Hermione Lyall

Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006

Aim:In the United Kingdom (UK) and Ireland, avoidance of breastfeeding and alternative combinations of antiretroviral therapy regimen and mode of delivery are recommended according to maternal clinical status. The aim of this analysis was to explore the impact of different strategies to prevent mother-to-child transmission at a population level. Design:Comprehensive national surveillance study. Methods:Pregnancies in diagnosed HIV-infected women in the UK and Ireland are notified to the National Study of HIV in Pregnancy and Childhood; infant infection status is subsequently reported. Factors associated with transmission in this observational study were explored for singleton births between 2000 and 2006. Results:The overall mother-to-child transmission rate was 1.2% (61/5151, 95% confidence interval: 0.9–1.5%), and 0.8% (40/4864) for women who received at least 14 days of antiretroviral therapy. Transmission rates following combinations recommended in British guidelines were 0.7% (17/2286) for highly active antiretroviral therapy with planned Caesarean section, 0.7% (4/559) for highly active antiretroviral therapy with planned vaginal delivery, and 0% (0/464) for zidovudine monotherapy with planned Caesarean section (P = 0.150). Longer duration of highly active antiretroviral therapy was associated with reduced transmission after adjusting for viral load, mode of delivery and sex (adjusted odds ratio = 0.90 per week of highly active antiretroviral therapy, P = 0.007). Among 2117 infants born to women on highly active antiretroviral therapy with viral load less than 50 copies/ml, only three (0.1%) were infected, two with evidence of in-utero transmission. Conclusion:Sustained low HIV transmission rates following different combinations of interventions in this large unselected population are encouraging. Current options for treatment and delivery offered to pregnant women according to British guidelines appear to be effective.

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.

Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011

Objectives:To analyze mother-to-child HIV transmission (MTCT) rates over time in light of changes in management, demographic, and pregnancy characteristics. Design:Population-based surveillance data on diagnosed HIV-positive women and their infants are routinely collected in the UK and Ireland. Methods:A total of 12 486 singleton pregnancies delivered in 2000–2011 were analyzed. HIV infection status was available for 11 515 infants (92.2%). Results:The rate of MTCT declined from 2.1% (17/816) in 2000–2001 to 0.46% (nine of 1975, 95% confidence interval: 0.21–0.86%) in 2010–2011 (trend, P = 0.01), because of a combination of factors including earlier initiation of antenatal combination antiretroviral therapy (cART). Excluding 63 infants who were breastfed or acquired HIV postnatally, MTCT risk was significantly higher for all modes of delivery in women with viral load of 50–399 copies/ml (1.0%, 14/1349), compared with viral load of less than 50 copies/ml (0.09%, six of 6347, P <0.001). Among the former (viral load 50–399 copies/ml), the risk of MTCT was 0.26% (two of 777) following elective cesarean section and 1.1% (two of 188) following planned vaginal delivery (P = 0.17), excluding in-utero transmissions. MTCT probability declined rapidly with each additional week of treatment initially, followed by a slower decline up to about 15 weeks of cART, with substantial differences by baseline viral load. Conclusion:MTCT rates in the UK and Ireland have continued to decline since 2006, reaching an all-time low of 5 per 1000 in 2010–2011. This was primarily because of a reduction in transmissions associated with late initiation or nonreceipt of antenatal cART, and an increase in the proportion of women on cART at conception.

British HIV Association guidelines for the management of HIV infection in pregnant women 2012

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV)-positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection.

Outcomes for human immunodeficiency virus-1-infected infants in the United kingdom and Republic of Ireland in the era of effective antiretroviral therapy.

Background: There are few data about disease progression and response to antiretroviral therapy (ART) in vertically HIV-infected infants in the era of effective therapy. Design: Cohort study. Methods: We examined progression to acquired immunodeficiency syndrome (AIDS) and death over calendar time for infants reported to the National Study of HIV in Pregnancy and Childhood in the United Kingdom/Ireland. The use of ART and CD4 and HIV-1 RNA responses were assessed in a subset in the Collaborative HIV Pediatric Study. Results: Among 481 infants, mortality was lower in those born after 1997 (HR 0.30; P < 0.001), with no significant change in progression to AIDS. Of 174 infants born since 1997 in the Collaborative HIV Pediatric Study, 41 (24%) were followed from birth, 77 (44%) presented pre-AIDS and 56 (32%) presented with AIDS. Of 125 (72%) children on 3- or 4-drug ART by the age of 2 years, 59% had HIV-1 RNA <400 at 12 months; median CD4 percentage increased from 24% to 35%. Among 41 infants followed from birth, 12 progressed to AIDS (5 while ART naive) and 3 died; 1 of 10 infants initiating ART before 3 months of age progressed clinically. Conclusion: Mortality in HIV-infected infants is significantly lower in the era of effective ART, but symptomatic disease rates remain high. Infrequent clinic attendance and poor compliance with cotrimoxazole prophylaxis and/or ART in infants born to diagnosed HIV-infected women and late presentation of infants identified after birth appear to be major contributors. Poor virologic response to ART during infancy is of concern because of increased likelihood of early development of resistance.

Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities

Objectives: To assess use of antiretroviral therapy (ART) by HIV positive pregnant women in London since 1994 and the risk of congenital abnormalities associated with multidrug exposure during the first trimester of pregnancy. Methods: Retrospective multicentre study of medical, obstetric, and paediatric notes of all mother-infant pairs, where the mother was known to be HIV infected before delivery, using a standardised proforma. Results: In this study of 195 mother-infant pairs, use of ART during any stage of pregnancy increased from 33.3% in 1994 to 92.5% in 1999 (p=0.01, trend). First trimester exposure increased from 0% in 1994 to 27.5% in 1999 (p=0.00045, trend). Congenital malformations were observed in nine infants (4.6%). Compared with infants not exposed to ART or folate antagonists during the first trimester (n=148), exposure to both ART and folate antagonists during the first trimester (n=13) was associated with an increased risk of congenital abnormalities (4% v 23.1%; OR 7.10, 95% CI 1.5, 34.2). No malformations were observed in the 34 children exposed to either ART or folate antagonists alone during the first trimester. Conclusion: An increasing number of HIV infected women conceived while on ART. Although there is no evidence of teratogenicity caused by ART if given alone during the first trimester, exposure to the combination of ART and folate antagonists was associated with a significantly higher risk of congenital abnormalities in this cohort.

Rapid development of genotypic resistance to lamivudine when combined with zidovudine in pregnancy

The prevention of mother to child transmission of HIV‐1 by zidovudine monotherapy is well known, but increasingly combination anti‐retroviral therapy is prescribed during pregnancy. In this prospective study, 19 pregnant women with human immunodeficiency virus‐1 (HIV‐1) infection who elected to take anti‐retroviral therapy during the second and third trimesters were treated with zidovudine or zidovudine plus lamivudine. Fourteen women treated with zidovudine monotherapy had a mean 0.3 log10 reduction in viral load and a mean 52 × 106/L (17%) increase in CD4+ lymphocytes at delivery compared with pre‐treatment samples. Genotypic mutations associated with decreased susceptibility to zidovudine were detected in 2 of 10 women at delivery. Five women with more advanced HIV‐1 infection were treated with zidovudine plus lamivudine and a mean 1.5 log10 reduction in viral load together with a mean 30 × 106/L (33%) increase in CD4+ lymphocytes was observed in this group. However, four of five women in the dual therapy arm had the M184V mutation in the reverse transcriptase gene associated with decreased susceptibility to lamivudine at delivery. We conclude that zidovudine plus lamivudine reduced HIV‐1 plasma viraemia to low levels in pregnant women with advanced HIV‐1 disease but the rapid development of genotypic resistance to lamivudine indicates that additional therapy is required both for the long‐term benefit of the mothers and to prevent the development of resistant virus that may be transmitted to the infant. J. Med. Virol. 59:364–368, 1999.

Tenofovir use in human immunodeficiency virus-1-infected children in the United kingdom and Ireland.

Background: Tenofovir disoproxil fumarate (TDF) is neither licensed for use nor extensively studied in HIV-infected children. The only available formulation is an adult tablet, introducing the possibility of dosing errors in children. TDF interacts with other antiretrovirals and has been associated with decline in renal function and CD4 count. We describe the use of TDF in a cohort of HIV-1–infected children in the United Kingdom and Ireland. Methods: Children ever prescribed TDF and followed in the Collaborative HIV Pediatric Study cohort since 2001 were included in analyses of dosing, adverse events, and virologic and immunologic response. Suspected adverse drug reactions to TDF reported to the Medicines and Healthcare products Regulatory Agency during the same time were also reviewed. Results: One hundred fifty-nine of 1253 children had taken TDF. They were older and had clinically more advanced disease than the rest of the cohort. Eighteen percent received >120% and 37% received <80% of the suggested pediatric dose (8 mg/kg). Thirty-seven percent of new TDF regimens contained didanosine (ddI), though few since 2005. Twelve of 159 (7.5%) children experienced serious adverse events and stopped TDF permanently, 11 taking concurrent lopinavir-ritonavir, and 10 ddI; 5 had renal toxicity. Viral load suppressed to ≤50 copies/mL at 12 months in 38% of those starting TDF. Median increase in CD4 count at 12 months was +110 cells/mL (interquartile range, 9–270), but only 3 cells/mL in those taking concurrent ddI. Conclusions: TDF seems to be an effective antiretroviral drug in this pediatric cohort, although considerable underdosing and overdosing occurs. A small number of children experienced serious adverse events while taking TDF; half were renal toxicity, most associated with concurrent ddI and lopinavir-ritonavir use.

British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review)

Emtricitabine/tenofovir/rilpivirine as a single‐tablet regimen (STR) is widely used without licence in treatment‐experienced patients. The purpose of this retrospective observational study was to assess viral suppression of ART‐experienced patients switching to STR.