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Nevirapine Resistance After Single Dose to Prevent Mother-To-Child HIV Transmission
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Reported by Jules Levin
Several years ago we could have predicted that resistance to nevirapine would emerge from single dose use, as resistance might emerge from single dose use of any drug with a long half-life in the blood. So it shouldn't be a surprise that we are seeing nevirapine resistance emerging from the studies using it for prevention of mother-to-child transmission of HIV. This was reported at the 11th CROI in early 2004. At the Resistance Workshop in Tenerife in Spain similar reports were presented. Development of drug resistance in this manner may reduce future treatment options. But, until better treatments are available single-dose nevirapine is useful because it is effective in preventing transmission. And the manufacturer of nevirapine, Boerhinger Ingelheim is making the drug available.
A French group (Chaix et al) reported at Tenerife that nevirapine resistance developed in a significant percent of women who received a single dose in a study in Africa, but it also developed in a significant number of children who were infected with HIV. Nevirapine resistance persisted at 12 months for children whose samples were available. In a second study presented at Tenerife researchers (Eshleman et al) reported from the Ugandan HIVNET 012 trial, where single dose nevirapine was used for preventing mother-to-child transmission, findings that suggest that HIV-1 subtype influences how specific resistance mutations impact viral replication in the presence and absence of ART; and HIV-1 subtype influences selection and fading of nevirapine resistance mutations after single-dose nevirapine. Details of these studies follow.
"Persistance 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, Côte d'Ivoire"
ML Chaix1, DK Ekouevi2, G Peytavin3, F Rouet4, L Bequet2, C Montcho4, I Viho2, P Fassinou5, V Leroy6, F Dabis6, C Rouzioux1 and TheDitrame Plus Study Group1 Virologie, CHU Necker-EA MRT 3620, Paris, France; 2 Projet ANRS Ditrame Plus, Programme PACCI, Abidjan, Côte d'Ivoire; 3 Pharmacologie, CHU-Bichat, Paris, France; 4 CeDreS, ProgrammePACCI, Abidjan, Côte d'Ivoire; 5 Pédiatrie, CHU Yopougon, Abidjan, Côte d'Ivoire; and 6 INSERM U593, Bordeaux, France
The authors of the study concluded that the main points from this study are:
(1)--33% of the women developed nevirapine resistance and 2/3 of them had detected NVP resistance in their PBMC.
--emergence of NVP resistance was significantly associated with a high level of NVP concentration: considering the long half-life of NVP, a higher concentration was more likely to induce a prolonged viral replication under suboptimal drug-selective pressure therefore increasing the probability of emergence of resistant viruses.
(2)--23% of the infected children developed NVP-associated mutations in the plasma & all had resistance mutations archived in PBMC. This raises concerns regarding the use of NVP in the prevention of mother-to-child transmission: in mothers, recent studies have reported a negative impact of NVP associated mutations selected after PMTCT on a subsequent regimen including NVP (Jourdain, CROI 2004). Children presenting with resistant viruses in this study had acquired resistant virus close to primary infection. These viruses are therefore likely to persist for prolonged periods and to impact subsequent response to ARV treatment.
THE STUDY
Ditrame Plus was an open-labelled non-randomized trial. Consenting women with HIV-1 infection started oral ZDV (300 mg twice daily) >=36 weeks gestation. One oral dose of 600 mg ZDV+200 mg NVP was given just before beginning of labour. Neonates were treated for 1 week with ZDV syrup (2 mg/kg/6 h) + one single dose of NVP syrup (2 mg/kg on day 2--3). 381 women were enrolled in the DitramePlus trial and the vertical transmission rate was 6.4% at week 6 post-partum (PP). 74/381 women were included in resistance substudy.
Genotypic resistance analysis by sequencing reverse transcriptase gene was performed on mothers DNA-PBMC at week 4 PP when a NVP-R (resistant) mutation was detected in concomitant plasma samples. The same analysis was performed at week 4 of life, 3 months and 12 months, on DNA-PBMC of children who had detectable NVP-R in plasma samples at week 4. Mothers' NVP-plasma concentrations were determined by a validated HPLC assay at 48 h PP (LOQ 50 ng/ml).
63 women with samples were available at baseline prior to treatment (32 weeks of amenorrhoea: abnormal suppression or absence of menstruation) and at 4 weeks post-partem:
--21 whose infant was infected (cases)
--42 whose infant was uninfected (controls) (viral load at baseline is relevant to resistance development):
>= 3.53 and <= 4.2 log copies/ml (15 mothers)
>= 4.21 and <= 4.68 log copies/ml (15 mothers)
>= 4.69 log copies/ml (12 mothers)
Samples of the 26 infected children were also studied (21 + 5 whose mothers did not take NVP while children received NVP).
RESULTS
21 of 63 (33%) women developed resistance to NVP at week 4 post-partem (PP) with a predominance of mutation 103N: none of these mutations were present prior to treatment. No AZT-associated mutation was observed.
--NVP concentration analysis showed wide inter-patient variability (median concentration: 684 [417-954] ng/ml). No NVP resistance=598 ng/ml vs 851 ng/ml for mothers with NVP-resistance (p=0.014).
--Emergence of NVP-resistance was significantly associated to a high level of NVP concentration, owing to a prolonged period of viral replication under NVP selective pressure.
--Moreover, 3 out of the 4 mothers who received double dose of NVP developed NVP-resistance mutation.
At week 4, 15/20 (75%) harbored NVP-resistant viruses archived in PBMCs.
At month 12, for 3 women who had available samples, only wild-type was observed in plasma and in PBMC.
MOTHERS: PREDICTIVE FACTORS ASSOCIATED WITH NVP-R MUTATIONS
Univariate Analysis
--median viral load at inclusion 4.93 (NVP-R) vs (4,54 (Np NVP-R, OR [95% CI}: 3.11 (1.04-9.29] p=0.020.
--median NVP concentration, 851 [633-1063] (NVP-R) vs 598 [315-885] (No NVP-R) p=0.014).
--CD4 cell count <350, 81% NVP-R vs 19% NVP-R among women with CD4 cell count >=350 (p=0.06).
MULTIVARIATE ANALYSIS
Two factors were independently predictive of acquisition of NVP-R virus:
--viral load at inclusion, OR [95% CI]: 4 [1.13-14.09] p=0.012).
--plasma NVP concentration at day 2, OR [95% CI]: 1.20 [1.05-1.50] p=0.031.
NVP-R was significantly more common in women with subtype CRF02 vs subtype A. 8% were subtype CRF06 (5/63), and among them 3/5 NVP-R.
CHILDREN
6 of the 26 infected children (23%) developed NVP-R mutations in plasma at week 4. NVP-R mutations were detected in the PBMCs for all the 6 children.
PERSISTENCE of NVP-R MUTATIONS IN CHILDREN'S PBMC
They found a persistence of NVP-R mutated viruses in the plasma and detected in the PBMC for the two children samples available and tested: 1 child at 3 months of age & 1 child at 12 months of age.
Distinct patterns of selection and fading of K103N and Y181C areseen in women with subtype A vs D HIV-1 after single dose nevirapine: HIVNET 012
SH Eshleman1, J Wang2, LA Guay1, SP Cunningham1, A Mwatha2, ER Brown3,P Musoke4, F Mmiro4 and JB Jackson1 1 The Johns Hopkins Medical Institutions, Baltimore, Md., USA; 2 Fred Hutchinson Cancer Research Center, Seattle, Wash., USA; 3 University of Washington, Seattle, Wash., USA; and 4 Makerere University, Kampala, Uganda
OBJECTIVES: The Ugandan HIVNET 012 trial demonstrated that a single dose nevirapine (NVP) regimen can prevent HIV-1 mother-to-child transmission. NVP resistance (NVPR) mutations were detected in 25% of women 6--8 weeks after NVP. Women with subtype D had a higher rate of NVPR than women with subtype A. In an exploratory study of 65 women, the major NVPR mutation detected shifted from Y181C at 7 days to K103N at 6--8 weeks. This study examined emergence and fading of Y181C and K103N in women with subtype A vs D.
METHODS: Plasma HIV-1 was analysed with the ViroSeq HIV-1 Genotyping System. HIV-1 subtypes were determined by phylogenetic analysis of pol region sequences. Genotypes were obtained for 7 day and 6--8 week samples (paired data) for 159 women, including 83 with subtype A and 57 with subtype D. The rate of NVPR at the two time points was compared in women with subtype A vs D using the Generalized Estimating Equation (GEE).
RESULTS: In the subset of 140 women with subtypes A and D, the rate of NVPR increased from 7 days to 6--8 weeks. The rate of NVPR was similar in women with subtype A vs D at 7 days, but was higher in women with subtype D at 6--8 weeks. The higher rate of NVPR in women with subtype D at 6--8 weeks was explained by at least two factors: 1) Y181C faded from detection at a significantly greater rate in women with subtype A (OR: 3.06; 95% CI: 1.04, 8.90); and 2) K103N tended to accumulate at a greater rate in women with subtype D, although that difference was not statistically significant (OR: 1.74; 95% CI: 0.62, 4.87).
Other NVPR mutations were detected, but the number of women with those mutations was too small for meaningful statistical analysis.
CONCLUSION: HIV-1 subtype influences selection and fading of NVPR mutations after single-dose NVP. Different patterns of selection and fading were observed for K103N and Y181C in women with subtypes A vs D. This suggests that HIV-1 subtype influences how specific drug resistance mutations impact viral replication in the presence and absence of antiretroviral drugs.
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