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1.  Does pregnancy increase the risk of ART-induced hepatotoxicity among HIV-positive women? 
Journal of the International AIDS Society  2014;17(4Suppl 3):19486.
High rates of hepatotoxicity have been observed among HIV-positive pregnant women using antiretroviral therapy (ART). However, the extent to which pregnancy affects the risk of ART-induced hepatotoxicity is unclear since studies in this area have generated conflicting results.
Material and Methods
Combined data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC) were used. Alanine aminotransferase (ALT) data were assessed according to the Division of AIDS toxicity guidelines to identify factors associated with liver enzyme elevation (LEE) (grade 1–4). Women starting ART in 2000–11 aged 16–49 years were included irrespective of pregnancy status at ART start. Cox proportional hazards were used to assess the associations between fixed (ethnicity, exposure group, HBV/HCV co-infection, prior ART use, and age, year, pregnancy status, viral load and CD4 count at ART start) and time-dependent covariates (pregnancy status, age, year, CD4 count, viral load, duration on ART) and the risk of LEE.
Of the 3426 women included, one-quarter (25.0%, n=857) were pregnant during follow-up and 14.4% (n=492) started ART during pregnancy. The rate of LEE was 15/100 person-years (PY) during pregnancy and 6.1/100 PY outside pregnancy. The risk of LEE was increased during pregnancy (adjusted hazard ratio (aHR) 1.61 [1.26–2.06], p<0.001), including in secondary analysis excluding 493 women pregnant when starting ART. Other factors independently associated with LEE were lower CD4 count (<250 cells/mm3 vs. 251–350 cells/mm3 aHR 1.25 [1.02–1.54], p=0.03), HBV/HCV co-infection (aHR 1.94 [1.58–2.39], p<0.001), HIV acquired via injecting drug use (aHR 1.61 [1.15–2.24], p=0.01 vs. heterosexually) and calendar year (aHR 1.05 [1.02–1.08], p<0.001 per one year increase). Three ART drugs were associated with increased risk of LEE (efavirenz aHR 1.27 [1.06–1.50], p-value 0.008; maraviroc 4.19 [1.34–13.1], p=0.01; and nevirapine 1.59 [1.30–1.95], p-value <0.001). Use of zidovudine was associated with decreased risk of LEE (aHR 0.74 [0.63–0.87], p<0.001) as was increasing time on an NNRTI-based regimen (aHR 0.91 [0.86–0.96], p<0.001 per additional year).
Pregnant women were at increased risk of LEE, highlighting the importance of close monitoring of toxicity biomarkers during pregnancy.
PMCID: PMC4224861  PMID: 25393995
2.  Loss to follow-up of HIV-infected women after delivery: The Swiss HIV Cohort Study and the Swiss Mother and Child HIV Cohort Study 
Journal of the International AIDS Society  2014;17(4Suppl 3):19535.
HIV-infected pregnant women are very likely to engage in HIV medical care to prevent transmission of HIV to their newborn. After delivery, however, childcare and competing commitments might lead to disengagement from HIV care. The aim of this study was to quantify loss to follow-up (LTFU) from HIV care after delivery and to identify risk factors for LTFU.
We used data on 719 pregnancies within the Swiss HIV Cohort Study from 1996 to 2012 and with information on follow-up visits available. Two LTFU events were defined: no clinical visit for >180 days and no visit for >360 days in the year after delivery. Logistic regression analysis was used to identify risk factors for a LTFU event after delivery.
Median maternal age at delivery was 32 years (IQR 28–36), 357 (49%) women were black, 280 (39%) white, 56 (8%) Asian and 4% other ethnicities. One hundred and seven (15%) women reported any history of IDU. The majority (524, 73%) of women received their HIV diagnosis before pregnancy, most of those (413, 79%) had lived with diagnosed HIV longer than three years and two-thirds (342, 65%) were already on antiretroviral therapy (ART) at time of conception. Of the 181 women diagnosed during pregnancy by a screening test, 80 (44%) were diagnosed in the first trimester, 67 (37%) in the second and 34 (19%) in the third trimester. Of 357 (69%) women who had been seen in HIV medical care during three months before conception, 93% achieved an undetectable HIV viral load (VL) at delivery. Of 62 (12%) women with the last medical visit more than six months before conception, only 72% achieved an undetectable VL (p=0.001). Overall, 247 (34%) women were LTFU over 180 days in the year after delivery and 86 (12%) women were LTFU over 360 days with 43 (50%) of those women returning. Being LTFU for 180 days was significantly associated with history of intravenous drug use (aOR 1.73, 95% CI 1.09–2.77, p=0.021) and not achieving an undetectable VL at delivery (aOR 1.79, 95% CI 1.03–3.11, p=0.040) after adjusting for maternal age, ethnicity, time of HIV diagnosis and being on ART at conception.
Women with a history of IDU and women with a detectable VL at delivery were more likely to be LTFU after delivery. This is of concern regarding their own health, as well as risk for sexual partners and subsequent pregnancies. Further strategies should be developed to enhance retention in medical care beyond pregnancy.
PMCID: PMC4224899  PMID: 25394044
3.  Outcomes related to 4864 pregnancies with exposure to lopinavir/ritonavir (LPV/r) 
Journal of the International AIDS Society  2014;17(4Suppl 3):19613.
During pregnancy, LPV/r is a common anchor drug employed to treat the mother's HIV-1 infection in addition to reducing the risk of mother-to-child transmission (MTCT). The National Study of HIV in Pregnancy and Childhood (NSHPC) conducts a comprehensive population-based surveillance of HIV infection in pregnant women exposed to antiretroviral therapy (ART) in the UK and Ireland; in 2003–2012 over a third of pregnancies reported to the NSHPC involved exposure to LPV/r.
We undertook a retrospective were descriptive analysis of individual NSHPC patient data, using pregnancy as the unit of observation. Clinical outcomes for pregnancies reported by June 2013, where women were exposed to LPV/r and due to deliver between January 2003 and December 2012, are described.
A total of 4864 LPV/r exposed pregnancies in 4118 women were identified. These resulted in 4702 deliveries with 4759 live and 46 stillborn infants. Seventy five percent of women were born in sub-Saharan Africa, 13% in the UK or Ireland. Median maternal age at conception was 30 years. Nine hundred and eighty (20%) pregnancies were conceived while taking LPV/r, with a median duration of LPV/r exposure of 270 days. A total of 3884 (80%) pregnancies initiated LPV/r after conception, with a median duration of LPV/r exposure of 107 days. Viral load (VL) close to delivery was available for 4083/4702 (87%) deliveries, with VL <50 c/mL in 73% and <1000 c/mL in 94% of women. VL by timing of LPV/r initiation is shown in Table 1. Sixty three percent of deliveries were by C-section, of which 62% were classified as elective and 38% as emergency. Among singleton liveborn infants, 13% were born prior to 37 weeks gestation (2.5% <32 weeks) and 15% had birth weight <2500 g (2.3% <1500 g). HIV infection status was available for 4039 (89%) singleton infants. For the periods 2003–2007 and 2008–2012, MTCT rates were 1.1% (95% CI 0.6–1.6) and 0.5% (95% CI 0.2–0.8) respectively. Hundred and thirty four live born children (2.8%) had at least one congenital abnormality reported.
In the NSHPC database, in women exposed to LPV/r during pregnancy in the UK and Ireland, MTCT rates are low and continue to decline, and are similar to rates in the entire NSHPC cohort of women with diagnosed HIV [1]. The congenital abnormality rate is comparable with that reported for the uninfected population in this geographic region.
PMCID: PMC4224945  PMID: 25394117
4.  Pregnancy outcomes in women growing up with perinatally acquired HIV in the United Kingdom and Ireland 
Journal of the International AIDS Society  2014;17(4Suppl 3):19693.
In the United Kingdom and Ireland more than 40% of individuals living with perinatally acquired HIV are now aged >16. Globally, increasing numbers of women with perinatally acquired HIV are becoming pregnant, but data on fertility and pregnancy outcomes is scarce. We present pregnancy outcome data for this emerging cohort.
Pregnancies in diagnosed HIV-infected women in the United Kingdom and Ireland, and children diagnosed with HIV, are reported to the National Study of HIV in Pregnancy and Childhood. We analyzed data on pregnancies in women diagnosed aged ≤13 with perinatally acquired HIV, reported by June 2014.
A total of 759 females born before 2001, diagnosed with perinatally acquired HIV aged ≤13 years, and in care in the UK and Ireland have been reported. Forty-four of these (6%) have had at least one pregnancy reported, with nineteen 2nd and four 3rd/4th pregnancies. Women's year of birth ranged from 1985 to 1996; 60% of women were UK/Irish-born and 39% African-born. Twenty one percent were diagnosed at <2 years, 39% at 2–7 and 41% at 8–13 years. Nine pregnancies were conceived in 2005–07, 22 in 2008–10 and 36 in 2011–13. Median age at conception of first pregnancy was 19 years. CD4 count was >500 cells/µL in 36% of first pregnancies, 350–499 in 15% and <350 in 49%. Women were on antiretroviral therapy (ART) at conception in 71% of pregnancies. There were 51 singleton live births, 2 miscarriages, 9 terminations and 5 continuing to term. In 17 live births to women not on ART at conception, median gestational age at start of ART was 17 weeks (range 3–29). HIV viral load was <50 copies/mL near delivery in 64% of live births, 51–1000 in 31% and >1000 in 5%. Forty four percent of live births were delivered by elective caesarean section (CS), 27% by emergency CS, 27% by planned vaginal delivery and with one unplanned vaginal delivery. Of 29 live births with viral load <50, 31% were delivered by elective CS, 17% by emergency CS and 52% by vaginal delivery. Fifteen percent of infants were delivered at 32–36 weeks gestation, and 2% at 30 weeks; 16% weighed 1.5–2.5 kg and 16% weighed <1.5 kg. Among 38 of the 51 infants where infection status is already reported, one is perinatally infected.
Currently at least 6% of perinatally infected women in care in the UK and Ireland have experienced one or more pregnancies. Linking paediatric, pregnancy and second generation data will enable further monitoring of pregnancy outcomes in this newly emerging population.
PMCID: PMC4225415  PMID: 25397443
5.  Adherence to antiretroviral therapy during pregnancy and the first year postpartum among HIV-positive women in Ukraine 
BMC Public Health  2014;14(1):993.
Poor adherence to antiretroviral therapy (ART) is associated with HIV disease progression and, during pregnancy, increased mother-to-child transmission risk. In Ukraine, access to combination ART is expanding but data on adherence are scarce.
Cross-sectional surveys of HIV-positive women were conducted i) at delivery (on antenatal ART adherence) and ii) during the first year postpartum (on ART adherence in the preceding four weeks). Factors associated with a score ≤11 on the self-report Case Adherence Support Evaluation (CASE) index or ≥1 self-reported missed dose were assessed using Fisher’s exact test.
Of 185 antenatal participants and 102 postnatal participants, median ages were 27.5 and 29.5 years respectively: 28% (50/180) and 27% (26/98) reported an unplanned pregnancy, and 13% (24/179) and 17% (17/98) an illicit drug-use history (excluding marijuana). One quarter (49/180 antenatally, 27/101 postnatally) screened positive for depression. The proportion reporting ‘low’ ART-related self-efficacy (i.e. unable to do ≥1/5 ART-taking activities) was 20% (28/141) antenatally and 17% (11/66) postnatally. Antenatally, 14% (95% CI 10-21%) had a CASE score ≤11 and 35% (95% CI 28-42%) reported missing ≥1 dose. Factors associated with a CASE score ≤11 were unplanned pregnancy (25% (12/48) vs. 11% (13/120) where planned, p = 0.03) and living with extended family (23% (13/57) vs. 10% (12/125) living with partner/alone, p = 0.04). Self-report of ≥1 missed dose antenatally was additionally associated with younger age (p = 0.03) and lower self-efficacy (50% (14/28) reported ≥1 missed dose vs. 28% (30/108) of those with high self-efficacy, p = 0.04). Of 102 postnatal participants, 8% (95% CI 4-15%) had a CASE score ≤11 and 31% (95% CI 22-41%) reported ≥1 missed dose. Of 11 women with low self-efficacy, 3 (27%) had a CASE score ≤11 compared with 3/55 (5%) of those with high self-efficacy (p = 0.05). Current smokers more commonly reported ≥1 missed dose postnatally (50% (13/26) vs. 25% (18/72) of non-smokers, p = 0.03).
Our results highlight unmet needs for counselling and support. We identify some groups at risk of poor ART adherence, including women with markers of social vulnerability and those with low ART-related self-efficacy, who may benefit from targeted interventions.
PMCID: PMC4180980  PMID: 25248469
HIV; Antiretroviral therapy; Adherence; Self-efficacy; Ukraine; Eastern Europe; Women; Pregnancy; Prevention of mother-to-child transmission
6.  Response to antiretroviral therapy (ART): comparing women with previous use of zidovudine monotherapy (ZDVm) in pregnancy with ART naïve women 
BMC Infectious Diseases  2014;14:127.
Short-term zidovudine monotherapy (ZDVm) remains an option for some pregnant HIV-positive women not requiring treatment for their own health but may affect treatment responses once antiretroviral therapy (ART) is subsequently started.
Data were obtained by linking two UK studies: the UK Collaborative HIV Cohort (UK CHIC) study and the National Study of HIV in Pregnancy and Childhood (NSHPC). Treatment responses were assessed for 2028 women initiating ART at least one year after HIV-diagnosis. Outcomes were compared using logistic regression, proportional hazards regression or linear regression.
In adjusted analyses, ART-naïve (n = 1937) and ZDVm-experienced (n = 91) women had similar increases in CD4 count and a similar proportion achieving virological suppression; both groups had a low risk of AIDS.
In this setting, antenatal ZDVm exposure did not adversely impact on outcomes once ART was initiated for the woman’s health.
PMCID: PMC3995971  PMID: 24593018
HIV; Pregnancy; Antiretroviral therapy; United Kingdom
7.  Tuberculosis and HIV co-infection in children 
BMC Infectious Diseases  2014;14(Suppl 1):S5.
HIV is the top and tuberculosis is the second leading cause of death from infectious disease worldwide, with an estimated 8.7 million incident cases of tuberculosis and 2.5 million new HIV infections annually. The World Health Organization estimates that HIV prevalence among children with tuberculosis, in countries with moderate to high prevalence, ranges from 10 to 60%. The mechanisms promoting susceptibility of people with HIV to tuberculosis disease are incompletely understood, being likely caused by multifactorial processes.
Paediatric tuberculosis and HIV have overlapping clinical manifestations, which could lead to missed or late diagnosis. Although every effort should be made to obtain a microbiologically-confirmed diagnosis in children with tuberculosis, in reality this may only be achieved in a minority, reflecting their paucibacillary nature and the difficulties in obtain samples. Rapid polymerase chain reaction tests, such as Xpert MTB/RIF assay, are increasingly used in children. The use of less or non invasive methods of sample collection, such as naso-pharyngeal aspirates and stool samples for a polymerase chain reaction-based diagnostic test tests and mycobacterial cultures is promising technique in HIV negative and HIV positive children. Anti-tuberculosis treatment should be started immediately at diagnosis with a four drug regimen, irrespective of the disease severity. Moreover, tuberculosis disease in an HIV infected child is considered to be a clinical indication for initiation of antiretroviral treatment. The World Health Organization recommends starting antiretroviral treatment in children as soon as anti-tuberculosis treatment is tolerated and within 2- 8 weeks after initiating it. The treatment of choice depends on the child’s age and availability of age-appropriate formulations, and potential drug interactions and resistance. Treatment of multi-drug resistant tuberculosis in HIV-infected children follows same principles as for HIV uninfected children. There are conflicting results on effectiveness of isoniazid preventive therapy in reducing incidence of tuberculosis disease in children with HIV.
Data on HIV/TB co-infection in children are still lacking. There are on-going large clinical trials on the prevention and treatment of TB/HIV infection in children that hopefully will help to guide an evidence-based clinical practice in both resource-rich and resource-limited settings.
PMCID: PMC4016474  PMID: 24564453
8.  Management of hepatitis B in pregnant women and infants: a multicentre audit from four London hospitals 
Pregnant women with hepatitis B virus (HBV) infection can transmit the infection to their infants, screening of patients and appropriate interventions reduce vertical transmission. This audit was conducted to assess adherence to the national guidelines for management of HBV infection in pregnancy.
A retrospective audit was conducted on pregnant women diagnosed with hepatitis B on screening in antenatal clinics, across four hospitals in London over 2 years (2009–2010). Data was collected from antenatal records and discharge summaries using a standard audit form. The outcomes measured included HBV serological markers, HBV DNA, detection of other blood borne viruses and referral to hepatology services, administration of active and passive prophylaxis to infants at birth. Descriptive statistics are presented. Proportions were compared using the χ2 test and 95% confidence intervals (CI) were calculated for prevalence estimates. Analyses were conducted using STATA 12.
HBsAg was detected in 1.05% (n = 401, 95% CI 0.95-1.16) of women attending an antenatal appointment, 12% (n = 48) of the women were at a high risk of vertical transmission (HBe Ag positive or antiHBe and HBeAg negative or HBV DNA >106 IU/ml). Only 62% (n = 248) women were referred to hepatology or specialist clinics and 29% (n = 13) of women of high infectivity were on antiviral agents. Testing for hepatitis C and delta virus was suboptimal. 75% (n = 36) of the infants at a high risk of acquisition of HBV received both active and passive prophylaxis.
In certain sectors of London, implementation of the pathway for management of women with hepatitis B and their infants is suboptimal. National guidelines should be followed and improved intersectorial sharing of information is needed to reduce the risk of women of high infectivity being lost to follow up.
PMCID: PMC3879069  PMID: 24289183
Infection; Pregnancy; Hepatitis B; Antivirals; High risk
9.  Predictors of pregnancy and changes in pregnancy incidence among HIV-positive women accessing HIV clinical care at 13 large UK clinics 
AIDS (London, England)  2013;27(1):95-103.
To describe predictors of pregnancy and changes in pregnancy incidence among HIV-positive women accessing HIV clinical care.
Data were obtained through the linkage of two separate studies; the UK Collaborative HIV Cohort study (UK CHIC), a cohort of adults attending 13 large HIV clinics, and the National Study of HIV in Pregnancy and Childhood (NSHPC), a national surveillance study of HIV-positive pregnant women. Pregnancy incidence was measured using the proportion of women in UK CHIC with a pregnancy reported to NSHPC. Generalised estimating equations were used to identify predictors of pregnancy and assess changes in pregnancy incidence in 2000-2009.
The number of women accessing care at UK CHIC sites increased as did the number of pregnancies (from 72 to 230). Older women were less likely to have a pregnancy (adjusted Relative Rate (aRR) 0.44 per 10 year increment in age [95% CI [0.41-0.46], p<0.001) as were women with CD4<200 cells/mm3 compared with CD4 200-350 cells/mm3 (aRR 0.65 [0.55-0.77] p<0.001) and women of white ethnicity compared with women of black-African ethnicity (aRR 0.67 [0.57-0.80], p<0.001). The likelihood that women had a pregnancy increased over the study period (aRR 1.05 [1.03-1.07], p<0.001). The rate of change did not significantly differ according to age group, ART use, CD4 group or ethnicity.
The pregnancy rate among women accessing HIV clinical care increased in 2000-2009. HIV-positive women with, or planning, a pregnancy require a high level of care and this is likely to continue and increase as more women of older age have pregnancies.
PMCID: PMC3495056  PMID: 22713479
HIV; pregnancy; pregnancy rate; maternal age; highly active antiretroviral therapy; maternal-fetal infection transmission; United Kingdom
10.  Cell-Free (RNA) and Cell-Associated (DNA) HIV-1 and Postnatal Transmission through Breastfeeding 
PLoS ONE  2012;7(12):e51493.
Transmission through breastfeeding remains important for mother-to-child transmission (MTCT) in resource-limited settings. We quantify the relationship between cell-free (RNA) and cell-associated (DNA) shedding of HIV-1 virus in breastmilk and the risk of postnatal HIV-1 transmission in the first 6 months postpartum.
Materials and Methods
Thirty-six HIV-positive mothers who transmitted HIV-1 by breastfeeding were matched to 36 non-transmitting HIV-1 infected mothers in a case-control study nested in a cohort of HIV-infected women. RNA and DNA were quantified in the same breastmilk sample taken at 6 weeks and 6 months. Cox regression analysis assessed the association between cell-free and cell-associated virus levels and risk of postnatal HIV-1 transmission.
There were higher median levels of cell-free than cell-associated HIV-1 virus (per ml) in breastmilk at 6 weeks and 6 months. Multivariably, adjusting for antenatal CD4 count and maternal plasma viral load, at 6 weeks, each 10-fold increase in cell-free or cell-associated levels (per ml) was significantly associated with HIV-1 transmission but stronger for cell-associated than cell-free levels [2.47 (95% CI 1.33–4.59) vs. aHR 1.52 (95% CI, 1.17–1.96), respectively]. At 6 months, cell-free and cell-associated levels (per ml) in breastmilk remained significantly associated with HIV-1 transmission but was stronger for cell-free than cell-associated levels [aHR 2.53 (95% CI 1.64–3.92) vs. 1.73 (95% CI 0.94–3.19), respectively].
The findings suggest that cell-associated virus level (per ml) is more important for early postpartum HIV-1 transmission (at 6 weeks) than cell-free virus. As cell-associated virus levels have been consistently detected in breastmilk despite antiretroviral therapy, this highlights a potential challenge for resource-limited settings to achieve the UNAIDS goal for 2015 of eliminating vertical transmission. More studies would further knowledge on mechanisms of HIV-1 transmission and help develop more effective drugs during lactation.
PMCID: PMC3532207  PMID: 23284701
Journal of viral hepatitis  2011;18(8):533-541.
Despite the introduction of blood donor screening, worldwide, children continue to become infected with HCV via un-sterile medical injections, receipt of unscreened blood and isolated hospital contamination outbreaks. It is plausible that the natural history and disease progression in these children might differ from that of their vertically infected counterparts.
Materials and Methods
Vertically and parenterally HCV infected children were prospectively followed within the European Paediatric HCV Network and the UK National HCV Register respectively. Biological profiles were compared.
Vertically and parenterally HCV infected children differed in terms of some key characteristics including the male:female ratio and the proportion of children receiving therapy. Parenterally infected children were more likely to have at least one hepatomegaly event during follow-up, 20% vs. 10%. Parenteral infection did not significantly affect the odds of being consistently viraemic, AOR 1.14 p=0.703 and there was no significant difference in the odds of having consistently elevated ALT levels and mode of acquisition, AOR 0.83 p=0.748. The proportion of children with 2 or more markers of HCV infection did not differ significantly by mode of acquisition, χ21.13 p=0.288.
This analysis does not support substantial differences between vertically and parenterally infected groups but there are specific mechanisms identified requiring further investigation. Given the continued parenteral infection of children worldwide it is vital that knowledge of disease progression in this group is accurate and that the differences in comparison to vertically infected children are clarified to inform more accurate and individualised clinical management.
PMCID: PMC3433032  PMID: 21762285
biological markers; children; hepatitis C virus; mode of acquisition
12.  Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence and risk factors 
To estimate the prevalence of, and identify risk factors for Lipodystrophy Syndrome (LS) and body fat abnormality in a population of HIV-infected children and adolescents.
Cross-sectional observational study.
HIV-infected subjects aged 2-18 years were recruited from 15 HIV centres in Belgium, Italy and Poland between January 2007 and December 2008. Standardized assessments by the patient’s long-term clinician were performed to establish presence of abnormality. Risk factors were explored in logistic regression models for fat abnormality outcomes and LS (abnormality plus dyslipidemia).
Among 426 subjects (70% white), median age was 12.2 (Inter quartile range, IQR: 9.0, 15.0) years and median duration of antiretroviral therapy (ART) was 5.2 (IQR: 2.2, 8.8) years. Prevalence was 57% (n=235) for LS and 42% (n=176) for fat abnormality; 90 subjects with abnormality were affected in ≥3 locations. Lipoatrophy occurred in 28% (n=117) subjects, and lipohypertrophy in 27% (n=115), most commonly in the face and trunk respectively. In multivariable analysis, white ethnicity, BMI, ritonavir/lopinavir and NNRTIs were each associated with increased risk of LS (p<0.05). White ethnicity, history of CDC-defined disease and stavudine were associated with risk of lipoatrophy (p<0.05). Increased risk of lipohypertrophy was associated with BMI and prior HIV disease.
Fat abnormality was prevalent in close to half of children and adolescents, who had accumulated long treatment durations. Risk of fat redistribution was associated with specific drugs, including stavudine and ritonavir, and other variables. Our results underline the importance of continued surveillance of children treated with ART.
PMCID: PMC3433033  PMID: 22205436
Children; adolescents; lipodystrophy syndrome; fat redistribution; ART
13.  Incidence, patterns, and predictors of repeat pregnancies among HIV-infected women in the United Kingdom and Ireland, 1990-2009 
To explore the pattern of repeat pregnancies among diagnosed HIV-infected women in the UK and Ireland, estimate the rate of these sequential pregnancies, and investigate the demographic and clinical characteristics of women experiencing them.
Diagnosed HIV-infected pregnant women are reported through an active confidential reporting scheme to the National Study of HIV in Pregnancy and Childhood.
Pregnancies occurring during 1990-2009 were included. Multivariable analyses were conducted fitting Cox proportional hazards models.
There were 14,096 pregnancies in 10,568 women; 2737 (25.9%) had two or more pregnancies reported. The rate of repeat pregnancies was 6.7 (95% CI: 6.5-7.0) per 100 woman-years. The proportion of pregnancies in women who already had at least one pregnancy reported increased from 20.3% (32/158) in 1997 to 38.6% (565/1465) in 2009 (p<0.001).
In multivariable analysis the probability of repeat pregnancy significantly declined with increasing age at first pregnancy. Parity was also inversely associated with repeat pregnancy. Compared with women born in the UK or Ireland, those from Europe, Eastern Africa, and Southern Africa were less likely to have a repeat pregnancy, while women from Middle Africa and Western Africa were more likely to. Maternal health at first pregnancy was not associated with repeat pregnancy.
The number of diagnosed HIV-infected women in the UK and Ireland experiencing repeat pregnancies is increasing. Variations in the probability of repeat pregnancies, according to demographic and clinical characteristics, are an important consideration when planning reproductive health services and HIV care for people living with HIV.
PMCID: PMC3378493  PMID: 22227490
HIV; Women; Pregnancy; Surveillance; Epidemiology; United Kingdom and Ireland
14.  Insufficient antiretroviral therapy in pregnancy: missed opportunities for prevention of mother-to-child transmission of HIV in Europe 
Antiviral therapy  2011;16(6):895-903.
Although mother-to-child transmission (MTCT) rates are at an all-time low in Western Europe, potentially preventable transmissions continue to occur. Duration of antenatal combination antiretroviral therapy (ART) is strongly associated with MTCT risk.
Data on pregnant HIV-infected women enrolled in the Western and Central European sites of the European Collaborative Study between January 2000 and July 2009 were analysed. The proportion of women receiving no antenatal ART or 1-13 days of treatment was investigated, and associated factors explored using logistic regression models.
Of 2148 women, 142 (7%) received no antenatal ART, decreasing from 8% in 2000-03 to 5% in 2004-09 (χ2 =8.73, p<0.01). A further 41 (2%) received 1-13 days of ART. A third (64/171) of women with “insufficient” (no or 1-13 days) antenatal ART had a late HIV diagnosis (in the third trimester or intrapartum), but half (85/171) were diagnosed pre-conception. Preterm delivery <34 weeks was associated with receipt of no and 1-13 days antenatal ART (AOR 2.9 p<0.01 and AOR 4.5 p<0.01 respectively). Injecting drug use history was associated with an increased risk of no ART (AOR 2.9 p<0.01) and severe symptomatic HIV disease with a decreased risk (AOR 0.2, p<0.01). MTCT rates were 1.1% (15/1318) among women with ≥14 days antenatal ART and 7.4% (10/136) among those with insufficient ART.
Over the last 10 years, around 1 in 11 women in this study received insufficient antenatal ART, accounting for 40% of mother-to-child transmissions. Half of these women were diagnosed pre-conception, suggesting disengagement from care.
PMCID: PMC3428867  PMID: 21900722
15.  Treating HIV infected mothers reduces mortality in children under 5 years of age to levels seen in children of HIV uninfected mothers: evidence from rural South Africa 
Antiviral therapy  2012;17(1):81-90.
Maternal and child survival are highly correlated, but the contribution of HIV infection on this relationship, and in particular the impact of HIV treatment has not been quantified. We estimate the association between maternal HIV and treatment and under-5 child mortality in a rural population in South Africa.
All children born between January 2000-January 2007 in the Africa Centre Demographic Surveillance Area were included. Maternal HIV status information was available from HIV surveillance; maternal antiretroviral treatment (ART) from the HIV Treatment Programme database and linked to surveillance data. Mortality rates were computed as deaths per 1000 person-years observed. Time-varying maternal HIV effect (positive, negative, ART) on U5MR was assessed in Cox regression, adjusting for other factors associated with under-5 mortality.
9,068 mothers delivered 12,052 children, of whom 947 (7.9%) died before age 5. Infant mortality rate (IMR) declined by 49% from 69.0 in 2000 to 35.5 in 2006 deaths per 1000 person-years observed; a significantly decline was observed post-ART (2004-2006). The estimated proportion of deaths across all age groups were higher among the children born to the HIV-positive and HIV-not reported status women than among children of HIV-negative women. Multivariably, mortality in children of mothers on ART was not significantly different from children of HIV-negative mothers (aHR 1.29, 0.53-3.17; p=0.572).
These findings highlight the importance of maternal HIV treatment with direct benefits of improved survival among all children under-5. Timely HIV treatment for eligible women is required to benefit both mothers and children.
PMCID: PMC3428894  PMID: 22267472
16.  Treatment switches during pregnancy among HIV-positive women on antiretroviral therapy at conception 
AIDS (London, England)  2011;25(13):1647-1655.
To describe antiretroviral therapy (ART) use and clinical status, at start of and during pregnancy, for HIV-positive women receiving ART at conception, including the proportion conceiving on drugs (efavirenz and didanosine) not recommended for use in early pregnancy.
Women with a pregnancy resulting in a live birth after 1995 (n=1,537) were identified in an observational cohort of patients receiving HIV care at 12 clinics in the UK by matching records with national pregnancy study data. Treatment and clinical data were analysed for 375 women conceiving on ART, including logistic regression to identify factors associated with changing regimen during pregnancy.
Of the 375 women on ART at conception, 39 (10%) conceived on dual therapy, 306 (82%) on triple therapy and 30 (8%) on >3 drugs. In total, 116 (31%) women conceived on a regimen containing efavirenz or didanosine (69 efavirenz, 54 didanosine, 7 both). Overall, 38% (143) switched regimen during pregnancy, of whom 41% (n=48) had a detectable viral load (≥50 copies/ml) around that time. Detectable viral load was associated with increased risk of regimen change (adjusted odds ratio 2.2, 95% confidence interval [1.3, 3.8]), while women on efavirenz at conception were three times more likely to switch than women on other drugs (3.3, [1.8, 6.0]). Regimen switching was also associated with calendar year at conception (0.9, [0.8-1.0]).
These findings reinforce the need for careful consideration of ART use among women planning or likely to have a pregnancy in order to reduce viral load before pregnancy and avoid drugs not recommended for early antenatal use.
PMCID: PMC3428898  PMID: 21673558
HIV; pregnancy; antiretroviral agents; antiretroviral therapy; United Kingdom
18.  Factors associated with abandonment of infants born to HIV positive women: results from a Ukrainian birth cohort 
AIDS care  2010;22(12):1439-1448.
Social marginalisation and other challenges facing HIV-positive pregnant women in Ukraine may put them at increased risk of relinquishing their infants to the state. We described rates of infant abandonment (exclusive non-parental care to most recent follow up, censored at two years of age) and investigated associated factors using logistic regression models, in 4759 mother-infant pairs enrolled across six Ukrainian sites in the European Collaborative Study from 2000 to May 2009. Median maternal age was 26.0 years, 81.8% were married or cohabiting and 60.6% were nulliparous at enrolment. An injecting drug use (IDU) history was reported by 18.4%, 80.2% took antiretroviral therapy (ART) antenatally and most deliveries were vaginal. A small but significant proportion of infants had been cared for exclusively in institutions by their second birthday (2.1% overall), decreasing from 3.8% (15/393) in 2000-02 to 1.6% (49/3136) in 2006-09 (p<0.01), concurrent with prevention of mother-to-child transmission (PMTCT) scale-up. A further 1% of infants spent some time in non-parental care. Antenatal ART was associated with an 88% reduced abandonment risk (AOR 0.12), versus receipt of single dose nevirapine only, and this was reflected in HIV infection prevalence in the two groups (17.1% of abandoned infants versus 6.6% in parental care). Mothers without a cohabiting partner or husband were more likely to abandon (AOR 4.08), as were active IDUs (AOR 3.27) and those with ≥1 previous children (AOR 1.89 for second-born, AOR 2.56 for subsequent births). Women delivering by elective caesarean section were less likely to abandon (AOR 0.37 versus vaginal), as were those leaving full time education later (AOR 0.61 for 17-18 years versus ≤16 years, AOR 0.23 for ≥19 years versus ≤16 years). Interventions to extend family planning and IDU harm reduction services along with non-stigmatising antenatal care to marginalised women are needed, and may reduce abandonment.
PMCID: PMC3428901  PMID: 20824547
HIV; infant abandonment; antenatal antiretroviral therapy; injecting drug use; Ukraine
19.  Using two on-going HIV studies to obtain clinical data from before, during and after pregnancy for HIV-positive women 
The UK Collaborative HIV Cohort (UK CHIC) is an observational study that collates data on HIV-positive adults accessing HIV clinical care at (currently) 13 large clinics in the UK but does not collect pregnancy specific data. The National Study of HIV in Pregnancy and Childhood (NSHPC) collates data on HIV-positive women receiving antenatal care from every maternity unit in the UK and Ireland. Both studies collate pseudonymised data and neither dataset contains unique patient identifiers. A methodology was developed to find and match records for women reported to both studies thereby obtaining clinical and treatment data on pregnant HIV-positive women not available from either dataset alone.
Women in UK CHIC receiving HIV-clinical care in 1996–2009, were found in the NSHPC dataset by initially ‘linking’ records with identical date-of-birth, linked records were then accepted as a genuine ‘match’, if they had further matching fields including CD4 test date. In total, 2063 women were found in both datasets, representing 23.1% of HIV-positive women with a pregnancy in the UK (n = 8932). Clinical data was available in UK CHIC following most pregnancies (92.0%, 2471/2685 pregnancies starting before 2009). There was bias towards matching women with repeat pregnancies (35.9% (741/2063) of women found in both datasets had a repeat pregnancy compared to 21.9% (1502/6869) of women in NSHPC only) and matching women HIV diagnosed before their first reported pregnancy (54.8% (1131/2063) compared to 47.7% (3278/6869), respectively).
Through the use of demographic data and clinical dates, records from two independent studies were successfully matched, providing data not available from either study alone.
PMCID: PMC3475121  PMID: 22839414
Data linkage; HIV; Pregnant women; Antiretroviral therapy; Cohort analysis; United Kingdom
20.  Cervical Screening within HIV Care: Findings from an HIV-Positive Cohort in Ukraine 
PLoS ONE  2012;7(4):e34706.
HIV-positive women have an increased risk of invasive cervical cancer but cytologic screening is effective in reducing incidence. Little is known about cervical screening coverage or the prevalence of abnormal cytology among HIV-positive women in Ukraine, which has the most severe HIV epidemic in Europe.
Poisson regression models were fitted to data from 1120 women enrolled at three sites of the Ukraine Cohort Study of HIV-infected Childbearing Women to investigate factors associated with receiving cervical screening as part of HIV care. All women had been diagnosed as HIV-positive before or during their most recent pregnancy. Prevalence of cervical abnormalities (high/low grade squamous intraepithelial lesions) among women who had been screened was estimated, and associated factors explored.
Overall, 30% (337/1120) of women had received a cervical screening test as part of HIV care at study enrolment (median 10 months postpartum), a third (115/334) of whom had been tested >12 months previously. In adjusted analyses, women diagnosed as HIV-positive during (vs before) their most recent pregnancy were significantly less likely to have a screening test reported, on adjusting for other potential risk factors (adjusted prevalence ratio (APR) 0.62, 95% CI 0.51–0.75 p<0.01 for 1st/2nd trimester diagnosis and APR 0.42, 95% CI 0.28–0.63 p<0.01 for 3rd trimester/intrapartum diagnosis). Among those with a cervical screening result reported at any time (including follow-up), 21% (68/325) had a finding of cervical abnormality. In adjusted analyses, Herpes simplex virus 2 seropositivity and a recent diagnosis of bacterial vaginosis were associated with an increased risk of abnormal cervical cytology (APR 1.83 95% CI 1.07–3.11 and APR 3.49 95% CI 2.11–5.76 respectively).
In this high risk population, cervical screening coverage as part of HIV care was low and could be improved by an organised cervical screening programme for HIV-positive women. Bacterial vaginosis testing and treatment may reduce vulnerability to cervical abnormalities.
PMCID: PMC3335834  PMID: 22545087
21.  Use of Zidovudine-Sparing HAART in Pregnant HIV-Infected Women in Europe: 2000–2009 
Increasing numbers of women in resource-rich settings are prescribed zidovudine (ZDV)-sparing highly active antiretroviral therapy (HAART) in pregnancy. We compare ZDV-sparing with ZDV-containing HAART in relation to maternal viral load at delivery, mother-to-child transmission (MTCT) of HIV, and congenital abnormality.
This is an analysis of data from the National Study of HIV in Pregnancy and Childhood and the European Collaborative Study. Data on 7573 singleton births to diagnosed HIV-infected women between January 2000 and June 2009 were analyzed. Logistic regression models were fitted to estimate adjusted odds ratios (AORs).
Overall, 15.8% (1199 of 7573) of women received ZDV-sparing HAART, with increasing use between 2000 and 2009 (P < 0.001). Nearly a fifth (18.4%) of women receiving ZDV-sparing HAART in pregnancy had a detectable viral load at delivery compared with 28.6% of women on ZDV-containing HAART [AOR 0.90; 95% confidence interval (CI): 0.72 to 1.14, P = 0.4]. MTCT rates were 0.8% and 0.9% in the ZDV-sparing and ZDV-containing groups, respectively (AOR 1.81; 95% CI: 0.77 to 4.26, P = 0.2). The congenital abnormality rate was the same in both groups (2.7%, AOR 0.98; 95% CI: 0.66 to 1.45, P = 0.9), with no significant difference between the groups in a subanalysis of pregnancies with first trimester HAART exposure (AOR 0.79; 95% CI: 0.48 to 1.30, P = 0.4).
We found no difference in risk of detectable viral load at delivery, MTCT, or congenital abnormality when comparing ZDV-sparing with ZDV-containing HAART. With increasing use of ZDV-sparing HAART, continued monitoring of pregnancy outcomes and long-term consequences of in utero exposure to these drugs is required.
PMCID: PMC3319104  PMID: 21499113
antiretroviral agents; highly active antiretroviral therapy; HIV; pregnancy outcome; viral load; congenital abnormalities
22.  Maternal HIV infection associated with small-for-gestational age infants but not preterm births: evidence from rural South Africa 
Human Reproduction (Oxford, England)  2012;27(6):1846-1856.
 Human immunodeficiency virus (HIV) is prevalent in many countries where small-for-gestational age (SGA) and premature delivery are also common. However, the associations between maternal HIV, preterm delivery and SGA infants remain unclear. We estimate the prevalence of SGA and preterm (<37 weeks) births, their associations with antenatal maternal HIV infection and their contribution to infant mortality, in a high HIV prevalent, rural area in South Africa.
Data were collected, in a non-randomized intervention cohort study, on all women attending antenatal clinics (2001–2004), before the availability of antiretroviral treatment. Newborns were weighed and gestational age was determined (based on last menstrual period plus midwife assessment antenatally). Poisson regression with robust variance assessed risk factors for preterm and SGA birth, while Cox regression assessed infant mortality and associated factors.
Of 2368 live born singletons, 16.6% were SGA and 21.4% were preterm. HIV-infected women (n= 1189) more commonly had SGA infants than uninfected women (18.1 versus 15.1%; P = 0.051), but percentages preterm were similar (21.8 versus 20.9%; P = 0.621). After adjustment for water source, delivery place, parity and maternal height, the SGA risk in HIV-infected women was higher [adjusted relative risk (aRR) 1.28, 95% confidence interval (CI): 1.06–1.53], but the association between maternal HIV infection and preterm delivery remained weak and not significant (aRR: 1.07, 95% CI: 0.91–1.26). In multivariable analyses, mortality under 1 year of age was significantly higher in SGA and severely SGA than in appropriate-for-gestational-age infants [adjusted hazard ratio (aHR): 2.12, 95% CI: 1.18–3.81 and 2.77, 95% CI: 1.56–4.91], but no difference in infant mortality was observed between the preterm and term infants (aHR: 1.18 95% CI: 0.79–1.79 for 34–36 weeks and 1.31, 95% CI: 0.58–2.94 for <34 weeks).
Maternal HIV infection increases the risk of SGA, but not preterm births, in this cohort.
PMCID: PMC3357196  PMID: 22442245
HIV; SGA; preterm; Africa; low birthweight
23.  Treatment and disease progression in a birth cohort of vertically HIV-1 infected children in Ukraine 
BMC Pediatrics  2010;10:85.
Ukraine has the highest HIV prevalence (1.6%) and is facing the fastest growing epidemic in Europe. Our objective was to describe the clinical, immunological and virological characteristics, treatment and response in vertically HIV-infected children living in Ukraine and followed from birth.
The European Collaborative Study (ECS) is an ongoing cohort study, in which HIV-1 infected pregnant women are enrolled and followed in pregnancy, and their children prospectively followed from birth. ECS enrolment in Ukraine started in 2000 initially with three sites, increasing to seven sites by 2009.
A total of 245 infected children were included in the cohort by April 2009, with a median age of 23 months at most recent follow-up; 33% (n = 77) had injecting drug using mothers and 85% (n = 209) were infected despite some use of antiretroviral prophylaxis for prevention of mother-to-child transmission. Fifty-five (22%) children had developed AIDS, at a median age of 10 months (IQR = 6-19). The most prevalent AIDS indicator disease was Pneumocystis jiroveci pneumonia (PCP). Twenty-seven (11%) children had died (median age, 6.2 months). Overall, 108 (44%) children had started highly active antiretroviral treatment (HAART), at a median 18 months of age; median HAART duration was 6.6 months to date. No child discontinued HAART and 92% (100/108) remained on their first-line HAART regimen to date. Among children with moderate/severe immunosuppression, 36% had not yet started HAART. Among children on HAART, 71% (69/97) had no evidence of immunosuppression at their most recent visit; the median reduction in HIV RNA was 4.69 log10 copies/mL over a median of 10 months treatment. From survival analysis, an estimated 94%, 84% and 81% of children will be alive and AIDS-free at 6, 12 and 18 months of age, respectively. However, survival increased significantly over time: estimated survival rates to 12 months of age were 87% for children born in 2000/03 versus 96% for those born in 2004/08.
One in five children had AIDS and one in ten had died. The half of children who received HAART has responded well and survival has significantly improved over time. Earlier diagnosis and prompt initiation of HAART remain key challenges.
PMCID: PMC2997768  PMID: 21092301
24.  Progress in prevention of mother-to-child transmission of HIV infection in Ukraine: results from a birth cohort study 
Ukraine was the epicentre of the HIV epidemic in Eastern Europe, which has the most rapidly accelerating HIV epidemic world-wide today; national HIV prevalence is currently estimated at 1.6%. Our objective was to evaluate the uptake and effectiveness of interventions for prevention of mother-to-child transmission (PMTCT) over an eight year period within operational settings in Ukraine, within the context of an ongoing birth cohort study.
The European Collaborative Study (ECS) is an ongoing birth cohort study in which HIV-infected pregnant women identified before or during pregnancy or at delivery were enrolled and their infants prospectively followed. Three centres in Ukraine started enrolling in 2000, with a further three joining in September 2006.
Of the 3356 women enrolled, 21% (689) reported current or past injecting drug use (IDU). Most women were diagnosed antenatally and of those, the proportion diagnosed in the first/second trimester increased from 47% in 2000/01 (83/178) to 73% (776/1060) in 2006/07 (p < 0.001); intrapartum diagnosis was associated with IDU (Adjusted odds ratio 4.38; 95%CI 3.19–6.02). The percentage of women not receiving any antiretroviral prophylaxis declined from 18% (36/205) in 2001 to 7% in 2007 (61/843) (p < 0.001). Use of sdNVP alone substantially declined after 2003, with a concomitant increase in zidovudine prophylaxis. Median antenatal zidovudine prophylaxis duration increased from 24 to 72 days between 2000 and 2007. Elective caesarean section (CS) rates were relatively stable over time and 34% overall. Mother-to-child transmission (MTCT) rates decreased from 15.2% in 2001 (95%CI 10.2–21.4) to 7.0% in 2006 (95%CI 2.6–14.6). In adjusted analysis, MTCT risk was reduced by 43% with elective CS versus vaginal delivery and by 75% with zidovudine versus no prophylaxis.
There have been substantial improvements in use of PMTCT interventions in Ukraine, including earlier diagnosis of HIV-infected pregnant women and increasing coverage with antiretroviral prophylaxis and the initial MTCT rate has more than halved. Future research should focus on hard-to-reach populations such as IDU and on missed opportunities for further reducing the MTCT rate.
PMCID: PMC2674441  PMID: 19351387
25.  Characteristics and management of HIV-1-infected pregnant women enrolled in a randomised trial: differences between Europe and the USA 
Rates of mother-to-child transmission of HIV-1 (MTCT) have historically been lower in European than in American cohort studies, possibly due to differences in population characteristics. The Pediatric AIDS Clinical Trials Group Protocol (PACTG) 316 trial evaluated the effectiveness of the addition of intrapartum/neonatal nevirapine in reducing MTCT in women already receiving antiretroviral prophylaxis. Participation of large numbers of pregnant HIV-infected women from the US and Western Europe enrolling in the same clinical trial provided the opportunity to identify and explore differences in their characteristics and in the use of non-study interventions to reduce MTCT.
In this secondary analysis, 1350 women were categorized according to enrollment in centres in the USA (n = 978) or in Europe (n = 372). Factors associated with receipt of highly active antiretroviral therapy and with elective caesarean delivery were identified with logistic regression.
In Europe, women enrolled were more likely to be white and those of black race were mainly born in Sub-Saharan Africa. Women in the US were younger and more likely to have previous pregnancies and miscarriages and a history of sexually transmitted infections.
More than 90% of women did not report symptoms of their HIV infection; however, more women from the US had symptoms (8%), compared to women from Europe (4%). Women in the US were less likely to have HIV RNA levels <400 copies/ml at delivery than women enrolling in Europe, and more likely to receive highly active antiretroviral therapy, and to start therapy earlier in pregnancy. The elective caesarean delivery rate in Europe was 61%, significantly higher than that in the US (22%). Overall, 1.48% of infants were infected and there was no significant difference in the rate of transmission between Europe and the US despite the different approaches to treatment and delivery.
These findings confirm that there are important historical differences between the HIV-infected pregnant populations in Western Europe and the USA, both in terms of the characteristics of the women and their obstetric and therapeutic management. Although highly active antiretroviral therapy predominates in pregnancy in both settings now, population differences are likely to remain.
Trial registration
PMCID: PMC1913528  PMID: 17584491

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