New dawn in TB prevention therapy

It is estimated that around 1.7 billion people on earth are infected with tuberculosis (TB). In these so-called latent infections, people have TB in their bodies, but they have the bacteria well enough under control so as not to get sick. The risk to these people is that the TB might “activate” and make them ill should their immune system become weak, which could for example happen due to HIV infection.

Without a broadly effective vaccine that could give protection for TB to either prevent TB infection, or prevent infection from activating into TB disease, currently, the best option for TB prevention is to treat such TB infections with medicine.

The benefits of using isoniazid, one of the oldest and most powerful anti-TB medicines, to prevent TB infection from activating have been known for years. Studies published recently have provided very compelling evidence showing that providing people living with HIV with isoniazid substantially reduces their risk of TB and of dying. Yet, uptake of isoniazid preventative therapy around the world has been very slow – with recent scale-up in South Africa being a notable exception.

Isoniazid can prevent TB disease when given daily for anywhere from six to 36 months, with nine months being most common. These days isoniazid is also available in a single tablet along with cotrimoxazole (an important medicine for preventing other kinds of infections in people with advanced HIV) and vitamin B6 (which must be given along with isoniazid to prevent isoniazid’d from damaging nerves).

The long duration of treatment with isoniazid might be one reason why uptake has been poor. Another is that people taking preventative therapy are by definition not ill with TB and might thus lack motivation to take the pills, especially when they come with potential side effects such as liver damage.

New shorter regimens

In recent months and years, three new options for TB preventative therapy have done well in clinical trials. The two common factors in these trials are that (a) the length of treatment is reduced and that (b) they all make use of a class of drugs called the rifamycins.

The most well-studied, and at this stage the most likely new regimen to reach public sector clinics in South Africa, is called 3HP. The 3HP regimen consists of three months during which two medicines are taken just once a week. The two medicines are isoniazid (often abbreviated as H) and rifapentine (abbreviated as P). Like with isoniazid alone, these must also be given with vitamin B6. This regimen is relatively well studied and is already included in the treatment guidelines of the United States Centres for Disease Control and the World Health Organization. Its use is recommended in both people with and without HIV infection, including children age 2 years and older. South Africa’s National Strategic Plan for HIV, TB and STIs 2017 – 2022 specifically mentions 3HP and commits to making this regimen available should further evidence support it.

The 3HP regimen has significant advantages over isoniazid alone. It has much less effect on the liver than the daily isoniazid regimen. Because it is so much shorter—just 12 weeks compared to months or even years of isoniazid—people may prefer it. Indeed, trials have shown that participants complete the 3HP regimen much more often than a longer isoniazid-based regimen.

One concern with the 3HP regimen is that rifapentine may have an interaction with a critical new HIV medicine called dolutegravir. We expect to learn in early 2019 about findings from a study designed to give a definitive answer on whether it is safe to use rifapentine with dolutegravir, and whether dosing changes to dolutegravir will be needed when using the two medicines together.

The other concern with 3HP is that rifapentine is still quite expensive, at USD $45 for the rifapentine portion of the 3HP regimen (this does not include the isoniazid or vitamin B6). The good news, however, is that rifapentine is off patent and more companies are expected to bring rifapentine products to market in the coming years – thus pushing the price down through competition. And even before then, this cost of preventing TB cases is far less than the economic and social costs of allowing the TB infection to progress to active disease and infect others.

A second new option is the so-called 1HP regimen. This regimen requires taking two medicines plus vitamin B6 a day for only one month. This is even shorter than the 3HP regimen, and the daily rather than weekly dosing may be preferred by people with HIV who are taking daily antiretrovirals anyway. The two drugs used in 1HP are the same as in 3HP – rifapentine and isoniazid – accordingly, the same pricing and drug interaction concerns seen with 3HP are also concerns with 1HP. A study reported in March 2018 found that 1HP was non-inferior to nine months of isoniazid in people living with HIV and resulted in fewer adverse events. 1HP is however less well studied than 3HP, and has not yet been studied in people without HIV – something that makes it unlikely that the regimen will beat 3HP to clinics.

A third new option is called 4R and involves four months of daily rifampicin pills. Rifampicin is of the same drug family as rifapentine but has been much more widely used given that, like isoniazid, it forms part of the standard four-drug treatment for active TB. A large study published in August 2018 found that this four-month rifampicin regimen is non-inferior to nine months of isoniazid. Like rifapentine, rifampicin does interact with some HIV medicines and can require dosing adjustments of antiretrovirals. Additionally, there were few people living with HIV in this trial, so it is not yet certain how well 4R works in this population.

One advantage of 4R is that Rifampicin is much less expensive than rifapentine. Another advantage is that this regimen could be good for people who cannot tolerate isoniazid. At four months, 4R is however longer than the rifapentine-based regimens.

In any case, it seems likely the days of isoniazid-only TB prevention are over, with shorter options that may help people start, and finish, therapy to prevent TB. For now, its most likely replacement is 3HP.

 

 

 

AIDS2018: Humans in the Age of HIV-Young people & SRHR

By Ngqabutho Mpofu

Nosipho Soga is a 19-year-old learner who hails from Kuyasa, a Khayelitsha township in Cape Town. She can best be described as bubbly, intelligent, engaged and relatively small for her age. It is clear that she is used to people questioning her age, assuming that she is much, much younger. So much so that she carries her Identity Document with her everywhere she goes just to prove that she is above the age of 18.

Nosipho has seen many of her peers fall pregnant and contract Sexually Transmitted Infections and HIV. It is their experiences, as well as the high prevalence of HIV in this group that has fueled her activism. According to South Africa’s National Strategic Plan for HIV, TB and STIs 2017-2022 adolescent girls still face high rates of HIV making up 37% of new infections with around 100, 000 new infections a year[1].

It is such concerns that encouraged Nosipho to join the Treatment Action Campaign (TAC), a membership-based organisation that advocates for the rights and interests of people living with and affected by HIV and TB.

Nosipho’s work is centered around ensuring that adolescent girls understand sexual and reproductive health rights and make sure they access these services.  TAC’s youth groups meet every Wednesday to engage on issues affecting them. These mainly relate to sugar daddies, and knowledge sharing in a context of very little sexuality education.

Nosipho argues  that “sugar daddies that engage in inter-generational relationships are a big part of the problem”. She locates this in South Africa’s socio-economic problems, arguing that many young girls resort to such relationships in order to eke out a more dignified existence in a context of extreme poverty, inequality and unemployment. These relationships typically involve a older man with greater resources and power and a significantly younger woman with no financial resources or social capital. Such distorted power relations have left many young women susceptible to intimate partner violence and less able to negotiate safe sex.

Furthermore, the short-comings of the Department of Basic Education’s Life Orientation programmes in schools, according to her, also further accentuates the problem because it is foundational in nature and does not teach learners much more than they already know.

In many instances learners are unaware of the numerous ways they can protect themselves from HIV and STI infection, as well as from unwanted pregnancies, placing them at great risk, she says.

In 2016, the State introduced the ‘She Conquers’ programme, with the intention of ensuring more economic opportunities for adolescent girls; reducing gender-based violence; significantly reducing teen pregnancies and ensuring access to youth friendly sexual and reproductive health (SRH) services. However, many youths do not know about it, says Nosipho. “we do not have access to youth friendly sexual and reproductive health services because we feel like we cannot talk about sex and sexuality to nurses at the local clinics without being judged.”

This article is part of a Spotlight special series on people who form part of so-called key populations.

[1] SANAC, “National Strategic Plan for HIV, TB and STIs: 2017-2022”, http://sanac.org.za/wp-content/uploads/2017/05/NSP_FullDocument_FINAL.pdf, accessed 16 July 2018.

AIDS2018: Humans in the Age of HIV-All about Love

By Ngqabutho Mpofu

Dressed in a Robert Sobukwe Dashiki and trendy shoes, Thando Jack draws

Thando Jack
by Joyrene Kramer

gazes from the mainly white upper middle-class folk in Cape Town who can afford to be taking a stroll in the Company Gardens during a week day. They obviously try not to but there is something about him that captivates them.

When we start engaging, it becomes clear that it Is a genuine sense of love and concern about members of a community that embraced him that makes Thando do the work he does. It is alarming figures such as those released by UNAIDS that spur him on. According to UNAIDS, Men who have sex with Men (MSM) globally are a staggering 24 times more likely to be living with HIV than the general population[1]. A 2015 study in South Africa found that 33.9% of gay-identified men in a research sample of 378 black MSM in the historic township of Soweto were found to be HIV positive[2]. This is compounded by the finding that between 88% and 94% of MSM in South Africa were reported to not know their HIV status, in a context where high levels of concurrent sexual partners among the Soweto cohort, for instance, was reported by 73% of respondents[3].

It is these figures and his own lived experience as an MSM that led 28-year-old Thando Jack to becoming an activist since his late teens. His extreme passion for ensuring that MSM access affordable, quality health care services is clear from the moment he starts engaging.

Working as a data capturer at a prominent men’s health non-governmental organisation (NGO) in Cape Town, South Africa, Thando is at the coalface of clinical consultations focusing on ensuring that data involving HIV tests results, on the treatment programme, including the rate of defaulting, and on the outcomes of TB test results are meticulously captured. The organisation runs programmes in Cape Town and Johannesburg, as a result of the high MSM populations and the corresponding high risk of infections in these two cities.

Despite many gains, including a progressive Constitution and law reform that allows the LGBTI+ community to enjoy the same rights as heterosexual people, Thando is worried about numerous factors that continue to affect MSM’s access to healthcare services in South Africa, including stigma. “Many health workers are still not informed or sensitive about MSM issues when providing healthcare despite the numerous interventions of organisations such as Anova Health and Health4Men, who conduct sensitization trainings in health facilities across South Africa”, says Thando. “Just from engaging with a clinician in history taking and explaining how you got anal warts or Gonorrhea, you can see from the reaction that you are being discriminated against. It’s sad. You would hope that someone who has the courage to get out of bed to seek medical health care is not treated that way”, he says.

Sensitisation trainings occur for health practitioners in both public and private practice. The programme has a website that directs MSM to health practitioners who are MSM friendly. These are services that do involve greater awareness, tolerance of others and less stigmatization of health seekers on the basis of their sexual orientation. For Thando, it is imperative that programmes such as these are amplified to reach areas beyond just Johannesburg and Cape Town, as MSM in other areas will be better placed to seek health care services knowing they won’t face the discrimination they often still face. “There is still a need for more public and private health care workers to undergo this MSM sensitization training throughout the country, as only a certain portion have gone through this programme”, he says.

Ivan Toms clinic in Cape Town, which Thando highlights as an essential health care facility in improving the fight against HIV amongst MSM and the site from which they work has about 13 000 patients who leave their own communities and local clinics from areas as far flung as Paarl, Atlantis, Fish Hoek, Wellington, as well as nearby areas such as Khayelitsha, Phillipi, Gugulethu and Kraaifontein in order to access critical health care services from practitioners who are MSM friendly. They acknowledge the importance of the right to food through providing food and/or energy drinks to underweight patients in their road to health[4].

Having been born and raised in Gugulethu, and realizing the continued stigma faced by MSMs in his community when attempting to access healthcare, a critical worry of Thando’s is that safe spaces such as the health facility he works for will have to shut down their doors as a result of potential funding cuts from prominent international donor organisations. This could quite conceivably result in many defaulting and in an increase in avoidable deaths of many people, some of whom make up his close community.

The external stigma; continued fear of help seeking among men and the potential funding crisis form a deadly cocktail that would effectively place the gains made among MSM through the ‘universal test and treat’ policy[5] from the national Department of Health in jeopardy.

For Thando, “when it comes to the needs of the MSM population and significantly reducing the rate of infections, it is important to find innovative ways and systems to help in fighting HIV. We need to keep up with new technologies and knowledge to do so, something we aren’t really doing at the moment.”

This article is part of a Spotlight special series on people who form part of so-called key populations.

[1] UNAIDS (2017), “Blind Spot: Reaching out to Men and Boys – Addressing a Blind Spot in the Response to HIV”, PDF.

[2] Lane T, Raymond HF, Dladla S, Rasethe J, Struthers H, McFarland W, et al. “High HIV prevalence among men who have sex with men in Soweto, South Africa: Results from the Soweto Men’s Study” in AIDS Behav. 2011;15(3):626–634.

[3] Ibid and Burrell E, Mark D, Grant R, Wood R, Bekker LG, “Sexual risk behaviours and HIV-1 prevalence among urban men who have sex with men in Cape Town, South Africa” in Sexual Health. 2010; 7 (2):149–153.

[4] Ivan Toms Clinic (2018), http://search.info4africa.org.za/Organisation?Id=83901., accessed 10 July 2018.

[5] Department of Health, “Re: Implementation of the Universal Test and Treat Strategy for HIV Positive Patients and Differentiated Care for Stable Patients”,  http://www.sahivsoc.org/Files/22%208%2016%20Circular%20UTT%20%20%20Decongestion%20CCMT%20Directorate.pdf, accessed 10 July 2018.

SA ahead of World Health Organisation in recommending new TB medicine

The Department of Health this week announced it will be making a new tuberculosis medicine available more widely than recommended by the World Health Organization (WHO). The department deserves credit for this brave decision that will both save lives and prevent many patients from suffering irreversible hearing loss.

The current WHO guidelines recommend that most people take a combination of medicines including an injectable until a change in treatment is forced by side effects

There has been substantial debate in recent years on how to best use the only two new drugs registered for the treatment of TB in the last half-a-century. Evidence for the use of these drugs have been slow in accumulating and in the generally conservative world of TB, people have opted to stick with the drugs they know, which are mainly drugs developed around the middle of the 20th century.

This conservatism in TB treatment has been particularly disturbing when it comes to the treatment of multi-drug resistant TB – that is TB for which two of the most widely used TB medicines no longer work. Even today, the WHO recommends treating people with MDR-TB with a set of old, and pretty toxic medicines. These medicines may save your life about half of the time, but they may also cause irreversible hearing loss – with studies estimating hearing loss in as many as 50% of people taking the so-called injectables (also known as aminoglycosides). Medicines in the injectable class include amikacin, capreomycin, and kanamycin.

The current WHO guidelines recommend that most people take a combination of medicines including an injectable until a change in treatment is forced by side effects. In practice, that often means that you wait until someone has some level of irreversible hearing loss, and only then do you take them off the medicines that cause the hearing loss. It should also be noted that the injectables literally refer to medicines that are injected into the body. The toll taken by months of daily, often painful, injections is surely something people should only be exposed to if it is truly essential to their health and survival.

Over the last few years many have suggested replacing the hearing loss-causing injectables with one of the two new TB medicines called bedaquiline. Bedaquiline is registered in South Africa, the United States, and a number of other countries, even though its phase III trial has not yet reported – usually drugs only get registered after phase III results are available.

Through some smaller studies, through pre-approval access, and an ambitious treatment programme in South Africa, we have learnt a lot about bedaquiline. We can say with a high level of confidence that it has a better side-effect profile than the injectables and on balance it seems likely that it is more effective than the injectables – although the latter point has not definitively been proven either way. Just this week South Africa’s Department of Health reported findings suggesting that people receiving bedaquiline were much more likely to be cured of MDR-TB and to survive the disease than people taking older medicines. We now know that bedaquiline’s impact on heart rhythms is not as clinically relevant as we feared it might be. We also now know that deaths that occurred in a phase II trial of the drug was most probably a statistical fluke. Maybe most importantly, bedaquiline is not injected and does not cause hearing loss.

Even so, as scientific evidence goes, the MDR-TB waters are still murkier than the waters in most fields of medicine. Yet, with only about half of people being cured with current treatments, waiting for the waters to clear up is not a luxury we have – we have to make the best decisions we can based on the currently available evidence. Some ongoing studies will clarify how to best use bedaquiline in the treatment of MDR-TB, but results from those studies will only start coming in in 2019, and some of the most important ones only in 2021.

It is in this context that the Department of Health’s decision this week to make bedaquiline part of the standard treatment for MDR-TB in South Africa should be seen. While the Department could probably have gotten away with waiting for the WHO to first update its guidelines, they did not. They applied their minds to the available evidence, considered the seriousness of the side effects, and made a decision that is both scientifically sound and humane. For this they deserve credit.

In February this year the Global TB Community Advisory Board and over 30 organisations wrote to the WHO urging them to update their guidelines to recommend the wider use of bedaquiline – but the response from the WHO has until now been lukewarm. New MDR-TB treatment guidelines are however expected from the WHO in the next few months. It is not a foregone conclusion that they will follow South Africa’s lead and recommend wider use of bedaquiline.

Most serious TB doctors and researchers I’ve spoken to have no doubt that if they were diagnosed with MDR-TB, they would prefer to be treated with a drug combination that includes bedaquiline and that excludes the injectables. A sober assessment of the limited evidence available supports this view – and yet the WHO has dithered and failed to update its guidelines. It is hard not to see in the WHO’s failure a reflection of the fact that poor people’s lives, and poor people’s hearing loss, is implicitly considered by many not to matter as much as those of wealthy people. Hopefully, in the year of the first UN High Level Meeting on TB, this underlying double standard in our global response to TB will be abandoned and we will start giving all patients the option of being treated with the same medicines we would choose for ourselves.

Some technical details

  • The regimen: The Department of Health’s statement this week not only indicates that bedaquiline will replace the injectables, but also that it will replace the injectables in the shortened regimen. In response to Spotlight, Department of Health Director of Communications Foster Mohale explained that the short regimen referred to is essentially that used in the STREAM stage I trial and that it contains the following medicines: Kanamycin, Moxifloxacin, Ethionamide, Clofazimine, High dose Isoniazid, Ethambutol and Pyrazinamide. We assume bedaquiline will replace Kanamycin in this regimen.
  • Timeline: Mohale told Spotlight that introduction of the new regimen will start on 1 July 2018 at “a significant number” of initiation sites that are ready and then “rapidly scale-up at sites that are not ready”.
  • Price: Mohale says the department is currently purchasing a six-month course of bedaquiline (188 tablets) for R 9950. “Between 2013 and 2015 we used a donation for 200 patients who were enrolled in the Bedaquiline Clinical Access Programme,” says Mohale. “In 2015 when we started purchasing bedaquiline the price was $ US 1000; by then 1 US $ was equal to R 9,95. The price has not increased, it has decreased from $ US 1000 to $ US 820.” Research conducted at the University of Liverpool suggests that bedaquiline can be sold profitably at a price of $98 for a six-month course.
  • Savings: Mohale claims that by introducing the shortened MDR-TB regimen the department is making huge savings on medicines and laboratory costs. “Laboratory tests that were done over a 24 months period are now done for 9 months for most patients. Also, medicines are administered for 9 months instead of 24 months, “says Mohale. “These gains will absorb the price increase due to bedaquiline.”

 

Note: Low is a member of the Global TB Community Advisory Board, which is mentioned in this article. He is writing in his personal capacity.

 

8 key findings from new district health report

The Health Systems Trust last week published the latest edition of the District Health Barometer (DHB). The DHB provides a wealth of district, provincial and national level data on a wide variety of indicators. Below we have picked out eight interesting national-level findings. You can access the DHB 2016/2017 report and an associated data file by clicking here.

1. In 2016 only an estimated 72.8% of people in South Africa with diagnosed TB were started on TB treatment. The rate was slightly lower at 68% for people with TB resistant to rifampicin (one of the standard first line medicines to treat TB). The fact that around 27% of people with diagnosed TB do not start treatment timeously puts the health of these people at risk and makes it more likely that they will transmit TB in their communities.

2. According to current treatment guidelines almost all patients with both HIV and TB should be receiving antiretroviral therapy (ART). According to the DHB only 28% of people in this group received ART in 2011 (partly due to different treatment guidelines at the time). This number climbed rapidly to 90.8% in 2015 and then dropped to 88.3% in 2016. We do not know whether this drop from 2015 to 2016 is real or whether it is due to a statistical or reporting error.

3. According to the DHB the annual death rate for people with drug-resistant TB (DR-TB) is around 23%. The rate of loss to follow up is around 17% and only around 50.5% of people with DR-TB are successfully treated.

4. There has been a steady rise in the number of male condoms distributed in recent years – growing from 15.7 per male over 15 in 2011 to 47.5 in 2016.

5. The percentage of total life years lost due to non-communicable diseases (NCDs) in South Africa has risen over the last four years from 34.5% to 38.2%. This provides further evidence of the growing threat of NCDs to people living in South Africa and to the country’s healthcare system and economy.

6. In 2016/2017 only 82.3% of infants received all the required immunisations in the first year of life. This was a substantial drop from the previous two years – something the report ascribes to both vaccine shortages and poor distribution.

“During 2016/17, immunisation coverage nationally was 82.3%, almost 10 percentage points lower than the national target of  92.0%. This  was a 6.9 percentage  point  reduction  from  the  immunisation  coverage  of  89.2%  reported  in   2015/16 and lowest during the last five years. Between 2012/13 and 2014/15 there has been a general upward trend, with  immunisation  coverage  increasing  from 83.6% in 2012/13 to 89.8% in 2014/15.  The  rate  then declined slightly between 2014/15 and 2015/16 but showed a huge drop in 2016/17. The main reasons that contributed to this decline were: the global  shortage of Hexavalent that lasted approximately nine months and was resolved at a national level in October 2016; in some  provinces and/or districts the available stock was distributed equally to different areas without considering the demands  and population targets, thus painting an extremely heterogeneous picture of coverage.” – DHB

7. In 2016 there was 18 119 stillbirths in South Africa. While there is a downward trend over the last three years, the DHB also reports a downward trend in live births – which suggests that the decrease in still births is at least in part due to a reduction in the overall birth rate.

8. According to the DHB the period from 2014/2015 to 2016/2017 has seen steady reductions in the following three child-health-related indicators: Diarrhoea deaths under five years (1 514 to 886), pneumonia deaths under five years (1 411 to 1 003), and severe acute malnutrition death under five years (1 851 to 1 188). While the trend is encouraging, it is nevertheless unacceptable that over a thousand children in South Africa died of severe acute malnutrition in 2016/2017.

Editorial: The new hiv & TB plan – Three months to get it right

Delays at the South African National AIDS Council (SANAC) has meant that the new NSP (National Strategic Plan) will now only be ready in March 2017. While the delay itself is not of any great concern, the kind of plan that will be produced by an unsettled SANAC and a weakened, unrepresentative civil society is concerning and brings into question the very idea of SANAC and the NSP. Already we are hearing rumours of a back-track on various things contained in draft zero of the NSP – including a back-track on the recommendation to decriminalize sex work.

There is a risk that over the next three months an NSP will take shape that will lack many of the targets and deadlines it needs to make an impact. It is understandable that government doesn’t want what they see as an external plan to interfere with their internal plans. But civil society should not accept this. We need leaders who can stand up to government, when needed work with them, but ultimately demand we do better on key issues such as sex work, condoms in schools, active case-finding for TB and community healthcare workers. Unfortunately, from what we’re hearing, civil society is capitulating on these issues without much of a fight.

Even though many critical issues will be mentioned in the eventual NSP, mere mentions are not enough. We need plans, timelines and budgets. We need an NSP that is highly focused and concrete. The decriminalization of sex work, for example,  has been on the agenda for years – but simply having it on the agenda is not enough. We need to have a roadmap from where we are now to an actual amendment in our laws. Without such a roadmap, we do not in fact have a plan.

Similarly, setting targets for providing more people with HIV treatment and helping people adhere to treatment is all good and well, but targets are not a plan. How do we improve treatment adherence? Do we need to employ more community healthcare workers to provide adherence support and to trace patients who default? We think we should. How do we provide differentiated care through adherence clubs, if we don’t pay people to run those adherence clubs? How do we ensure there are no drug stockouts which endanger trust in the health system. How do we build a Medicines Control Council that can cope with the workload or registering new drugs and investigation unlawful treatment and activities? These are the issues the NSP must map out in detail and force action on. It should make the case so clearly and convincingly that the Department of Health and treasury has no option but to fund it.

In the same way, we can say whatever nice things we wish about active case-finding for TB (possibly the most critical TB intervention we are not implementing), but if we don’t map out what that means in the real world then it will be just an another aspirational target. The NSP has to make it explicit that we can’t do active case-finding without people and that we need to train and pay people to start doing active case-finding. In two words Community Health Workers.

Another  critical area on which the new NSP must move the dial is HIV and pregnancy prevention in schools. We need a programme that is explicit about the right to comprehensive sex education and the right to access condoms – the latter being a right in terms of the right to access healthcare services.  But again there appears to be no clear plan on the table on how we get from here to there.

If the new NSP doesn’t deliver on these critical issues with detailed  timelines and budgets then it will be hard for us to support it. As has become clear in recent issues of Spotlight (previously NSP Review), our HIV and TB response is at code red. Our public healthcare system is in crisis. We need a plan that deals with this emergency seriously and based on the best available evidence. Anything less is not good enough.

A difficult political environment

The development of the new NSP comes at a very difficult time in South Africa’s history. Amid the Public Protector’s State Capture Report, the various scandals relating to the Gupta family, spurious charges against Finance Minister Pravin Gordhan and widespread calls for President Jacob Zuma to stand down, Deputy President and SANAC chair Cyril Ramaphosa has had a lot on his plate. In this fraught political context the new NSP has hardly elicited the national conversation or leadership that is needed – that it is needed is clear from the fact that around seven million people in South Africa now live with HIV and tens of thousands still die of tuberculosis every year.

To some extent, our HIV and TB response is also falling victim to the wider crisis in our politics. It is thus very encouraging that Health Minister Dr Aaron Motsoaledi and deputy Minister Joe Phaahla took a public stand against corruption when late in October they publically declared their support for Minister Gordhan. The spurious charges against Minister Gordhan has since been withdrawn. We trust that these leaders will not lose their jobs or be victimised for having taken this correct and principled stance. We will watch closely.

While the fight against corruption and state capture in South Africa is urgent and critical, the development of the new NSP is also critical. We urge the Deputy President, the Minister of Health, the rest of the national cabinet and all provincial cabinets to engage with both these urgent issues. Just like corruption, HIV and TB impacts the lives of millions of people in this country.

While the big picture politics are deeply concerning, there are also some signs that all is not what it should be at SANAC. The position of SANAC CEO Dr Fareed Abdullah was recently advertised amid rumours of a campaign to replace him with a person more compliant to the whims of some in government. Whether there is any veracity to these rumours we do not know, but it has reached us from various sources.

What is clear though is that in the current political context we need SANAC to be stronger than ever. Abdullah has done well in steering SANAC over the last five years and much of what concerns us at SANAC is beyond his control. Removing him now will threaten operational continuity at SANAC – something we cannot afford.

Civil society leadership crisis

While operational continuity is critical at SANAC, we urgently need new energy and ideas on the political side. This political energy has to come from civil society leaders at SANAC. Many people we have spoken to have expressed their disappointment with the failure of the current civil society representatives to raise critical issues impacting on ordinary people living with HIV and/or TB over the last five years.

Activists in SANAC have expressed their unhappiness with that is currently happening in SANAC, or more specifically in SANAC civil society.

There is a strong feeling that SANAC needs a civil society that is fully representative, that speaks with the voices of the marginalized, speaks with the voices of the poor and that the only way in which this can happen is if the current civil society is disbanded.

The new NSP provides an opportunity to make a clean start where we avoid the pit-falls of the past and ensure that people living with HIV and TB in South Africa feel they are properly represented. One way to avoid these pit-falls is to set some guidelines of what we expect from our civil society representatives.

To start with, we should insist that civil society leaders must represent constituencies and not just themselves (academics and other technical experts can of course contribute in their personal capacities to technical questions). Ideally, we want people who have been elected by affected people and who must account back to those people on what they have or have not done at SANAC.

Secondly, we should insist on transparency regarding the financial affairs of all civil society representatives. Where people represent NGOs, the finances of those NGOs should be open for public scrutiny – as is the case with all NGOs. If people do business with government, then that potential conflict of interest should be disclosed.

Looking back, there is much to be proud of, but what lies ahead is what matters now and what we do in the next three months will set the course of the next five years.

 

How do we get to zero TB?

By Salmaan Keshavjee MD, PhD, ScM
Department of Global Health and Social Medicine
Harvard Medical School

 

Tuberculosis (TB) has surpassed HIV/AIDS as the biggest infectious killer of adults worldwide.  In 2015, an estimated 10.4 million people became sick with the disease—one million of whom were children—and 1.8 million people died.  That’s one person dying every 18 seconds from a disease that has been largely treatable since 1948.

Why do so many people die from this treatable disease?  Mostly because they are not diagnosed in time or do not receive the correct care.  In 2015, more than 40 percent of the estimated number of people with TB were not diagnosed and received no treatment.  An estimated 580 thousand people became sick with multidrug-resistant TB (MDR-TB), disease caused by Mycobacterium tuberculosis resistant to the two main drugs of the first-line anti-TB treatment regimen; only 22 percent of those individuals received treatment and less than half were cured.  Because the disease is airborne, those who are not diagnosed or do not receive the correct treatment continue to spread the disease in their families, communities and places of work.

Until recently, many countries faithfully adhered to the World Health Organization’s (WHO) DOTS strategy to tackle TB.  Introduced in 1993, the DOTS strategy proposed a limited set of interventions for low- and middle-income settings, aimed at “controlling” the epidemic. For the most part, the approach ignored some of the pillars of TB epidemic control that had nearly eliminated TB in rich countries: active case finding (including the screening of close contacts); rapid treatment of people sick with any form of the disease, including drug-resistant strains; and prophylaxis for individuals with TB infection that has not yet progressed to disease (e.g. isoniazid prophylaxis therapy, or IPT).

Why was this the case?  Sadly, the reasons had little to do with science.  For example, as early as 1964, the WHO’s Expert Committee on Tuberculosis discouraged the use of IPT outside of rich countries, “arguing that cost, logistical difficulties, the likelihood of defaulting, and other concerns all made it unfeasible.” (Macmillan 2015: 195).  This decision was reaffirmed in 1974 by another WHO expert committee, which, despite overwhelming data showing the benefits of IPT from the work of George Comstock and others in the United States, deemed the use of IPT “irrational”.  It was again reaffirmed in 1982 because of fears that treating TB infection would divert resources away from tackling active disease.  The WHO and its partner, the International Union Against Tuberculosis and Lung Disease (IUATLD), argued then that “in practice [IPT] has virtually no role in developing countries.” (Ibid).  Similar arguments—based primarily on dogma about cost and the belief that countries outside the “global north” would not be able to deliver more than a rudimentary level of care to their populations—were made about active case-finding and about the treatment of MDR-TB.  Instead, the DOTS strategy relied on passive case-finding—waiting for the sick to make it to a clinic—as well as diagnosis with sputum smear microscopy, a low-sensitivity test ill-suited for the diagnosis of children, people co-infected with HIV, people with extra-pulmonary TB, and those with disease caused by drug-resistant bacteria.  While the policies of the WHO have changed in some of these areas, systems built around delivering the DOTS strategy have not.

The result of ignoring these important facets of TB epidemic control—both a moral and scientific failure—has been the death of millions and a largely unabated epidemic.  Over the last decade, the decline in TB has been paltry: roughly 1.5% per year. If this trend continues, this means that it will take approximately 200 years for the global TB rate to reach the level seen today in North America and Europe.  It does not have to take this long.  In order to change this trajectory, countries like South Africa, India, China, Russia, Brazil, Indonesia, Kenya, Peru, Pakistan and many others, must take the bold step of instituting a comprehensive package of tried and tested approaches to stopping the TB epidemic.

So what should be done?  This comprehensive approach, which has been outlined by scholars and practitioners from 11 countries in a series in The Lancet called How to Eliminate Tuberculosis, is conceptually simple, but requires that we rethink the way we are struggling against TB.  The series outlines how we should clearly know the TB epidemic, using data and deploying epidemic control strategies as needed to different hotspots.  It also outlines a strategy of three interlinked components: SEARCH, TREAT, and PREVENT.

search

SEARCH means to actively find people sick with TB, as well as those infected with TB but who are at high risk of becoming sick.  Finding those people who are already sick with TB is critical because they are infectious and continue to spread the disease in their families and communities.  Finding out who has been infected or exposed to TB—and who may later become sick—is also a critical part of searching.  Data have clearly shown that people infected with TB have at least a five percent chance of becoming sick with active disease within the first two years after infection.  That’s one in twenty people that will get the disease and continue to transmit the disease in families and communities, even after the original index patient has been treated.  Thus, stopping the epidemic means finding these people and offering them post-exposure treatment. Where does one find individuals at most risk of developing TB?  Again, the data are quite clear: people living in the household of a TB patient have a one to five percent chance of having active TB; those seeking care in general health care facilities have a five to ten percent chance of having active TB; and individuals receiving HIV-associated care have a one to 25 percent chance of having active TB.  There are other high-risk groups—such as people working in mines, garment factories, or spending considerable time in other over-crowded areas—but households and health care facilities are certainly an important place to start looking.

TREAT means ensuring that people sick with TB get the quickest correct treatment for their TB, regardless of whether they have a drug-sensitive or drug-resistant strain.  The correct treatment of the disease stops people from dying, from having long-term sequelae from the disease, and stops transmission.  Studies from the 1950s, 1960s, and even recently, have shown that if a sick person is started on the correct therapy—a therapy capable of killing the strain of TB with which he or she is infected—he or she is no longer infectious.  Part and parcel of this is ensuring rapid and ready access to new anti-TB drugs and fast-tracking research on shorter and more efficacious regimens.  One can never forget that TB leads to an almost certain death—like many cancers—so the risk of initiating treatment with new drugs or drugs with adverse events is far outweighed by the benefits.

PREVENT means engaging in a set of activities that will help stop the transmission of TB.  First, it is critical to ensure that infection control measures are taken in health care facilities so that TB does not spread.  Second, it means ensuring that individuals infected with the TB bacillus, but who are not yet sick with TB disease, receive post-exposure treatment that will prevent their infection from progressing.  Pathbreaking studies from the 1960s showed that prophylaxis after infection—coupled, of course, with active case finding and treatment of people sick with TB—not only helped bring down the rates of TB dramatically, but reduced TB deaths for at least 20 years after the intervention.

As we know, TB is a disease that moves preferentially among the poor, the malnourished, and the immunocompromised.  People with HIV coinfected with TB have a 5 to 10 percent chance each year of becoming sick with TB; malnourished people with a low body mass index (BMI) have a ten-fold risk of getting TB.  This means that treatment and prevention will require ensuring that people sick with TB and those receiving post-exposure treatment have enough food to eat, that they have access to appropriate housing, and that their co-morbid conditions (e.g. HIV, diabetes, malnutrition) are cared for.  Because TB is itself a driver of poverty, prevention also requires health systems to engage in a multi-sectoral approach, including linking people and families sick with TB to innovative poverty-alleviation mechanisms.

The interventions that are part of the SEARCH, TREAT, and PREVENT (S-T-P) strategy will take a major push, and many will be tempted to implement them piecemeal.  This would be a mistake.  Both global experience and mathematical models suggest that deploying these interventions in combination will rapidly lower both TB cases and deaths.  Creating systems capable of implementing the S-T-P strategy will require resources, and in many cases, reorganization and integration of activities with other programs.  If done properly this will not only move us rapidly towards eliminating the scourge of TB, but the systems developed can be used to give care to people with asthma, diabetes, hepatitis C, and a number of other diseases.  Taking the correct steps to end the TB epidemic is vital to building our collective capacity to provide high quality universal health care.

References:

Cavalcante SC, Durovni B, Barnes GL, et al. Community-randomised trial of enhanced DOTS for tuberculosis control in Rio de Janeiro, Brazil. International Journal of Tuberculosis and Lung Disease 2010; 14: 203–09.

Cegielski JP, Arab L, Cornoni-Huntley J.  Nutritional risk factors for tuberculosis among adults in the United States, 1971-1992, American Journal of Epidemiology 2012; 176(5):409-22.

De Cock KM, Chaisson RE. Will DOTS do it? A reappraisal of tuberculosis control in countries with high rates of HIV infection. International Journal of Tuberculosis and Lung Disease 1999; 3: 457–65.

Dye C, Glaziou P, Floyd K, Raviglione M. Prospects for tuberculosis elimination.  Annual Review of Public Health 2013; 34: 271–86.

McMillen, CW.  Discovering Tuberculosis: A global history 1900 to the present.  New Haven: Yale University Press, 2015.

Obermeyer Z, Abbott-Klafter J, Murray CJL. Has the DOTS strategy improved case finding or treatment success? An empirical assessment. PLoS One 2008; 3: e1721.

Ortblad KF, Salomon JA, Bärnighausen T, Atun R. Tuberculosis control for sustainable development. Lancet 2015; 386(10010): 2354-2362.

Rangaka MX, Cavalcante SC, Marais BJ, et al.  Controlling the seedbeds of tuberculosis: diagnosis and treatment of tuberculosis infection. Lancet 2015; 386(10010): 2344-53.

Theron G, Jenkins HE, Cobelens F, et al. Data for action: collecting and using local data to more effectively fight tuberculosis. Lancet 2015; 386(10010): 2324-33.

Yuen C, Amanullah F, Dharmadhikari A, et al. Turning off the tap: Stopping tuberculosis transmission through active case-finding and prompt effective treatment. Lancet 2015; 386(10010):2334-43.

 

 

TB: What the numbers tell us about political will

By Marcus Low

Last month the annual Union World Conference on Lung Health was held in Liverpool, United Kingdom. As always at this conferences, much was said about how the world needs to step up the fight against tuberculosis (TB) – about how we need new agendas and paradigm shifts.

Unfortunately, new data released at the conference and in the preceding weeks paint a very bleak picture of the global TB response. The severity of the crisis is unquestionable. Per the World Health Organisation’s Global Tuberculosis Report 2016, 1.8 million people died of TB in 2015, there were 10.4 million new TB infections in the same year and over half a million (580 000) of those cases were drug resistant forms of TB.

How is the world responding to this crisis? Well, according to Treatment Action Groups (TAG) annual report into TB R&D, not good. Their report reveals that the already low investment in TB research has declined even further in 2015. The entire global investment in that year was $621 million. This is less than a third of the $2 billion that the WHO estimates is needed per year. That the entire world together can’t even come up with this comparatively small amount (given the size of national budgets) is mind-boggling.

As Mike Frick of TAG recently pointed out in Spotlight, the situation is even bleaker when looking at high burden countries. The BRICS (Brazil, Russia, India, China, South Africa) have roughly half of the world’s TB cases and TB deaths, but only contribute 4.3% of public funding for TB research. South African universities received more TB research funding from the US National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation than from the South African Medical Research Council or other domestic agencies. With a Trump presidency in the United States, it is unclear whether even these NIH funds will be there in future. (For those who are interested, there is a petition calling for BRICS to triple investment in TB R&D.)

The inescapable conclusion is that, even though TB is killing their citizens, BRICS nations do not see TB research as a priority. This is fundamentally a political problem. Most people who die of TB are poor and not politically well-enough organised to advocate for a better TB response. And, unfortunately, with a lack of grassroots political pressure most politicians remain indifferent to TB – the one notable exception being South Africa’s Minister of Health Dr Aaron Motsoaledi.

India has more TB cases and TB deaths than any other country. It is the epicentre of the TB epidemic much like South Africa is the epicentre of the HIV epidemic. Yet, while the Indian government has made several encouraging announcements regarding its TB response, almost two years after making these announcements they have failed to implement many of the things they have promised. These include absolute no-brainers like daily fixed-dose combination TB treatment for people with HIV and the provision of appropriately dosed pediatric FDC treatment for children. When activists interrupted Jagdish Prasad, Director General of Health Services of the Government of India, he responded by telling media that the activists are “unstable” and “mentally unwell”.

But one wonders why it was left mostly to activists to call out India’s broken TB promises. For all the talk of paradigm shifts and new agendas, most of the TB establishment seems more committed to politeness and quiet diplomacy than to doing what it takes to bring about a paradigm shift.

This inertia may in part be explained by the fact that many in the TB establishment are from and live in countries where there is very little TB. Incidentally, as pointed out in a recent civil society letter, of the 10 Union World Conferences on Lung Health from 2007 to 2016, six were held in Europe (none of which were in Eastern Europe), two in Africa (both in Cape Town), one in North America and one in Asia. Mostly, the conferences are where the TB is not.

There is nevertheless some limited reasons for hope. Firstly, there are a number of good researchers and healthcare professionals dedicating themselves to TB research under often very difficult conditions. As with the very encouraging early results from a trial of a new XDR TB treatment, these efforts are already resulting in life-saving advances. We must urgently do more to support these researchers and to encourage more medical researchers to work in TB a big part of that will be finding more money for TB research.

Secondly, and getting back to TB’s bigger picture political problem, there appears to be a growing awareness among at least a small group of committed people that we need to politicise TB outside of these annual conferences. Two things stand out in this regard: the push for a UN High Level Meeting (HLM) on TB and the growth of the Global TB Caucus of parliamentarians. In both the HLM and in the work of the TB Caucus, it will be difficult to find the correct balance between staying politically correct and saying what needs to be said – for example in relation to India. As was the case with HIV, we will need bureaucrats, diplomats and researchers to step out of their comfort zones and to become activists.

As always, most governments and government officials will attempt to underplay the TB crisis in their countries and the short-comings in their own responses. We should not stand for such short-sightedness. The numbers make it clear that TB is an urgent crisis in the lives of millions. We should allow it to become a political crisis as well. Only then will we see the paradigm shift people keep talking about.

 

Less money for TB research

By Mike Frick

Treatment Action Group

The world spent less on tuberculosis (TB) research in 2015 than it did in 2009. This decrease in spending does not track a similar decline in TB incidence or mortality.

The World Health Organisation (WHO) recently announced that the TB epidemic is larger than previously estimated, a grim truth uncovered by improved surveillance data from India. More than 10 million people fell ill with TB in 2015 and 1.8 million died from the disease, making TB the leading cause of death from a single infectious agent globally. Yet research by the Treatment Action Group (TAG) shows that funding for research to develop the diagnostic tests, preventive interventions, and combination drug treatments needed to eliminate TB fell for the second year in a row, landing at US$620,600,596 – the lowest level of funding since 2008.

The TAG’s 2016 Report on Tuberculosis Research Funding Trends: No Time to Lose is the 11th in a series of reports that track annual spending on TB research and measure actual spending against the targeted funding called for by the Stop TB Partnership’s Global Plan to Stop TB, 2011-2015.

Only one third of needed investment

The Stop TB Partnership estimated that the world needed to spend $9.84 billion on TB R&D between 2011 and 2015 to end TB as a public health threat. Instead, actual funding for TB R&D amounted to $3.29 billion, just one-third of this target. Most alarming, funding for TB R&D fell in three of the last five years – by $36.5 million in 2012, $12.3 million in 2014, and $53.4 million in 2015. This downward trend belies the upward revisions to the extent of the TB epidemic over the same time period and points to an acute anemia of political will to address TB. The fact that spending on TB research is falling as estimates of TB mortality rise is a damning illustration of how governments have failed to mobilise against TB.

All sectors – including the pharmaceutical industry – have an obligation to fight TB by investing in the science required to end this epidemic, but the heavy lift will need to come from governments. (In 2015, the private sector spent $86.8 million on TB R&D, 40 percent less than the $145 million industry invested in 2011.) Over 60 percent of TB research funding comes from the public sector, and over half of all public money for TB R&D from 2011 to 2015 came from a single country: the United States. This degree of concentration has produced a precarious reliance on the political commitment of a single country.

BRICS: Half of TB, 4.3 percent of TB R&D

Countries that shoulder the heaviest burdens of TB are conspicuously absent from the list of leading TB R&D funders. Together, the BRICS countries (Brazil, Russia, India, China, and South Africa) accounted for nearly half of all TB cases and deaths in 2015, but only contributed 4.3 percent of public financing for TB R&D. In absolute terms, India led the BRICS countries with $11.1 million, followed by South Africa with $3.9 million and Brazil with $1.9 million. (Despite repeated requests, the governments of China and Russia did not return TAG’s survey.)

South African universities – which conduct some of the world’s most cutting-edge TB research – received more funding from the US National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation (Gates Foundation) than from the South African Medical Research Council or other domestic agencies.

In 2015, the South African Medical Research Council disbursed $3.1 million in support of TB research (some of these funds came from budgetary allocations by the Department of Science and Technology and the Department of Health). By comparison, the Gates Foundation gave $17.5 million to South African research organisations, and the NIH gave $3.9 million.

A crisis of political will

The growing recognition that the deficit of TB R&D funding is a crisis of political will owes a lot to the unflinching analysis of South African TB and HIV activists. After reviewing TAG’s 2015 TB R&D funding data, Lynette Mabote of the AIDS and Rights Alliance of Southern Africa offered this frank diagnosis: ‛There can be no end to TB without an end to political indifference in this R&D agenda.’

Mabote’s words echoed a point Anele Yawa, General Secretary of the Treatment Action Campaign, made in his closing speech at the 46th Union World Conference on Lung Health in Cape Town: ‛The lack of investment in TB is a political problem. It is political, because at its essence it is about governments not being held accountable for failing to respond to TB. We are not going to change it if we accept business as usual. We can’t win this battle if we don’t make it a political battle.’

Key UN processes

The tools, frameworks, and platforms for making TB R&D a political battle are starting to coalesce. In particular, two UN-led processes that culminated in September 2016 have created unprecedented opportunities for TB research activists to engage political leaders on the global stage.

The first is the final report of the UN Secretary-General’s High-Level Panel on Access to Medicines, which issued a formidable set of recommendations to address the market failures that have resulted in meager research funding for diseases like TB.

The second is a political declaration adopted at the first-ever UN High-Level Meeting on Antimicrobial Resistance in which UN member states expressed a broad intention to tackle the threat of antimicrobial resistance through joint action, including fixing the ‛lack of investment in research and development’.

The TB field should not let this flurry of ‛high-level’ activity dislodge its grounding in the organising and mobilisation work that must take place at the country level and in the communities hit hardest by TB. In the words of Mabote, there is a need for ‛actionable strategies which support R&D resource mobilisation’, both within countries and regionally.

Previous attempts to harness more support from the BRICS countries for TB R&D – for example, the 2012 Delhi Communiqué of the 4th BRICS Ministers of Health Summit – have resulted in mellifluous statements about the need to collaborate without any actual commitments of funding. Future statements of intent must come with all the ingredients of accountability – clear targets, action plans, and timelines – that have previously been missing, and empowered civil societies in the BRICS countries and elsewhere must ensure that promises to support TB research are followed by a real increase in funding.

 

Ten patents on two TB drugs

An online tool launched last week sheds light on what patents have been granted for which medicines in a number of developing countries. While the tool is still a work in progress, it is a massive step forward for the transparency of patent status information in South Africa relating to medicines for HIV, tuberculosis (TB) and hepatitis.

The tool called MedsPaL was developed by the Geneva-based Medicines Patent Pool. It can be accessed at www.medspal.org

TB kills 1.8 million people per year and is currently the infectious disease that kills most people on the planet. After 50 years of stagnation, two new TB drugs – bedaquiline and delamanid – have recently been developed. While trials to determine their optimal use are still ongoing, they seem set to revolutionise the way TB is treated, especially drug-resistant forms of TB (DR-TB).

Bedaquiline patents in SA

A search on MedsPaL shows that South Africa has granted five different patents on bedaquiline. The base patent was granted in 2005 and will expire in 2025.

Two so-called ‘new use’ patents were granted in 2006 (for treatment of DR-TB) and 2007 (for treatment of latent TB). South Africa currently grants patents for mere new uses of existing medicines, even though this is not a requirement under international law and these two patents would not have been granted in a number of other countries.

A process patent (2007) and a new formulation patent (2009) were also granted – the latter expiring in 2029, four years after the base patent. New formulation patents are mere reformulations of existing drugs and contains no new active pharmaceutical ingredient. Argentina, for example, does not grant such new formulation patents. India only grants them when they provide a therapeutic benefit.

Delamanid patents in SA

MedsPaL also finds five patents on delamanid in South Africa. We see a similar pattern as with bedaquiline. A base patent was granted in 2005. The base patent was followed by a new use patent (for the treatment of TB) in 2006. There then follows what appears to be two new formulation patents – delamanid in combination with other TB drugs (2008) and delamanid compositions (2007).

As with bedaquiline, South Africa is under no obligation in international law to grant these new use and new formulation patents. Should we wish, we could change our laws to prohibit such secondary patents.

The fifth patent, granted for ‘delamanid intermediate compounds’, only expires in 2032 – more than seven years after the base patent.

Secondary patents like these eight patents on bedaquiline and delamanid often delay generic competition. Due to this lack of competition the prices of medicines in South Africa are often higher than prices for the same medicines in countries with laws that restrict secondary patenting.