One of the things that was so shocking about the initial outbreak of XDR-TB in Tugela Ferry was that 98% of XDR-TB patients coinfected with HIV died, with a median time of death of only 16 days from the time of specimen collection for DST — well before a diagnosis of drug-resistant TB could be obtained.25
Since that time, there has been some debate on whether the prognosis of M/XDR-TB is always so consistently bad in people with HIV and how much can it be improved by early case detection, and aggressive treatment with second- or third-line TB treatment and ART?
One thing to keep in mind is that, according to the recent WHO surveillance report, “less than 3% of the estimated total number of MDR and XDR cases of TB receive treatment according to WHO recommended standards.” For the remaining 97% of 440,000 estimated people with M/XDR-TB, (most of whom are undiagnosed) outcomes can be expected to be poor. WHO estimates that MDR-TB caused about 150,000 deaths in 2008.26
Standards for treatment of MDR-TB differ widely between countries, but even for people who live in the European Union, receiving an MDR-TB diagnosis was strongly associated with the risk of dying from any cause (adjusted OR=3.9, 95% CI 3.3–4.6) after adjustment for confounders such as age, sex, and previous anti-TB treatment. According to the recent WHO MDR-TB surveillance report, the overall success rate for MDR-TB treatment was 60% (95% CI 55–66%) (roughly half of the remainder die or fail treatment, while the other continue treatment or are transferred). These results were probably strengthened somewhat due to the efforts of a programme known as the Green Light Committee, which was established to increase access of appropriate second-line TB therapy for people with MDR-TB.
XDR-TB can take even longer to recognise, and effective treatment regimens are more difficult to assemble. Along with Tugela Ferry, some of the earliest reports were of poor outcomes, such as in Estonia.27 However, a number of programmes have reported better success treating XDR-TB. With aggressive treatment, a project set up in Tomsk, Russia achieved a cure or treatment completion in two-thirds of the people with MDR-TB (n= 579) and almost half of those with XDR-TB (n=29).28
The programme was the result of a partnership between the regional TB programme, local prison services, and the NGOs Partners in Health and the Open Society Institute, who equipped a laboratory to carry out DST. Individual treatment regimens (ITRs) were chosen using a standard algorithm based on DST results and their previous treatment history. The rate of mortality in this small cohort was only 7%. Some of the participants were prisoners, the remainder were hospitalised for the period they were on parenteral therapy.
In a South Korean study, involving 155 people, 132 with MDR-TB and 27 with XDR-TB, 66% of the participants were cured or completed treatment — and there was no difference between MDR-TB and XDR-TB in positive outcomes.29 Again early aggressive treatment with an individualised tretament regimen based on drug sensitivity testing (including at least 4 effective drugs), was associated with better results. In addition, surgical resection, a procedure in which lung tissue containing infected lesions or cavities is surgically removed, was performed in subjects who were not responding to treatment (including almost half of the people with XDR-TB) and was associated with improved outcomes. For the most part, treatment was provided on an outpatient basis.
Mitnick et al reported similar results in a study from Peru that included 651 subjects, 48 with XDR-TB and 603 with MDR-TB.30 Based on treatment and contract history, the initial treatment regimen was empirical and then individualised based upon DST results with the goal of using at least 5 drugs to which the individual was susceptible, including cycloserine, an injectable drug, and a fluoroquinolone. 29 (60.4%) of those with XDR-TB completed treatment or were cured, which was almost as good as in MDR-TB (400 patients (66.3%)). Community health workers supervised daily ambulatory treatment, though patients could be hospitalised if warranted.
Another Peruvian study described poorer outcomes when regimens for people with XDR-TB were started before diagnosis and DST results, with 17(46%) cured, 8 (22%) deaths and 11(30%) who either failed or defaulted treatment.31 However, in 14 XDR-TB cases who received a diagnosis before ITR treatment initiation, 10 (71%) were cured and the median conversion time was 2 months.”
Notably, none of the people with XDR-TB in the Tomsk, Korean or Peruvian studies had HIV — and even when it isn’t cured, the course of disease seems to be somewhat tempered by aggressive treatment.
“Unlike XDR tuberculosis in populations with high rates of HIV, most patients in our cohort with poor treatment outcomes did not die, but continued to be ill (treatment failures or defaulters),” wrote Keshavjee et al.
“Our data show that in the absence of HIV, XDR-TB is a treatable disease,” wrote Bonilla et al.
In an editorial that accompanied the report from Tomsk, Drs Helen Cox and Cheryl McDermid, who work with Médecins Sans Frontières in South Africa noted, “We should be cautious in our hope to attain such success rates in settings with a high prevalence of HIV.”32
But in South Africa, outcomes seem worse — even in people without HIV. According to a study from the Western Cape, which included 486 people with MDR-TB who started treatment, only 49% were cured, while 29% defaulted, and 14% died even though less than 10% were HIV-positive in the cohort.33
Another study presented at the 2nd SATB Conference analysed relative survival and found a very high rate of mortality among people with MDR-TB and HIV.34 The study included 2079 people with MDR-TB who enrolled in a standardised MDR-TB treatment programme in South Africa between 2000 to 2004, and followed for up to two years. HIV status was only available for about two-thirds of the participants, but 26.65% were known to be HIV positive, and these had a 6.183 excess hazard ratio (95% CI 3.223-12.86). Of course, not all of these deaths are necessarily attributable to MDR-TB (especially over a couple of years of follow-up) since HIV status is an independent risk predictor of mortality.
In the Tugela Ferry cohort, Dr Moll shared the results of an analysis of M/XDR-TB survival from 2005-2007, which found very poor outcomes when the analysis includes people who had drug-resistant TB that wasn’t diagnosed in time for treatment initiation.
“At 30 days, there was an MDR-TB mortality of 40% and an XDR-TB mortality of 50%. So really, before these patients could be started on treatment or before their result actually was available to us as healthcare workers, these patients had already demised. The overall MDR-TB mortality was 71% and the XDR-TB mortality was really high at 83%,” he said. But he also presented a separate analysis for survival after sixty days — after culture and DST result come back and more effective treatment can be initiated.
“Sixty days is important because that is more or less the time that we get our culture results back and the time that we can initiate treatment on these patients. By then, the survival after sixty days for MDR is 60% and your survival for XDR is 43%. These numbers would be very similar to the numbers that you would be getting from the tertiary hospitals - in other words, these are patients that have survived up to the time that their results come out and they survived to the time where you can initiate treatment. There’s already a survival bias for these guys that reach the tertiary hospitals.”
This was a reference to Dr Dheda’s recently published study that found somewhat better outcomes overall in 174 people diagnosed with XDR-TB elsewhere in South Africa, with a 12-month mortality rate of about 36%, and an overall mortality rate of about 42%. Fifty-two percent of the cohort was HIV-negative but there was no difference observed in mortality between people with or without HIV.
“I’m not really sure, why, even in the HIV patients, our mortality was not as bad as in the Tugela Ferry outbreak,” said Dr Dheda during another presentation. “I think those patients did have more advanced immunosuppression. There may be strain differences, the drug resistance profiles may be very different. The issue of [what TB drugs] were available etc. So there’s a whole bunch of reasons… we found no significant difference in death in HIV compared to HIV-uninfected patients, but I think this is just a bias of our retrospective studies. It’s very likely in fact that many HIV-infected patients died very quickly and were not captured by our study.”
However, those who made it into the study had much higher CD4 cell counts than the people in Tugela Ferry and many went on to ART anyway. About 29 out of 82 people with HIV started on ART with a median CD4 cell count of 277 (160-365), while those who did not had a median CD4 count of 477 (170-477). But despite that high CD4 cell count, those who started ART had dramatically fewer deaths (0·38, 0·18–0·80; p=0·01).
“Highly active antiretroviral therapy, despite its overlapping toxicity and adverse effects with antituberculosis drugs, and the high pill burden, substantially improves survival in patients with concomitant HIV/AIDS and XDR tuberculosis, and was generally well tolerated. Our data suggest that highly active antiretroviral therapy should be used at an early stage in patients with HIV infection and XDR tuberculosis."
Note, earlier this year, South Africa announced that all M/XDR-TB patients with HIV infection qualify for ART regardless of CD4 count.
Having more effective drugs available to add to a treatment regimen also made a difference. Dr Moll noted that in Tugela Ferry, there were clear differences in survival depending upon how many drugs a person was resistant to.
“As you increase the number of drug resistance patterns that the person has, the mortality increases until you get the worse mortality of the six-drug resistance pattern,” said Dr Moll.
Or in other words, the more resistance there is, the fewer effective drugs in the treatment regimen. Of note, 2nd-line DST had been discontinued in 2002 in South Africa, following the implementation of the WHO-recommended standardised MDR-TB regimens (rather than individualised treatment regimens). But following the outbreak in Tugela Ferry, 2nd-line DST again became available and in January 2007, capreomycin and para-aminosalicylic acid (PAS) also became available for treatment.
Over time, survival could also be improving. In the Tugela Ferry cohort, one-year MDR-TB survival was 76%, in 2005. By 2007, it had improved to 55%. XDR-TB survival at one year went from 85% to 75% in 2007.
“By year, the mortalities of MDR-TB have definitely improved,” said Dr Moll. “We started treatment earlier as we found the cases earlier and as we put the patients on treatment earlier. But the difference was not so marked with XDR, just because of poor treatment options.”
“The more drugs you used in the regimen the better the patients did,” said Dr Dheda of his study. He noted that later in the study, the drug moxifloxacin became available for treatment in the Eastern Cape and some NGO-supported institutions — and had a significant impact.
“No matter how we analyse the data, whether in HIV-positive or HIV-negative, and by doing all sorts of sensitivity analysis and limiting the data and correcting with all sorts of things — moxifloxacin still came out as an independent predictor of survival in these patients, which by definition are fluoroquinolone-resistant. So there is in fact data suggesting that there’s incomplete cross-resistance within the fluoroquinolone class,” said Dheda.
But even though Dr Dheda’s cohort had better outcomes than in Tugela Ferry, he is no optimist about treatment. In addition to having a much worse survival than the studies in Peru, the culture conversion rate was only 19% (33/174). There was no difference in culture conversion in HIV-infected and HIV-uninfected people). The median time to conversion was also much longer (only 70% of those who had a culture conversion had done so by six months) — compared to culture conversions within two or three months in Peru.
Dr Dheda said that 14 of the culture conversions were in the Western Cape, and they have recently gone to see what had happened to those people.
“About one-third of those patients have died (most of these patients are HIV-negative) and another third in fact have reverted. So in fact even if your patient converts with XDR-TB, frequently culture reversion may occur in the South African setting,” said Dr Dheda. In the South African setting, the outcomes are poor and the disease, in my opinion, is virtually untreatable and this is despite adherence to therapy, accessibility to surgery and intensive therapy.”
Dr Moll concurred. “MDR-TB survival improves after diagnosis because there are treatment options available. XDR-TB survival does not improve, and the lack of effective treatment options leaves patients to suffer the natural history of TB disease.”
Dr Dheda theorised that perhaps the long duration of TB and prior TB treatment before XDR-TB diagnosis could be a factor that could explain why even HIV-negative South African outcomes are worse. One clear negative predictor of culture conversion in the study was weighing less than 50 kg. This raises questions about wasting and malnutrition. One audience member remarked that nutritional support might be an essential adjunctive therapy, and may actually be the real reason why industrialised countries achieve better outcomes.
But it is worth pointing out, that perhaps the hospitalisation model of care is partly to blame for the poor outcomes — and there is a chance that adopting community-based care in South Africa could speed the time to getting on effective treatment (rather than waiting for a bed to become available), and provide the person with M/XDR-TB with more love and support.