Antiretroviral Strategies to Prevent Mother-to-Child Transmission of HIV: Striking a Balance between Efficacy, Feasibility, and Resistance

Dara Lehman and colleagues discuss a randomized trial that found that adding up to a week of twice-daily zidovudine+lamivudine to single-dose nevirapine reduces the risk of resistance in mothers and infants

Increased Cervical Human Immunodeficiency Virus (HIV) RNA Shedding Among HIV-Infected Women Randomized to Loop Electrosurgical Excision Procedure Compared to Cryotherapy for Cervical Intraepithelial Neoplasia 2/3

Background Treatment of human immunodeficiency virus (HIV)–infected women to prevent cervical cancer may stimulate HIV RNA cervical shedding and risk HIV transmission. Methods From 2011 to 2014, 400 HIV-infected women diagnosed with cervical intraepithelial neoplasia 2/3 in Kenya were randomized to loop electrosurgical excision procedure (LEEP) or cryotherapy. Cervical samples were collected at baseline and 3 weekly intervals. Samples were tested for HIV RNA using the Gen-Probe Aptima HIV assay with a minimum detection level of 60 copies/swab and analyzed using generalized estimating equations. Results Women who received LEEP had significantly higher cervical HIV RNA levels than those who received cryotherapy at weeks 2 (adjusted incident rate ratio [aIRR], 1.07; P = .038) and 3 (aIRR, 1.08; P = .046). Within LEEP, significantly higher cervical shedding was found at weeks 2 (2.03 log10 copies/swab; P < .001) and 3 (2.04 log10 copies/swab; P < .001) compared to baseline (1.80 log10 copies/swab). Cervical HIV RNA was significantly higher following LEEP for up to 3 weeks among women on antiretroviral treatment (ART) (0.18 log10 copies/swab increase; P = .003) and in ART-naive women (1.13 log10 copies/swab increase; P < .001) compared to baseline. Within cryotherapy, cervical shedding increased in ART-naive women (0.72 log10 copies/swab increase; P = 0.004) but did not increase in women on ART. Conclusions Women randomized to LEEP had a larger increase in post-procedural cervical HIV shedding than cryotherapy. Benefits of cervical cancer prevention outweigh the risk of HIV sexual transmission; our findings underscore the importance of risk-reduction counseling

Incidence and Correlates of HIV-1 RNA Detection in the Breast Milk of Women Receiving HAART for the Prevention of HIV-1 Transmission

The incidence and correlates of breast milk HIV-1 RNA detection were determined in intensively sampled women receiving highly active antiretroviral therapy (HAART) for the prevention of mother-to-child HIV-1 transmission.Women initiated HAART at 34 weeks of pregnancy. Breast milk was collected every 2-5 days during 1 month postpartum for measurements of cell-associated HIV DNA and cell-free HIV RNA. Plasma and breast milk were also collected at 2 weeks, 1, 3 and 6 months for concurrent HIV-1 RNA and DNA measurements. Regression was used to identify cofactors for breast milk HIV-1 RNA detection.Of 259 breast milk specimens from 25 women receiving HAART, 34 had detectable HIV-1 RNA (13%, incidence 1.4 episodes/100 person-days 95% CI = 0.97-1.9). Fourteen of 25 (56%) women had detectable breast milk HIV-1 RNA [mean 2.5 log(10) copies/ml (range 2.0-3.9)] at least once. HIV-1 DNA was consistently detected in breast milk cells despite HAART, and increased slowly over time, at a rate of approximately 1 copy/10(6) cells per day (p = 0.02). Baseline CD4, plasma viral load, HAART duration, and frequency of breast problems were similar in women with and without detectable breast milk HIV-1 RNA. Women with detectable breast milk HIV-1 RNA were more likely to be primiparous than women without (36% vs 0%, p = 0.05). Plasma HIV-1 RNA detection (OR = 9.0, 95%CI = 1.8-44) and plasma HIV-1 RNA levels (OR = 12, 95% CI = 2.5-56) were strongly associated with concurrent detection of breast milk HIV-1 RNA. However, no association was found between breast milk HIV-1 DNA level and concurrent breast milk HIV-1 RNA detection (OR = 0.96, 95%CI = 0.54-1.7).The majority of women on HAART had episodic detection of breast milk HIV-1 RNA. Breast milk HIV-1 RNA detection was associated with systemic viral burden rather than breast milk HIV-1 DNA

Maternal Highly Active Antiretroviral Therapy Reduces Vertical Cytomegalovirus Transmission But Does Not Reduce Breast Milk Cytomegalovirus Levels

To evaluate the impact of highly active antiretroviral therapy (HAART) on CMV transmission and breast milk level in the context of maternal HIV. Specimens from a randomized trial conducted in Nairobi, Kenya between 2003–2005 were used to compare CMV transmission and breast milk levels between mother-infant pairs randomized to HAART versus short-course antenatal zidovudine plus single-dose nevirapine (ZDV/sdNVP) for prevention of mother-to-child HIV transmission (PMTCT). Fifty-one antiretroviral-naïve women ≤32 weeks gestation, and CD4 between 200–500 cells/mm3 were randomized at 34 weeks to begin either antenatal ZDV/sdNVP, or HAART through 6 months postpartum. Mean breast milk CMV levels and transmission were compared between arms. Age, sociodemographics, CD4%, and HIV plasma RNA viral load were similar between arms at baseline. CMV viral loads were measured from 243 infant plasma and 185 breast milk specimens during the first year postpartum. The probability of infant CMV infection at 12 months was 19% lower in the HAART arm compared to ZDV/sdNVP (75% vs. 94%, p = .04). All women had CMV detected in breast milk, with 72%, 98%, and 97% testing positive during the first, second, and third weeks postpartum, respectively. There was a trend for early higher mean breast milk CMV level in the HAART arm at 1 week (p = .08), and there was significantly slower decline in breast milk CMV levels (area under the curve, p = .01). HAART started during the third trimester may decrease infant CMV infections, by mechanisms independent of breast milk CMV levels. Clinical trials registration: NCT00167674

Superinfection Drives HIV Neutralizing Antibody Responses from Several B Cell Lineages that Contribute to a Polyclonal Repertoire

Summary: Eliciting broad and potent HIV-specific neutralizing antibody responses represents the holy grail of HIV vaccine efforts. Data from singly infected individuals with broad and potent plasma neutralizing activity targeting one epitope have guided our understanding of how these responses develop. However, far less is known about responses developed by superinfected individuals who acquire two distinct HIV strains. Here, we isolated HIV-specific mAbs from a superinfected individual with a broad plasma response. In this superinfection case, neutralizing activity resulted from multiple distinct B cell lineages that arose in response to either the initial or the superinfecting virus, including an antibody that targets the N332 supersite. This nAb, QA013.2, was specific to the superinfecting virus and was associated with eventual reemergence of the initial infecting virus. The complex dynamic between viruses in superinfection may drive development of a unique collection of polyclonal nAbs that present a higher barrier to escape than monoclonal responses. : Superinfection occurs when an HIV-infected person acquires a second infection with a genetically distinct HIV virus. Williams et al. isolate HIV-specific mAbs from a superinfected individual with a broad plasma response. In this superinfection case, neutralizing activity resulted from multiple distinct B cell lineages that arose in response to the initial or superinfecting virus, including an antibody that targets the N332 supersite. Keywords: HIV, antibody, broadly neutralizing antibody, HIV viral escap

Dynamics of HIV DNA reservoir seeding in a cohort of superinfected Kenyan women.

A reservoir of HIV-infected cells that persists despite suppressive antiretroviral therapy (ART) is the source of viral rebound upon ART cessation and the major barrier to a cure. Understanding reservoir seeding dynamics will help identify the best timing for HIV cure strategies. Here we characterize reservoir seeding using longitudinal samples from before and after ART initiation in individuals who sequentially became infected with genetically distinct HIV variants (superinfected). We previously identified cases of superinfection in a cohort of Kenyan women, and the dates of both initial infection and superinfection were determined. Six women, superinfected 0.2-5.2 years after initial infection, were subsequently treated with ART 5.4-18.0 years after initial infection. We performed next-generation sequencing of HIV gag and env RNA from plasma collected during acute infection as well as every ~2 years thereafter until ART initiation, and of HIV DNA from PBMCs collected 0.9-4.8 years after viral suppression on ART. We assessed phylogenetic relationships between HIV DNA reservoir sequences and longitudinal plasma RNA sequences prior to ART, to determine proportions of initial and superinfecting variants in the reservoir. The proportions of initial and superinfection lineage variants present in the HIV DNA reservoir were most similar to the proportions present in HIV RNA immediately prior to ART initiation. Phylogenetic analysis confirmed that the majority of HIV DNA reservoir sequences had the smallest pairwise distance to RNA sequences from timepoints closest to ART initiation. Our data suggest that while reservoir cells are created throughout pre-ART infection, the majority of HIV-infected cells that persist during ART entered the reservoir near the time of ART initiation. We estimate the half-life of pre-ART DNA reservoir sequences to be ~25 months, which is shorter than estimated reservoir decay rates during suppressive ART, implying continual decay and reseeding of the reservoir up to the point of ART initiation

Comparison of women by detection of breast milk HIV-1 RNA.

<p>Notes. Median (IQR) or frequency (n/N) are shown for each correlate. VL, viral load; p-d, person-days 95%CI, 95% confidence interval;</p><p>*At any time (includes antenatal and on HAART).</p><p>**Includes clinical mastitis, cracked nipples, localized swelling, and breast abscess.</p><p>***Measurements at delivery or first postpartum visit.</p

Detection of breast milk HIV-1 RNA in women receiving HAART for PMTCT.

<p>The detection of HIV-1 RNA is shown for 25 women on HAART postpartum. Visits were ranked by date, and are shown only for visits while HAART was being administered. *The first postpartum HIV-1 plasma RNA measurement is provided for each woman. M-586 and -538 did not have a plasma viral load measured within a week of delivery; plasma viral loads shown for these two women coincide with visit 1.</p

Predictors of concurrent HIV-1 cell-free RNA detection in breast milk during PMTCT HAART.

<p>Notes. N, number of subjects in analysis. The association between breast milk HIV-1 RNA detection and each covariate is examined separately in an unadjusted model, and adjusted for days on HAART.</p><p>*Analysis for breast milk HIV-1 DNA was restricted to the first month postpartum because the majority of HIV-1 DNA measurements (154/163) were made during this time interval.</p><p>**In all models adjusted for time, days on HAART remained insignificant with an OR of approximately 1.0 (not shown).</p

HIV and SARS-CoV-2 infection in postpartum Kenyan women and their infants.

BackgroundHIV may increase SARS-CoV-2 infection risk and COVID-19 severity generally, but data are limited about its impact on postpartum women and their infants. As such, we characterized SARS-CoV-2 infection among mother-infant pairs in Nairobi, Kenya.MethodsWe conducted a nested study of 62 HIV-uninfected and 64 healthy women living with HIV, as well as their HIV-exposed uninfected (N = 61) and HIV-unexposed (N = 64) infants, participating in a prospective cohort. SARS-CoV-2 serology was performed on plasma collected between May 1, 2020-February 1, 2022 to determine the incidence, risk factors, and symptoms of infection. SARS-CoV-2 RNA PCR and sequencing was also performed on available stool samples from seropositive participants.ResultsSARS-CoV-2 seropositivity was found in 66% of the 126 mothers and in 44% of the 125 infants. There was no significant association between SARS-CoV-2 infection and maternal HIV (Hazard Ratio [HR] = 0.810, 95% CI: 0.517-1.27) or infant HIV exposure (HR = 1.47, 95% CI: 0.859-2.53). Maternal SARS-CoV-2 was associated with a two-fold increased risk of infant infection (HR = 2.31, 95% CI: 1.08-4.94). Few participants (13% mothers, 33% infants) had symptoms; no participant experienced severe COVID-19 or death. Seroreversion occurred in about half of mothers and infants. SARS-CoV-2 sequences obtained from stool were related to contemporaneously circulating variants.ConclusionsThese data indicate that postpartum Kenyan women and their infants were at high risk for SARS-CoV-2 infection and that antibody responses waned over an average of 8-10 months. However, most cases were asymptomatic and healthy women living with HIV did not have a substantially increased risk of infection or severe COVID-19