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
findings from the ACTG 5208/OCTANE study are published online in advance of
print in the journal AIDS.
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.
(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.
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).
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.
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.
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
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 (CLweek4=CLweek2+CL additional).
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).
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
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.
(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
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.
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).
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
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.”
include a lack of pharmacogenetic data to link with the pharmacokinetic
findings because patient consent was not initially obtained.
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
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