A number of studies of the prevention of mother to child transmission (PMTCT) now appear to point to an ominous conclusion: single-dose nevirapine (NVP) may not be the prophylactic panacea for the developing world.
Whilst single-dose NVP has been successful in limiting transmission rates of HIV as proven by the HIV-NET 012 trial, the emergence of resistance mutations after a single dose of NVP due to its long half-life is raising increasing alarm.
NNRTI-associated mutations have been shown to persist for over one year and exposure to short-course NVP has been shown to compromise virologic response to treatment in Thai women who begin treatment less than six months after giving birth.
Emergence of resistance in non-B HIV subtypes
Since a majority of the women likely to be treated in this context will have non-clade B virus, research has been focused on the consideration of resistance evolution in the different subtypes.
In a sub-study from HIV-NET 012, Susan Eshleman from Johns Hopkins reported on the incidence of resistance in women with HIV subtype A or D , in particular the emergence and decay of the Y181C and K103N mutations. The study found that in a subset of 140 women with subtypes A and D, the rate of NVP resistance increased from seven days to six to eight weeks. NVP resistance was similar at day 7 but at weeks 6 or 8 was higher in patients with subtype D. In women with A type virus, the Y181C was more difficult to detect over time compared to women who had HIV-1 subtype D. They also accumulated higher rates of the K103N mutation. This study confirms that there is a correlation between subtype and the selection and decay of NVP related resistance following single-dose NVP (Eshleman).
This finding is supported by findings from other trials such as data reported at last year’s workshop by David Katzenstein from Stanford, from the HPTN 023 Study of C infected women receiving single-dose nevirapine. The trial described the emergence of both Y181C and K103N at 2 weeks post-partum and the persistence of K103N which continued through to week 8 in this study (Kantor R et al. Rapid flux in NNRTI resistance mutations among subtype C HIV-1 infected women after single dose nevirapine, abstract 85, 2003).
Another interesting PMTCT study from ANRS (Ditrame Plus ANRS 1202/02) in Cote d’Ivoire considered the pharmacokinetic properties of NVP and its impact on resistance. This open-label randomised trial involved administration of AZT (300mg bid) at 36 or more weeks of gestation followed by a single oral dose of AZT (600mg) and nevirapine (200mg) just before start of labour. Babies were treated for one week with AZT syrup and one single dose of NVP syrup. Of the 381 women in the study, the transmission rate at week 6 post-partum was 6.4%.
33% of the 74 women enrolled in the substudy developed NVP-related resistance at week 4 and 23% of children had resistance at the same time point. Plasma and DNA-PBMC samples collected at week 4 showed that 15 out of 20 women sampled (75%) had resistance to NVP, but at 12 months after delivery three women did not show detectable mutations. In contrast, all six children had NVP resistance in plasma sampled at week 4 and had persistence of resistance at month 3 (1 child) and still at twelve months (1 child).
Plasma concentrations of NVP normalised to 48 hours post-partum revealed that NVP levels were lower in women who had not acquired NVP resistance compared to the mothers who did acquire resistance (598 ng/mL versus 851 ng/mL. The researchers conclude that NVP drug exposure has wide inter-patient variability and higher levels that persist over a prolonged period after delivery may account for the differing rates and persistence of resistance accumulation observed. Given that access to treatments remain atrociously scarce, these studies caution not so much against the use of NVP treatment, but the urgent need to explore more viable options that prevent transmission but do not compromise treatment during subsequent pregnancies or treatment for children (Chaix).
Read related reports from the XIII International HIV Drug Resistance Workshop, June 8-12, Tenerife, Spain
Take home messages
What were the key messages from this year's Resistance Workshop?
Entry and attachment inhibitors
As researchers learn more about the ways in which HIV develops resistance to entry and attachment inhibitors, the future shape of therapy with these new classes of drugs becomes clearer.
New concepts for the clinician
This year's workshop heard more about the clinical relevance of replication capacity and hypersusceptibility, and began to debate the potential therapeutic exploitation of interactions between resistance mutations.
Population surveys of resistance
What sort of resistance is occurring in clinic populations, and what does this tell us about clinical practice today?
Non-B HIV subtypes
As treatment access expands and the proportion of patients in Europe with non-B subtypes grows, understanding differences in resistance patterns between B and non-B HIV subtypes becomes more and more important.
Eshleman SH et al. Distinct patterns of selection and fading of K1-3N and Y181C are seen in women with subtype A vs D HIV-1 after single-dose nevirapine: HIV-NET 012. (Abstract 50) Antiviral Therapy 2004, 9:S59.
Chaix ML et al. Persistence of nevirapine-resistant virus and pharmacokinetic analysis in women who received intrapartum NVP associated to a short course of zidovudine (ZDV) to prevent perinatal HIV-1 transmission: the Ditrame Plus ANRS 1201/02 Study, Abidjan, Cote d’Ivoire. (Abstract 160) Antiviral Therapy 2004, 9:S176.