Evidence of Subclinical mtDNA Alterations in HIV-Infected Pregnant Women Receiving Combination Antiretroviral Therapy Compared to HIV-Negative Pregnant Women.

INTRODUCTION: Combination antiretroviral therapy (cART) can effectively prevent vertical transmission of HIV but there is potential risk of adverse maternal, foetal or infant effects. Specifically, the effect of cART use during pregnancy on mitochondrial DNA (mtDNA) content in HIV-positive (HIV+) women is unclear. We sought to characterize subclinical alterations in peripheral blood mtDNA levels in cART-treated HIV+ women during pregnancy and the postpartum period. METHODS: This prospective longitudinal observational cohort study enrolled both HIV+ and HIV-negative (HIV-) pregnant women. Clinical data and blood samples were collected at three time points in pregnancy (13-<23 weeks, 23-<30 weeks, 30-40 weeks), and at delivery and six weeks post-partum in HIV+ women. Peripheral blood mtDNA to nuclear DNA (nDNA) ratio was measured by qPCR. RESULTS: Over a four year period, 63 HIV+ and 42 HIV- women were enrolled. HIV+ women showed significantly lower mtDNA/nDNA ratios compared to HIV- women during pregnancy (p = 0.003), after controlling for platelet count and repeated measurements using a multivariable mixed-effects model. Ethnicity, gestational age (GA) and substance use were also significantly associated with mtDNA/nDNA ratio (p≤0.02). Among HIV+ women, higher CD4 nadir was associated with higher mtDNA/nDNA ratios (p<0.0001), and these ratio were significantly lower during pregnancy compared to the postpartum period (p<0.0001). CONCLUSIONS: In the context of this study, it was not possible to distinguish between mtDNA effects related to HIV infection versus cART therapy. Nevertheless, while mtDNA levels were relatively stable over time in both groups during pregnancy, they were significantly lower in HIV+ women compared to HIV- women. Although no immediate clinical impact was observed on maternal or infant health, lower maternal mtDNA levels may exert long-term effects on women and children and remain a concern. Improved knowledge of such subclinical alterations is another step toward optimizing the safety and efficacy of cART regimens during pregnancy.

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.

Perinatal exposure to antiretroviral therapy is associated with increased blood mitochondrial DNA levels and decreased mitochondrial gene expression in infants.

BACKGROUND: The effects of perinatal antiretroviral therapy (ART) on infant mitochondrial function are not well known. We compared blood mitochondrial DNA (mtDNA) levels and mtDNA gene expression (mtRNA) in human immunodeficiency virus (HIV)-uninfected, ART-exposed infants born to HIV-positive mothers with mtDNA levels and mtDNA gene expression in control infants born to uninfected women. METHODS: In this prospective cohort study, longitudinal mtDNA:nuclear DNA and mtRNA:beta-actin mRNA ratios were compared in blood samples obtained at various time points from birth to 8 months, using generalized estimating equation linear regression models. RESULTS: Log(10) mtDNA levels at birth were higher in ART-exposed infants, compared with levels in control infants, although the difference did not reach statistical significance (P = .07 for comparison of samples obtained 0-3 days after birth). ART-exposed infants' mtDNA levels increased further during the zidovudine prophylaxis period-from age 4 days to age 6 weeks-(P = .001) and remained significantly higher than the levels observed in control infants until the end of the study. In contrast, log(10) mtRNA levels at birth were lower in ART-exposed infants than in control infants (P = .03), but were not statistically different later. CONCLUSIONS: When control infants and ART-exposed infants were compared, the mtDNA level was increased but mitochondrial gene expression was decreased in ART-exposed infants. These differences persisted after zidovudine was discontinued, suggesting that changes in mitochondrial proliferation and/or expression take place during and after ART exposure. These changes are likely the effects of the antiretroviral drugs on mitochondria. The clinical relevance and long-term impact of these alterations must be studied.

Fertility intentions of women of reproductive age living with HIV in British Columbia, Canada.

BACKGROUND: We undertook a study to examine the fertility intentions and reproductive health issues of women living with HIV in a broad-based sample in British Columbia, Canada. METHODS: Between November 2003 and December 2004, we invited women with HIV at all HIV clinics and AIDS service organizations in the province of British Columbia, Canada, to complete the survey instrument 'Contraceptive Decisions of HIV-positive Women'. Logistic regression analysis was conducted to calculate adjusted odds ratios to identify factors that may be significant predictors of the intention of women living with HIV to have children. RESULTS: Of the 230 surveys completed, 182 women (79.1%) were of reproductive age (

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 chi2 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.

Use of Sno Strip filter-paper wicks for collection of genital-tract samples allows reproducible determination of human immunodeficiency virus type 1 (HIV-1) RNA viral load with a commercial HIV-1 viral load assay.

To assess the reproducibility of measurements of cervical and vaginal human immunodeficiency virus (HIV) viral load, 92 duplicate cervical and 88 duplicate vaginal samples were collected from 13 HIV-infected women using Sno Strip filter-paper wicks. RNA was eluted from the strips, extracted, and assayed using a modified protocol for the Roche Cobas Amplicor HIV-1 Monitor assay. Pearson's correlation coefficient (R), coefficient of determination (D), and Bland-Altman plots (BA) were used to compare paired log10-transformed viral loads. Analysis of duplicate same-site samples showed good reproducibility (cervix: R = 0.72, D = 52%, BA = 89% within range; vagina: R = 0.72, D = 51%, BA = 87% within range); paired cervix/vagina measurements showed moderate correlation only (R = 0.56; D = 31.3%). Standardized sample collection and simple modification of the Roche Cobas Amplicor HIV-1 Monitor assay allows reproducible measurement of genital viral load.

Psychometric assessment of the Multidimensional Quality of Life Questionnaire for Persons with HIV/AIDS (MQOL-HIV) in a sample of HIV-infected women.

Since the late 1980s, several HIV-specific quality of life instruments have been developed; however, little testing has been done in terms of their validity and reliability for HIV-infected women. The purpose of this study was to test the content validity, concurrent validity, internal consistency, and test-retest reliability of the Multidimensional Quality of Life Questionnaire for Persons with HIV/AIDS (MQOL-HIV) in a sample of 85 HIV-infected women. The MQOL-HIV is a 40-item scale comprised of 10 dimensions. Most of the items and all of the domains were determined content valid but revision of some of the items and domains is recommended. Concurrent validity was measured between the MQOL-HIV and the MOS-HIV and ranged from 0.51-0.81 between similar domains. Of the 10 domains and the entire instrument, 7 had a Cronbach's alpha over 0.70 (range 0.43-0.92). Eight domains and the entire instrument achieved test-retest correlation coefficients over 0.70 (range 0.60-0.96). Although some revision may make the scale more content-valid for HIV-infected women, given due care in the interpretation of results, the MQOL-HIV can be used with female populations in its current form.

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 > or =5 mmol/l in 10 (26%) infants. Overall 78 of 117 (68%) lactate measurements were elevated, with 11 (10%) in the serious (> or =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 > or =5 mmol/l and careful long term follow up of these children.

Genital tract and plasma human immunodeficiency virus viral load throughout the menstrual cycle in women who are infected with ovulatory human immunodeficiency virus.

OBJECTIVE: The purpose of this study was to determine the vaginal, cervical, and plasma viral load through the menstrual cycle in women who are positive for human immunodeficiency virus. STUDY DESIGN: A prospective cohort study was performed on 14 women with ovulatory menstrual cycles who have human immunodeficiency virus. Duplicate cervical and vaginal viral load samples (n = 301) were taken at four stages (menstrual, follicular, periovulatory, and luteal) of two consecutive cycles. RESULTS: Participant characteristics were mean age of 32.7 years, median human immunodeficiency virus helper cell count value of 355, and median plasma viral load of 24,000 copies/mL. Through the menstrual cycle, there was no statistically significant difference in plasma viral load, but there was a significant decrease in genital tract viral load at the periovulatory phase (vagina, P =.018; cervix, P =.007). Vaginal and cervical viral load were correlated (r = 0.582, P <.001). CONCLUSION: Although the plasma viral load remained constant throughout the menstrual cycle, the genital viral load decreased at the periovulatory phase. These results suggest that local factors may affect the genital viral load compartment independent of plasma viral load.

Age, adherence and injection drug use predict virological suppression among men and women enrolled in a population-based antiretroviral drug treatment programme.

OBJECTIVES: To characterize 1-year virological response to antiretroviral therapy and its determinants by sex. METHODS: This is a population-based analysis of antiretroviral therapy naive HIV-positive adult men and women. Factors associated with sex and with plasma HIV RNA viral load suppression to below 500 copies/ml were examined using non-parametric tests and logistic regression analyses. RESULTS: A total of 739 subjects (92 women and 647 men) were eligible. Female participants were younger (34 vs 37 years; P < 0.001), less likely to have AIDS (6.5 vs 14.4%; P = 0.039), more frequently injection drug users (44.6 vs 25.2%; P = 0.001) and were less likely to be adherent to therapy (34.8 vs 62.9%; P < 0.001) than male participants. There was no difference in baseline median CD4 count (P = 0.424) or HIV RNA levels (P = 0.140), physician experience (P = 0.057), or with respect to antiretroviral regimens containing protease inhibitors or non-nucleoside reverse transcriptase inhibitors (P = 0.911). With treatment, 46.7% (43/92) of women and 64.8% (419/647) of men (P = 0.001) suppressed HIV RNA viral load to below 500 copies/ml at 1 year. In a multivariate analysis, the association of sex with HIV RNA response to antiretroviral therapy fell from statistical significance (odds ratio 1.18; 95% CI: 0.72-1.95) after adjusting for adherence, injection drug use and age. CONCLUSION: Our data indicate that in this population-based setting, sex differences in 1-year virological response to antiretroviral therapy are explained by age, adherence and injection drug use.