Tuberculosis

CROI 2016: South Africa XDR-TB Epidemic Due to Transmission Rather than Viral Evolution

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A study in KwaZulu-Natal, South Africa, evaluating the social networks as well as clinical and genotypic data from individuals with extensively drug resistant tuberculosis (XDR-TB)has concluded that transmission -- in both hospitals and households -- has been the primary driver of the XDR-TB epidemic in the province, according to a presentation at the annual Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston.

"We identified epidemiologic links, either person-to-person or hospital-based, for 30% of study participants, indicating that transmission is happening in both community and healthcare settings," presenter Sara Auld from Emory University said on the final day of the conference.

Alarmingly, the findings also suggest that there could be a large pool of latent XDR-TB in the community that could still become active disease -- the epidemic is far from over. The risk posed by ongoing transmission of the drug resistant strains highlights the need for better TB prevention and focusing on improving infection control.

Background

XDR-TB involves resistance to a minimum of 4 of the most potent first- and second-line TB drugs. Its treatment is complex, costly, can cause severe side effects, and is successful only about a quarter of the time.

South Africa has one of the world’s highest burdens of TB and drug-resistant TB, compounded by the concurrent HIV epidemic. In 2006 there was an outbreak of XDR-TB detected at a rural hospital in Tugela Ferry in KwaZulu-Natal, which drew widespread international attention due to its extremely high mortality rates, which ranged from 50% to 80%.

TB drug resistance generally evolves due to inadequate treatment regimens or incomplete adherence to treatment, but once a drug-resistant strain emerges, it can be spread by airborne transmission from person to person. Determining how XDR-TB cases are occurring can help public health officials more effectively prevent the disease. If resistance TB is evolving, more resources should be devoted to adherence support and better TB regimens, but if it is being transmitted, health departments should focus on early diagnosis and better infection control measures to prevent its onward spread.

At last year's CROI Auld and her colleagues shared data showing that 69% of the XDR-TB cases in their study had never been treated for multidrug-resistant (MDR) TB -- which meant that they would never have had the opportunity to develop resistance to second-line drugs -- and therefore had to have contracted an XDR-TB strain via transmission. Genotypic data showed that 84% of the cohort had a matching genotype with another study participant, which again is an indication of transmitted resistance.

Knowing this, the researchers decided to perform a cross-sectional study in order to characterize where and how XDR-TB was being transmitted.

Study Design

The study enrolled patients diagnosed with XDR-TB as determined by culture and drug-susceptibility testing in KwaZulu-Natal from 2010 to 2014. Participants, or if deceased their family members, were interviewed about basic demographics, and previous TB and HIV history. They also completed a social network questionnaire in which they named all of their contacts at home, work, and any other location where they spent more than two hours each week, and were asked to report the TB status of their contacts. Additionally, they were asked to report all hospitalizations in the 5 years before the interview.

TB isolates from all participants underwent genotyping with targeted sequencing of gene regions commonly involved in resistance. Whole genome sequencing was also performed on the isolates.

The researchers conducted a social network analysis, which involved defining the participants' epidemiological links. A person-to-person link was either a direct or indirect connection between 2 study participants. When 1 participant named another, it was considered a direct connection, and an indirect connection was defined as 2 study participants both naming a common intermediary. These connections were determined based on matching name, sex, and age.

Hospital-based links used 2 criteria:

Study Results

Between August 2011 and November 2014 there were over 1000 cases of XDR-TB diagnosed in KwaZulu-Natal. The study included 404 of these.

More than half (59%) of study participants were women and the median age was 34. About three-quarters of participants were HIV-positive, of whom 76% were receiving antiretroviral therapy at the time of study enrollment. The median CD4 count was 340 cells/mm3 and half had suppressed viral load. 11% were deceased at the time of enrollment.

In the social network analysis, the 404 study participants named 2901 contacts, with a median of 7 contacts per participant. The vast majority (79%) of these contacts were from their homes, but many were also from the workplace and other locations such as churches and schools. 293 (10%) of the named contacts had prior or current TB and 25 were reported as having XDR-TB. Person-to-person epidemiologic links were identified for 59 (15%) participants.

Auld described one example of a contact network in one large family spread out over 3 separate households. The genotypic data showed that their XDR-TB strains were identical or very closely related.

Looking at the hospital networks, close to 80% of participants reported a hospitalization during the previous 5 years. Nearly a third had been hospitalized at more than 1 hospital. Overall, participants had stayed at 54 hospitals across the province, and the mean length of stay was 2.9 months.

Nearly 40% of participants were hospitalized prior to collection of their XDR-TB diagnostic sample during a vulnerable' period. The stays of about half of these participants (18%) overlapped with other study participants.

Clearly, this does not explain all of the transmission linkages, but the study was not able to enroll even half of the XDR-TB cases diagnosed in the province and many XDR-TB cases probably went undiagnosed, as patients may have died before being diagnosed.

Conclusion and Implications

"XDR TB remains prevalent and widespread in KwaZulu-Natal, South Africa, despite effective HIV programs with good virologic suppression in our cohort," said Auld, and our data also point to a large potential pool of future XDR TB as the 404 enrolled study participants had many named contacts and hospitalizations."

In order the curb the epidemic, Auld believes the province must focus on improving infection control by:

"Lastly, there is an urgent need for research on treatment regimens for latent XDR-TB, as preventive treatment will be critical to controlling this epidemic," Auld concluded.

3/4/16

Reference

SC Auld, JC Burst, B Mathema, et al. HIV-Associated XDR TB Is Transmitted in Households and Hospitals in South Africa‚Ä®. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 157.