Linsay Gray

Perinatal Transmission of Human Immunodeficiency Virus Type 1 by Pregnant Women with RNA Virus Loads <1000 Copies/mL

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

Combination antiretroviral therapy and duration of pregnancy.

ObjectiveTo assess the association between type and timing of initiation of antiretroviral therapy in pregnancy and duration of pregnancy. DesignProspective study. MethodsData on 3920 mother–child pairs were examined (3015 mother–child pairs from the European Collaborative Study and 905 from the Swiss Mother + Child HIV Cohort Study). Factors examined included gestational age, antiretroviral therapy during pregnancy, maternal CD4 count, viral load, illicit drug use (IDU) and mode of delivery. Deliveries at less than 37 weeks were defined as premature. ResultsThe prematurity rate was 17% and median gestational age 39 weeks. Twenty-three per cent (896 of 3920) of women received antiretroviral therapy during pregnancy: 64% (573 of 896) zidovudine monotherapy, 24% (215) combination therapy without protease inhibitors (PI) and 12% (108) combination therapy with PI. In multivariate analysis, adjusted for maternal CD4 count and IDU, odds ratio (OR) of prematurity was 2.60 [95% confidence interval (CI), 1.43–4.75] and 1.82 (95% CI, 1.13–2.92) for infants exposed to combination therapy with and without a PI, respectively, compared to no treatment. Exposure to monotherapy was not associated with prematurity, but severe immunosuppression and IDU in pregnancy were. Women on combination therapy from before pregnancy were twice as likely to deliver prematurely as those starting therapy in the third trimester (OR, 2.17; 95% CI, 1.03–4.58). ConclusionsPregnancy issues should be discussed when making decisions about initiation of combination antiretroviral therapy for HIV-infected women. Elective caesarean section to reduce vertical transmission at 36 weeks rather than 38 weeks may be advisable in women on combination therapy with PI.

Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis.

BACKGROUND Data on the short-term risk of disease progression in HIV-1-infected children are needed to address the question of when to begin combination antiretroviral therapy. We estimated 12-month risks of progression to AIDS and death, by age and most recent measurement of CD4 T-cell percentage (CD4%) or viral load, in children receiving no antiretroviral therapy or zidovudine monotherapy only. METHODS We undertook a meta-analysis of individual longitudinal data for 3941 children from eight cohort studies and nine randomised trials in Europe and the USA. Estimates of risk were derived from parametric survival models. FINDINGS 997 AIDS-defining events were recorded over 7297 person-years of follow-up in the analysis of CD4%, and 284 events over 2282 person-years in the viral load analysis, corresponding to 568 deaths (9087 person-years) and 129 deaths (2816 person-years), respectively. In children older than 2 years, risk of death increased sharply when CD4% was less than about 10%, or 15% for risk of AIDS, with a low and fairly stable risk at greater CD4%. Children younger than 2 years had worse outlook than older children with the same CD4%. Risk of progression increased when viral load exceeded about 10(5) copies per mL, although this association was more gradual compared with CD4%. Both markers had independent predictive value for disease progression; CD4% was the stronger predictor. INTERPRETATION This information is important for paediatricians making decisions, and for researchers designing trials, about when to initiate or restart antiretroviral therapy.

Blood Pressure in Early Adulthood, Hypertension in Middle Age, and Future Cardiovascular Disease Mortality: HAHS (Harvard Alumni Health Study)

OBJECTIVES We sought to examine the association of early adulthood blood pressure with cardiovascular disease (CVD) mortality, while accounting for middle-age hypertension. BACKGROUND Elevated blood pressure in middle age is an established CVD risk factor, but evidence for association with measurements earlier in life is sparse. METHODS The HAHS (Harvard Alumni Health Study) is a cohort study of 18,881 male university students who had their blood pressure measured at university entry (1914 to 1952; mean age 18.3 years) and who responded to a questionnaire mailed in either 1962 or 1966 (mean age 45.8 years) in which physician-diagnosed hypertension status was reported. Study members were subsequently followed for mortality until the end of 1998. RESULTS Following adjustment for age, body mass index, smoking, and physical activity at college entry, compared with men who were normotensive according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria (<120/<80 mm Hg), there was an elevated risk of coronary heart disease (CHD) mortality (1,917 deaths) in those who were pre-hypertensive (120 to 139/80 to 89 mm Hg) (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.07 to 1.36), stage 1 (140 to 159/90 to 99 mm Hg) (HR: 1.46; 95% CI: 1.25 to 1.70), and stage 2 hypertensive (≥160/≥100 mm Hg) (HR: 1.89; 95% CI: 1.46 to 2.45), incremental across categories (p(trend) < 0.001). After additionally accounting for middle-age hypertension, estimates were somewhat attenuated, but the pattern remained. Similar associations were apparent for total and CVD mortality, but not stroke mortality. CONCLUSIONS Higher blood pressure in early adulthood was associated with elevated risk of all-cause mortality, CVD, and CHD, but not stroke, several decades later. Effects largely persisted after taking into account mediation by middle-age hypertension. Thus, the long-term benefits of blood pressure lowering in early adulthood are promising, but supporting trial data are required.

Cohort Profile: The Scottish Health Surveys Cohort: linkage of study participants to routinely collected records for mortality, hospital discharge, cancer and offspring birth characteristics in three nationwide studies

Background Although life expectancy is increasing in Scotland, the nation still has the highest rates of coronary heart disease (CHD) and selected malignancies in the UK and higher rates than most countries in Western Europe. The Scottish Health Surveys (SHeSs)—conducted in 1995, 1998 and 2003––were established to provide detailed, contemporary health information on a large, representative sample of the Scottish population. By capturing a range of behavioural, biological, psychological and social characteristics, their purpose was to monitor health in order to assist in policy formulation and the development of new health initiatives across the whole of Scotland.

Cigarette smoking and site-specific cancer mortality: testing uncertain associations using extended follow-up of the original Whitehall study

BACKGROUND The relation between cigarette smoking and several malignancies is still unclear. We examined the association of cigarette smoking with death attributed to 15 cancer sites, 7 of which are regarded as having an uncertain relation with tobacco. PATIENTS AND METHODS The original Whitehall study is a prospective cohort of 17 363 London-based male government employees (age 40-69 years) who were examined in the late 1960s and then followed up for a maximum of 38 years. RESULTS Following adjustment for demographic characteristics, risk factors, and prevalent disease, established positive cigarette smoking--cancer gradients were confirmed for carcinoma of the lung, stomach, pancreas, bladder, upper aero-digestive (including oesophagus), and liver, and for myeloid leukaemia. Among the cancers of uncertain relation with smoking, mortality rates for malignancy of the colon, rectum and prostate and for lymphatic leukaemia were elevated in current and/or former smokers. There was essentially no apparent relation between smoking and mortality from carcinoma of the brain or from lymphoma. CONCLUSION In this study, cigarette smoking appears to be a risk factor for several malignancies of previously unclear association with tobacco use.

Level and pattern of HIV-1-RNA viral load over age: Differences between girls and boys?

Objective To estimate RNA viral load patterns over age in vertically infected children that account for between- and within-individual variation, treatment and assay cut-off detection level. To investigate possible sex-based differences. Design A total of 118 infected children with 894 RNA viral load measurements enrolled in the European Collaborative Study were prospectively followed from birth for up to 15 years. Methods Fractional polynomial and mixed effects models with censored data to assess the non-linear pattern of viral load over age, allowing for repeated measures. Results The RNA viral load peaked at approximately 3 months of age, and gradually declined thereafter. The sex by age interaction was significant (χ2 = 19.7, P < 0.001); viral load peaked higher for girls than boys, but after 4 years the RNA load was consistently 0.25–0.5 log10 lower for girls than boys. The effects of sex and treatment on viral load vary over age (χ2 = 6.31, P = 0.043). Sex differences in RNA viral load relating to measurement without treatment were more pronounced than those under treatment. Disease progression was more rapid for girls than for boys up to the age of 4 years, and less rapid thereafter; the overall difference was not statistically significant. Conclusion Differences in RNA viral load over age between untreated boys and girls may have implications for policies for the initiation of antiretroviral therapy, but do not seem to translate into differences in progression to serious disease. The findings would suggest underlying biological explanations, which need further investigation.

Trends in adult cardiovascular disease risk factors and their socio-economic patterning in the Scottish population 1995-2008: cross-sectional surveys.

Objectives To examine secular and socio-economic changes in cardiovascular disease risk factor prevalences in the Scottish population. This could contribute to a better understanding of why the decline in coronary heart disease mortality in Scotland has recently stalled along with a widening of socio-economic inequalities. Design Four Scottish Health Surveys 1995, 1998, 2003 and 2008 (6190, 6656, 5497 and 4202 respondents, respectively, aged 25–64 years) were used to examine gender-stratified, age-standardised prevalences of smoking, alcohol consumption, physical activity, fruit and vegetable consumption, discretionary salt use and self-reported diabetes or hypertension. Prevalences were determined according to education and social class. Inequalities were assessed using the slope index of inequality, and time trends were determined using linear regression. Results There were moderate secular declines in the prevalence of smoking, excess alcohol consumption and physical inactivity. Smoking prevalence declined between 1995 and 2008 from 33.4% (95% CI 31.8% to 35.0%) to 29.9% (27.9% to 31.8%) for men and from 36.1% (34.5% to 37.8%) to 27.4% (25.5% to 29.3%) for women. Adverse trends in prevalence were noted for self-reported diabetes and hypertension. Over the four surveys, the diabetes prevalence increased from 1.9% (1.4% to 2.4%) to 3.6% (2.8% to 4.4%) for men and from 1.7% (1.2% to 2.1%) to 3.0% (2.3% to 3.7%) for women. Socio-economic inequalities were evident for almost all risk factors, irrespective of the measure used. These social gradients appeared to be maintained over the four surveys. An exception was self-reported diabetes where, although inequalities were small, the gradient increased over time. Alcohol consumption was unique in consistently showing an inverse gradient, especially for women. Conclusions There has been only a moderate decline in behavioural cardiovascular risk factor prevalences since 1995, with increases in self-reported diabetes and hypertension. Adverse socio-economic gradients have remained unchanged. These findings could help explain the recent stagnation in coronary heart disease mortalities and persistence of related inequalities.

Co-receptor usage of HIV-1 primary isolates, viral burden, and CCR5 genotype in mother-to-child HIV-1 transmission

ObjectiveTo investigate the relationship between CC chemokine receptor 5 (CCR5) genotype, viral load and co-receptor usage of maternal HIV-1 isolates in perinatal HIV-1 transmission. Patients and methodsA total of 181 mothers and infants were studied at the time of delivery. Wild-type (wt) and Δ32 CCR5 alleles were determined by means of polymerase chain reaction (PCR). The viral load in maternal plasma samples was determined by a quantitative reverse transcriptase–PCR assay; co-receptor usage of maternal isolates was determined by viral infection in cells stably expressing CCR5 or CXC chemokine receptor 4 (CXCR4) co-receptors. ResultsHIV-1 transmission rates in wt/wt and wt/Δ32 mothers (14.7 versus 15.8%), and in wt/wt and wt/Δ32 infants (14.6 versus 14.3%) were similar. Mothers transmitting infection to wt/Δ32 infants had significantly higher HIV-1-RNA levels than those who transmitted infection to wt/wt infants (5.4 versus 4.1 log10 copies/ml, P = 0.03). In wt/wt children there was a positive relationship between transmission rate and maternal viral load over the entire range of HIV-1 values, whereas in wt/Δ32 children transmission occurred only at viral loads greater than 4.0 log10 copies/ml. Logistic regression analysis confirmed that the relationship between viral load and transmission varied according to the childs CCR5 genotype (P = 0.035; adjusted for zidovudine prophylaxis and mode of delivery, P = 0.090). Moreover, the majority of wt/wt transmitting mothers had R5-type isolates, whereas none of the wt/Δ32 mothers with an R5-type virus transmitted HIV-1 to their wt/Δ32 infants. ConclusionTaken together, these findings suggest that CCR5 Δ32 heterozygosity exerts a protective effect against perinatal transmission in children exposed to a low maternal viral burden of an R5-type isolate.

Impact of smoking and smoking cessation on overweight and obesity: Scotland-wide, cross-sectional study on 40,036 participants

BackgroundWeight control is cited by some people, especially adolescent girls, as a reason for commencing smoking or not quitting. The aim of this study was to explore the relationship between smoking behaviour and being overweight or obese, overall and by age and sex sub-groups.MethodsWe used data from the six Scottish Health Surveys conducted to date (1995–2010) to undertake a population-based, cross-sectional study on 40,036 participants representative of the adult (≥16 years) Scottish population. Height and weight were measured by a trained interviewer, not self-reported.Results24,459 (63.3%) participants were overweight (BMI ≥25 kg/m2) and 9,818 (25.4%) were obese (BMI ≥30 kg/m2). Overall, current smokers were less likely to be overweight than never smokers. However, those who had smoked for more than 20 years (adjusted OR 1.54, 95% CI 1.41-1.69, p < 0.001) and ex-smokers (adjusted OR 1.18, 95% CI 1.11-1.25, p < 0.001) were more likely to be overweight. There were significant interactions with age. Participants 16–24 years of age, were no more likely to be overweight if they were current (adjusted OR 1.01, 95% CI 0.84-1.20, p = 0.944) or ex (adjusted OR 0.88, 95% CI 0.67-1.14, p = 0.319) smokers. The same patterns pertained to obesity.ConclusionsWhilst active smoking may be associated with reduced risk of being overweight among some older adults, there was no evidence to support the belief among young people that smoking protects them from weight gain. Making this point in educational campaigns targeted at young people may help to discourage them from starting to smoke.