Ariane Alimenti

Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy

Objective. To investigate potential mitochondrial toxicity in HIV-uninfected infants exposed to highly active antiretroviral therapy (HAART) in utero and/or neonatal zidovudine. Design. A prospective observational study performed in a tertiary referral center for HIV-infected women and their infants and children. Methods. Plasma lactate was measured repeatedly during the first 6 months of life in a consecutive cohort of infants exposed to HAART in utero and/or neonatal zidovudine. Maternal CD4, HIV RNA concentration, antiretroviral and substance use histories, mode of delivery, infant gender, cord pH, Apgar score and birth weight were collected. Results. The plasma lactate was above normal on at least 1 occasion in 35 of 38 (92%) infants and reached levels ≥5 mmol/l in 10 (26%) infants. Overall 78 of 117 (68%) lactate measurements were elevated, with 11 (10%) in the serious (≥5 mmol/l) range. None of the infants received antiretrovirals beyond 6 weeks, yet elevated lactates persisted up to age 6 months. Two infants had reversible symptoms consistent with those of lactic acidemia. No association was found between the infant peak lactate and the type of therapy during pregnancy, its duration or maternal substance use. Conclusion. Transient lactic acidemia was observed in the majority of HIV uninfected infants exposed to HAART in utero and/or zidovudine neonatally. We hypothesize that the hyperlactatemia is a consequence of persistent, primarily subclinical, mitochondrial toxicity from the transplacental and neonatal exposure to antiretrovirals and of impaired hepatic lactate clearance. Although the clinical relevance of our findings is unknown, we recommend lactate monitoring in these infants, considering discontinuation of neonatal zidovudine in symptomatic infants with lactate ≥5 mmol/l and careful long term follow up of these children.

A national review of vertical HIV transmission

Objectives:Prevention of vertical HIV transmission has evolved significantly in Canada over the last two decades. The aim of this analysis is to describe the surveillance programme used, rate of vertical HIV transmission and changing epidemiology of HIV-affected pregnancies in Canada. Design:National perinatal HIV surveillance programme. Methods:From 1990, annual retrospective data was collected on demographic and clinical characteristics of HIV-infected mothers and their infants referred to 22 participating sites across Canada either before/during pregnancy or within 3 months after delivery. Factors impacting HIV transmission and demographic features were explored. Results:Two thousand, six hundred and ninety-two mother–infant pairs were identified. The overall rate of vertical HIV transmission was 5.2%, declining to 2.9% since 1997. The rate of transmission for mothers who received HAART was 1%, and 0.4% if more than 4 weeks of HAART was given. Forty percent of women delivered by caesarean section, with no difference in transmission rate compared with vaginal delivery for women treated with HAART (1.4 vs. 0.6%, P = 0.129) but significant risk reduction for those who did not receive HAART (3.8 vs. 10.3%, P = 0.016). Black women were the largest group; proportions of black and aboriginal women increased significantly over time (P < 0.001 for both). Heterosexual contact was the most common risk category for maternal infection (65%), followed by injection drug use (IDU) (25%). Conclusion:Vertical HIV transmission in Canada has decreased dramatically for women treated with HAART therapy. All pregnant women should be evaluated for HIV infection and programmes expanded to reach vulnerable populations including aboriginal, immigrant and IDU women.

A Prospective Controlled Study of Neurodevelopment in HIV-Uninfected Children Exposed to Combination Antiretroviral Drugs in Pregnancy

OBJECTIVE. Our intent was to investigate the neurodevelopment of HIV-uninfected children exposed to combination highly active antiretroviral therapy in pregnancy compared with children not exposed to highly active antiretroviral therapy but with similar socioeconomic backgrounds. PATIENTS AND METHODS. A prospective controlled cross-sectional study of the neurodevelopment of children exposed to highly active antiretroviral therapy versus those not exposed was performed by using the Bayley Scales of Infant Development and Vineland Adaptive Behavior Scales at 18 to 36 months of age. The highly active antiretroviral therapy–exposed children were born to HIV-infected women but were uninfected themselves. The control children were born to HIV-uninfected women with similar anticipated socioeconomic background (hepatitis C infected and high proportion of substance use). Sociodemographic, clinical, highly active antiretroviral therapy (antenatal, intrapartum, neonatal), and substance-use histories were collected. Results were compared by using analyses of covariance and χ2 analysis. RESULTS. Thirty-nine highly active antiretroviral therapy–exposed and 24 control children were assessed. All mean scores were lower for those in the highly active antiretroviral therapy–exposed group than those in the control group (Bayley Mental Development Index: 85.4 vs 94.3; Bayley Psychomotor Development Index: 93.4 vs 96.6; Vineland mean communication score: 90.1 vs 94.4; Vineland mean daily-living score: 91.2 vs 93.6; Vineland mean socialization score: 97.1 vs 98.4). However, when maternal substance use during pregnancy was controlled for, there were no significant differences between the groups in any domains assessed. Children in both groups exposed to maternal substance use scored significantly lower than children not exposed in all domains except communication skills. It is important to note that there were no differences between the highly active antiretroviral therapy–exposed children with no substance exposure and the control children with no substance exposure in any of the scores. CONCLUSIONS. HIV- and highly active antiretroviral therapy–exposed HIV-uninfected children had lower development and adaptive behavior scores when compared with children who had not been exposed. However, these differences were not significant after correcting for maternal substance use, which had a greater impact on neurodevelopment than highly active antiretroviral therapy exposure. These results suggest that perinatal highly active antiretroviral therapy exposure is not associated with altered development and behavior at 18 to 36 months of age.

Leukocyte Telomere Length in HIV-Infected and HIV-Exposed Uninfected Children: Shorter Telomeres with Uncontrolled HIV Viremia

Objectives Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV antiretroviral therapy can inhibit human telomerase reverse transcriptase. We therefore investigated whether in utero or childhood exposure to NRTIs affects leukocyte telomere length (LTL), a marker of cellular aging. Methods In this cross-sectional CARMA cohort study, we investigated factors associated with LTL in HIV -1-infected (HIV+) children (n = 94), HIV-1-exposed uninfected (HEU) children who were exposed to antiretroviral therapy (ART) perinatally (n = 177), and HIV-unexposed uninfected (HIV−) control children (n = 104) aged 0–19 years. Univariate followed by multivariate linear regression models were used to examine relationships of explanatory variables with LTL for: a) all subjects, b) HIV+/HEU children only, and c) HIV+ children only. Results After adjusting for age and gender, there was no difference in LTL between the 3 groups, when considering children of all ages together. In multivariate models, older age and male gender were associated with shorter LTL. For the HIV+ group alone, having a detectable HIV viral load was also strongly associated with shorter LTL (p = 0.007). Conclusions In this large study, group rates of LTL attrition were similar for HIV+, HEU and HIV− children. No associations between children’s LTL and their perinatal ART exposure or HIV status were seen in linear regression models. However, the association between having a detectable HIV viral load and shorter LTL suggests that uncontrolled HIV viremia rather than duration of ART exposure may be associated with acceleration of blood telomere attrition.

Serious toxicity associated with continuous nevirapine-based HAART in pregnancy

Objective  This study was designed to determine the safety of nevirapine (NVP)‐based highly active antiretroviral therapy (HAART) in a cohort of HIV‐positive pregnant women.

HIV viral suppression results in higher antibody responses in HIV-positive women vaccinated with the quadrivalent human papillomavirus vaccine.

OBJECTIVE To evaluate the immunogenicity and safety of the quadrivalent HPV (qHPV) vaccine in HIV-positive women over 24months. DESIGN Between November 2008 and December 2012, 372 women aged 15 and older were enrolled from 14 Canadian HIV outpatient clinics in an open label cohort study. The qHPV vaccine (0.5mL) was administered intramuscularly at months 0, 2 and 6. The primary study endpoint was seroconversion to any of the HPV types targeted by the qHPV vaccine. Antibody levels were measured at 0, 2, 7, 12, 18, and 24months. Adverse events were recorded throughout. RESULTS Of 372 participants enrolled, 310 (83%) received at least one dose of the qHPV vaccine and 277 (74%) received all three doses. Ninety-five percent (293/308) were seronegative for at least one vaccine type at baseline. The median age was 38years (IQR 32-45, range 15-66), 36% were white, 44% black and 13% were of Indigenous origin. Seventy-two percent of participants had a suppressed HIV viral load (VL<40c/ml) at baseline, with a median CD4 count of 510cells/mm(3) (376-695). Month 7 HPV type-specific seroconversion rates were 99.0%, 98.7%, 98.1% and 93.6% for HPV types 6, 11, 16 and 18 respectively in the per-protocol population. Participants with suppressed HIV VL at first vaccine had a 1.74-3.05fold higher peak antibody response compared to those without (p from 0.006 to <0.0001). CONCLUSIONS This study is the first to examine the qHPV vaccine in HIV-positive women out to 24months and the first to include HIV-positive women through to age 66. The qHPV vaccine was well tolerated, and highly immunogenic. As women with suppressed viral load had higher antibody responses, planning HPV vaccination to occur when persons are virologically suppressed would be optimal for maximizing immune response. Findings provide strong evidence that older HIV-positive women can still benefit from HPV vaccination. CLINICAL TRIAL REGISTRATION http://www.isrctn.com/ISRCTN33674451.

Guidelines for the Care of Pregnant Women Living With HIV and Interventions to Reduce Perinatal Transmission: Executive Summary

OBJECTIVE This guideline reviews the evidence relating to the care of pregnant women living with HIV and the prevention of perinatal HIV transmission. Prenatal care of pregnancies complicated by HIV infection should include monitoring by a multidisciplinary team with experts in this area. OUTCOMES OUTCOMES evaluated include the impact of HIV on pregnancy outcome and the efficacy and safety of antiretroviral therapy and other measures to decrease the risk of vertical transmission. EVIDENCE Published literature was retrieved through searches of PubMed and The Cochrane Library in 2012 and 2013 using appropriate controlled vocabulary (HIV, anti-retroviral agents, pregnancy, delivery) and key words (HIV, pregnancy, antiretroviral agents, vertical transmission, perinatal transmission). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English or French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to June 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).

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.

Evaluation of an Emergency Prevention Program for Mother to Child Transmission of HIV in British Columbia

INTRODUCTION The objective of this study was to evaluate a province-wide program designed to identify HIV infection accurately and to prevent mother to child transmission among high-risk pregnant women of unknown serostatus. METHODS Between 2000 and 2007, 347 high-risk women were identified through the Prevention of Mother to Child Transmission (PMTCT) program implemented in 27 hospitals across British Columbia. Rates of HIV transmission and details of the implementation of prophylaxis kits were assessed. RESULTS Of the 346 high-risk mother-infant pairs identified and included in the provincial program, 35.4% of the mothers and 95.7% of infants received antiretroviral therapy for prevention of vertical transmission. Of 309 pairs who subsequently underwent HIV testing, five mothers were found to be HIV positive, an infection rate of 16.2/1000 in this cohort; the overall rate in BC is 0.68/1000 births. One of the five infants born to an HIV positive mother was infected with HIV. DISCUSSION The program was successful in identifying a subgroup of pregnant women at increased risk of HIV infection; however, mother to child transmission occurred in one of five cases (20%). To reduce the risk of mother to child HIV transmission in BC to the lowest possible level, additional strategies such as increasing uptake of prenatal screening and point-of-care testing in labour and delivery may need to be explored.

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.