CROI: Antiretroviral therapy reduces the high incidence of TB in South African children with HIV

Children with HIV in South Africa have an extremely high incidence of tuberculosis (TB), but antiretroviral therapy (ART) substantially reduces TB (suspected cases) according to a study reported at the Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver. (The presentation can be viewed or listened to here).

However, the benefit was not as clear-cut when looking at cases of confirmed TB. “There is some difference to the degree that doctors are willing to investigate children not yet on ART,” explained the presenter, Dr Neil Martinson of the University of the Witwatersrand.

This corresponded with another finding of the operational study: a greater tendency to treat suspected TB in children who were going to receive ART. Taken together, this may have represented another benefit of the ART rollout — the reversal of what Dr Martinson called “the pessimism effect,” when doctors under-investigate or under-treat TB because “there is nothing really to offer these children.”

TB and the South African rollout

“Community rates of TB in both adults and children are very high in South Africa,” said Dr Martinson “and rates of over a thousand per hundred thousand have been reported.” It is estimated that about 15% of the total TB case load is contributed by children up to 14 years of age in regions with a high burden of HIV and TB. But paediatric TB is relatively under-reported in South Africa and sub-Saharan Africa because most cases are smear-negative and thus go uncounted by National TB Control Programmes or the World Health Organization. However, a higher incidence of TB has been suggested by findings in autopsy studies and in studies performed in children admitted to hospitals.

With the national rollout of ART in South Africa, a 50-80% reduction in the incidence of TB has been observed in ART-treated adults with HIV. Since about 10% of those on ART in South Africa now are children, Dr Martinson and colleagues set out to see whether there has been a similar reduction in the incidence of TB diagnosis and the incidence of confirmed TB in children treated with ART when compared to those who have not received ART.

Methods

The study involved a retrospective record review from ART-treated and untreated children attending four South African ART clinics: three in Johannesburg and one in Cape Town. Three of these clinics were national ART rollout sites, and the fourth was a research clinic (the Perinatal HIV Research Unit in Johannesburg) where access to ART was initially funded by the French Government and then the US Emergency Fund (PEPFAR).

Children under 15 years of age were eligible if clinic visits were recorded at least twice every six months. Follow-up time started when the first CD4 percentage was recorded and stopped at the last clinic visit. Records were scanned for any mention of a TB diagnosis, the basis for that diagnosis, date(s) and duration of treatment. Confirmed TB required a diagnosis by smear, culture or biopsy. Children were temporarily censored while on TB treatment (defined as treatment for longer than one month). If ART was prescribed, the date of initiation and duration of treatment was recorded for a subset analysis.

Results:

Children receiving ART tended to be more immune compromised. However, despite this, they had dramatically fewer TB diagnoses. The incidence of TB in all the patients not on ART was 16.3 per 100 child years, which was reduced to 6.3 per 100 child years for those on ART, which represents a crude incidence rate ratio (IRR) of about 0.39 (95% CI 0.3-0.5). When just looking at the children who received ART, comparing the time before and after, this effect was magnified from 21.6 per 100 child years to 6.3 per 100 child years, crude IRR 0.29 (95% CI 0.2-0.4).

In contrast, “the effect was markedly reduced – both in the all patients and slightly less in the patients that had both ART exposures,” said Dr Martinson. Very few of the TB cases were actually confirmed by microscopy or culture. Only about a third of the suspected cases in children on ART had a confirmed TB diagnosis compared to about 18% of the suspected cases not yet on ART. Overall, the incidence of confirmed TB in all the patients not on ART was 2.9 per 100 child years versus 2.3 per 100 child years on ART, crude IRR 0.79 (95% CI 0.4-1.3). Looking just at the children who received ART, the incidence of confirmed TB was 3.7 per 100 child years while not on ART and 2.2 per 100 child years for those not on ART, crude IRR 0.59 (95% CI 0.3-1.09)

Some of the confirmed diagnosis of TB in ART treated children may have been a result of ART-associated immune reconstitution inflammatory syndrome (IRIS), which can ‘unmask’ TB previously subclinical TB. But as previously noted, many confirmed diagnoses were the result of doctors pursuing diagnostic investigations in patients who are being regularly seen for ART. This coincided with evidence that treatment for suspected TB cases peaked just before the initiating of ART treatment.

“In discussions with the doctors who were initiating TB and ART treatment,” said Dr Martinson, “it appears that the doctors are more willing to give TB treatment by itself when there is a suspected TB case than to wait till they are on antiretrovirals and then have to deal with treating children with both TB treatment as well as antiretrovirals.”

When stratifying for CD4% and viral load, the study found that the risk reduction of ART was sustained over all CD4 strata, but that there appeared to be a dose response effect with viral load. At levels of less than 400 copies/ml, the rate of TB fell to only 1.76 per 100 child years.

The reductions in risk of TB were consistent across all three government sites, but not at the research PEPFAR site, suggesting that the children at this site were receiving a somewhat different standard of diagnosis and care.

Baseline characteristics

The study included 992 children. At the start of follow-up, the median age was around seven years of age, CD4 percentage was about 17% and viral loads were around 40,000 copies/ml. Both sexes were equally represented.

Two thirds of the cohort received HAART for more than three months. The median follow up time was 9 months for those without ART and 11.5 months for those who received ART.

Study limitations

As a retrospective record review, this study has a number of limitations. For instance, TB case definitions may not have been as consistent as they would be in a prospective trial. Also, there were no data on mortality because there was no follow-up for children who did not return to the clinic. However, the results are consistent with data from other small studies conducted in the Côte d’Ivoire and Haiti and with what has been observed in adults on ART.