IAS: Botswanan study finds low concentrations of TB drugs common in HIV-positives, predict TB treatment failure

A pharmacokinetic (PK) study conducted in people on directly observed tuberculosis (TB) treatment in Botswana calls into question whether the standard TB drug dosing is really adequate for all populations, particularly among people with advanced HIV living in sub-Saharan Africa.

The study, which was presented today at the 4^th IAS Conference on HIV Pathogenesis, Treatment and Prevention in Sydney, Australia, found that low concentrations of TB drugs were common in the population, regardless of HIV status.

However, when people also had advanced HIV disease, concentrations of some of the TB drugs were significantly lower — which could have contributed to poorer treatment outcomes. However, having a low level of pyrazinamide, in particular, was independently associated with having a worse outcome on treatment.

Background

First-line TB treatment has for many years relied chiefly on a combination of four drugs: rifampicin, isoniazid, ethambutol and pyrazinamide, but the pharmacokinetic profiles of these medications were typically established in healthy adults in Europe and the US.

Over the years, lower than expected levels of some TB drugs have been reported worldwide, associated with gastrointestinal illnesses, drug-drug interactions, patient demographics and HIV infection. This could potentially lead to prolonged infectiousness, treatment failure and/or death as well as the development of drug-resistant TB.

“Given this, we think it is very important that population-specific pharmacokinetic norms be established for those in whom they are relatively unknown, and who make up the majority of cases in the TB epidemic today, mainly people living with HIV and AIDS in sub-Saharan Africans, ” said Dr. Sekai Chideya of the US Centers for Disease Control and Prevention, who presented the study’s findings.

Furthermore, she believes that the emergence of extensively drug resistant TB (XDR-TB) indicates a pressing need to reassess how the PK parameters of TB drugs affect patient outcomes worldwide.

So she and her and colleagues performed a study to determine the incidence of sub-therapeutic drug levels among adults with TB (both HIV-infected and uninfected) in Botswana, to look for associations between patient risk factors and low drug levels, as well as the associations with poorer outcomes.

Between 1997 through 1999, the study enrolled consenting adults with TB at Gaborone, Botswana’s largest public outpatient clinic, who agreed to have an HIV test and who had initiated TB treatment within the previous seven to 13 days.

Participants were hospitalised, and fasted for eight hours before receiving all four TB drugs simultaneously. Serum was drawn at 1, 2, and 6 h after TB treatment dosing. Specimens were then frozen and shipped to a US laboratory that specialises in drug level analysis (using high performance liquid chromatography, however this was only recently performed). “Low drug levels” were defined using previously published reference points for the maximum serum drug levels (C_max).

Patients were then discharged and monitored regularly for 18 months for either treatment failure (defined as either being sputum-positive after six months of treatment or showing no clinical improvement after 6 months on treatent) or death during TB treatment.

Results

The final sample size was 225; 69% were HIV-infected and none were taking antiretrovirals. The median CD4 cell count was 269, (606 in the HIV-negative patients and 189 in the HIV-positive).

Low concentrations of rifampicin occurred in 84%; ethambutol in 39%; isoniazid in 37%; and pyrazinamide in 5% of patients. However, the median C_max in people with HIV was significantly lower (p<0.04) for rifampicin and pyrazinamide.This was mostly powered by those with CD4 cell counts < 200 (93% of those with CD4 cells below 200 had low rifampicin levels, vs 80% in those with CD4 cells above 200, p=0.005).

27% of the people with low CD4 cell counts had poor treatment outcomes, vs 11% in the HIV-negative group and 12% in the HIV-positive subjects with higher CD4 counts. In a multivariate analysis, having a CD4 cell count ≤ 200 put people at a higher risk of a poor outcome (Odds Ratio 3.2 (95% confidence interval 1.1- 11.7, p=0.3).

In a multivariate analysis, having a low concentration of pyrazinamide was also a risk factor for poorer outcome (OR 7.7 (95% CI 1.8-3.3; p = 0.003). After controlling for HIV status, and CD4 cell count, the relative risk for treatment failure was 5.7 (95% CI 1.5-20.7) and for death during treatment, 4.5 (95% CI 1.5-13.3).

Discussion

The study is somewhat unique because it is a prospective cohort with a rather large sample size (most PK studies are much smaller). However, the results may look particularly bleak because of the very high mortality rate due to HIV (no one was receiving antiretroviral treatment). Also, the study only evaluated PK on one day during the course of treatment.

The importance of pyrazinamide was rather surprising, although it should be noted, that low levels generally occurred within the context of the other drugs being low as well. It however, appeared to be the proverbial straw that broke the camel’s back. “We’re still not quite sure why,” Dr Chideya said but she suspects that when the drug is low, it may be more difficult to sterilise mycobacteria from some parts of the body.

According to Dr Chideya, the low levels were not associated with poor gut absorption in these patients — and appeared to occur in those with normal liver function tests. This suggests that there could be some change in drug metabolism brought on by HIV.

This does not mean that she recommends increasing the dose of any of these drugs (in fact, this could cause unwanted toxicity and may not have the desired affects on serum drug levels anyway). Nevertheless, it suggests that some of the assumptions about the optimal doses of TB drugs may have to be re-evaluated.

“We are hopeful that future steps will include establishing TB drug pharmacokinetic norms for people living with HIV/AIDS, people of colour and women,” concluded Dr. Chideya.