Can speeding up nevirapine clearance reduce the risk of resistance after PMTCT use?

In a bid to reduce the risk of nevirapine resistance after the use of single-dose nevirapine to prevent mother-to-child HIV transmission, several research groups are now experimenting with the use of drugs that can speed up the clearance of nevirapine from the mother’s bloodstream after giving birth.

For example, adding single-dose carbamazepine, a cheap, readily available anti-convulsant and enzyme inducer, to single-dose nevirapine for the prevention of mother-to-child transmission (PMTCT) in HIV-infected women in Tanzania at the start of labour had no effect on nevirapine levels in the blood at delivery. But it considerably reduced them one week later and at six weeks showed a significant decrease in nevirapine resistance mutations, researchers report in the advance online edition of the Journal of Acquired Immune Deficiency Syndromes.

Another study is testing the effect of a seven-day course of the antiepileptic drug phenytoin on nevirapine levels and drug resistance when used in conjunction with a seven-day tail of AZT and 3TC.

While it is the least effective treatment for PMTCT, single-dose nevirapine (sdNVP) given to the mother at the start of labour and to the infant within 24 to 72 hours after birth is widely used in many resource-poor settings. It is effective in reducing MTCT by 40%, simple to use and affordable.

A non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine is a highly effective antiviral. However, it has a low genetic barrier which means one mutation can result in high-level resistance. It is quickly absorbed and passes rapidly through the placenta. It has a long elimination half-life (61 to 66 hours) in pregnant women given a single dose of 200mg, meaning sub-therapeutic levels remain in the blood. This results in primary nevirapine resistance from a single dose in 15 to 75% of mothers.

Clinically this has three important consequences, note the authors:

1. Having resistant virus means the efficacy of combinations of ART that include nevirapine or another NNRTI are reduced.

2. Resistant virus can be transmitted to others so limiting their treatment options.

3. Nevirapine resistance may reduce the effectiveness of single-dose nevirapine in future pregnancies.

However, they add, there is no evidence to support this last point.

To address this issue of extended time on sub-therapeutic levels of nevirapine and the development of resistance, the World Heath Organization (WHO) now recommends adding zidovudine (AZT) and lamivudine (3TC) for seven days after birth. Other studies in which single-dose tenofovir and emtricitabine (FTC) have been added to sdNVP and short-course zidovudine also showed reduced NNRTI resistance. Yet, note the authors, these have not been successful in eliminating nevirapine resistance, “which remains a serious and growing concern.”

The authors chose to look at an alternative strategy involving a pharmacological intervention to reduce the nevirapine elimination half-life.

Nevirapine is eliminated primarily through a pathway known as cytochrome P-450 3A4 and 2B6 enzymes. So an inducer of these enzymes might speed up the process of elimination and so reduce the development of resistance.

In a pilot study of healthy volunteers comparing eight different enzyme inducers, the authors found nevirapine elimination half-life was reduced the most (by 35%) by adding single-dose carbamazepine. As a follow-up the authors undertook a phase II trial to see what the levels of nevirapine in the blood would be at one week after delivery and nevirapine resistant mutations at six week after birth.

ART-naive HIV-infected pregnant women aged 18 to 40, with CD4 cell counts greater than 200 cells/mm³ and attending antenatal clinics in Moshi, Tanzania, were enrolled on a 1:1 basis at alternate allocations to get either 200mg of sdNVP alone or in combination with open-label 400 mg single-dose carbamazepine (sdNVP/CBZ) at delivery.

Between February 2006 and April 2009, 354 women were screened, of whom 54% (192) were eligible for the study, with a final number of 158 taking part at delivery. In 61 (83%) of the women who got sdNVP, and in 72 (87%) of those who got sdNVP/CBZ, median levels of nevirapine in the blood at delivery was comparable to findings in other studies: 1.55 (0.88-1.84mg/L) and 1.40 (0.93-1.97) mg/L, p=0.91 respectively. Importantly, the addition of an enzyme inducer did not take away from the protective effect of nevirapine, note the authors.

One week after giving birth, nevirapine levels were 36% lower in the sdNVP/CBZ group. Levels of nevirapine in the blood are determined by nevirapine elimination half-life, so this means a significantly higher elimination half-life in the sdNVP/CBZ group. There was also a trend to a greater proportion with undetectable nevirapine levels (<0.05 mg/L) in the sdNVP/CBZ groups, compared to those in the sdNVP groups (24% [15/63] and 12% [6/52] respectively [chi-squared p=0.09]).

Six weeks after having given birth, nevirapine mutations were seen in 21% (11/52) and 11% (6/55) in the sdNVP and sdNVP/CBZ groups respectively (OR: 0.46, 95% CI: 0.16-1.34, p=0.15).

The authors note their approach - in common with that of Chi and colleagues (single-dose emtricitabine + tenofovir with sdNVP in 400 women resulting in a 50% reduction in resistance) - maintains simplicity. Their pharmacologic approach, however, targets a different mechanism and so may have an additive effect, they note.

Limitations include a high loss to follow-up. The randomisation list was only partially randomised; and sample sizes were far smaller for resistance testing than designed, so limiting the power to determine resistance between the groups. Standard HIV genotyping assays could only detect viral mutations found in more than 20% of the overall HIV population.

Carbamazepine was chosen because of it simplicity. The authors believe it could improve adherence, and is likely to reduce the emergence of NNRTI resistance further. It is very low cost and is available in most clinics in resource-poor settings.

The authors conclude: “Enzyme inducers such as carbamazepine, show new possibilities for PMTCT programmes to reduce the development of nevirapine resistance in settings where other options are limited.”