Co-administration of rifampicin and efavirenz does not reduce efavirenz concentrations or efficacy

Standard dosing of efavirenz, that was not adjusted for patient weight, resulted in therapeutic efavirenz concentrations and excellent virological outcomes in patients coinfected with TB and HIV who were also taking a rifampicin-containing TB treatment, according to results from the ACTG 5221 STRIDE study presented at the 19th International AIDS Conference (AIDS 2012) in Washington DC.

These findings have important implications for guidelines on rifampicin and efavirenz co-administration in TB/HIV co-infected patients. Rifampicin is known to cause drug-drug interactions, especially with efavirenz, which is recommended in first-line ARV treatment. Rifampicin co-administration is associated with an approximately 30% decrease in efavirenz trough concentrations (C_min). Previous studies have showed that efavirenz dosing should be increased from the standard dose of 600mg to 800mg in TB/HIV patients who weigh more than 50kg when taking rifampicin; a recommendation which the Food and Drug Administration of the United States of America made in January this year.

Efavirenz concentrations were measured using high-performance liquid chromatography where the lower limits of quantification was defined as 1mg/l. C_min samples were obtained 20to 28 hours after efavirenz administration. Efavirenz levels were evaluated at antiretroviral (ARV) treatment weeks 4, 8, 16 and 24 for those patients on rifampicin, and weeks 4 and 8 for those not on rifampicin. Samples were only collected in participants with no self-reported missed efavirenz or rifampicin doses in the previous three days.

According to Dr Annie Luetkemeyer, higher weight did not jeopardise efavirenz efficacy in patients taking rifampicin-containing TB treatment. In 505 patients who were taking both efavirenz and rifampicin, none reached below the minimum recommended plasma concentration of <1 mg/l of efavirenz. The median efavirenz C_min was found to be 1.96 mg/l (IQR: 1.24 – 3.7).

Heavier patients did have significantly lower efavirenz concentrations, but only when heavier patients were defined as weighing 60kg or above. The median efavirenz C_min in patients weighing below 50kg was 2.08 (IQR:1.33-4.33) compared to 1.86 (IQR:1.18-3.64) in those patients weighing 50kg and above (p=0.09). In contrast, the median efavirenz C_min in patients weighing below 60kg was higher at 2.02 (IQR: 1.29-4.09) compared to 1.68 (IQR: 1.07-3.06) in those patients weighing 60kg and above (p=0.02).

When examining the efavirenz C_min in patients also taking rifampicin compared to those who were not, there was no significant difference found across patient weight levels, except when disaggregated by race. There was a significant difference in efavirenz C_min in black patients taking efavirenz with or without rifampicin. For the black patients taking rifampicin (n=367), the efavirenz C_min level was 2.1 compared to those not taking rifampicin (n=269) whose efavirenz C_min level was 1.8 (p=0.01). The researchers suggested that this paradoxical finding is likely to be due to genetic distinctions in metabolism in black patients. The study did not include enough members of other races to show significant differences.

Subtherapeutic efavirenz C_min of less than 1 mg/l was not associated with rifampicin coadminstration, according to the study results. These showed that 27.3% on rifampicin (versus 26.2% not taking rifampicin) had an efavirenz C_min less than 1mg/l and this finding was not found to be statistically significant (p=0.72).

Rates of HIV virological suppression were also found not to be reduced in patients above 50 kg or 60 kg taking efavirenz and rifampicin. The investigators concluded that these data do not support weight-based increase of efavirenz during rifampicin-containing TB treatment.

Efavirenz and rifampicin co-administration in pregnant women

Rifampicin was also shown to have no significant effect of on efavirenz C_min levels in pregnant women and their infants, according to the preliminary results from the TSHEPISO efavirenz pharmacokinetic substudy presented at AIDS 2012.

The combined effect of pregnancy and rifampicin-containing TB treatment on efavirenz C_min, virologic suppression and prevention of maternal-to-child transmission of HIV (PMTCT) has not been studied before.

TSHEPISO is a prospective cohort study among HIV-infected pregnant women with TB (n=250 cases) and without TB (n=500 controls), currently enrolling in Soweto, South Africa. Women (n=150) with and without TB, on efavirenz-containing ARV will enrol in the substudy, along with their infants.

The preliminary results from 76 women and 70 infants in the substudy to date show that the estimated efavirenz C_min among women pre/intrapartum and postpartum were not significantly different. The model, which also took weight and CYP2B6 genotype (the enzyme central to the metabolism of efavirenz) into account, was unable to show a significant effect of rifampicin on efavirenz C_min (except among slow efavirenz metabolizers).

The median efavirenz C_min of the 40 pre/intrapartum women taking rifampicin was 1.76 (IQR: 0.89-3.13), with 29.6% with an efavirenz C_min  of less than 1mg/l. In the 46 women not taking rifampicin six weeks postpartum, the median efavirenz C_min was 1.52 (IQR: 1.14-2.02) with 17.1% with an efavirenz C_min of less than 1mg/l.

Despite the 29.6% of women on rifampicin with C_min less than 1 mg/l, the viral load was suppressed in most women taking efavirenz for three months or more at the time of delivery. There were no cases of mother-to-child transmission of HIV.

The effect of genotype CYP2B6 showed that 56.3% with extensive, 5.7% with intermediate, 16.7% with slow and 0% with very slow efavirenz metabolism had an efavirenz C_min of less than 1mg/l.

Difference in weight did not prove a significant factor for EFV C_min levels in those taking rifampicin or not taking rifampicin. The median C_min levels were both 1.91 for women below and above 60kg in those taking rifampicin, but 20% of those less than 60kg had a C_min less than 1mg/l compared to 31.6% in the women weighing more than 60kg. The median C_min for women less than 60kg was 1.33 (IQR: 1.12-1.64, 11.1% with a C_min  less than 1mg/l) and 1.55 (IQR:1.13-2.07,16.7% with a Cmin  less than 1mg/l) in women not on rifampicin treatment.

Preliminary results also showed that 70% of TB/HIV co-infected women and 83% of HIV-only infected women had undetectable viral load counts at delivery, although this difference was not statistically significant (p=0.24).Of those taking efavirenz for at least 12 weeks at delivery, 82% of TB/HIV co-infected women and 93% of HIV-only infected women had undetectable viral loads, although this difference was again statistically insignificant (p=0.26).

Blood samples taken from infant umbilical cords in 45 infants showed the median efavirenz C_min to be 1.15 (IQR: 0.628-1.91, 8.9% with a C_min less than 1mg/l. Cord and maternal pre-partum concentrations were highly correlated (r=0.93). However, the median efavirenz C_min in infant blood at seven days after birth was 0.079 (61.4%with a C_min less than 1mg/l). However, quantifiable values were related to larger cord-blood concentrations.