Dataset Information

Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV-1 variants in breast milk following single-dose nevirapine prophylaxis.

ABSTRACT:

Background

Intrapartum administration of single-dose nevirapine (sdNVP) reduces perinatal HIV-1 transmission in resource-limiting settings by half. Yet this strategy has limited effect on subsequent breast milk transmission, making the case for new treatment approaches to extend maternal/infant antiretroviral prophylaxis through the period of lactation. Maternal and transmitted infant HIV-1 variants frequently develop NVP resistance mutations following sdNVP, complicating subsequent treatment/prophylaxis regimens. However, it is not clear whether NVP-resistant viruses are transmitted via breastfeeding or arise de novo in the infant.

Findings

We performed a detailed HIV genetic analysis using single genome sequencing to identify the origin of drug-resistant variants in an sdNVP-treated postnatally-transmitting mother-infant pair. Phylogenetic analysis of HIV sequences from the child revealed low-diversity variants indicating infection by a subtype C single transmitted/founder virus that shared full-length sequence identity with a clonally-amplified maternal breast milk virus variant harboring the K103N NVP resistance mutation.

Conclusion

In this mother/child pair, clonal amplification of maternal NVP-resistant HIV variants present in systemic and mammary gland compartments following intrapartum sdNVP represents one source of transmitted NVP-resistant variants that is responsible for the acquisition of drug resistant virus by the breastfeeding infant. This finding emphasizes the need for combination antiretroviral prophylaxis to prevent mother-to-child HIV transmission.

SUBMITTER: Permar SR

PROVIDER: S-EPMC3765243 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Publications

Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV-1 variants in breast milk following single-dose nevirapine prophylaxis.

Permar Sallie R SR Salazar Maria G MG Gao Feng F Cai Fangping F Learn Gerald H GH Kalilani Linda L Hahn Beatrice H BH Shaw George M GM Salazar-Gonzalez Jesus F JF

Retrovirology 20130814

<h4>Background</h4>Intrapartum administration of single-dose nevirapine (sdNVP) reduces perinatal HIV-1 transmission in resource-limiting settings by half. Yet this strategy has limited effect on subsequent breast milk transmission, making the case for new treatment approaches to extend maternal/infant antiretroviral prophylaxis through the period of lactation. Maternal and transmitted infant HIV-1 variants frequently develop NVP resistance mutations following sdNVP, complicating subsequent trea ...[more]

PMID: 23941304

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Project description:BackgroundDaily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the "six-week extended-dose nevirapine" (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.Methods/findingsStandard population sequencing and cloning for viral subpopulations present at > or =5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant's blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.Conclusions/significanceUse of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.Trial registrationClinicalTrials.gov NCT00061321.

Project description:BackgroundSub-optimal adherence to infant prophylaxis has been associated with mother-to-child-transmission of HIV. However, the factors associated have not been well characterised in different settings. This study describes barriers and enablers of adherence to infant prophylaxis among 6-week-old HIV exposed infants in Lira district, Northern Uganda.MethodsThis prospective cohort study was conducted from 2018-2020 at the PMTCT clinic at Lira Regional Referral Hospital and included 472 mother-infant pairs. HIV-infected pregnant women were recruited, followed up at delivery and 6 weeks postpartum. We used a structured questionnaire to obtain data on socio-demographic, reproductive-related, HIV-related characteristics and adherence. Data were analysed using Stata to estimate adjusted risk ratios using Poisson regression models to ascertain barriers and enablers of adherence to infant nevirapine prophylaxis.ResultsBarriers to infant adherence are maternal characteristics including: younger age (≤20 years adjusted risk ratio (ARR) = 1.55; 95% CI: 1.1-2.2), missing a viral load test during pregnancy (ARR: 1.4; 95% CI: 1.1-1.7) and not receiving nevirapine syrup for the baby after childbirth (ARR = 6.2; 95% CI: 5.1-7.6). Enablers were: having attained ≥14 years of schooling (ARR = 0.7; 95% CI: 0.5-0.9), taking a nevirapine-based regimen (ARR = 0.6; 95% CI: 0.4-0.9), long-term ART (≥ 60 months ARR = 0.75; 95% CI: 0.6-0.9), accompanied by a husband to hospital during labour and childbirth (ARR = 0.5; 95% CI: 0.4-0.7) and labour starting at night (ARR = 0.7; 95% CI: 0.6-0.8).Conclusion and recommendationsDespite mothers receiving nevirapine syrup from the health workers for the infant, non-adherence rates still prevail at 14.8%. The health system needs to consider giving HIV infected pregnant women the nevirapine syrup before birth to avoid delays and non-adherence. There is need to pay particular attention to younger women and those who recently started ART.

Project description:BackgroundMalnutrition is highly prevalent in HIV-exposed perinatally uninfected infants (HEUs) increasing the risk of morbidity and mortality throughout the life course. We set out to compare the effect of postnatal exposure to maternal antiretroviral therapy (mART) in breastmilk versus infant Nevirapine prophylaxis (iNVP) on somatic growth of HEUs in the randomized PROMISE trial.Methods and findingsWe randomized 2431 mothers with HIV and their 2444 HEUs from six African countries and India 6-14 days after delivery to mART or iNVP for prevention of breastmilk HIV transmission. The mART regimen contained tenofovir/emtricitabine (99%) plus lopinavir/ritonavir. Infant growth parameters were compared at postnatal week 10, 26, 74 and 104 using World Health Organization (WHO) z-scores for length-for-age (LAZ), weight-for-age (WAZ), and head circumference-for-age (HCAZ). Week 26 LAZ was the primary endpoint measure. Student T-tests compared mean LAZ, WAZ, and HCAZ; estimated mean and 95% confidence interval (CI) are presented. Maternal and infant baseline characteristics were comparable between study arms. The estimated median breastfeeding duration was 70 weeks. After a mean follow-up of 88 weeks, mean LAZ and WAZ were below the WHO reference population mean at all timepoints, whereas mean HCAZ was not. The mART and iNVP arms did not differ for the primary outcome measure of LAZ at week 26 (p-value = 0.39; estimated mean difference (95%CI) of -0.05 (-0.18, 0.07)) or any of the other secondary growth outcome measures or timepoints (all p-values≥0.16). Secondary analyses of the primary outcome measure adjusting for week 0 LAZ and other covariates did not change these results (all p-values≥0.09). However, infants assigned to mART were more likely to have stunting compared to iNVP infants at week 26 (odds ratio (95% CI): 1.28 (1.05, 1.57)).ConclusionsIn HEUs, growth effects from postnatal exposure to mART compared to iNVP were comparable for measures on length, weight and head circumference with no clinically relevant differences between the groups. Despite breastfeeding into the second year of life, length and weight were below reference population means at all ages in both arms. Further investment is needed to optimize postnatal growth of infants born to women with HIV.Clinical trial registrationClinicalTrials.gov number NCT01061151.

Dataset Information

Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV-1 variants in breast milk following single-dose nevirapine prophylaxis.

Background

Findings

Conclusion

Publications

Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV-1 variants in breast milk following single-dose nevirapine prophylaxis.

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