the industry must learn to price with greater restraint.”
Financial Times, August 16, 2016.
“The patent system is expensive. A decade-old study reckons that in 2005, without the temporary monopoly patents bestow, America might have saved three-quarters of its $210-billion bill for prescription drugs. The expense would be worth it if patents brought innovation and prosperity. They don’t.”
In recent years we have discovered an entirely new form of HIV prevention – providing antiretroviral treatment to people who are not living with HIV in order to prevent HIV infection. Large numbers of studies have been done to determine which specific medicines and which specific delivery methods (pills, gels, or rings) work best. This field is fast evolving. Here is how we see the current state of play.
Pills containing tenofovir and emtricitabine
The most effective form of pre-exposure prophylaxis (PrEP), according to the currently available evidence is a once-daily pill containing the two antiretroviral drugs tenofovir and emtricitabine.
However, the efficacy of this combination pill has varied substantially in different studies. This variation appears to be linked to two factors: the level of treatment adherence and the nature of the population in which the drug is being tested. In almost all PrEP studies, people who take the pills as prescribed have significantly better outcomes than people who do not.
The tenofovir/emtricitabine combination has generally had better results in studies of men who have sex with men (MSM) than in studies conducted in heterosexual women. These differences appear in part to be due to biological differences between the rectum and the vagina – but also seem to reflect better adherence among MSM – at least in the studies conducted so far.
In general though, a pretty clear picture has formed in recent years. If people take tenofovir/emtricitabine daily they are much less likely to contract HIV. With good adherence the risk is dramatically reduced, but there is some recent evidence suggesting that even with perfect adherence the risk is not reduced to zero. We thus recommend that whenever possible tenofovir/emtricitabine PrEP should be taken in addition to using condoms.
Both the World Health Organisation and the Southern African HIV Clinicians Society recommend the use of daily for people at high risk of HIV infection. We fully support this recommendation.
What about the gel and the ring?
Apart from the tenofovir/emptracitabine combination, tenofovir as a pill alone, tenofovir in a gel form, and a vaginal ring containing the ARV dapivirine have also been tested. None of these interventions has been as effective as the tenofovir/emtricitabine pill taken daily.
While there was great excitement about 1% tenofovir gel a few years ago, this excitement has evaporated following a series of disappointing trial results. As with PrEP pills, adherence seems to play a crucial role in how well the gel works. In the key studies conducted on the gel, women generally did not use the gel as prescribed. Whatever the reasons, the failure of 1% tenofovir gel in two very large trials has essentially put an end to hopes of the gel becoming a viable option for HIV prevention.
A more promising intervention is a vaginal ring containing the ARV dapivirine. The ring is inserted into the vagina and then replaced every month. The hope is that such a ring – one that women could leave in place and forget about – would help get around the problem of poor treatment adherence. Two recently reported phase III studies found the dapivirine ring to be effective in preventing HIV infection. There is a snag however: both studies only showed moderate levels of protection – less than 40%. In addition, the findings in both studies had unusually high levels of statistical uncertainty. Thus, while the concept of the ring is very compelling, the efficacy achieved so far does not compete favourably with a daily tenofovir/emtricitabine pill.
Treatment vs PrEP
While it is clear that governments and donors should invest both in treatment for people living with HIV and in PrEP, there may be situations where policy-makers may feel forced to choose between the two due to resource constraints. A number of modelling studies have teased out the impact these different interventions are likely to have on new infections.
A 2014, study by Alistar and colleagues concluded that universal ART treatment, with either a marginal or a broad scale-up, was cost effective, cost saving, and provided more health benefits than general PrEP. The study evaluated the population health outcomes and cost-effectiveness of implementing expanded ART treatment and oral PrEP in South Africa. Different strategies, in which ART, PrEP, or both were scaled up to 25%, 50%, 75%, or 100% were assessed. In general, the strategies involving a scale-up of ART for all people with HIV averted more infections than the strategies involving an equal scale-up of PrEP for all eligible people. The best strategy considered was a 100% scale up of universal ART (which averts 75% of new infections without any PrEP) and PrEP focused on high-risk populations (which averts 57% of all new HIV infections without any ART scale-up). This strategy costs only US$150 per quality-adjusted life year (QALY) gained and was the most effective of all strategies at preventing new HIV infections.
A 2012 modelling study by Cremin et al came to similar conclusions. They found that “at a population-level maximal cost-effectiveness is achieved by providing ART to more infected individuals earlier rather than providing PrEP to uninfected individuals. However, early ART alone cannot reduce HIV incidence to very low levels and PrEP can be used cost-effectively in addition to earlier ART to reduce incidence further. If implemented in combination and at ambitious coverage levels, medical male circumcision, earlier ART and PrEP could produce dramatic declines in HIV incidence, but not stop transmission completely.”
Apart from the type of cost/benefit analysis described above there is also an important ethical consideration. There is a moral responsibility first to treat people living with HIV – given that since the Strategic Timing of AntiRetroviral Treatment (START) trial we know that all people living with HIV should be offered treatment for their own health.
Marcus Low is an editor of Spotlight.
Kristanna Peris is an undergraduate student at Northeastern University and an intern at the TAC.
Size of Study
Key Finding as Point Estimate and Confidence Interval
Key finding relating to efficacy in sub groups with better adherence
Heterosexual men and women in a serodiscordant relationship
Daily oral TDF-FTC associated with risk reduction of 75% (95% CI, 55 to 87; P<0.001)
A detectable level of tenofovir (vs. non-detectable) is associated with a relative risk reduction of 90%
A strong and statistically significant finding.
PROUD (deferred arm offered earlier PrEP due to efficacy)
At-risk MSM aged 18+ years. Given PrEP immediately or deferred one year
Proportionate reduction of 86% (90% Ci, 64 to 96).
In the immediate group, HIV incidence was 1.2 per 100 person-years (90% CI; 0.4 to 2.9)
In the deferred group, HIV incidence was 9.0 per 100 person-years (90% CI; 6.1 to 12.8)
Strong and statistically significant
High-risk MSM aged 18+
Took 2 pills 2-24 hours before sex, took a third pill 24 hours after the 1st dose, and a 4th pill 24 hours after that
Approx. 900 men
Relative reduction in HIV incidence of 82% (95% CI, 36 to 97; P=0.002)
Many people were having sex every week. This meant the event-based dosing was similar to minimum 4-doses a week for men in the iPrEX study. Not enough data to comment on isolated use of event-based strategy
Strong statistically significant findings
CDC TDF2 Study
Heterosexual men and women in Botswana aged 18-39 years
Relative reduction in HIV incidence of 62.2% (95% CI, 21.5 to 83.4; P=0.03)
Statistically significant finding showing good efficacy
TDF-FTC PrEP Efficacy in MSM
MSM 18+ y.o
Estimated PrEP Efficacy:
2 doses per week was 76% (95% CI: 56 to 96%)
4 doses per week was 96% (95% CI: 90 to >99%)
7 doses per week was 99% (95% CI: 96 to >99%)
Statistically significant. This is not a clinical trial, but an analysis of previous clinical trials (which is why we code it as orange). It does underline though that the efficacy of oral PrEP is highly correlated with adherence.
High-Risk MSM 18+ y.o.
44% reduction in the incidence of HIV (95% CI, 15 to 63; P= 0.005)
92% reduction in risk of HIV (95% CI, 40 to 99; P<0.001)
This finding is highly statistically significant and the prevention effect is clear—particularly in sub-groups with better adherence.
ADAPT (final results not yet published)
MSM in USA and Thailand and women in South Africa
179 women in South Africa
7 seroconversions total:
Two during first 6 weeks of observed PrEP dosing (Incidence: 8.9 per 100 person-years)
Five during 24-week self-administration of PrEP (Incidence: 5.4 per 100 person-years)
Points to effectiveness
(Study stopped early due to lack of efficacy)
Women from sub-Saharan Africa aged 18-35 y.o. at risk for HIV
Estimated hazard ratio was 0.94 (95% CI; 0.59 to 1.52: P= 0.81)
34 infections in the active arm vs 39 in the placebo group (hazard ratio: 0.87; 95% CI, 0.55 to 1.38; P= 0.56)
Oral TDF-FTC did not work for women in this study, likely due to low adherence. Adherence to PrEP likely needs to be higher for vaginal sex than for anal sex to be as effective.
Women from sub-Saharan Africa aged 18-45 y.o.
-4.4% with TDF-FTC (95% CI; 0.733 to 1.49)
Oral TDF-FTC did not work for women in this study, likely due to low adherence. Adherence to PrEP likely needs to be higher for vaginal sex than for anal sex to be as effective.
We are in a very exciting time for HIV treatment (ART) for three reasons.
South Africa, the country with the biggest HIV treatment programme, has agreed to make ART available to everyone who is living with HIV.
An important new HIV drug – called dolutegravir – is expected to be available soon in low-income countries at a low price.
Other developments may lead to treatment with only one or two drugs – instead of three, and two-monthly injections – instead of pills.
Over 17 million people with HIV are receiving ART worldwide. This is less than half of the over 36 million people living with HIV.
In 2015, the Strategic Timing of AntiRetroviral Treatment (START) and TEMPRANO studies showed the benefit of ART at all CD4 counts – even when higher than 500. This led the World Health Organisation (WHO) to recommend that everyone with HIV should start treatment. South Africa has also recently adopted this “treat all” strategy, doubling the number of HIV-positive people eligible for treatment.
The WHO also decided to recommend one main first-line combination for everyone in low- and middle-income countries (LMIC) including South Africa. This is a single pill with efavirenz (EFV), tenofovir disoproxil fumarate (TDF) and either emtricitabine (FTC), or lamivudine (3TC). This simplified first-line ART in low-and middle-income countries including South Africa.
This is a very good combination. It is good at reducing even high viral load and it has been used by millions of people for over ten years.
However, a newer combination might have fewer side effects and therefore might be better. It will also reduce viral load quicker and have less risk or drug resistance. This will use dolutegravir instead of efavirenz and a new version of TDF called TAF.
Will everyone switch to the new combination straight away?
Even though studies have already proven the advantages of the newer drugs, there are still some gaps in the studies. The needs of HIV-positive people are different in LMIC. This is because there are larger populations of women of childbearing age, children, and people with TB and other co-infections.
Data from using these newer drugs universally on these groups of people are not yet available. The studies that approved dolutegravir and TAF were run in high-income countries. Information about the dose and compatibility with other antiretrovirals were mostly gained from studies in men – and not from studies in women in countries like South Africa.
What are the new drugs and what studies are still needed?
The integrase inhibitor dolutegravir (DTG) has many properties that make it an important potential drug for use in LMIC:
It only needs a 50mg once-daily dose. This means pills can be much smaller and cheaper to produce.
It has a very high barrier to drug resistance.
It is good at reducing viral load quickly and keeping it undetectable.
It has few side effects.
It has the potential to be low-cost.
It is easy to co-formulate with other HIV drugs in a single pill.
DTG was superior to EFV in the so-called SINGLE () trial in people receiving first-line treatment. Other DTG studies have shown it to be superior – or non-inferior – to other commonly used antiretrovirals in high-income countries both in first- and second-line treatment. But DTG studies have not yet included significant numbers of people who would be treated in LMIC.
The main studies for DTG had approximately 80% men and few non-white participants. They enrolled very few people co-infected with other diseases (a few with hepatitis B and none with TB or malaria). People with drug resistance were not included (especially with resistance to NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors).
Information about treating HIV/TB coinfection with a DTG-based regimen is limited.
A Phase I study in HIV-negative people showed that the TB drug rifampicin lowers drug levels of DTG. This study suggested a higher DTG dose will overcome the interaction – ie. taking 50 mg twice a day rather than once a day. Another study will give results on this strategy later in 2016. Other studies are looking at drug levels in people with TB, they could show that the current 50mg once-daily dose might be okay, despite the lower levels.
Information about DTG in pregnant women is also limited – although this is always the case with every new HIV drug. Early results suggest DTG drug levels in pregnancy are similar to those in non-pregnant adults but that they are lower compared with postpartum.
A small number of women became pregnant in the DTG studies and early-use programme, and numbers of use during pregnancy will increase in high-income countries. So far only 10 first trimester and 18 second/third trimester exposures have been reported to the Antiretroviral Pregnancy Registry (APR) of 31 July 2015. From these data there were none and one congenital defect respectively.
Several studies are planned or ongoing to look at DTG use in pregnancy.
Tenofovir alafenamide (TAF)
TAF is a new version of tenofovir and has the potential to replace TDF.
It only uses a low dose (25mg as opposed to TDF at 300mg once-daily doses).
It has lower risk of bone and kidney side effects.
The lower dose should make it less expensive than TDF.
TDF is currently the major driver of cost in LMIC generic first-line combinations. The Clinton Health Access Initiative (CHAI) estimates that TAF could lower the cost of first-line ART by as much as 50%. In South Africa this would allow a US$160 million reduction on the annual cost of ART by 2018.
As with DTG, there is currently less information about TAF with TB treatment and during pregnancy. Very few studies have used TAF in combination with DTG.
There are no data yet on interactions between TAF and rifampicin, but a significant interaction is predicted. This comes from modelling drug interactions between TAF and carbamazepine.
A drug-drug interaction study in HIV-negative participants to look at the interaction between TAF and rifampicin is being planned, followed by a study in people with TB.
Other pending studies will look at using TAF during pregnancy, including one looking at DTG and TAF together in an ART regimen in pregnant women.
How studies in South Africa will help global treatment
One very important study will start this year in South Africa. This will provide important new results for both dolutegravir and TAF.
The study – called ADVANCE will include approximately 1050 HIV positive people to compare three combinations for first-line treatment.
DTG/TAF plus FTC
DTG/TDF plus FTC
EFV/TDF plus FTC
The results will be used to decide whether DTG/TAF/FTC (or 3TC) becomes the preferred first-line in WHO guidelines.
The main results will be the proportion of people with undetectable viral load after 48 weeks, though the study will run for two years.
There will also be sub-studies that will help to address the potential issues with TB coinfection and with pregnancy.
These three study groups will clarify when dolutegravir and TAF are best used – including with each other.
The DTG/TDF/FTC arm is included in the case drug interactions between TAF and rifampicin result in different side effects or in cases there are difference in pregnant women. Having data to support DTG use with TDF will still be able to show benefits over current standard of care.
The efavirenz group is the current standard of care in first-line in all LMIC. FTC and 3TC are interchangeable in almost all guidelines. Because this combination has been so widely used, the WHO needs a large new study to prove whether newer drugs are better before guidelines can be changed.
If successful, at least one generic manufacturer has already agreed to produce the new DTG/TAF/FTC FDC at a lower price than EFV/TDF/FTC.
Other future ARVs and strategies
Several other exciting advances might offer new options for treatment.
The first of these is the potential for ART to be given by long-acting (LA) injections rather than daily pills.
This research has always created a lot of interest and two drugs in late stage development show this can work. The two drugs are a new integrase inhibitor called cabotegravir LA and NNRT called rilpivirine LA. Both drugs have produced good results as oral drugs. Both are combined into the same dual injection, which only needs to be given every two months.
There are a few important cautions to be aware of.
The first is that the injection needs quite a large volume. Currently each treatment needs several injections into the buttocks. Even though most people reported discomfort from the injection, overall people in studies were happy with results compared to taking pills.
Secondly, these drug stay in the body for a long time. This makes it important to start with oral medication in case someone has serious side effects.
Thirdly, we need to understand how to safely stop long-acting drugs in order to minimise the chance of drug resistance. This will be especially important if there are problems with drug supply.
The following three drugs are also worth watching out for:
A new entry inhibitor (called fostemsavir).
A drug from a new class – a maturation inhibitor – currently called BMS-955176.
Very early results from a compound called EFdA. This drug might be available from a slow release deport that only needs to be replaced once a year.
Finally, tentative results from several small studies suggest that the properties of dolutegravir might enable this drug to be used in a unique way.
Early results reported that some people might be able to reduce their combination to a two-drug combination of dolutegravir plus 3TC. Even more surprising was that most people kept their viral load undetectable for up to six months after switching to dolutegravir as a single drug.
Together with the discussions earlier in this article on the cost of ART and the importance of wider access to ART, if larger studies show this reduced drug strategy to be safe, this will have global implications for how ART is used.
This could result in better treatment, using fewer drugs and which is therefore also less expensive. But this definitely needs further research before anyone tries this outside of a study.
Polly Clayden is the Co-founder of i-Base and an advocate, activist and journalist.
Simon Collins is a Treatment Advocate and co-founder of HIV i-Base.
Every day, I passed three funeral parlours on my 5km drive to work in central Durban. Shiny hearses lined up in the street, one behind the other. Fetching, taking, waiting.
When I moved to the city in 2001, death was everywhere. The city’s streets were filled with women wearing black and men with pieces of black cloth pinned to their sleeves.
In the rabbit warren of inner city offices, a proliferation of quacks offered expensive “immune boosters”. HIV was too raw and too stigmatised to mention, but the red ribbon accompanying their advertisements made it clear who their treatments were aimed at.
Over the years, I saw many elderly parents escorting their skeletal adult children into these offices, searching for something that would arrest their children’s rapid weight loss, diarrhoea, skin cancer, dementia and other AIDS symptoms.
By 2002, St Mary’s Hospital in Mariannhill outside Durban, was having a problem of abandoned bodies, according to the hospital’s superintendent, Dr Douglas Ross. Families were so overwhelmed by funeral costs that they were prepared to risk ancestral wrath, leaving their relatives’ bodies unclaimed in the hospital morgue.
Around half the patients admitted to St Mary’s medical wards ended up in the morgue, while tiny babies infected by HIV at birth died almost every day at the small hospital. Sister Philomena Pakade, who headed the paediatric ward, showed me a small brown exercise book filled with names with “RIP” written next to them.
“Children are dying like flies, more especially the very small babies. These little ones suffer so much. They have just come into the world and the world is so cruel to them,” said Pakade, who confided that she felt like quitting nursing as she could do nothing to save her HIV-positive patients other than alleviate their suffering.
At King Edward V Hospital, about 15 people died every day at the 1 300-bed facility – a staggering 450 deaths a month. Every day, around 240 outpatients came to the hospital with HIV-related problems. HIV was overwhelming the staff and hospital resources.
Later, the Medical Research Council found that reported deaths had increased by 57% between 1997 and 2002, while deaths amongst those aged 25 to 49 years had increased by 116%.
Despite Cabinet approval of a comprehensive AIDS treatment plan that would offer free ARVs in all districts of the country in November 2003, years of foot-dragging followed. Health Minister Manto Tshabalala-Msimang, encouraged by President Thabo Mbeki, did her best to elevate various herbal treatments and diets to the same level as ARVs, while Mbeki stressed the toxic side effects of ARVs.
As a series of improper relationships between politicians and business people offering dubious HIV treatments started to flourish, patients’ health was compromised.
Tshabalala-Msimang developed a close relationship with Tine van der Maas, who claimed that her diet – made up of garlic, lemons, ProNutro, olive oil and a supplement called “Africa’s Solution” – was an AIDS cure.
Tshabalala-Msimang invited Van der Maas to address all MECs, and she then went on to administer her diet as a “trial” to desperately sick AIDS patients in public hospitals and clinics nationally. Results of this “trial” were never made public.
Without understanding the irony, Tshabalala-Msimang screened a film shot at KwaNgcolosi outside Durban that promoted Van der Maas’ diet at a meeting to promote the launch of the country’s ethical guidelines for scientific research.
In nearby Pinetown, a taciturn former truck driver called Zeblon Gwala made a fortune selling a concoction called uBhejane, a bitter, smoky tasting liquid that was sold in unlabelled two litre milk containers. One of Gwala’s business partners was Dr Herbert Vilakazi, special adviser to the KwaZulu-Natal premier at the time, Sbu Ndebele. Peggy Nkonyeni, then Health MEC, openly promoted uBhejane, while Durban mayor Obed Mlaba sponsored its supply to a hospice in Inchanga.
Controversial German doctor, Matthias Rath, who promoted vitamins as an AIDS cure also had a friendly reception from Tshabalala-Msimang, and she introduced him to a number of influential people.
In a foreshadowing of the state capture South Africa is experiencing today, the country’s health department was “captured” by AIDS denialists and quacks at the invitation of the president. Scientists were sidelined and ignored, and scientific trials were replaced by personal testimonies.
But since 2008, when South Africa rolled out ARV treatment under Health Minister Aaron Motsoaledi, the ground lost has been regained. South Africa has the biggest ARV treatment programme in the world, and one-third of people on treatment live in KwaZulu-Natal.
The best advertisement for ARVs has been the reversal of deaths, forcing the quacks who promoted “cures” for AIDS to retreat into selling “cures” for flagging penises and lost lovers. But thousands of people died unnecessarily during a bizarre time when politics trumped science, thanks to the whims of a president and all those politicians who indulged him.
Kerry Cullinan is the managing editor of Health-e News Service.
It is the 20th anniversary of the International AIDS conference in Vancouver where the successful use of combination antiretroviral therapy for the treatment of HIV was first announced.
It is the sixteenth anniversary of the landmark International AIDS Conference in Durban where Nelson Mandela defied Thabo Mbeki noting that “in the face of the grave threat posed by HIV/ AIDS, we have to rise above our differences and combine our efforts to save our people” and calling for “large-scale actions to prevent mother-to-child transmission”.
It is the tenth anniversary of the Conference in Toronto which saw Stephen Lewis, then the UN Special Envoy on AIDS in Africa, denounce the South African governments deadly and denialist response to AIDS as “more worthy of a lunatic fringe than of a concerned and compassionate state” and as “wrong, immoral [and] indefensible”.
At each of these conferences civil society’s loud, unapologetic truth talking activism was crucial in breaking the log-jam, as it has been through the epidemic.
In the 1990s activists in the United States had organised angry and effective demonstrations to speed up research into treatment. They started the tradition of exposing pharmaceutical company profiteering from AIDS. When the treatment breakthrough was announced they refused to be pacified, immediately turning attention to the prohibitive cost of treatment for people with HIV in developing countries. One activist famously warned that “if AIDS treatment was a glass of clean water, 90% of people in developing countries who needed it would still not be able to access it.” On the back of this unpalatable truth AIDS activism went global.
Ten years later, in Toronto TAC activists trashed South Africa’s country exhibition to protest that our then Minister of Health, Manto Tshabalala-Msimang, had displayed beetroot and garlic cloves as treatments for people with HIV. We protested the death of a prisoner with AIDS and called on the world to show its rejection of AIDS denialism.
A few weeks later, back home in South Africa, talks began between TAC and the Presidency that led to the restructuring of the SA National AIDS Council (SANAC) and the 2007-2012 National Strategic Plan on HIV, TB and STIs that set a target of two and a half million people on ARV treatment by 2012.
These were examples of the uncompromising activism that has been the engine of the AIDS response for 30 years. Its importance is acknowledged in the UNAIDS-Lancet Commission report Defeating AIDS – Advancing Global Health * where it is stated:
“Activism constitutes a global public good, deserving investment commensurate with the role it plays in improving health outcomes. The independent, sometimes confrontational, legacy of activism should be revitalized and nurtured because it provides political incentives for attention and support to AIDS and health.” (my emphasis)
The report also recognises that:
“A global health movement can transform a lofty set of global goals into community realization. Civil society actors will need to find new ways to organise activism, while governments and international organisations must create conditions for activism – including direct investments, a free and open media, protection of rights to speech, and assembly to raise inconvenient truths – be they related to emerging pandemics or environmental health issues.”
But what is activism? And what is independent? In fact, what is this mysterious creature called civil society that everyone talks about? These questions need honest answers. They are also crucial in the context of a growing recognition by some donors, PEPFAR included, that activism must be funded.
They need honest answers because in recent years the smell of dollars and per diems has drawn a range of charlatans under the broad umbrella of civil society. Frequently these are people whose actions and motives cause division and confusion within communities as well as amongst governments and donors. They are also a waste of money.
So how to distinguish independent activism from its pretenders? I would argue that it has five intrinsic characteristics:
It is connected to impoverished and marginalized communities – the people still most at risk of HIV and AIDS. It does not usurp the voice of these communities but empowers and amplifies it. Activists come from and constantly return to their communities. They should be seen to be accountable, mandated and to share what they learn (and what they earn).
Activists are self-sacrificing rather than self-advancing. They do not use their positions to solicit jobs or cosy-up to power.
Activism is not a job. But it must be professional. Activists are thirsty for knowledge that can advance our cause, we follow evidence and base advocacy on facts.
Independence means not being beholden to or afraid of any power, public or private. It means independence from private companies and from governments, the willingness to speak out without fear or favour. Activists are not anti-government. In fact we try our best to build effective governments because governments have the power and the duty to save our lives and ensure our dignity. But democracy is our oxygen and we will protect or fight for it.
Activism is based on the continuous promotion of human rights, equality and social justice. This is not only something it does externally, but it must live its practice. It can’t tolerate racism, sexism or homophobia.
Put simply: Independent civil society activism is vital to the success of ending AIDS. It’s crucial to 90-90-90. Let’s put it another way: the world will not end AIDS or TB without activism.
In juxtaposition to activism there is slacktivism. Slacktivism is the opposite of almost all of these. In South Africa and elsewhere slacktivism has smuggled its way into the AIDS response by wearing camouflage. From my observations these are some of its features:
It likes proximity to political power. It seeks public stages and photo opportunities, mainly so it can advance its own self or organizational interests.
It creates organisations with rights sounding names, it talks about “our people”, and likes to claim to be the sole representative of people living with HIV.
But it is neither transparent or accountable to any community or constituency.
It loves to travel – by business class whenever possible. One South African ‘leader’ made 18 international trips in one year.
Finally, when it is challenged it claims that divisions are about territory or jealousy, giving the impression that petty-division is inherent to civil society organization. It is not. Genuine activism doesn’t need to fight over territory – the territory of need and human rights violations is bigger than us all.
As we consider the challenges that face the next phase of the AIDS epidemic we have to be honest with ourselves. Frank talk about these issues is not about causing division. It is about ensuring the legitimacy of NGOs and social movements, of Country Co-ordinating Mechanisms (CCMs) and civil society delegates to the important institutions that have been created to advance the response to AIDS and TB, in the eyes of the ordinary people. It is about ensuring that AIDS money is spent on AIDS.
Civil society must accept and embrace the same standards that we demand of others, particularly transparency and accountability. We call for an activist Code of Conduct, developed by ourselves, that donors can use as a basis of assessment.
TAC believes we have done our best for the last 17 years to hold ourselves to these standards. We are not without fault and we have not avoided mistakes. But when we have encountered corruption in our ranks we have expelled it. We have maintained openness. Our books have been audited every year. Our leaders remain elected and accountable to our members. Our organization is open for inspection. We call on all civil society organisations to embrace this standard.
Mark Heywood is a co-founder TAC, Director SECTION27
South Africa is gearing up for the International AIDS Conference, which starts on July 18th, Mandela Day. And nobody is gearing up more than the SA Government. That’s a very good thing.
AIDS denialism is dead! Long live AIDS? Uh? No, long live a united campaign to overcome HIV, TB and the social inequalities that drive them. But unity needs truth-telling. Worryingly, truth-telling about where we were with AIDS and where we are with AIDS sometimes seems in short supply. There’s a new denialism in the air and unless we nip it in the bud we are in trouble.
As part of its ‘good-story-to-tell’ offensive, the Presidency is on overdrive with media statements in the run up to the conference. These statements, welcome as they are, tell only half truths.
At the weekend, a statement came out reporting that the Deputy President, Cyril Ramphosa, would address the opening plenary of the conference with such luminaries as ….. Charlize Theron. The statement did not mention that he would also share the stage with civil society organisations like TAC—who have sacrificed just a little more than the honourable Charlize to get us to where we are.
Which seems to confirm that our government seems not to want TAC to engage in telling the others truths at the conference. This should worry us. TAC, very responsibly, has not fed the media with details of a recent incident in which smutty untruths were told to try and stop Nkhensani Mavasa, the TAC chairperson, from speaking on the opening plenary. An e-mail from the conference co-chair, Dr Olive Shisana, to all the members of the Conference Co-ordinating Committee a few weeks ago stated:
“I went … to a SANAC meeting chaired by the Deputy President and this was followed by the inter-ministerial committee last week, and the chorus is the same: “Withdraw Khensani Mavasa from speaking at the opening”.
Is this not just a little bit Hlaudi-esque?
Yesterday, the Deputy President published an important article in the Daily Maverick. It starts by paying tribute to Nkosi Johnson. Yet the truth is that Nkosi was not treated well by our government. During his life or after. President Mbeki rudely left before Nkosi finished his speech at the International AIDS Conference in 2000. The Department of Social Development has declined to fund Nkosi’s dream of a Haven for mothers and children like himself. An apology for the way young Nkosi was treated by President Thabo Mbeki 16 years ago might have been nice.
In the same article, Mr Ramaphosa, or more likely his article writer, bends time and truth to fit a new narrative about AIDS. In the truth-according-to-the-DP, in 2005 the government miraculously experienced a Damascan conversion in which its AIDS denialism just melted serenely away. In his words: “In 2005 South Africa embraced the problem with energy, rolling out a massive antiretroviral treatment programme through its public health system.”
Really? “Pull the other one…” as the Brits like to say…
That is not true.
What really happened was this.
In March 2003, TAC had launched a civil disobedience campaign to demand a national ARV treatment programme. The campaign was suspended after a meeting with then Deputy President Zuma, and the promise that an ARV treatment plan was in the offing. Then more delays. In late 2003, TAC threated to resume its civil disobedience campaign. This forced the government to announce its ARV plan. I know because I was I was phoned by , then the Head of the AIDS Directorate, in tears of relief, immediately after the Cabinet decision. I remember the moment well. I was driving in Fourways and nearly crashed my car.
But another delay soon followed. ARV treatment wasn’t provided officially until April 2004. Then, even when it did start, it was rolled out in as difficult, grudging, confusing and miserly way as possible, thanks to Dr Manto Tshabalala-Msimang and her lieutenant, the former DG, Thami Mseleku.
As a result, between 2004 and 2006, people continued to die at a rate of 1000 a day; and as a result, the conflict between TAC and the government intensified again. It peaked at another International AIDS Conference, this time in Toronto, where Manto made such a disgrace of our country with her exhibition booth of garlic and lemons that TAC activists trashed it.
While the head cat was away the mousy members of Thabo Mbeki’s cabinet decided enough was enough. A rebellion was provoked by Zola Skweyiya’s report-back on the conference in which he said he felt “ashamed”. At this point, the government sued for peace with TAC. I know this, too, because in September 2006, I was part of the meeting at Tuynhuys with then Deputy President Phumzile Mlambo-Ngcuka.
The result of these talks was a process of genuine consultation that led to SA’s first rational and reasonable National Strategic Plan on HIV, TB and STIs, launched in May 2007.
That, DP Ramaphosa, is when the change really began.
Am I raking over coals? No. In those two conveniently overlooked years, the truth is hundreds of thousands more preventable AIDS deaths took place. That is people with a capital P died unnecessarily. We knew quite a few of them. We were there throwing earth on their coffins. We owe the truth to them. They died at the hand of AIDS denialists and a government that couldn’t stand up to No 1. TAC doesn’t want awards, but we do want honesty about our past or we are doomed to repeat it.
TAC wants peace. TAC wants to do all it can under government leadership to stop AIDS and TB. TAC commends the sterling leadership of Dr Aaron Motsoaledi, our Minister, DG Precious Matsoso, Dr Yogan Pilay, Dr Anban Pillay, Dr Fareed Abdullah, Dr Gavin Steele, and others who work tirelessly to fix AIDS.
Raise your hats to them. They are model public servants. They all deserve a standing ovation. Really.
But, DP Ramaphosa—this is not time for self-congratulation and for burying the ugly truths. Next week, the ugly truths must be put on the table before the whole world and we must discuss what can be done to overcome them.
What is an ugly truth?
It’s ugly that, according to Stats SA, in 2015 2015 30% of all deaths were due to AIDS; that is 18 People with a capital P an hour, 440 People a day.
It’s ugly that, according to SANAC, 30% of all new HIV infections take place in girls and young women.
It’s ugly that Multi Drug Resistant (MDR)-TB has doubled in the last five years. These are truths of equal weight to the good-story-to-tell truths DP Ramaphosa wants to boast about.
You can find a great deal of truth in the Enhanced Progress Report on AIDS, a recent publication of SANAC. Here are some of the good truths and the bad truths it reveals:
Good truth: The mother to child HIV transmission rate has been reduced to 1.5%.
Good truth: Over 17 million people in SA had tested for HIV by 2012 and over three million people were on ARV treatment by 2015.
Bad truth: the percentage of adults adhering to their ARV treatment after 5 years is less than 50%.
Bad truth: the percentage of young people who have sexual intercourse before the age of 15 has not changed, whilst the number of people having sexual intercourse with more than one partner in the last 12 months has increased by 80%. Condom distribution has increased but condom use has not.
Bad truth: although we have conducted three million voluntary medical male circumcisions in the last five years, it’s not yet enough to contribute to an overall reduction in HIV incidence.
Ugly truth: rates of HIV infection amongst female sex workers range from 39 – 71%. Sex workers, that is young girls who have no other way to eat or dream, are still a prohibited people.
Ugly truth: South Africa still has no recent to measure gender-based violence.
Ugly truth: No municipalities have reported on having HIV programmes despite the fact that they are Ground Zero for the AIDS epidemic.
Finally, at this conference TAC will have to tell some truths about our government. We cannot not pretend to the world that we can separate AIDS prevention (both of the virus and the illnesses it gives rise to) from our deepening social inequalities and the infection of corruption.
One truth is, that if one of the only things South Africa did for the next two years was to fix our basic education system and focus on ensuring that girls and boys who are still at school have access to condoms, HIV testing, friendly clinics that provide ARVs, the offer of medical circumcision for boys and proper information about sex and sexuality, we would be on our way.
Is the need to tell half-truths about finding absolution? If it is, then sorry DP Ramaphosa, our government can never achieve absolution for so many lost lives. There can only be regret, some repair and a commitment to do everything in your power to protect the next generation from HIV. TAC will fight until the end of AIDS and we will do this hand-in-hand with our government, but to do so needs truth, transparency and accountability from all of us.
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