Antiretroviral therapy-associated modulation of Th1 and Th2 immune responses in HIV-infected pregnant women.
ABSTRACT A successful pregnancy is characterised by an increase in Th2 cytokines and suppression of Th1 cytokine production. A Th1 to Th2 cytokine shift is also observed in the disease progression of HIV infection. Highly active antiretroviral therapy (HAART) suppresses HIV viremia, increases CD4+ cell counts and counteracts the Th1 to Th2 shift. We hypothesised that the increased risk of premature delivery reported in HIV-infected, HAART-treated pregnant women is mediated through changes in the cytokine environment in pregnancy. Here, we present results relating to levels of interleukin (IL)-2 (Th1) and IL-10 (Th2) in peripheral blood mononuclear cells (PBMCs) measured three times during pregnancy in 49 HIV-infected women. Slope values representing the trend of repeated cytokine (IL-2-PHA, IL-2-Env, IL-10-PHA and IL-10-Env) measurements within women during pregnancy were estimated and median values compared by prematurity and HAART use. Multiple regression adjusted for HAART and cytokine slope clarified the additional and independent effect of HAART on prematurity risk. Results showed favourable immunomodulation induced by HAART with increased IL-2 and decreased IL-10. HAART use and IL-10-Env slopes were not significantly associated with prematurity risk, but each unit increase in IL-2-PHA slope was associated with an 8% increased risk of premature delivery (AOR, 1.08; 95% CI, 1.0-1.17; p=0.005). HAART use in pregnancy provides significant benefits in delaying HIV disease progression and reducing the risk of mother-to-child-transmission, but may be counterproductive in terms of successful pregnancy outcome.
Article: Authors?? reply, Kourtis et alAIDS 01/2007; 21(12):1657-1658. DOI:10.1097/QAD.0b013e32826fb763 · 6.56 Impact Factor
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ABSTRACT: 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.Drug Safety 02/2007; 30(3):203-13. DOI:10.2165/00002018-200730030-00004 · 2.62 Impact Factor
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ABSTRACT: To explore the association between antiretroviral therapy in pregnancy and premature delivery, birthweight, stillbirth and neonatal mortality, in pregnancies in HIV-infected women delivering between 1990 and 2005. Pregnancies in women with diagnosed HIV infection in the UK and Ireland are notified to the National Study of HIV in Pregnancy and Childhood (NSHPC) through a well-established surveillance scheme. The prematurity rate (< 37 weeks gestation) was higher in women on highly active antiretroviral therapy (HAART) (14.1%, 476/3384) than in women on mono/dual therapy (10.1%, 107/1061), even after adjusting for ethnicity, maternal age, clinical status and injecting drug use as the source of HIV acquisition [adjusted odds ratio (AOR) = 1.51, 95% confidence interval (CI), 1.19-1.93; P = 0.001]. Delivery at < 35 weeks was even more strongly associated with HAART (AOR = 2.34; 95% CI, 1.64-3.37; P < 0.001). The effect was the same whether or not HAART included a protease inhibitor. In comparison with exposure to mono/dual therapy, exposure to HAART was associated with lower birthweight standardized for gestational age (P < 0.001), and an increased risk of stillbirth (AOR = 2.27; 95% CI, 0.96-5.41; P = 0.063). These findings, based on comprehensive population surveillance, demonstrate an increased risk of prematurity associated with HAART, and a possible association with other perinatal outcomes, including stillbirth and birthweight. Although the beneficial effects of antiretroviral therapy on mother-to-child transmission are indisputable, monitoring antiretroviral therapy in pregnancy remains a priority.AIDS 05/2007; 21(8):1019-26. DOI:10.1097/QAD.0b013e328133884b · 6.56 Impact Factor