Severe nevirapine rash linked to slow clearance of drug

The risk of severe rash when taking the antiretroviral drug nevirapine is greater in women who clear the drug from their bloodstreams slowly, and clearance of the drug appears to be slower in African women, according to a pharmacokinetic analysis of the relationship between drug levels and severe nevirapine side-effects in a recent large trial of first-line antiretroviral therapy in sub-Saharan Africa.

The findings from the ACTG 5208/OCTANE study are published online in advance of print in the journal AIDS.

This pharmacokinetic (PK) study from the ACTG A5208/OCTANE clinical trial showed that the odds of developing a severe rash were estimated to be 50% higher for every 20% decrease in the rate of nevirapine clearance (p=0.046), and clearance of nevirapine was approximately 40% slower than previously reported in studies carried out in the United States and the Netherlands, suggesting that African women may be genetically predisposed to slower clearance of this drug.

Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor (NNRTI), is part of standard first-line ART in resource-poor settings. During the first weeks of ART NVP has been linked to a serious and sometime life-threatening rash and/or liver damage. NVP rash is seen more often in women than in men.

The precise cause of NVP toxicity is unclear. Studies suggest that there is a link between how NVP is absorbed (NVP PK) and an increased risk for toxicity. These findings, however, are from studies with a majority of male subjects. Yet, it appears that women are exposed to the drug for longer since it takes longer to clear. Other factors that may contribute to how the drug is absorbed include: body weight, ethnicity, pre-existing liver disease and pharmacogenetics (how genetic make-up affects the response to medications).

So the authors chose to undertake this study to try and clarify the link of NVP PK with increased risk of rash and/or liver damage among a large cohort of HIV-infected, but not pregnant, women from 10 sites in seven sub-Saharan countries who started NVP-based ART. And secondarily to see if there was a link between these adverse effects and pre-treatment CD4 cell count and weight.

All women enrolled in the trial had a CD4 cell count under 200 cells/mm³ before starting treatment, were ART-naïve or had taken zidovudine or single dose nevirapine for PMTCT. They were randomised to get either lopinavir/ritonavir twice a day or NVP twice a day after a 14 day period of once daily NVP each in combination with tenofovir and emtricitabine (Truvada).  Those randomised to NVP were included in the PK trial. Single nevirapine blood samples were taken after randomisation at 14 (±7) days (before dose escalation to twice a day) and at 28 (± 7) days if no NVP doses had been missed in the previous three days. They were followed until the last woman randomised had finished 48 weeks of follow-up.

Toxicity was defined as rash and liver damage that happened during therapy or within seven days of the last dose of nevirapine and before starting another ART regimen.

Population pharmacokinetic analysis modelled NVP pharmacokinetics. The authors note since only a single NVP blood sample was taken at week 2 and week 4 for each subject a simple additive clearance (CL) model was used to capture any additional CL after week 2 (CL_week4=CL_week2+CL _additional).

Among the 359 women, included in the analysis, at baseline median age was 33 years (IQR: 28-38); median weight 57 kg (IQR: 52-67); and median CD4 cell count 128 cells/mm³ (IQR: 80-176).

While the screening CD4 count had to be under 200 cells/mm³ there were no restrictions on the baseline CD4 count. 47 women with a CD4 count over 200 cells/mm³ were enrolled with a median of 262 cells/mm³ (IQR: 250-386).

Women weighing less than 50 kg compared to those at or over 50 kg were significantly younger (median 30 compared to 34 years, p=0.012)) had higher viral loads (median 199526 compared to 125893 copies/mL) and more advanced WHO stage 3 or 4 (44% compared to 28%), p=0.013.

54% (194) developed a rash of any grade of which 23% (82) had grade 2+ and 9 (3%) had grade3+ of which one had grade 3+ liver damage. The link between NVP PK exposure and a significantly increased risk of severe rash was seen at week 4 but not at week 2

Median clearance at 28 days (week 4) was 1.7L/hr for women with a severe rash (grade 3+) compared to 2.0L/hr for women without a severe rash, p=0.046.

Discontinuing nevirapine because of rash and/or liver damage was more frequent among women with CD4 cell counts over 250 cells/mm³ before starting treatment (p=0.003). 

The authors note this is is the first study to show a link between NVP exposure and grade 3+ rash. While other studies have shown a link between exposure and increased liver enzymes none have shown such a consistent relationship, they add.

The authors note these findings “add to previous data suggesting vigilance and close monitoring for NVP toxicity are required for all African women starting NVP at any CD4 count, but toxicity is more likely in those with CD4 cell counts at or above 250 cellsmm³.”

Limitations include a lack of pharmacogenetic data to link with the pharmacokinetic findings because patient consent was not initially obtained.

The authors suggest caution in interpreting the findings as they are based on the differences between screening and pre treatment CD4 cell counts of a small number of women and the potential for change within the subject between the two measurements.

Guidelines now recommend starting ART at a higher CD4 cell count leading the authors to stress the importance of further PK and pharmacogenetic studies; in particular in resource-poor settings, notably among African women, to determine the most effective dose of nevirapine to give the best results while minimising toxicity.