The growing problem of multidrug-resistant (MDR) tuberculosis threatens to derail TB control efforts unless there is greater investment in control and diagnosis, TB experts warned this week in the run-up to the 38th World Lung Health conference, which opens tomorrow in Cape Town, South Africa.
This year’s conference is taking place in South Africa in order to highlight the growing challenge of drug-resistant tuberculosis in the regions of the world most seriously affected by HIV.
Last year’s discovery of an outbreak of extensively drug-resistant TB among HIV-positive patients in the rural KwaZulu Natal town of Tugela Ferry rocked the worlds of TB and HIV treatment, and highlighted the need for greater integration of TB and HIV care.
“XDR TB is a wake-up call to ensure a better future of HIV treatment by strengthening TB control,” said Dr Haileyesus Getahun of the World Health Organization Stop TB department, speaking at a workshop on XDR and MDR-TB in the context of HIV, organised by the Treatment Action Group and the Stop TB Partnership.
The XDR outbreak has now spread to every province in South Africa, and two cases have been identified in Mozambique, Dr Lindewe Mvusi, TB director of the South African department of health, reported at the International Union Against Tuberculosis and Lung Disease African regional meeting on Wednesday.
Four hundred and eighty-one cases have now been identified in South Africa, 188 in KwaZulu Natal, 157 in Eastern Cape and 64 in the Western Cape, with 281 deaths to date. Two hundred and thirty-five patients are currently receiving treatment in hospital, while 18 patients have been discharged to receive directly observed therapy in the community following conversion to a smear-negative state.
Although extensively drug-resistant tuberculosis has been spotted before, notably in China, India and the Russian Federation, this is the first time it has emerged in a region where HIV prevalence is high. The consequences have been particularly bleak in people with HIV, said Dr Neel Gandhi, part of the research team that identified the Tugela Ferry outbreak.
Almost all HIV-positive patients died within weeks of being examined for suspected tuberculosis, often before the results of sputum tests could confirm tuberculosis, and XDR-TB was confirmed retrospectively in many patients.
The Church of Scotland hospital in Tugela Ferry has seen little improvement in survival rates since the initial outbreak was identified in April 2006, Dr Gandhi said this week.
Where has the XDR-TB outbreak come from? Although there’s little doubt that the current outbreak is due in large part to transmission from person to person, particularly in health care settings, and that proper implementation of infection control measures could greatly reduce the incidence, the initial XDR case must have developed as a result of the evolution of drug resistance in persons receiving first and second-line TB treatment.
Molecular analysis of the XDR-TB strains present in Tugela Ferry patients has been able to uncover the gradual accumulation of resistance to more and more drugs. The road to XDR-TB in KwaZulu Natal began around 1994, when patients first began to develop strains resistant to all first-line drugs. As the decade went on, these drug-resistant strains, circulating in the community, began to accumulate resistance to additional drugs used in second-line TB treatment, until by 2001 the first strain classified as extensively drug resistant is now known to have been present in a patient in KwaZulu Natal.
But at the time no one knew just how much drug resistance was already present in some TB patients due to the lack of drug sensitivity testing.
The critical step appears to have been presumptive treatment of patients who had failed first-line TB therapy, using a standard regimen of second-line drugs.
Why should it have emerged in KwaZulu Natal? Probably because the province has consistently had the lowest TB cure rate in South Africa; just 45% of patients who commenced TB treatment were pronounced cured in 2006, compared with just over 70% in the Western Cape province.
A national drug sensitivity survey carried out in 2001/2002 showed that although the highest prevalence of MDR-TB per capita occurred in the northern provinces of Mpumalanga and Limpopo, the largest numbers of cases of multi-drug resistance were found in KwaZulu Natal and the Western Cape.
In addition, KwaZulu Natal has the highest HIV prevalence in South Africa, in excess of 30% in many communities, compared with levels closer to 10% in the Western Cape. HIV-positive people are particularly vulnerable to TB, and likely to have a faster and more virulent course of MDR-TB.
All these factors explain why KZN was the site of emergence, but what’s still unclear is whether the outbreak spread across the country from the province, or whether greater vigilance coupled with drug sensitivity testing uncovered a phenomenon that was emerging simultaneously in every province of South Africa.
Other countries in Africa have reason to be concerned about the potential for home-grown outbreaks of XDR-TB. The World Health Organization estimates that alongside South Africa, Nigeria and Ethiopia are the hotspots for MDR-TB in Africa, followed by Tanzania, Malawi, Zambia, Rwanda, Mozambique and the Democratic Republic of Congo.
Countries in southern and central Africa are currently investigating whether XDR-TB is present, but surveillance will be hampered by the severe shortage of drug sensitivity testing. Few laboratories are equipped to do it, the equipment is expensive and trained staff are thin on the ground.
For most countries, the likelihood that XDR-TB is present will be present is governed by the extent to which patients already have access to second-line TB treatment.
Second-line TB treatment is expensive ($1500 - $4000 for a course of treatment), it’s hugely labour intensive and requires hospital beds to be set aside for six to eight months until the patients achieves conversion to smear-negative. Just under 40% of TB programmes in Africa and Asia currently include MDR TB treatment as part of their routine activities, says Dr Haileyesus Getahun of WHO.
The WHO and Stop TB Partnership has set a target for the expansion of MDR-TB treatment from 30,000 patients worldwide in 2007 to 1.6 million in 2015. The target is based on the estimated number of patients who fail TB treatment and develop drug resistance to components of the first-line regimen.
Unless efforts to control MDR-TB succeed, said Dr Mario Raviglione, director of WHO’s Stop TB department, “MDR-TB will replace the drug-susceptible strain as the dominant strain. There are countries in the former Soviet Union already approaching 15 – 20% [of new TB cases MDR] today.”
But, says Dr Rhehab Chimzizi of Malawi’s National TB Programme, “What is slowing us [in MDR response] is laboratory capacity. We have one lab to do drug sensitivity testing and sputum culture for a country of 12.8 million people!”
Until countries can carry out drug sensitivity testing, their requests for free or subsidised second-line drugs are likely to be turned down by WHO’s Green Light Committee, which approves requests for second-line TB drugs based on the capacity of a country to preserve the efficacy of those drugs.
Currently, drug sensitivity testing is not only expensive but slow. It can take five to six weeks to establish whether a TB isolate is resistant to rifampicin or isoniazid, or both, often leading to presumptive treatment with an inappropriate combination of drugs that can serve to increase the level of drug resistance.
Tests of a new method of diagnosing isoniazid and rifampicin resistance without the need for culturing TB bacteria are currently underway in southern Africa, and if successful, could lead to the approval of a new diagnostic method by WHO within a year.
This would have the potential to speed up MDR treatment, if the investment in laboratory standards takes place now.
But, as Dr Mario Raviglione points out, unless donors begin to invest in combating the MDR-TB crisis now, we will fall further and further behind in the fight against MDR-TB. Earlier this year WHO and the Stop TB Partnership issued a call for $2.15 billion to back an extensive plan to combat MDR and XDR TB. So far, he says, there is a funding gap of close to half a billion dollars in 2007, despite the fact that more than 400,000 MDR-TB cases are expected to be diagnosed this year alone.