Claire Thorne

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.

Prevention of mother-to-child transmission of HIV infection.

Purpose of review Mother-to-child transmission of HIV infection is the primary cause of paediatric HIV infections worldwide. Although clinical trials show that antiretroviral therapy, elective caesarean section and formula feeding can significantly reduce the peripartum or postpartum risk of transmission, their application on a population basis is challenging. There is a need for alternative, easier and more effective interventions for population-based programmes. Recent findings This review addresses recent advances in our understanding of mother-to-child transmission risk factors, including maternal viral load (in plasma, genital tract and breast milk) and gender, and determinants and rates of postnatal transmission. New information on prophylactic antiretroviral therapy includes results from randomized trials in Africa and Thailand, in addition to new information on implementation of prevention of mother-to-child transmission programmes in nontrial settings, in both developed and developing countries. Two important issues relating to use of antiretroviral prophylaxis are discussed: safety and toxicity, including new findings on haemopoiesis, prematurity and mitochondrial abnormalities in antiretroviral therapy-exposed infants and children, and resistance. Recent trends and controversies relating to mode of delivery in HIV-infected pregnant women are outlined. Regarding infant feeding, preliminary results on use of mono-antiretroviral therapy to prevent postnatal transmission in breastfeeding HIV-exposed infants are discussed. Summary In resource-rich settings, virtual elimination of mother-to-child transmission is theoretically possible. Even in these settings, however, a substantial number of infected women are not being identified early enough for optimum application of prevention of mother-to-child transmission interventions. In developing country settings, focus is being directed towards scaling-up prevention programmes now that trials have established a variety of effective antiretroviral prophylactic approaches.

Safety of Agents Used to Prevent Mother-to-Child Transmission of HIV Is There Any Cause for Concern?

Antiretroviral drugs have been used routinely to reduce the risk of mother-to-child transmission of HIV infection since 1994, following the AIDS Clinical Trials Group 076 trial, which demonstrated the efficacy of zidovudine in reducing the risk of in utero and intrapartum transmission. The use of antiretroviral drugs in pregnancy varies geographically, with widespread use of highly active antiretroviral therapy (HAART) in resource-rich settings for delaying maternal HIV disease progression as well as the prevention of mother-to-child transmission; however, in low- and middle-income settings, abbreviated prophylactic regimens focus on the perinatal period, with very limited access to HAART to date.The potential risks associated with antiretroviral exposure for pregnant women, fetuses and infants depend on the duration of this exposure as well as the number and type of drugs. As the benefits of HAART regimens in reducing the risk of mother-to-child transmission and in delaying disease progression are so great, their widespread use has been accepted, despite the relative lack of safety data from human pregnancies.Animal studies have suggested an increased risk of malformations associated with exposure to specific antiretroviral drugs, although evidence to support this from human studies is limited. Trials, cohorts and surveillance studies have shown no evidence of an increased risk of congenital malformations associated with in utero exposure to zidovudine, or other commonly used antiretroviral drugs, with an estimated 2–3% prevalence of birth defects (i.e. similar to that seen in the general population). Exposure to prophylactic zidovudine for prevention of mother-to-child transmission is associated with a usually mild and reversible, but rarely severe, anaemia in infants. However, a medium-term impact on haematological parameters of antiretroviral-exposed infants has been reported, with small but persistent reductions in levels of neutrophils, platelets and lymphocytes in children up to 8 years of age; the clinical significance of this remains uncertain. To date, there is no evidence to suggest that exposure to antiretroviral drugs in utero or neonatally is associated with an increased risk of childhood cancer, but the potential for mutagenic and carcinogenic effects at older ages cannot be excluded. Nucleoside analogue-related mitochondrial toxicity is well recognised from studies in non-pregnant individuals, whilst animal studies have provided evidence of mitochondrial toxicity resulting from in utero antiretroviral exposure. Clinically evident mitochondrial disease in children with antiretroviral exposure has only been described in Europe, with an estimated 18-month incidence of ‘established’ mitochondrial dysfunction of 0.26% among exposed children.Regarding pregnancy-related adverse effects, increased risks of prematurity, pre-eclampsia and gestational diabetes mellitus have been reported by a variety of observational studies with varying strengths of evidence and with conflicting results. Based on current knowledge, the immense benefits of antiretroviral prophylaxis in prevention of mother-to-child transmission far outweigh the potential for adverse effects. However, these potential adverse effects require further and longer term monitoring because they are likely to be rare and to occur later in childhood.

Maternal and infant factors and lymphocyte, CD4 and CD8 cell counts in uninfected children of HIV-1-infected mothers.

Objective:To evaluate the effects of antiretroviral treatment (ART) for mother-to-child transmission of HIV and infant/maternal characteristics on total lymphocytes (TLC) and lymphocyte subsets in uninfected children of HIV-1-infected mothers. Design:The European Collaborative Study followed 1663 uninfected children from birth until at least 8 years of age using a standard protocol. Methods:Smoothers (running medians) illustrated patterns of immune markers over age by ART exposure and race. Associations between lymphocyte parameters and maternal/infant characteristics were quantified in linear regression analyses using z-scores obtained after modelling log10-transformed TLC, CD4 and CD8 cell counts using the LMS method. Cox proportional hazard models assessed time to TLC, CD4 and CD8 cell counts below the defined cut-off. Covariates included prematurity, gender, race, drug withdrawal and ART exposure. Results:Overall, black children had lower TLC, CD4 and CD8 cell counts than white children, and an increased risk of TLC, CD4 and CD8 cell counts below the cut-off. ART exposure was associated with TLC levels (but not with TLC below the cut-off for lymphopenia), with reduced CD4 cell counts in the first year of life, and with reduced CD8 cell counts until at least 8 years of age. Duration and intensity of ART exposure was associated with TLC levels. Conclusion:The effect of ART exposure in fetal and early life on TLC and CD8 cell counts was prolonged until at least 8 years. These results add to the growing list of adverse effects associated with ART used as prevention of mother-to-child transmission of HIV.

Mode of delivery in HIV-infected pregnant women and prevention of mother-to-child transmission: changing practices in Western Europe.

The aim of the study was to examine temporal and geographical patterns of mode of delivery in the European Collaborative Study (ECS), identify factors associated with elective caesarean section (CS) delivery in the highly active antiretroviral therapy (HAART) era and explore associations between mode of delivery and mother‐to‐child transmission (MTCT).

Disease Progression in Children with Vertically-Acquired HIV Infection in Sub-Saharan Africa: Reviewing the Need for HIV Treatment

Approximately 700,000 children become newly infected with HIV annually, mainly through mother-to-child transmission (MTCT), making paediatric HIV a leading cause of morbidity and mortality worldwide. The substantial interest in preventing MTCT (PMTCT) has generated information on rates of transmission and associated factors, but there is a lack of information on disease progression and mortality in vertically-infected children, especially from resource-poor settings. Peer-review journals with titles or abstracts containing reference to the reviews themes were selected using widely available search engines. We review relevant literature on mortality in children born to HIV infected mothers; morbidity and mortality associated with paediatric HIV infections; eligibility to and efficacy of antiretroviral therapy (ART). Child mortality is independently associated with maternal HIV status and maternal death, with paediatric infection resulting in approximately 4 fold increase in mortality by age 2 years. Morbidities seen in infected children were similar to those seen in uninfected children, although the rates and recurrences of illness were greater. There is some evidence that progression to AIDS may be more rapid in resource poor settings, although data on this are very limited. PMTCT and paediatric ART have been shown to be highly successful in resource-limited settings, but are not universally applied. Further efforts to increase coverage of both PMTCT and paediatric ART could substantially reduce the numbers of children becoming infected and improve survival of those infected. Additionally, improvements in health infrastructures could improve care provision, not only through improved detection and monitoring but also through treatment of co-morbidities and nutritional support.

Older children and adolescents surviving with vertically acquired HIV infection

Summary: This article describes the characteristics of children infected vertically with HIV surviving 10 years or more who were enrolled in the prospective European Collaborative Study. Thirty‐four of 187 infected children were identified with a median age of 11.4 years (range, 10.1‐15.9 years). Factors examined included clinical status, immunologic and virologic characteristics, type of antiretroviral therapy, and psychosocial characteristics. By 10 years of age, 6 (18%) children had progressed to Class A as determined by the system of the U.S. Centers for Disease Control and Prevention (CDC), 17 (52%) to class B, 7 (21%) to class C, and 3 (9%) had remained asymptomatic. At 73% (904 of 1234) of scheduled clinic visits, these children had no symptoms of HIV disease. Most children were in CDC immune categories 1(18, 56%) or 2 (11, 34%) at their last visit. Three quarters (24 patients) were on combination therapy with three or more drugs, although 3 children had never received any antiretroviral therapy. Nineteen (56%) children were living with at least 1 parent and the mothers of 13 (38%) children had died. Most (77%) children had been told about their HIV infection. Children infected vertically with HIV who have survived their first 10 years are mainly free of serious symptoms. As they enter adolescence, additional services are needed including support with disclosure to others, therapy, and sexual health.

Maternal HIV infection associated with small-for-gestational age infants but not preterm births: evidence from rural South Africa

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS Maternal HIV infection increases the risk of SGA, but not preterm births, in this cohort.

Vertically acquired paediatric coinfection with HIV and hepatitis C virus

Both HIV and hepatitis C virus (HCV) can be transmitted from mother to child during pregnancy and delivery. Vertical transmission of HIV and HCV separately is most likely from HIV/HCV-coinfected mothers; however, transmission of both infections is less frequent. The effect of HCV coinfection on HIV-related disease remains unclear; whereas most studies indicate no effect, recent results suggest HCV in adults accelerates HIV progression. Little is known about how HIV coinfection affects HCV progression in children and the information available is based on small numbers of patients. Paediatric HIV treatment is extremely successful and it is vital to determine if HCV coinfection alters the effectiveness of this treatment. The hepatotoxicity of many HIV therapies and the possible negative impact of HCV on this treatment, alongside the interactions and contraindications of many HIV and HCV therapies, further limits the choice of paediatric treatments for coinfected children. Future research must therefore focus on vertically acquired HIV/HCV coinfection to inform treatment trials addressing coinfection management.

Tuberculosis and HIV co-infection in children

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.ConclusionData 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.