Demographics of Youth With Newly Diagnosed Acute/Recent HIV Infection in Adolescent Trials Network 147: Early Treatment of Acute HIV Infection.

PURPOSE: Gay, bisexual, and other cisgender men who have sex with men, and racial minority youth are at elevated risk of acquiring HIV infection. The Adolescent Trials Network 147 recruited youth with acute/recent HIV-infection for early antiretroviral treatment. The cohort make-up is described here. METHODS: Treatment-naïve, recently identified HIV + youth, aged 12-24 years, from Los Angeles and New Orleans were recruited from community centers, clinics, social media, and a high-risk seronegative cohort (n = 1,727, the Adolescent Trials Network 149) using point-of-care assays. Acute HIV infection was determined by Fiebig staging. HIV RNA viral load (VL) and CD4 cell counts, along with demographic and behavioral data were assessed at enrollment. RESULTS: Between July 2017 and July 2021, 103 newly diagnosed youth were enrolled, initiating antiretroviral treatment within a week. Mean age was 20.8 years (standard deviation: 2.4); 90.3% identified as cis male, 83.5% were single or in casual relationships, 71.8% were gay, bisexual, and other cisgender men who have sex with men; 60.2% were Black. One-fourth (24.3%) reported homelessness ever; 10.7% within last 4 months. At enrollment, median plasma VL was 37,313 HIV RNA copies/ml (interquartile range: 5,849-126,162) and median CD4 count 445.5 cells/mm3 (interquartile range: 357-613). 40% of youth reported acute retroviral symptoms before or at enrollment. Acutely infected, seroconverting youth had the highest VL. Sexually transmitted coinfections were present at enrollment in 56% of the cohort, with syphilis being most frequent (39%). DISCUSSION: Early identification and treatment of HIV can increase positive HIV outcomes. A high sexually transmitted infection burden was present in recently HIV-infected youth. Acute retroviral symptoms were not reported by most participants, demonstrating that broad universal HIV screening is needed for identification of recent infection in youth.

Congenital Cytomegalovirus and HIV Perinatal Transmission.

BACKGROUND: Congenital cytomegalovirus (CMV) infection (cCMV) is an important cause of hearing loss and cognitive impairment. Prior studies suggest that HIV-exposed children are at higher risk of acquiring cCMV. We assessed the presence, magnitude and risk factors associated with cCMV among infants born to HIV-infected women, who were not receiving antiretrovirals during pregnancy. METHODS: cCMV and urinary CMV load were determined in a cohort of infants born to HIV-infected women not receiving antiretrovirals during pregnancy. Neonatal urines obtained at birth were tested for CMV DNA by qualitative and reflex quantitative real-time polymerase chain reaction. RESULTS: Urine specimens were available for 992 (58.9%) of 1684 infants; 64 (6.5%) were CMV-positive. Mean CMV load (VL) was 470,276 copies/ml (range: < 200-2,000,000 copies/ml). Among 89 HIV-infected infants, 16 (18%) had cCMV versus 42 (4.9%) of 858 HIV-exposed, uninfected infants (P < 0.0001). cCMV was present in 23.2% of infants with in utero and 9.1% infants with intrapartum HIV infection (P < 0.0001). Rates of cCMV among HIV-infected infants were 4-fold greater (adjusted OR, 4.4; 95% CI: 2.3-8.2) and 6-fold greater among HIV in utero-infected infants (adjusted OR, 6; 95% CI: 3-12.1) compared with HIV-exposed, uninfected infants. cCMV was not associated with mode of delivery, gestational age, Apgar scores, 6-month infant mortality, maternal age, race/ethnicity, HIV viral load or CD4 count. Primary cCMV risk factors included infant HIV-infection, particularly in utero infection. CONCLUSION: High rates of cCMV with high urinary CMV VL were observed in HIV-exposed infants. In utero HIV infection appears to be a major risk factor for cCMV in infants whose mothers have not received combination antiretroviral therapy in pregnancy.

Human Immunodeficiency Virus Antiretroviral Resistance and Transmission in Mother-Infant Pairs Enrolled in a Large Perinatal Study.

Background: The presence of antiretroviral drug-associated resistance mutations (DRMs) may be particularly problematic in human immunodeficiency virus (HIV)-infected pregnant women as it can lead to mother-to-child transmission (MTCT) of resistant HIV strains. This study evaluated the prevalence and the effect of antiretroviral DRMs in previously untreated mother-infant pairs. Methods: A case-control design of 1:4 (1 transmitter to 4 nontransmitters) was utilized to evaluate DRMs as a predictor of HIV MTCT in specimens obtained from mother-infant pairs. ViroSeq HIV-1 genotyping was performed on mother-infant specimens to assess for clinically relevant DRMs. Results: One hundred forty infants acquired HIV infection; of these, 123 mother-infant pairs (88%) had specimens successfully amplified using ViroSeq and assessed for drug resistance genotyping. Additionally, 483 of 560 (86%) women who did not transmit HIV to infants also had samples evaluated for DRMs. Sixty-three of 606 (10%) women had clinically relevant DRMs; 12 (2%) had DRMs against >1 drug class. Among 123 HIV-infected infants, 13 (11%) had clinically relevant DRMs, with 3 (2%) harboring DRMs against >1 drug class. In univariate and multivariate analyses, DRMs in mothers were not associated with increased HIV MTCT (adjusted odds ratio, 0.8 [95% confidence interval, .4-1.5]). Presence of DRMs in transmitting mothers was strongly associated with DRM presence in their infants (P < .001). Conclusions: Preexisting DRMs were common in untreated HIV-infected pregnant women, but did not increase the risk of HIV MTCT. However, if women with DRMs are not virologically suppressed, they may transmit resistant mutations, thus complicating infant management.

Cytomegalovirus Urinary Shedding in HIV-infected Pregnant Women and Congenital Cytomegalovirus Infection.

BACKGROUND: Cytomegalovirus (CMV) urinary shedding in pregnant women infected with human immunodeficiency virus (HIV) was evaluated to determine whether it poses an increased risk for congenital CMV infection (cCMV). METHODS: A subset of mother-infant pairs enrolled in the perinatal NICHD HPTN 040 study (distinguished by no antiretroviral use before labor) was evaluated. Maternal and infant urines were tested by qualitative real-time polymerase chain reaction (RT-PCR) for CMV DNA with quantitative RT-PCR performed on positive specimens. RESULTS: Urine specimens were available for 260 women with 85.4% from the Americas and 14.6% from South Africa. Twenty-four women (9.2%) had detectable CMV viruria by qualitative PCR. Maternal CMV viruria was not associated with mean CD4 cell counts or HIV viral load but was associated with younger maternal age (P = .02). Overall, 10 of 260 infants (3.8%) had cCMV. Women with detectable peripartum CMV viruria were more likely to have infants with cCMV than those without: 20.8% (5/24) versus 2.1% (5/236), (P = .0001). Women with CMV viruria had significantly higher rates of HIV perinatal transmission (29.2% vs. 8.1%, P = .002). They were 5 times (adjusted odds ratio [aOR] = 5.6, 95% confidence interval [CI] 1.9-16.8) and nearly 30 times (aOR, 29.7; 95% CI, 5.4-164.2) more likely to transmit HIV and CMV to their infants, respectively. Maternal gonorrhea (aOR, 19.5; 95% CI, 2.5-151.3) and higher maternal HIV log10 viral load (OR, 2.8; 95% CI, 1.3-6.3) were also significant risk factors for cCMV. CONCLUSION: In this cohort of HIV-infected pregnant women not on antiretrovirals, urinary CMV shedding was a significant risk factor for CMV and HIV transmission to infants. CLINICAL TRIALS REGISTRATION NUMBER: NCT00099359.

Chlamydia trachomatis and Neisseria gonorrhoeae in HIV-infected Pregnant Women and Adverse Infant Outcomes.

BACKGROUND: Sexually transmitted infections (STIs) in pregnancy such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) may lead to adverse infant outcomes. METHODS: Individual urine specimens from HIV-infected pregnant women diagnosed with HIV during labor were collected at the time of infant birth and tested by polymerase chain reaction for CT and NG. Infant HIV infection was determined at 3 months with morbidity/mortality assessed through 6 months. RESULTS: Of 1373 maternal urine samples, 277 (20.2%) were positive for CT and/or NG; 249 (18.1%) for CT, 63 (4.6%) for NG and 35 (2.5%) for both CT and NG. HIV infection was diagnosed in 117 (8.5%) infants. Highest rates of adverse outcomes (sepsis, pneumonia, congenital syphilis, septic arthritis, conjunctivitis, low birth weight, preterm delivery and death) were noted in infants of women with CT and NG (23/35, 65.7%) compared with NG (16/28, 57.1%), CT (84/214, 39.3%) and no STI (405/1096, 37%, P = 0.001). Death (11.4% vs. 3%, P = 0.02), low birth weight (42.9% vs. 16.9%, P = 0.001) and preterm delivery (28.6% vs. 10.2%, P = 0.008) were higher among infants of CT and NG-coinfected women. Infants who had any adverse outcome and were born to women with CT and/or NG were 3.5 times more likely to be HIV infected after controlling for maternal syphilis (odds ratio: 3.5, 95% confidence interval: 1.4-8.3). By adjusted multivariate logistic regression, infants born to mothers with any CT and/or NG were 1.35 times more likely to have an adverse outcome (odds ratio, 1.35; 95% confidence interval, 1.03-1.76). CONCLUSIONS: STIs in HIV-infected pregnant women are associated with adverse outcomes in HIV-exposed infected and uninfected infants.

Chlamydia and Gonorrhea in HIV-Infected Pregnant Women and Infant HIV Transmission.

BACKGROUND: Sexually transmitted infections (STIs) such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) can lead to adverse pregnancy and neonatal outcomes. The prevalence of STIs and its association with HIV mother-to-child transmission (MTCT) were evaluated in a substudy analysis from a randomized, multicenter clinical trial. METHODOLOGY: Urine samples from HIV-infected pregnant women collected at the time of labor and delivery were tested using polymerase chain reaction testing for the detection of CT and NG (Xpert CT/NG; Cepheid, Sunnyvale, CA). Infant HIV infection was determined by HIV DNA polymerase chain reaction at 3 months. RESULTS: Of the 1373 urine specimens, 249 (18.1%) were positive for CT and 63 (4.6%) for NG; 35 (2.5%) had both CT and NG detected. Among 117 cases of HIV MTCT (8.5% transmission), the lowest transmission rate occurred among infants born to CT- and NG-uninfected mothers (8.1%) as compared with those infected with only CT (10.7%) and both CT and NG (14.3%; P = 0.04). Infants born to CT-infected mothers had almost a 1.5-fold increased risk for HIV acquisition (odds ratio, 1.47; 95% confidence interval, 0.9-2.3; P = 0.09). CONCLUSIONS: This cohort of HIV-infected pregnant women is at high risk for infection with CT and NG. Analysis suggests that STIs may predispose to an increased HIV MTCT risk in this high-risk cohort of HIV-infected women.

Amniotic fluid exhibits an innate inhibitory activity against HIV type 1 replication in vitro.

Indirect evidence suggests that amniotic fluid (AF) may play a role in the pathogenesis of in utero HIV-1 transmission. The purpose of this study was to evaluate the potential innate inhibitory role of AF on HIV replication, which may contribute to protection of the fetus against intrauterine transmission. AF was collected from term HIV-1-negative women undergoing scheduled cesarean section. The inhibitory effect of AF against HIV-1(BA-L) replication was tested in vitro with or without the addition of protease inhibitor cocktail (PIC) in PHA-stimulated PBMC cultures. Quantitative measurement of human neutrophil peptides 1-3 (HNP1-3) was performed on all AF samples, using an ELISA assay. AF exhibited a dose-dependent inhibitory activity against HIV-1(BA-L) replication, with all samples (n=12) reaching significant inhibitory effect using 50% AF. In vitro, this activity decreased over time, but was able to be sustained with the addition of PIC. The HNP1-3 concentration in AF samples (n=12) ranged from undetectable (<41 pg/ml, n=3) to >250,000 pg/ml with a median of 5,146 pg/ml. AF exhibited a significant and dose-dependent innate inhibitory activity against HIV-1 replication, which was present in all AF samples tested. This effect was prolonged in the presence of PIC, suggesting that the inhibitory factor was in the cell-free protein fraction. The HNP1-3 concentration in AF was in the subinhibitory range for HIV with no correlation between its concentration and the HIV-1 inhibitory activity. These data show the presence of a significant innate inhibitory activity against HIV in AF.

Short communication: enhanced CD8+ T cell apoptosis in HIV-infected adolescents with virologic failure on protease inhibitor-based therapy.

In this study, we investigated the possibility of differential effects of protease inhibitor (PI)-containing (PI(+)) and PI-sparing (PI(-)) antiretroviral therapies (ART) on CD8(+) T cell apoptosis. We retrospectively analyzed both PD-1 expression and CD8(+) T cell apoptosis in a cross-sectional study of HIV-positive adolescents and young adults (mean age = 17.4 years), with perinatally or behaviorally acquired HIV infection. Fifty-one specimens of cryopreserved peripheral blood mononuclear cells (PBMCs) were analyzed using 7-color flow cytometry: 20 from patients receiving PI(+) ART, 14 from PI(-) ART, and 17 from the untreated. The results showed that percentages of PD-1(+) CD8(+) T cells were strongly correlated with plasma viral loads regardless of treatment (p = 0.0001). The percentage of PD-1(+) CD8(+) T cells was also positively associated with percentages of Annexin V(+) CD8(+) T cells (p = 0.04) in the PI(+)-treated group. The fraction of apoptotic (Annexin V(+)) CD8(+) T cells was associated with viral load in the patients receiving ART that contained one or more protease inhibitors (p = 0.029), but not in the PI(-) or untreated groups. In summary, we found a direct correlation between PD-1 expression on CD8(+) T cells and HIV levels that was not affected by types of medications used in the ART of those adolescents, suggesting that virological success is necessary for PD-1 downregulation. CD8(+) T cell apoptosis was linked to high levels of PD-1 expression and HIV viremia. However, there was a higher degree of apoptosis among viremic patients receiving PI therapy, suggesting an immunologically adverse effect of continuing PI(+) therapy after virological failure.

Pediatric HIV-1-specific cytotoxic T-lymphocyte responses suggesting ongoing viral replication despite combination antiretroviral therapy.

Human immunodeficiency virus-1 (HIV-1)-specific cytotoxic T-lymphocyte (CTL) responses are common in infected adults and usually exhibit rapid decay after combination antiretroviral therapy (ART). CTLs develop later in the first year of life, and the fate of HIV-1-specific responses in perinatally infected children after ART is less well described. HIV-1-specific CTL responses were measured in 17 perinatally infected children and adolescents (ages 3-20 y) receiving combination ART. Seven had prolonged viral suppression (<400 copies/mL) for 2.5-5.3 y and 10 had persistent viremia (median, 77,550 copies/mL). HIV-1-specific CTL responses were tested by interferon (IFN)-gamma enzyme-linked immunospot (ELIS-pot) assays using 53 overlapping peptide pools spanning the entire HIV-1 proteome. HIV-1-specific CTL responses were detected in 14 of 17 individuals. Responses to one to four viral proteins were found in eight of 10 individuals with persistent viremia and six of seven with prolonged viral suppression. The magnitude and breadth of CTL responses were similar between groups. HIV-1-specific CTL responses were present in the majority of perinatally infected subjects, irrespective of viremia at evaluation. Because ART-treated infected adults usually have rapid decay of responses, these data suggest viral replication below the limits of detection is more persistent in combination ART-treated perinatally infected pediatric subjects. The long-term clinical implications of these findings remain to be determined.

Cellular and humoral immune responses to a tetanus toxoid booster in perinatally HIV-1-infected children and adolescents receiving highly active antiretroviral therapy (HAART).

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infected children treated with highly active antiretroviral therapy (HAART) may develop a significant reduction of plasma viremia associated with an increase in CD4+ T-cell counts. Functional capacity of this reconstituted immune system in response to recall antigens is important to maintain protective immunity to vaccine-preventable diseases. We therefore determined cellular and humoral immune responses to tetanus toxoid (TT) booster in perinatally HIV-1-infected children and adolescents receiving HAART. METHODS: Immune responses were prospectively evaluated pre- and post-tetanus booster using lymphocyte proliferation assay (LPA) stimulation index (SI > or = 3.0) and tetanus antibody (TAb > or = 0.15) in 15 patients. The median interval from primary tetanus immunization series was 6 years (range 2-12 years). We compared patients by their virological response to HAART (complete responders, CR, n=7; incomplete responders, ICR, n=8). RESULTS: There were no significant differences in median age 12.6 years (CR: 12.9; ICR: 10.6) or median CD4 T-cell pre-booster (CR: 35%/819; ICR: 26%/429) between groups. Tetanus LPA responses were observed in one patient prior to booster and in seven patients post-booster. In contrast, 38% of patients had protective TAb pre-booster, but 92% developed protective TAb post-booster. All of the CR and 5/6 ICR patients developed protective TAb. CONCLUSIONS: HIV-1-infected children and adolescents had modest LPA responses to tetanus following booster, similar to HIV-1-infected adults. However, the majority of patients developed protective TAb levels after booster and maintained the response. Shorter intervals may need to be considered for TT immunization boosters in HIV-1-infected pediatric patients, as only 38% had protective TAb at baseline.

Interleukin-15 enhances cytotoxicity, receptor expression, and expansion of neonatal natural killer cells in long-term culture.

Newborn infants have a higher susceptibility to various pathogens due to developmental defects in their host defense system, including deficient natural killer (NK) cell function. In this study, the effects of interleukin-15 (IL-15) on neonatal NK cells was examined for up to 12 weeks in culture. The cytotoxicity of fresh neonatal mononuclear cells (MNC) as assayed by K562 cell killing is initially much less than that of adult MNC but increases more than eightfold after 2 weeks of culture with IL-15 to a level equivalent to that of adult cells. This high level of cytotoxicity was maintained for up to 12 weeks. In antibody-dependent cellular cytotoxicity (ADCC) assays using CEM cells coated with human immunodeficiency virus gp120 antigen, IL-15 greatly increased ADCC lysis by MNC from cord blood. IL-15 increased expression of the CD16+ CD56+ NK markers of cord MNC fivefold after 5 weeks of incubation. Cultures of neonatal MNC with IL-15 for up to 10 weeks resulted in a unique population of CD3- CD8+ CD56+ cells (more than 60%), which are not present in fresh cord MNC. These results show that IL-15 can stimulate neonatal NK cells and sustain their function for several weeks, which has implications for the clinical use of IL-15.