Fatima Kakkar

Early Initiation of Combination Antiretroviral Therapy in HIV-1–Infected Newborns Can Achieve Sustained Virologic Suppression With Low Frequency of CD4+ T Cells Carrying HIV in Peripheral Blood

BACKGROUND A human immunodeficiency virus type 1 (HIV-1)-infected infant started on combination antiretroviral therapy (cART) at 30 hours of life was recently reported to have no detectable plasma viremia after discontinuing cART. The current study investigated the impact of early cART initiation on measures of HIV-1 reservoir size in HIV-1-infected children with sustained virologic suppression. METHODS Children born to HIV-1-infected mothers and started on cART within 72 hours of birth at 3 Canadian centers were assessed. HIV serology, HIV-1-specific cell-mediated immune responses, plasma viremia, cell-associated HIV-1 DNA and RNA, presence of replication-competent HIV-1, and HLA genotype were determined for HIV-1-infected children with sustained virologic suppression. RESULTS Of 136 cART-treated children, 12 were vertically infected (8.8%). In the 4 who achieved sustained virologic suppression, HIV serology, HIV-1-specific cell-mediated immune responses (Gag, Nef), and ultrasensitive viral load were negative. HIV-1 DNA was not detected in enriched CD4(+) T cells of the 4 children (<2.6 copies/10(6) CD4(+) T cells), whereas HIV-1 RNA was detected (19.5-130 copies/1.5 µg RNA). No virion-associated HIV-1 RNA was detected following mitogenic stimulation of peripheral blood CD4(+) T cells (5.4-8.0 million CD4(+) T cells) in these 4 children, but replication competent virus was detected by quantitative co-culture involving a higher number of cells in 1 of 2 children tested (0.1 infectious units/10(6) CD4(+) T cells). CONCLUSIONS In perinatally HIV-1-infected newborns, initiation of cART within 72 hours of birth may significantly reduce the size of the HIV-1 reservoirs. Cessation of cART may be necessary to determine whether functional HIV cure can be achieved in such children.

Linking susceptibility to infectious diseases to immune system abnormalities among HIV-exposed uninfected infants

HIV-exposed uninfected (HEU) infants experience increased overall mortality from infectious causes when compared to HIV-unexposed uninfected (HU) infants. This is the case in both the resource-rich and resource-limited settings. Here, we explore the concept that specific types of infectious diseases that are more common among HEU infants could provide clues as to the potential underlying immunological abnormalities. The most commonly reported infections in HEU vs. HU infants are caused by encapsulated bacteria, suggesting the existence of a less effective humoral (antibody, complement) immune response. Decreased transplacental transfer of protective maternal antibodies has consistently been observed among HEU newborns, suggesting that this may indeed be one of the key drivers of their susceptibility to infections with encapsulated bacteria. Reassuringly, HEU humoral response to vaccination appears to be well conserved. While there appears to be an increase in overall incidence of acute viral infections, no specific pattern of acute viral infections has emerged; and although there is evidence of increased chronic viral infection from perinatal transmission of hepatitis C and cytomegalovirus, no data exist to suggest an increase in adverse outcomes. Thus, no firm conclusions about antiviral effector mechanisms can be drawn. However, the most unusual of reported infections among the HEU have been opportunistic infections, suggesting the possibility of underlying defects in CD4 helper T cells and overall immune regulatory function. This may relate to the observation that the immunological profile of HEUs indicates a more activated T cell profile as well as a more inflammatory innate immune response. However, both of these observations appear transient, marked in early infancy, but no longer evident later in life. The causes of these early-life changes in immune profiles are likely multifactorial and may be related to in utero exposure to HIV, but also to increased environmental exposure to pathogens from sicker household contacts, in utero and postnatal antiretroviral drug exposure, and, in certain circumstances, differences in mode of feeding. The relative importance of each of these factors will be important to delineate in an attempt to identify those HEU at highest risk of adverse outcomes for targeted interventions.

The Young and the Resistant: HIV-Infected Adolescents at the Time of Transfer to Adult Care

Combined antiretroviral therapy allows children with human immunodeficiency virus (HIV) to reach adulthood. We studied 45 adolescents at the time of transfer to adult care. Despite universal healthcare access, over two-thirds of the adolescents were failing treatment, which was manifested by detectable HIV-1 viral load, CD4 counts <200 cells/ mm(3), and/or triple-class drug resistance.

Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges.

ABSTRACT Introduction: The use of antiretroviral therapy (ART) in pregnancy to prevent vertical HIV transmission has been one of the most successful public health programs in the last decade. As a result, an unprecedented number of women are taking ART at conception and during pregnancy. Given few randomized studies evaluating safety of different ART regimens in pregnancy, ongoing drug safety surveillance is critical. Areas covered: This review aims to provide a rationale for ART drug safety surveillance, describe changing patterns of ART use and summarize current surveillance efforts in both low-resource and high-resource settings. Additionally, biostatistical approaches to and challenges in analysis of observational surveillance data are discussed. Expert opinion: The global landscape of ART use in pregnancy is rapidly increasing and evolving. Any increase in adverse effects of in-utero exposure to ART has the potential to reduce the impact of improvements in infant morbidity and mortality gained from decreased vertical HIV transmission. ART drug safety surveillance should therefore be a critical piece of programs to prevent mother to child transmission in both high- and low-resource settings. Current surveillance efforts could be strengthened with long-term follow-up of exposed children, pooling of data across cohorts and standardized approaches to analysis.

Prevention of Vertical HIV Transmission and Management of the HIV-Exposed Infant in Canada in 2014

The standard of care for the prevention of vertical transmission (VT) of HIV in Canada and other developed countries includes routine prenatal HIV testing for all pregnant women, and for those testing positive: antepartum combination antiretroviral therapy (cART); intrapartum intravenous zidovudine; six weeks of postnatal oral zidovudine to the infant; and exclusive formula feeding of the infant. With these interventions, the rate of VT has been reduced from 25% to 40%, to 4 weeks before delivery. The purpose of the present article is to highlight recent changes in management guidelines and important caveats to these changes with regard to prevention of VT in the Canadian context. There is a global trend to replace the use of the previous conventional terminology of ‘mother-to-child transmission’ with ‘vertical transmission’ or ‘perinatal transmission’ to remove implications of blame from the mother. In the present article, ‘vertical transmission’ is used throughout. HIV testing during pregnancy HIV testing is recommended for all pregnant women in Canada, with appropriate pre- and post-test counselling. Women whose HIV status is unknown at the time of delivery should undergo rapid HIV antibody testing. For women at increased risk for HIV infection (eg, intravenous drug use, commercial sex work, frequent unprotected intercourse with multiple partners, HIV-negative woman of a serodiscordant couple) who test negative early in pregnancy, repeat testing late in pregnancy (beginning of the third trimester) and at delivery is strongly encouraged. When such women present in labour, advice regarding maternal HIV diagnosis and management should be sought from obstetric and adult HIV experts on an urgent basis; similarly, pediatric HIV experts should be consulted regarding infant management in such situations. Women living with HIV, either previously diagnosed or identified during pregnancy, should be followed by a specialist with expertise in the management of HIV during pregnancy, treated with cART and monitored for viral suppression. Prelabour elective Cesarean section delivery should be planned for those not on cART and/or anticipated or documented to have inadequate viral suppression near delivery (viral load >1000 copies/mL). For women who were previously diagnosed with HIV in whom viral load is not documented to be fully suppressed in the four weeks preceding onset of labour and for women diagnosed with HIV infection at the time of labour, urgent consultation with adult and pediatric HIV experts and an obstetrician with expertise in the management of HIV is essential. Recommendation 1: Pediatricians and other health care providers involved in the care of HIV-infected pregnant women and their children should advocate for universal HIV testing of all pregnant women with appropriate pre- and post-test counselling so that appropriate preventive measures can be implemented in a timely manner. When this fails, testing of the mother at delivery, or of the infant if maternal testing is not possible, should be ensured. Ideally, no infant should be discharged from hospital without the HIV status of the mother being known. Pediatricians and family physicians who perform routine neonatal examinations should verify that the HIV status of the mother or child is known and documented. Recommendation 2: Urgent consultation with an obstetrician with HIV expertise and an adult HIV expert is recommended for diagnosis and management of women deemed to be at high risk for HIV infection with unknown status at the time of labour. Similarly, a pediatric HIV expert should be consulted regarding infant management in such situations.

Risk factors for pre-term birth in a Canadian cohort of HIV-positive women: role of ritonavir boosting?

The risk of pre‐term birth (PTB) associated with the use of protease inhibitors (PIs) during pregnancy remains a subject of debate. Recent data suggest that ritonavir boosting of PIs may play a specific role in the initiation of PTB, through an effect on the maternal–fetal adrenal axis. The primary objective of this study is to compare the risk of PTB among women treated with boosted PI versus non‐boosted PIs during pregnancy.

Diagnosis and management of infants with congenital cytomegalovirus infection

Congenital cytomegalovirus infection (cCMV) is the most common congenital infection, occurring in approximately 0.5% of live births. Most infected newborns are asymptomatic, but up to 20% develop sensorineural hearing loss or other permanent neurologic sequelae. The presentation of newborns with symptomatic cCMV is highly variable, and the infection is usually not diagnosed in the absence of a screening program. Newborn cCMV screening programs are estimated to be beneficial and cost-effective, and are increasingly being implemented. Diagnosis requires direct detection of virus in a sample obtained before 3 weeks of life, and is best performed by polymerase chain reaction (PCR) of saliva or urine, either of which is more sensitive than dried blood spot. Antiviral treatment of selected newborns with cCMV-related disease appears to improve hearing and neurocognitive outcomes. All infected infants should be evaluated promptly to determine appropriate therapy, and receive close audiologic and developmental follow-up.

Blood Mitochondrial DNA Content in HIV-Exposed Uninfected Children with Autism Spectrum Disorder

Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for mitochondrial dysfunction. In this cross-sectional, nested case-control study, HEU children with ASD were matched approximately 1:3 on age, sex, and ethnicity to HEU children without ASD, HIV-unexposed uninfected (HUU) controls, and HUU children with ASD. Leukocyte mtDNA content was measured using quantitative PCR. Among 299 HEU in this study, 14 (4.7%) were diagnosed with ASD, which is higher than the general population prevalence estimates. HEU children without ASD and HUU children with ASD had higher mtDNA content than HUU controls. HEU children with ASD had significantly higher mtDNA content than all other study groups. Our results suggest a clear association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence observed in our cohort.

Leukocyte Telomere Length at Birth and During the Early Life of Children Exposed to but Uninfected With HIV After In Utero Exposure to Antiretrovirals

Background Maternal combination antiretroviral therapy (cART) during pregnancy could impact the health of human immunodeficiency virus (HIV)-exposed, HIV-uninfected (HEU) children, because some antiretrovirals cross the placenta and can inhibit telomerase. Our objective was to compare leukocyte telomere length (LTL) in HEU children and HIV-unexposed, HIV-uninfected (HUU) children at birth and in early life and to investigate any relationship with cART exposure. Methods HEU and HUU childrens blood LTL was compared cross-sectionally at birth, and during the first three years of life. Longitudinal HEU LTL dynamics was evaluated over that same period. Results At birth, the LTL in HEU children (n = 114) was not shorter than that in HUU children (n = 86), but female infants had longer LTL than male infants. Maternal cART (duration or type) showed no association with shorter infant LTL. Among 214 HEU children age- and sex-matched at a 1:1 ratio to HUU children, LTL declined similarly in both groups. In a longitudinal analysis, LTL attrition in HEU children was rapid from birth to 1 year of age and gradual thereafter. Zidovudine prophylaxis did not significantly alter LTL. Conclusions Our results indicate that from birth to 3 years of age, the LTL in HEU children is not negatively affected by exposure to maternal HIV infection and cART, at least not to the regimens used within this Canadian cohort, a reassuring finding.

Missed opportunities for prevention of vertical HIV transmission in Canada, 1997-2016: a surveillance study

BACKGROUND Vertical HIV transmission has declined in Canada, but missed opportunities for prevention continue to occur. We sought to determine the adequacy, and changes over time in adequacy, of uptake of maternal and neonatal antiretroviral therapy for the prevention of vertical HIV transmission, and to determine the vertical transmission rate over time and according to adequacy of antenatal antiretroviral therapy during the combination antiretroviral therapy era in Canada. METHODS The Canadian Perinatal HIV Surveillance Program collects data annually through retrospective chart review concerning HIV-infected women and their infants. We determined receipt of adequate antiretroviral treatment (antenatal combination antiretroviral treatment for ≥ 4 wk, intrapartum intravenous zidovudine treatment and 4-6 wk of infant oral zidovudine treatment) and predictors of inadequate antenatal combination antiretroviral therapy (none or < 4 wk) in Canada in 1997-2016. RESULTS We identified 3785 mother-infant pairs. Uptake of 4 weeks or more of antenatal combination antiretroviral therapy increased over time across all provinces/territories and regardless of maternal race/ethnicity or risk category (p < 0.001). During 2011-2016, 92 women (6.5%) received no or less than 4 weeks of antenatal combination antiretroviral therapy, 146 women (10.7%) received no intrapartum zidovudine treatment, and 43 infants (3.1%) received less than 4 weeks of zidovudine treatment. In multivariate analysis restricted to 2011-2016, higher uptake of adequate antenatal combination antiretroviral therapy was seen among black women than among Indigenous (odds ratio [OR] 2.99, 95% confidence interval [CI] 1.23-7.26) or white (OR 1.87, 95% CI 0.99-1.27) women and in British Columbia/Yukon Territory than in Alberta (OR 3.31, 95% CI 1.06-10.32), Ontario (OR 3.16, 95% CI 1.08-9.26) or Quebec (OR 3.44, 95% CI 1.09-10.84). Among the 14 vertical HIV transmission events during 2011-2016 (vertical transmission rate 1.0%), maternal HIV infection was diagnosed before the onset of labour in 5 cases, and only 2 women received adequate antenatal combination antiretroviral therapy. INTERPRETATION Efforts to improve timely access to care, HIV screening and treatment for all women, combined with enhanced resources targeting populations at increased risk for HIV infection, will be needed if vertical HIV transmission is to be eliminated in Canada.