Nevirapine-resistant HIV present in the latent reservoir following single-dose nevirapine for MTCT prevention
Polly Clayden, HIV i-Base
Nevirapine (NVP) resistant virus often becomes undetectable in the months after discontinuation of NNRTI therapy and after single dose MTCT prophylaxis. Until now, investigators have not determined whether or not resistant virus remains present in the latent reservoir in resting CD4 cells after single dose NVP exposure in HIV-infected women.
A poster authored by Megan Wind-Rotolo and coworkers from Johns Hopkins University, Baltimore, United States and University of Witswatersrand, Johannesburg, South Africa, reported findings from a study investigating the presence of NVP resistant virus in the latent reservoir of women who had received a single dose at least six months before.
Sixty women with CD4 >200 cells/mm3 were included in this study. The investigators collected plasma and peripheral blood mononuclear cell (PBMC) samples.
Purified resting CD4 cells were cultured in the presence of 3TC, tenofovir, efavirenz and raltegravir in order to prevent the completion of reverse transcription and integration in cells without integrated virus.
A highly sensitive mutation-specific assay (LigAmp) was used to identify virus containing any of three NVP resistance mutations (K103N, Y181C, G190A) among virus from the latent reservoir and virus present in a matching plasma sample. The cut off value for the assay was 1% resistant virus.
Plasma was analysed from 58 women; NVP mutations were found in 2/58 (3.4%) of women.
Virus from the latent reservoir was isolated from 50 women (24 from Soweto, South Africa and 26 from Rakai, Uganda). Four of these women (8%) had NVP mutations in virus from the latent reservoir. Three of four (6%) women did not have NVP resistant virus in the matching plasma sample. One woman had low levels of K103N in virus from plasma but not from the latent reservoir (see Table 1).
Table 1: NVP resistance mutations detected among virus from plasma and latent reservoir
|Patient no.||NVP resistance in plasma virus||NVP resistance in latent reservoir virus|
The investigators wrote: NVP resistance mutations that arise following a single dose of NVP to prevent mother to child transmission of HIV-1 can be archived in the resting CD4+ T cell latent reservoir and persist for long periods of time and could provide a source of drug resistant virus that may contribute to future antiretroviral failure and development of new resistance mutations.
This poster provoked comment that finding the archived resistance in anyone is very significant, as the archive reservoir is so difficult to access and study and evidently represents over 3 years work.
Conversely, failure to detect archived virus with NVP associated mutations in 92% patients is encouraging.
Wind-Rotolo M, Durand C, Cranmer L et al. Identification of nevirapine-resistant HIV-1 in the latent reservoir following single-dose nevirapine. 15th CROI, February, 2008, Boston. Poster Abstract 634.