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Single-Dose Nevirapine and Drug Resistance: The More You Look, the More You Find
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Journal of Infectious Diseases July 1, 2005
Scott M. Hammer
Division of Infectious Diseases, Columbia University Medical Center, New York, New York
At the 14th HIV Drug Resistance Workshop which just ended on June 11 there were several study reports showing they could reduce resistance of nevirapine to women & newborns using various protocols. My report on these studies was emailed to NATAP Email Treatment Updates recipients & will be posted to the NATAP website today at http://www.natap.org. As well, I've include my report at the end of this Editorial. Jules Levin
......In 1999, the HIV Network for Prevention Trials (HIVNET) 012 trial, performed in Uganda, reported that a single 200-mg dose of NVP given to the mother at the time of delivery followed by a single 2-mg/kg dose given to the infant within 72 h of birth resulted in a reduction in MTCT of 50% at 14-16 weeks after treatment, compared with a short course of ZDV, and its persistent benefit extended to 18 months after treatment....
....However, the emergence of drug resistance in the setting of SD-NVP has created a gradually increasing challenge.....(20%) of the women were found to have the K103N mutation by standard sequencing assay. The real-time PCR assay detected the K103N mutation in an additional 16 (40%) of the remaining 40 women.
.....the more sensitive our virologic assays become, the more we will understand about HIV pathogenesis..... evidence is already accumulating to suggest that viral mutants circulating at low frequencies are clinically relevant. In an observational study by Jourdain et al., women exposed to NVP who had detectable NNRTI-associated resistance mutations early during the postpartum period had an inferior virologic response to a subsequent NNRTI-based treatment regimen at 24 weeks of therapy, compared with that in women not exposed to NVP. Women exposed to NVP who had no detectable resistance mutations early during the postpartum period had an intermediate-level virologic response, which suggests that NNRTI-resistant mutants were likely present at low frequencies and were possibly contributory to a less-than-ideal response to treatment. Importantly, the significance of NNRTI-resistant mutants circulating at low frequencies for subsequent virologic failure in adults receiving NNRTI-containing regimens has been reported by Mellors et al., who used 2 highly sensitive assays for the detection of mutants and phylogenetic analyses linking samples taken at baseline and during virologic failure.....
..... As economics and health care infrastructures permit, the alternative approach of providing potent combinations of antiretroviral agents to pregnant women to achieve full virologic suppression has the potential to reduce neonatal HIV infection to the levels seen in the developed world while preventing drug resistance in the mothers.
ARTICLE TEXT
Within the context of the historic development of drugs to treat HIV infection, there is perhaps no subject that has created more controversy than the use of these agents to interrupt the mother-to-child transmission (MTCT) of HIV-1. No one now takes issue with the fact that the AIDS Clinical Trials Group Protocol 076-in which zidovudine (ZDV), given to the mother pre- and intrapartum and to the infant for the first 6 weeks of life, reduced MTCT of HIV-1 by 70%-has been one of the most noteworthy advances in treatment of the past 20 years [1]. However, the development phase of that protocol was fraught with intense debate, particularly with respect to the ethics of the trial. The reduction in MTCT of HIV-1 from 25% to 8% immediately led to changes in public health policy in the developed world and, with the subsequent application of potent combinations of antiretroviral drugs for the mother and judicious use of caesarean section, neonatal HIV-1 infection is now a rare event in resource-unconstrained settings.
During the past 2 years, a revolutionary commitment to bring the life-saving benefits of antiretroviral treatment to the developing world has been evident. The President's Emergency Plan for AIDS Relief, the World Health Organization's 3 × 5 Initiative, and the Global Fund to Fight AIDS, Tuberculosis, and Malaria are the most publicized aspects of this effort. However, well before these recent actions to provide treatment to millions of persons with HIV, clinical researchers around the world were attempting to develop more cost-effective strategies than the relatively complex 076 regimen to reduce MTCT of HIV-1. A number of strategies have been tested, but the one that has had the greatest impact and has created the greatest stir is the use of single-dose nevirapine (SD-NVP). In 1999, the HIV Network for Prevention Trials (HIVNET) 012 trial, performed in Uganda, reported that a single 200-mg dose of NVP given to the mother at the time of delivery followed by a single 2-mg/kg dose given to the infant within 72 h of birth resulted in a reduction in MTCT of 50% at 14-16 weeks after treatment, compared with a short course of ZDV, and its persistent benefit extended to 18 months after treatment [2, 3]. This result was hailed as a dramatic breakthrough, because it was an easy regimen to administer, was inexpensive, required no additional health care infrastructure, and could potentially be deployed widely and rapidly in even the most rural of settings. In recent months, the HIVNET 012 trial has come under renewed scrutiny [4], prompting an Institute of Medicine review.
As with any new medical intervention, whether prophylactic or therapeutic, there are inevitable trade-offs. No major safety issues have arisen for mothers or infants who have received SD-NVP. However, the emergence of drug resistance in the setting of SD-NVP has created a gradually increasing challenge to the scientific, clinical research, and public health communities. In retrospect, it is not surprising that mutations associated with nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance would emerge with the administration of a drug for which the occurrence of rapid, single-step, high-level resistance and a prolonged half-life have been described for years [5]. It is also important to remember that the replication kinetics of HIV and the nature of reverse transcription result in a constant and inevitable mutation rate in the viral genome, such that drug resistance-associated mutations occur in the absence of exposure to any drug. The occurrence of new mutations during and after exposure to a drug is greatly facilitated by the selective pressure of an antiretroviral agent, particularly if it is administered in a regimen that will not ensure full virologic suppression. Thus, the appearance of reports describing the relatively high proportions of NVP-exposed mothers and infants with NNRTI-resistant viral strains was predictable [6].
Three articles in this issue of the Journal of Infectious Diseases extend our knowledge of the complexity of drug resistance that accompanies the administration of SD-NVP for the prevention of MTCT of HIV-1. Johnson et al. describe the application of a real-time polymerase chain reaction (PCR) assay to detect minority strains of HIV-1 possessing 1 of 2 key NNRTI-associated resistance mutations, K103N and Y181C, in 50 South African women who had received SD-NVP [7]. None of the women had detectable mutations before exposure to NVP. After exposure, 10 (20%) of the women were found to have the K103N mutation by standard sequencing assay. The real-time PCR assay detected the K103N mutation in an additional 16 (40%) of the remaining 40 women. For Y181C, none of 50 women had the mutation before exposure to NVP, 4 were found to have it by standard sequencing after exposure to NVP, and 5 (11%) of the remaining 46 were found to have it by the real-time PCR assay after exposure to NVP. Taken together, these data suggest that a majority of women (-65%) exposed to NVP will have detectable NNRTI-associated resistance mutations 6-36 weeks postpartum.
Flys et al. explore the utility of sensitive assays for the detection of NNRTI-resistant mutants [8]. In this study, Flys et al. used available samples from 9 women and 5 infants obtained at 6-8 weeks and 12-24 months after exposure to NVP in the HIVNET 012 trial. Standard sequencing techniques and 2 substantially more sensitive assays-LigAmp and TyHRT-were used. LigAmp involves oligonucleotide ligation and real-time PCR to interrogate specific regions of the viral genome. TyHRT is a labor-intensive assay that involves yeast transformation of the reverse-transcriptase gene from patient samples, the screening of colonies for phenotypic resistance to NVP, and clonal sequencing to define the mutations present. Standard sequencing analysis detected the K103N mutation in 8 of 9 women and 4 of 5 infants at 6-8 weeks after exposure to NVP but in none of the women or infants 12 months after exposure or later. In contrast, the LigAmp assay was able to detect the K103N mutation in 3 of 9 women at 14 months and in 1 of 5 infants at 12 months after exposure to NVP. Comparable, but not identical, results were obtained with the TyHRT assay. Given the small numbers and the selective nature of the study population, conclusions about the persistence of the K103N mutation in the overall HIVNET 012 population cannot be drawn, but the results are concordant with the findings of Johnson et al.
The technical achievements of Johnson et al. and Flys et al. illustrate, once again, that the more sensitive our virologic assays become, the more we will understand about HIV pathogenesis. Standard, population-based sequencing analysis generally cannot detect subpopulations of mutants that constitute <20% of the total viral population. In contrast, the real-time PCR assay described by Johnson et al. and the LigAmp assay described by Flys et al. have reported sensitivities of 0.2%-0.3% and 0.1% of the total viral populations, respectively.
The obvious question that arises from these data is whether viral mutants circulating at low frequencies are clinically meaningful. Specifically, will the presence of these mutants after prophylaxis with SD-NVP at delivery and birth compromise the future treatment of mothers and children with NNRTI-based regimens when they are required to treat disease, and will the use of SD-NVP during subsequent pregnancies be effective in the prevention of MTCT of HIV-1? Prospective studies under way or planned will answer these questions, but evidence is already accumulating to suggest that viral mutants circulating at low frequencies are clinically relevant. In an observational study by Jourdain et al., women exposed to NVP who had detectable NNRTI-associated resistance mutations early during the postpartum period had an inferior virologic response to a subsequent NNRTI-based treatment regimen at 24 weeks of therapy, compared with that in women not exposed to NVP [9]. Women exposed to NVP who had no detectable resistance mutations early during the postpartum period had an intermediate-level virologic response, which suggests that NNRTI-resistant mutants were likely present at low frequencies and were possibly contributory to a less-than-ideal response to treatment. Importantly, the significance of NNRTI-resistant mutants circulating at low frequencies for subsequent virologic failure in adults receiving NNRTI-containing regimens has been reported by Mellors et al., who used 2 highly sensitive assays for the detection of mutants and phylogenetic analyses linking samples taken at baseline and during virologic failure [10].
Eshleman et al. compared the frequency of NNRTI-associated mutations after exposure to NVP at 6-8 weeks postpartum by standard sequencing analysis in women enrolled in HIVNET 012 and in the trial of NVP and ZDV in Malawi [11]. The critical finding was that the frequency of NNRTI-associated resistance mutations was significantly higher in women infected with HIV-1 subtype C (69.2%) than in those infected with subtype A (19.4%) or D (36.1%) (P < .0001 for both comparisons). Data reported by a number of investigators suggest that baseline viral polymorphisms can differ among subtypes and that the pathways of resistance and/or the facility with which a particular mutation or set of mutations develops may vary. These possibilities require extensive further research and careful evaluations of the fitness cost that mutations may or may not confer in one subtype of HIV-1 versus another. Viral fitness may well influence how long such mutants persist in the absence of selective drug pressure in the host, as well as their transmissibility to others [12, 13].
SD-NVP substantially reduces the MTCT of HIV-1, but the resultant transmission rates are still much higher than those seen in the developed world, where availability of potent combination antiretroviral therapy is commonplace, and what can be achieved, as was reported in a study in Thailand, with a combination of ZDV and NVP [14]. Thus, there is a moral imperative to continue to reduce the rate of MTCT of HIV-1 and to try to minimize the emergence of drug resistance in the process. The optimal management of antiretroviral resistance is to prevent its occurrence in the first place. In areas of the world where SD-NVP remains the principal practical option, the strategic use of nucleoside-analogue agents to reduce exposure to NVP alone is being studied [15].As economics and health care infrastructures permit, the alternative approach of providing potent combinations of antiretroviral agents to pregnant women to achieve full virologic suppression has the potential to reduce neonatal HIV infection to the levels seen in the developed world while preventing drug resistance in the mothers. The articles by Johnson et al., Flys et al., and Eshleman et al. in this issue of the Journal of Infectious Diseases may help to bring us closer to this ultimate goal.
Nevirapine Resistance in Mother-To-Child Transmission
Reported by Jules Levin
In today's opening morning session at the 14th HIV Drug Resistance Workshop (Quebec City, Quebec, Canada, June 7-11, 2005) titled "Mother To Child Transmission", there were 4 oral presentations of studies looking at nevirapine use for reducing HIV transmission and reducing nevirapine resistance to mother & infant. Two studies looked at alternative regimens than sindle-dose nevirapine to prevent mother-to-child-transmission of HIV-1. Susan Eshleman of Hopkins examined avoiding nevirapine for the mother & giving either single-doseNVP or sdNVP+AZT to infant soon after delivery. Avoiding giving NVP to mother obviously prevents the mother from getting NVP resistance. The infant's resistance to NVP was from 74% to 57% by giving only infant sdNVP but more significantly to 27% by giving infant sdNVP+AZT. David Hall from Boehringer Ingelheim reported on a BI study where women were randomized to 1 of 3 regimens. Both the women and infant received either sdNVP, or sdNVP + Conbivir for 4 days, or sdNVP with Combivir for 7 days after delivery. The follow-up for this study was short, only 6 weeks & the number of participants in the BI & the first study by Eshleman were small. Use of Combivir for 4 or 7 days reduced the mother's HIV viral load from 8000 without Combivir to 400 copies/ml or below. There were no differences in results so far out to 6 weeks whether Combivir was used for 4 or 7 days. NVP resistance in the mother was reduced from 60% (41/68) for those receiving sdNVP to 12% (8/67) for mothers receiving sdNVP+Combivir for 4 days to 10% (7/68) for mothers who received sdNVP + Combivir for 7 days. The use of Combivir avoids 80% of the emergence of NVP resistance in the mothers. Similarly, NVP resistance was reduced for infants. Of 8 infants HIV-infected in utero 7 had NVP resistance mutaions (88%); the rates of resistance were reduced when Combivir was used: 7 infants were infected in utero when using Combivir for 4 days + sdNVP (14%), and 0 of 7 infants were infected in utero when using NVP + Combivir for 7 days (0%). No 3TC resistance was detected.
However, Sarah Palmer reported in an oral session immediately after these two studies were presented on the use of a sensitive resistance test compared to standard genotyping to look for NVP resistance in the mothers in the BI study. Using the sensitive test the percent of women with NNRTI mutations was higher than found when using the standard genotype test: 50% vs 75% (sdNVP); 0% vs 27% (sdNVP+CBV-4 days); 0% vs 27% (sdNVP+CBV-7 days).
Dara Lehman reported in the final oral talk on this session on the prevention of HIV transmission due to breast feeding comparing the use of AZT or nevirapine.
Between 3 and 21 days postpartum, treatment with NVP was associated with significantly greater suppression of breast milk log10 HIV-1 RNA: days 3 to 7 (1.98 vs 2.42, P=0.1); days 8 to 14 (1.78 vs 2.48, P=0.005); days 15 to 21 (1.90 vs 2.97, P=0.003). However, this is counterbalanced by the development of NVP resistance in the mothers. In preliminary studies, utilizing an allele-specific PCR assay, one-month postpartum blood samples were tested from the NVP-treated women and determined that 40% of the women tested to date had detectable levels of the K103N mutation. Breast milk samples are currently being tested.
There was discussion about the use of different antiretroviral therapy to prevent mother-to-child HIV transmission, to avoid the development of nevirapine resistance, but at this time access to nevirapine is the only option available.
"Infant NVP Resistance Can be Substantially Reduced After Single Dose NVP by Avoiding Maternal NVP Dosing and Providing Infants with AZT in Addition to Single Dose NVP After Birth"
The objective of this study is to compare the rates of NVP resistance among infants in the NVAZ study who were exposed to different maternal/infant prophylactic regimens than HIVNET 012, single-dose NVP for early presenting mother & infant. Eshleman concluded: avoiding maternal NVP and providing infants with NVP+AZT was optimal of the 4 regimens. NVP resistance in women was eliminated. NVP resistance in infants was dramatically reduced: 87% (HIVNET 012) vs 27% group 4 regimen), p<0.001, by avoiding pre-delivery maternal NVP and providing infants with nevirapine+AZT (14-15%). The risk of HIV-1 MTCT was comparable to HIVNET 012 and another regimen that administered NVP to the mothers. These results are encouraging, but require confirmation in other studies.
Susan Eshleman (Johns Hopkins) provided this background. Administration of single dose NVP to women in labor and infants after birth can prevent HIV-1 MTCT. However, NVP-based regimens for prevention of MTCT are associated with emergence of NVP resistance in some women and some infants who are HIV-infected despite prophylaxis. This may compromise use of the regimen in subsequent pregnancies and/or treatment of women and infants with NNRTI-based regimens.
SD (single dose) NVP AND DRUG RESISTANCE
"The more you look, the more you find"
Johnson et al: The rate of NVP resistance in women after SD NVP is underestimated by routine genotyping
Flys et al: NVP-resistant variants persist in some women and infants above baseline levels for a year or more after SD NVP
Eshleman et al: The rate of NVP resistance is even higher in women with subtype C than in other subtypes
JID In Press 7/05
Other approaches for prevention of HIV MTCT are needed to: (1) reduce NVP resistance in women & infants; (2) provide prophylaxis for women who present late in labor or after delivery; (3) reduce HIV-1 transmission post-partum (breast-feeding).
This study analyzed NVP resistance 6-8 weeks after single-dose NVP in 78 infants who became HIV-infected despite antiretroviral prophylaxis.
The NVAZ trial in Malawi compared 4 regimens for prevention of HIV-1 mother-to-child transmission:
--group 1: women and infants received single-dose NVP (HIVNET 012 regimen);
--group 2: women received single-dose NVP, infants received single-dose NVP+AZT twice a day for 7 days
--group 3: women (presenting in late labor) received no NVP, infants received single-dose NVP;
group 4: women presenting in late labor received no NVP, infants received single-dose NVP+AZT as above.
The HIV-1 transmission rate was similar for groups 1, 2, and 4:
Group 1: 14.1% overall; incident 6.5%
Group 2: 16.3% overall; 6.9% incident
Group 3: 20.9% overall; incident 12.1%
Group 4: 15.3% overall; 7.7% incident
Lancet 2003;362:1171-7
JAMA 2004;292:202-9
High Rates of Resistance were observed in women & infants who received the HIVNET 012 regimen (subtype C):
GROUP 1: NVP RESISTANCE at Weeks 6-8: 69% for women; 87% for infants.
RESULTS
Group 1: 87% (20/23) of infants with NVP resistance; OR 22.24
(Women SD NVP; Infants (SD NVP)
Group 2: 74% (14/19) of infants with NVP resistance; OR 8.38
(Women SD NVP; Infants SD NVP+AZT)
Group 3: 57% of infants (12/21) with NVP resistance; OR 5.07
(Women no NVP; Infant SD NVP)
Group 4: 27% (4/15) of infants with NVP resistance; OR 1.00
(women no NVP; Infants SD NVP+AZT)
OR adjusted for maternal viral load.
"Single Dose Nevirapine Combined with a Short Course of Combivir for Prevention of Mother To Child Transmission of HIV-1 Can Significantly Decrease the Subsequent Development of Maternal and Infant Resistant Virus"
David Hall (Boehringer Ingelheim) reported results from a trial of single-dose NVP+short course AZT.
Study participants were randomly assigned to 1 of 3 regimens:
--mother: SD NVP 200mg during labor
Infant: SD NVP 2 mg/kg
--mother SD NVP + 4 days Combivir
Infant: SD NVP + 4 days AZT+3TC
--mother: SD NVP + 7 days Combivir
Infant: SD NVP + 7 days AZT+3TC
NNRTI Mutations: K101E, K103N, V106AM, Y181C, Y188C, G190A.
MATERNAL RESISTANCE
Total with mutations:
NVP (68 treated): 41 (60%)
NVP/CBV4 days (67 treated): 8 (12%)
NVP/CBV7 days (68 treated): 7 (10%)
MEDIAN HIV RNA AT BASELINE & AT NADIR FOR MOTHERS:
NVP: 23,000 baseline; 8300 nadir viral load
NVP/CBV 4 days: 24,000; <400 nadir viral load
NVP/CBV 7 days: 35,000; 438 nadir viral load
INFANT RESISTANCE
Total with NNRTI mutations:
NVP (8 infected in utero): 7 (88%)
NVP/CBV 4 days (7 infected in utero): 1 (14%)
NVP/CBV 7 days (7 infected in utero): 0 (0%)
OBSERVATIONS:
Single dose NVP & 4 or 7 days of Combivir can produce a transient reduction of plasma HIV RNA to <400 copies/ml & avoid 80% of the emergence of NNRTI mutations seen with single dose NVP. There was no evidence of emergence of 3TC associated mutations at codon 184.
With SD NVP, NNRTI associated mutations emerge at different rates & remain for different durations. The pattern of mutations observed will depend on when samples are collected. Mutations were observed for the first time as late as 25 weeks.
CONCLUSIONS:
A short course of Combivir significantly reduces the emergence of NVP-associated mutations in mothers taking single-dose NVP to prevent mother-to-child transmission of HIV-1.
A short course of Combivir reduces the emergence of NVP-associated mutations in infants taking SD single dose NVP after intrauterine infection.
"Short Course Combivir After Single Dose Nevirapine Reduces But Does Not eliminate the Selection of Nevirapine-Resistant HIV"
Despite the positive findings reported above Sarah Palmer reported drug resistance was more prevalent using a sensitive resistance assay. The objective of this study was to use a sensitive allele-specific RT-PCR assay to determine the frequency of NNRTI-resistant mutants in women who had received single-dose nevirapine alone or in combination with Combivir for 4 or 7 days.
This assay detects & quantifies all alleles, variants encoding 181C or 103N, down to 0.1%.
32 women enrolled in BI study:
--10 received single-dose NVP
--11 received single-dose NVP + 4 days CBV
--11 received single-dose NVP + 7 days CBV
Plasma samples were collected at:
Baseline (pre-treatment), 2 weeks, 6 weeks
PERCENT of WOMEN with NNRTI MUTATIONS at WEEK 6
Using the sensitive test the percent of women with NNRTI mutations was higher than found when using the standard genotype test: 50% vs 75% (sdNVP); 0% vs 27% (sdNVP+CBV-4 days); 0% vs 27% (sdNVP+CBV-7 days).
Palmer concluded:
Six weeks after sdNVP alone, 75% of women had NNRTI-resistant variants in plasma detectable by allele-specific PCR.
Short course CNV for 4 or 7 days reduced this frequency to 27% of women at week 6.
At week 6, the median fraction of plasma virus that comprises 103N (AAC) & 181c variants appears to be lower in women who received sdNVP + CBV (4 or 7 days) versus sdNVP alone.
The frequency of NNRTI resistant variants selected by sdNVP with or without CBV varies among women.
NNRTi resistant variants, even at low frequencies, may compromise future treatments containing NNRTIs and limit the subsequent efficacy of sdNVP fpr pMTCT.
Additional studies are needed to:
--establish the clinical significance of low frequency NNRTI resistant vatiants
--define the optimal duration of CBV to eliminate the selection of NNRTI resistant variants
"Patterns of viral load and drug resistance in breastmilk and blood from women treated with single-dose nevirapine to reduce mother-to-child transmission of HIV-1"
DA Lehman1,3, MH Chung4, BA Richardson2,
GC John-Stewart4,5 and J Overbaugh1,3
1Division of Human Biology, Fred Hutchinson Cancer Research
Center, Seattle, USA
2Division of Public Health Sciences, Fred Hutchinson Cancer
Research Center, Seattle, USA
3Department of Molecular and Cellular Biology, University of
Washington, Seattle, USA
4Department of Medicine. University of Washington, Seattle,
USA
5Department of Epidemiology, University of Washington, Seattle,
USA
BACKGROUND: The use of single-dose nevirapine (NVP) to reduce mother-to-child transmission of HIV-1 is increasing in the developing world. However, little
is known regarding the effects of this regimen on viral loads in breast milk or on the temporal patterns of drug resistance that arise during the early postpartum
period. These are important to determine because considerable HIV-1 transmission occurs during the first 6 weeks postpartum in breastfeeding populations. We have determined the effect of NVP on breast milk viral
shedding and are examining the prevalence of NVP resistance during this early postpartum period.
METHODS: Thirty pregnant HIV-1 seropositive women in Nairobi, Kenya who planned to breastfeed were treated with the single-dose NVP regimen
(HIVNET 012). Two to four breast milk samples were collected each week between delivery and 6 weeks postpartum. Breast milk HIV-1 RNA was quantified using the Gen-Probe HIV-1 viral load assay. HIV-1 DNA was extracted from blood samples collected at 1 month postpartum and was tested for NVP resistance using an allele-specific PCR assay that detects the K103N mutation.
RESULTS: Breast milk viral loads in 30 women treated with single-dose NVP were compared to breast milk viral loads from 30 women treated with the Thai-CDC short-course zidovudine regimen. A total of 404 breast milk samples from the NVP-treated women were tested, with a median of 14 samples per woman during the first 6 weeks postpartum. Between 3 and 21 days postpartum,
treatment with NVP was associated with significantly greater suppression of breast milk log10 HIV-1 RNA: days 3 to 7 (1.98 vs 2.42, P=0.1); days 8
to 14 (1.78 vs 2.48, P=0.005); days 15 to 21 (1.90 vs 2.97, P=0.003). In preliminary studies, utilizing an allele-specific PCR assay, we tested one-month postpartum blood samples from the NVP-treated women and determined that 40% of the women tested to date had detectable levels of the K103N mutation. Breast milk samples are currently being tested.
CONCLUSIONS: Compared to the Thai-CDC shortcourse zidovudine regimen, single-dose NVP results in sustained suppression of breast milk viral loads during the first 3 weeks postpartum. However, the benefits of this suppression may be counterbalanced with a high prevalence of resistance.
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