/ 19 June 2014

TB: A dire struggle to keep up on path of increased resistance

Dr Jennifer Hughes says much of the treatment administered to TB patients is archaic.
Dr Jennifer Hughes says much of the treatment administered to TB patients is archaic.

There was recently a small celebration in one of the primary healthcare clinics in Khayelitsha near Cape Town. One more person was officially declared cured after more than two years of treatment for pre-XDR-TB.

XDR-TB stands for extensively drug-resistant tuberculosis. It is resistant to at least four of the drugs used to treat tuberculosis. Instead of the six-month treatment that is used for “standard” tuberculosis, treatment for XDR-TB is given for two years or more with drugs that are less potent, more toxic and much more expensive. Pre-XDR-TB is when the tuberculosis bug is resistant to at least three of the drugs used to treat the normal strain.

It may not seem especially significant for the locals who are used to the fact that, for many years now, patients with multidrug-resistant tuberculosis (MDR-TB), where the bacterium has become resistant to at least two tuberculosis medicines, have been diagnosed, treated, monitored, supported and, half of the time, even cured in the primary care clinics in Khayelitsha.

But for those who know the difference between MDR-TB and XDR-TB (MDR-TB is easier to treat than XDR-TB), this is hugely significant, given that the chance of a cure for someone with pre-XDR and XDR-TB is lower than 20%.

Siyabulela Qwaka was one of the earliest patients to be enrolled in a pilot project specifically aimed at improving outcomes among people with pre-XDR-TB and XDR-TB, and among those in whom MDR-TB treatment was failing. The pilot started just over two years ago in Khayelitsha and Médecins Sans Frontières (MSF) joined the local clinic staff to congratulate Qwaka for now been cured of this disease.

Shock of diagnosis
Tears pricked the eyes of all who listened to him as he recounted the difficulties of dealing with the shock of the diagnosis (“But I’m not even HIV positive”), the horrendous daily side-effects of the treatment, the stigma of being labelled a “bad TB patient” who brought the disease upon himself (despite never having had tuberculosis before), and the willpower needed to drag himself to the clinic every day for two years to wait for the pills, which he was told may or may not cure his disease.

The clinic staff and community workers who supported him in completing his treatment deserve to feel proud on this day. Qwaka was not always the easiest person to convince that this was his only option if he wanted to live to fulfil his dream of going to university.

But just as everyone was patting each other on the back, a recently diagnosed XDR-TB patient, Goodman Makhanda, stood up and gave a speech to remind us that this battle is far from being won. Makhanda’s voice was shaking as he expressed the anger inside him, and asked to whom he should best direct it. Makhanda wanted to know why Qwaka was so thankful.

XDR-TB patient Goodman Makhanda (David Harrison, M&G).

Was it because the doctors finally made the correct diagnosis of pre-XDR-TB only two months after he had been taking MDR-TB treatment (which was inadequate), or only three months after he first gave sputum, or in fact four months after he first came to the clinic with TB symptoms?

Was it because he was offered a drug regimen, which the doctors thought might work, but they couldn’t be sure, and he had to take it anyway and wait and see whether these were the last years of his life?

Was it because he was considered eligible that he qualified, that he was lucky to be in Khayelitsha so that he could get the drug Linezolid, which is too expensive for his own government to make available for people without medical aid?

Was Qwaka thankful because he was told to swallow 20 tablets every day for two years, and to expect to have numerous horrible side effects, which he had to just push on through, and count himself lucky because there were no other options?

Or in the end, was Qwaka thankful because he was not one of the other four people who started the same treatment at the same time as him, and who are all now long dead?

Makhanda wanted to know why, if there are thousands of people being diagnosed in South Africa every year, he had never even heard of drug-resistant tuberculosis (DR-TB). He is a diabetic patient who has attended his local clinic at least every month for many years; how can it be that the first time that he hears of DR-TB is when he is infected with it?

If this disease really is the killer bug that people get from just breathing, shouldn’t people be shouting about it from every clinic, taxi, shebeen, school and overcrowded shack in Khayelitsha? And shouldn’t they be demanding access to rapid diagnosis and effective treatment if they are unlucky enough to be infected?

Makhanda ended his speech by thanking God that at least he was diagnosed in a place where he has a slightly higher chance of cure, but it doesn’t mean that he is happy about it.

Pre-XDR-TB patient Siyabulela Qwaka, who was cured after two years of treatment. (Rowan Pybus)

Part of the reason I became a doctor was to make an impact in the lives of individual people, hopefully many people. Qwaka’s cure makes me happy to be a doctor, but the looks on the faces of the other patients, who started but didn’t finish their treatment journey with Qwaka, when they realised there really was nothing more I could offer them, sometimes make me wish I had become an engineer or city planner or school teacher instead.

How insignificant is the impact of doctors and nurses who have nothing to offer patients but a 20% chance (at best) to live.

How embarrassing for a government to have the means and resources to develop and deliver better treatment to combat a disease that kills but that can be cured, but not to have the political commitment to prioritise it.

How unjust for a doctor to have to decide between two individuals who is more deserving of a potentially life-saving drug, which is too expensive to provide for both. But I have been told that we should consider ourselves lucky to be working with DR-TB patients in Khayelitsha. We have, at least in theory, easy access and enough resources with the capacity to screen, diagnose and treat the majority of suspected tuberculosis and DR-TB cases. Many other areas of the world don’t even have access to a diagnostic laboratory test, never mind drugs to treat the disease.

Once patients have been diagnosed with DR-TB in South Africa, most of the World Health Organisation (WHO) recommended treatment options are available to treat patients, should they want the treatment. Most of them do when informed about DR-TB through the relatively widely available network of trained support workers.

Again, this access to information is a luxury, considering the resources available in many other countries with an equally high burden of the disease. For those patients with pre-XDR-TB and XDR-TB, there are plenty of stakeholders who are at least interested, aware and, sometimes, even committed to accessing the best treatment available in the world to offer them the best chance of cure.

And yet, despite all of these “luxuries”, treatment outcomes in South Africa still remain the same as, if not worse than, everywhere else in the world: a less than 50% treatment success rate, and a default rate of at least 30%.

The challenge is clear – we need better treatment regimens; treatment that actually works. We need treatment that hasn’t been dredged up from the Dark Ages and reused because “at least it is something”.

We need treatment that people can actually swallow and tolerate without fear of losing some of their bodily functions – over half of all patients suffer daily with vomiting, diarrhoea and nausea, and up to 30% of DR-TB patients have some level of permanent hearing loss. Treatment that isn’t a punishment or a prison sentence that takes years from people’s lives. Treatment that health departments can afford to provide to the thousands of people who really need it.

Alongside these regimens, the commitment should be to put systems and resources in place to ensure access to rapid diagnostics, which are available, to identify those in need of better treatment regimens. Without rapid diagnostic tests, it can take up to three months to diagnose the full extent of resistance of some tuberculosis strains.

These same systems should ensure that the treatment actually gets to all those who are diagnosed, and not only the lucky few who happened to be in the right place at the right time. Only then will people not be afraid to come forward to be tested for a disease, which does indeed belong in the Dark Ages.

So, even working in Khayelitsha, I don’t consider us very lucky at all. I’m tired of sticking plasters over gaping wounds. Give me something I can really work with.

Dr Jennifer Hughes is the Médecins Sans Frontières drug-resistant tuberculosis programme manager in Khayelitsha.

This article was published in the latest edition of the National Strategic Plan review report. The review is published quarterly by HIV advocacy group the Treatment Action Campaign and social justice organisation Section27. It critically evaluates the health department’s progress with achieving the goals of its National Strategic Plan for HIV, sexually transmitted infections and tuberculosis .

South Africa’s plan to fast-track TB treatment

South Africa has the third highest burden of tuberculosis (TB) in the world after China and India – about 1% of the country’s population develops it every year.

Although the number of patients started on treatment over the past four years under the national TB programme appears to be on the decrease, the number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) cases is increasing. The emergence of drug-resistant mycobacterium TB compromises the health department’s ability to address the disease.

We have the fifth highest number of MDR-TB patients on treatment, according to the World Health Organisation’s Global TB Report 2013. This is based on the number of MDR-TB patients in South Africa initiated on treatment in 2012, which was 6?494 out of 14?161 diagnosed MDR-TB patients. Our latest provisional report indicates that 10?263 MDR-TB cases were initiated on treatment during 2013.

We do not know yet how many MDR-TB cases were diagnosed by the National Health Laboratory Services (NHLS) for 2013, but we do not expect the figure to exceed 13?000 because the preliminary report of the NHLS shows that 7?271 MDR-TB cases were diagnosed between January and September 2013. Although this is a work in progress, it does appear that we are starting more MDR-TB patients on treatment, closing the gap between the number of patients diagnosed and the number of those who have started treatment.

Some key challenges include the centralisation of care in many areas of the country and the problems of treatment only being available at centralised points; poor treatment success rates and high treatment defaulter rates; and limited access to new drugs for drug-resistant TB.

What are we doing to address these challenges?

We are strengthening the decentralisation of MDR-TB services by organising workshops and meetings to draft and finalise policy on decentralisation and we have designed a tool for assessing the readiness of facilities, as well as a monitoring and evaluation tool.

We also support the development of provincial plans for decentralisation of MDR-TB care. Our target is to have one decentralised MDR-TB treatment site a district by 2016 and to strengthen community MDR-TB care. To date 38 of the 52 districts have at least one treatment site, but 14 districts don’t have any MDR-TB treatment sites. The number of treatment sites has increased from 11 to 63 since approval of the policy framework on decentralised management of MDR-TB.

The Western Cape, KwaZulu-Natal and the Eastern Cape are moving faster than other provinces. Recent grants from the Global Fund to fight HIV, TB and malaria and the United States Centres for Disease Control will help us to train nurses to initiate MDR-TB treatment. We are also aiming to have treatment linkage officers in each district to help us to close the gap between the number diagnosed and the number of patients started on treatment.

The treatment success rate has remained stagnant at 42% and the defaulter rate has been 20%, on average, for more than two years. There are many reasons for the low treatment outcomes, including poor linkage to care, poor tracing mechanisms and limited access to new drugs for treatment.

In terms of new treatment agents, I would like to comment on the use of Bedaquiline, Linezolid and Delamanid in South Africa.

Linezolid: this medicine has proven effective in improving XDR-TB clinical outcomes. The drug’s manufacturer Pfizer is not prepared to sell it to the government as TB treatment, as the company argues Linezolid is not licensed for this use (Linezolid is an antibiotic drug that has been on the market for several years for the treatment of bacterial infections such as pneumonia). At R9?000 a patient each month, Linezolid, sold under the trade name Zyvox, is costly as an XDR-TB treatment.

A company named Hetero has applied for registration of a generic version of Linezolid, which is likely to cost less than R3?000 a patient a month. South Africa’s Medicines Control Council (MCC) is reviewing the application for this product and has put it on the fast track. We are hopeful that Hetero will respond to all MCC queries satisfactorily and that the drug will be registered before the end of 2014. Linezolid is available globally through the Global Drug Facility, a partnership intended to make TB treatment more accessible.

Bedaquiline is in use under an open label trial (a clinical trial in which researchers and participants know which drug is being administered) within the programme. So far 74 patients have received Bedaquiline. I have been informed that the clinical committee of the MCC has approved registration of Bedaquiline in South Africa and we are awaiting formal communication from them.

Delamanid is not in use in South Africa. We are waiting for a guidance document to be released by the WHO within the next three months. My view is that Bedaquiline and Linezolid are within our reach. We will seek to use Delamanid in accordance with WHO guidance notes and the decision by our MCC. With these medicines available, we need to redesign our treatment regimens for MDR-TB and XDR-TB to include Linezolid and Bedaquiline. – Norbert Ndjeka

Dr Norbert Ndjeka is director of drug-resistant TB and HIV at the national health department.