“You see yourself vanishing and you think: I’m going to die”

Photo by Giorgos Moutafis. Courtesy of Medecins Sans Frontieres.

Daneel Knoetze

26 November 2014

Andaleeb Rinquest remembers the moment she accepted, with certainty, the imminence of her own death.

Lying in a state hospital ward for extensively drug resistant tuberculosis (XDR TB) patients, in the painful final throes of the disease, she looked to her left. There her friend Jolene, similarly weak and skeletal, lay.

Jolene’s family were too poor to travel 50 kilometres from Atlantis to Brooklyn Chest Hospital in Ysterplaat, Cape Town, for regular visits. But, on that afternoon in October 2011 Jolene’s mother had come to take her daughter home – to see the family and, if it was to be, to die.

The prospect of seeing her mom excited Jolene. She managed a faint smile for the first time in days. As the two waited, Rinquest strained to stretch out an arm to where Jolene lay and handed her a piece of watermelon. She encouraged her to eat, to regain some strength for the journey home.

A nurse came in, pushing an empty wheelchair. Jolene’s mother followed close behind. She sat with her daughter for a moment, whispering. Then, she hugged Jolene and began to lift her. In the midst of that embrace, Jolene went into a seizure. Her mother stopped lifting and held Jolene as the shakes subsided. When she unwrapped her arms, the dead body of her 23-year-old daughter was left on the bed.

As quietly as she had come, the woman was led out of the room. Jolene’s body was soon gone too. She was one of seven people that Rinquest had seen die within the space of three weeks, for lack of effective medicines. And so, 28-year-old Rinquest resigned herself to her fate and decided to call for her own mother to take her home – to see the family and to die.

Andaleeb Rinquest remembers accepting that she would die soon from drug-resistant TB. Photo by Daneel Knoetze.

A slow killer

Before death, the physical decline of a patient like Jolene with an unchecked or drug resistant TB infection can be a lengthy and horrible experience, explains Professor Linda-Gail Bekker at the Desmond Tutu HIV Centre in Cape Town.

Drug-resistant TB is a slow killer, especially when such infections are not sped up by an immune system implosion associated with HIV. The feeling of general illness lasts, and worsens progressively, for months. The bacteria slowly wear away the tissue in infected organs, usually the lungs. The body replaces lost, healthy lung tissue with scars or abscesses, resulting in shortness of breath, a chronic cough and bloody mucus.

The slow release of small proteins called cytokines, which are the body’s response to invading pathogens, results in lengthy bouts of illness. Fevers, chills and night sweats often become commonplace. The cytokines raise your rate of metabolism, so you burn more calories. You also lose your appetite. Chronic weight loss is the result.

“In the old days, TB was called ‘consumption’ because it wore the body away,” says Bekker.

Drug resistant TB in South Africa: a growing epidemic

The public health threat presented by XDR TB was only widely realised after reports of an outbreak at a rural hospital in Tugela Ferry, KwaZulu Natal, in 2006. Fifty-three patients at the hospital were diagnosed with the disease. All but one of them died.

XDR, like multi-drug resistant (MDR), TB describes strains of the TB bacteria which are resistant to two of the most important conventional TB antibiotics. In addition, XDR TB strains are resistant to two other medicines which can be effective for treating MDR TB.

The World Health Organisation (WHO) estimated that 480,000 people developed MDR TB globally in 2013, of whom fewer than 100,000 started treatment. But treatment is lengthy, running for up to two years, and the treatment regimens are poorly tested. The medicines can have terrible side effects such as hearing loss, psychosis and kidney problems. By contrast, the six-month regimen for treating drug-susceptible TB, that most patients still get, is thoroughly tested and works well.

The burden of TB is particularly high in South Africa. The country accounts for the second highest rate of new TB cases in the world, owing largely to the fact that over 70% of patients are infected with HIV, making them more susceptible to illness from TB. It also has the highest rate of new drug-resistant TB cases in Africa.

Government figures show that from 2004 to 2012 annual MDR TB diagnoses in South Africa more than quadrupled to 14,161 cases. Annual XDR TB diagnoses have increased 18 times to the 2012 figure of 1,545. In each case, only about half of these patients were treated for drug-resistant TB.

It is a gap that the Department of Health wants to close and in March, Dr Norbert Ndjeka, the department’s director for TB and HIV, outlined a strategy for achieving this by decentralising treatment. This, Ndjeka hopes, will allow more patients to be treated in their communities - because of the state’s limited capacity for hospitalising patients.

The inefficacy of the current drug regimens remains an unaddressed problem, though. Ndjeka’s figures show that success rates, after two years of treatment, are low: approximately 40% for MDR TB and 20% for XDR TB.

The toll of treatment failure

Rinquest knows the psychological and physical toll that treatment failure takes on the thousands of South Africans reflected in these statistics. After weeks of night sweats, nausea and weight loss, she was belatedly diagnosed with MDR TB in May 2011. Cared for by her family, she tried to manage the disease, with a prescription of 20 tablets daily, from home. By August that year she had lost a third of her body mass. The flow of pus from a swollen gland in her armpit could no longer be stalled and she began having seizures of the type which marked Jolene’s death knell. So, through necessity, Rinquest consented to quarantine at Brooklyn Chest Hospital. Here the degradation of her body simply continued.

“They weighed us each day, and every day there was less of me on the scale,” she said.

“Thirty-nine-, 38-, 37 kilograms. You see yourself vanishing and you think: ‘The treatment is failing me. I am going to die.’”

In October 2011, a lab diagnosis confirmed that Rinquest’s MDR TB had mutated into XDR TB. Her daily regimen was upped to 28 pills, to augment a daily injection. She would start with the small pills, and progress to the bigger ones which were harder to swallow. She took sips of water and pieces of fruit to help with the swallowing. And then there was the regular disappointment of vomiting most of the medication into a bucket which she kept permanently next to her bed.

A neglected disease

The evidence on the effectiveness of drug-resistant TB regimens recommended by the WHO and used in South Africa and other poor countries is insubstantial. Yet the investment in research is far short of what is needed, warns the US-based Treatment Action Group (TAG) in its recent report on TB funding trends between 2005 and 2013. The actual global investment in developing new drugs in 2013 was only $255 million, and total worldwide TB research expenditure was less than $700 million, far short of what experts say is needed to make serious progress against the disease.

In May this year former XDR TB patient Phumeza Tisile, sponsored by Doctors Without Borders (also known as Medecins Sans Frontieres, or MSF), travelled from her home in Khayelitsha to the 67th World Health Assembly in Geneva to lobby for improved treatment for people living with the disease. In her address, supported by a petition of 55,000 signatures, Tisile spoke of her own terrible experience with XDR TB and the treatment’s side effects:

“I wouldn’t wish anyone to go through what I went through with drug-resistant TB. The drugs alone are a nightmare; becoming deaf because of a drug’s side effects is life-destroying. Many of those whom I’ve called my friends in hospitals are no longer alive. Either the drugs didn’t work, or they simply quit because the side effects from 20 tablets a day for two years are too much. Change is what I’m hoping for. Better drugs. No toxic drugs.”

Phumeza Tisile, 23 years, at her home in Khayelitsha, South Africa on August 16, 2013, the day she celebrated her cure from XDR-TB. Photo by Sydelle Willow Smith. Caption and photo from MSF website.

Yet TAG has warned of the pharmaceutical industry’s “long good-bye” from the field. The private sector spent 31% less in 2013 than it did in the record year of 2011. Several companies exited TB research entirely, a trend started by Pfizer in 2012.

“Drug development in the pharmaceutical industry is driven more by the market than need for new and better treatments,” says Marcus Low, of the Treatment Action Campaign (TAC).

“When it comes to ‘third world’ diseases – be it Ebola or drug resistant TB – there is a lack of investment, because those affected are generally poor. Pharmaceutical companies maximise profits by developing patented drugs. They are accountable to their shareholders, not to patients in need.”

The exit of pharmaceutical giants has increased the demands on large public sector research institutes like the US’s National Institutes of Health (NIH) and philanthropic organisations. But here too, funding is often skewed towards health needs in the regions - mostly Europe and North America - where the funders are based.

The NIH, for example, spent more than $1 billion on diabetes research in 2013. It spent just shy of $3 billion on HIV research, a continuation of a sustained and successful global funding surge started in the 1980s to tackle an epidemic which did and continues to affect people in wealthy countries - albeit much less than in countries such as South Africa. By comparison the NIH spent much less ($240 million) on TB.

Access to experimental drugs

The dearth of investment is coupled with a lack of urgency in fast tracking promising experimental drugs for drug-resistant TB through the stringent clinical trials generally needed for a drug to be approved. Three in particular - linezolid, delamanid and bedaquiline - have shown promise.

Treatment activists, like the TAC and TAG, now lobby for patients with drug-resistant TB to get access to such drugs before they are approved by regulatory authorities like the Food and Drug Administration in the United States and the Medicines Control Council (MCC) in South Africa. This is known as pre-approval access or compassionate use.

In 2012, bedaquiline, one of the first new drugs developed for TB in over 50 years, had looked promising in preliminary clinical trials, but a final confirmatory trial had not yet started. Treatment activists pushed the MCC to allow pre-approval access to the drug, which eventually reached over 150 patients in South Africa. In October 2014, the MCC registered bedaquiline. The Department of Health has promised to roll out the drug to 3,000 MDR TB patients within a year.

However, pre-approval access to delamanid is far behind. Japanese pharmaceutical company Otsuka, which has developed the drug specifically to treat MDR-TB, has refused to make delamanid available for wide compassionate use, even though the drug is actually further ahead in clinical trials than bedaquiline.

Days after the registration of bedaquiline, Low represented the TAC, which had been at the forefront of the campaign for bedaquiline access in South Africa, during a picket at Otsuka’s symposium at the 45th Conference on Lung Health in Barcelona. Activists from around the world called for “immediate broad compassionate use access” to delamanid.

Activists call for delamanid to be made available on a pre-approval or compassionate use basis. Photo courtesy of TAC.

The lobby for pre-approved drugs inevitably enters murky water. Low warns that the needs of drug-resistant TB patients, many of whom face certain death without regimens strengthened by experimental drugs, must be balanced against the unknown risks of improperly tested drugs. The need for conclusive medical trials does not fall away, he says.

This need is particularly relevant to bedaquiline. One trial suggested the drug may have serious safety concerns. A large trial that will definitively test the drug’s safety and efficacy will start in early 2015, but it is only expected to deliver results by 2022. “We don’t want to break the regulatory system, or for the potential risks of these drugs to remain unknown,” Low warns.

Another potentially lifesaving experimental drug is available for private purchase in South Africa. Observational studies and small trials of linezolid, an antibiotic developed by Pfizer and approved for the treatment of other bacterial infections, have shown it is effective against TB when approved regimens have failed.

By the time Rinquest received her first dose of the drug, in November 2011, she was at death’s door, weighing 28 kilograms. She could no longer speak, never mind sit or stand unassisted. In a final bid to save her life, Rinquest’s family had manically raised funds - through raffles, variety shows, and petitioning family and friends - to finance treatment in a private hospital. These costs topped R120,000 a month. The linezolid treatment cost R700 for one tablet that needed to be taken daily. Part of the cost of her treatment was covered by Rinquest’s medical scheme, after a tussle.

As far as drugs currently available go, linezolid is “the crux” in the treatment of XDR TB, says Professor Paul Wilcox, who treated Rinquest.

“Linezolid has proven to have an 87% success rate of sputum culture conversion (from positive to negative) in XDR patients where state-administered regimens have previously failed,” he said.

After seven months, Rinquest was healthy and discharged from hospital. But she had fallen behind on the payments and owed the hospital R450,000.

MSF has also reported success in the expensive and limited roll out of linezolid at its Khayelitsha TB clinic since 2011. In June this year, the MCC granted the organisation permission to prescribe a generic of the drug to patients in South Africa.

At R80 a tablet, the generics have given MSF the capacity to treat many more patients on the same budget as before. The MCC’s granting of special permission is welcome and commendable, says Julia Hill, MSF’s access advocacy officer in South Africa, but falls far short of what is needed and possible to tackle XDR TB in the country’s public health sector.

Backed by MSF, patient activists Tisile and Rinquest are spearheading a campaign to lobby the MCC for registration of generic linezolid. On 30 October, the pair handed a letter to Mandisa Hela, the MCC’s Registrar of Medicines, asking her to account for the stalling of generic linezolid’s registration in South Africa. The petition was signed by 100 patients, doctors and civil society organisations:

“We urge the MCC to register [generic linezolid] as a matter of urgency, or to provide urgent clarification on why the registration is being delayed.”

A fast-tracked application for the registration has been with the MCC since June last year. But seven months after the deadline, set down in regulations for how the MCC should deal with fast track approval applications, no decision or feedback has been forthcoming. The MCC did not respond to a request for comment.

“I’m healthy now, but I haven’t forgotten.”

“Linezolid saved me. The debt has been crippling, yes. But can one put a price on one’s life?” said Rinquest, who is due to complete what she hopes will be a final linezolid treatment in January.

“I’m healthy now, but I haven’t forgotten. I think about those people, my friends, who I saw dying at Brooklyn Chest Hospital because their bodies rejected the drugs. I could have walked away from this experience, but I have decided to stay and to fight for people who were not as fortunate as me or wealthy enough to be cured … for people like Jolene.”

Thanks to Erica Lessem of TAG for assisting with fact-checking. GroundUp takes sole responsibility for any errors.