Malaria remains one of the leading health problems of the developing world, and Uganda bears a particularly large burden from the disease. Our understanding is limited by a lack of reliable data, but it is clear that the prevalence of malaria infection, incidence of disease, and mortality from severe malaria all remain very high. Uganda has made progress in implementing key malaria control measures, in particular distribution of insecticide impregnated bednets, indoor residual spraying of insecticides, utilization of artemisinin-based combination therapy to treat uncomplicated malaria, and provision of intermittent preventive therapy for pregnant women. However, despite enthusiasm regarding the potential for the elimination of malaria in other areas, there is no convincing evidence that the burden of malaria has decreased in Uganda in recent years. Major challenges to malaria control in Uganda include very high malaria transmission intensity, inadequate health care resources, a weak health system, inadequate understanding of malaria epidemiology and the impact of control interventions, increasing resistance of parasites to drugs and of mosquitoes to insecticides, inappropriate case management, inadequate utilization of drugs to prevent malaria, and inadequate epidemic preparedness and response. Despite these challenges, prospects for the control of malaria have improved, and with attention to underlying challenges, progress toward the control of malaria in Uganda can be expected.
Malaria; Plasmodium; Uganda; Insecticide-treated nets; Indoor residual spraying; Artemisinin-based combination therapy; Intermittent preventive therapy
In the recent past there have been several reports of successes in malaria control, leading some public health experts to conclude that Africa is witnessing an epidemiological transition, from an era of failed malaria control to progression from successful control to elimination. Successes in control have been attributed to increased international donor support leading to increased intervention coverage. However, these changes are not uniform across Africa. In Uganda, where baseline transmission is very high and intervention coverage not yet to scale, the malaria burden is not declining and has even likely increased in the last decade. In this article we present perspectives for the future for Uganda and other malaria endemic countries with high baseline transmission intensity and significant health system challenges. For these high burden areas,malaria elimination is currently not feasible, and early elimination programs are inappropriate, as they would further fragment already fragmented and inefficient malaria control systems. Rather, health impacts will be maximized by aiming to achieve universal coverage of proven interventions in the context of a strengthened health system.
Malaria; Plasmodium; Uganda; Insecticide-treated nets; Indoor residual spraying; Artemisinin-based combination therapy; Intermittent preventive therapy; health systems
Biliary atresia (BA) is characterized by progressive inflammation and fibrosis of bile ducts. A theory of pathogenesis entails autoimmune-mediated injury targeting bile duct epithelia. One of the strongest genetic associations with autoimmunity is with HLA genes. In addition, apparently dissimilar HLA alleles may have similar antigen-binding sites, called shared epitopes, that overlap in their capacity to present antigens. In autoimmune disease, the incidence of the disease may be related to the presence of shared epitopes, not simply the HLA allelic association. Aim: To determine HLA allele frequency (high-resolution genotyping) and shared epitope associations in BA. Results: Analysis of every allele for HLA-A, -B, -C, -DRB1, -DPB1 and -DQB1 in 180 BA and 360 racially-matched controls did not identify any significant HLA association with BA. Furthermore, shared epitope analysis of greater than 10 million possible combinations of peptide sequences was not different between BA and controls. Conclusions: This study encompasses the largest HLA allele frequency analysis for BA in the United States and is the first study to perform shared epitope analysis. When controlling for multiple comparisons, no HLA allele or shared epitope association was identified in BA. Future studies of genetic links to BA that involve alterations of the immune response should include investigations into defects in regulatory T cells and non-HLA linked autoinflammatory diseases.
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The online version of this article (doi:10.1186/2193-1801-2-42) contains supplementary material, which is available to authorized users.
HIV infection affects the clinical pattern of malaria. There is emerging evidence to suggest that previously documented interactions may be modified by recently scaled-up HIV and malaria interventions. Prophylaxis with trimethoprim–sulfamethoxazole (TS) in combination with use of insecticide-treated nets can markedly decrease the incidence of malaria in HIV-infected pregnant and nonpregnant adults and children even in the setting of antifolate resistance-conferring mutations that are currently common in Africa. Nonetheless, additional interventions are needed to protect HIV-infected people that reside in high-malaria-transmission areas. Artemether–lumefantrine and dihydroartemisinin–piperaquine are highly efficacious and safe for the treatment of uncomplicated malaria in HIV-infected persons. Coadministration of antiretroviral and antimalarial drugs creates the potential for pharmacokinetic drug interactions that may increase (causing enhancement of malaria treatment efficacy and post-treatment prophylaxis and/or unanticipated toxicity) or reduce (creating risk for treatment failure) antimalarial drug exposure. Further studies are needed to elucidate potentially important pharmacokinetic interactions between commonly used antimalarials, antiretrovirals and TS and their clinical implications. Data on the benefits of long-term TS prophylaxis among HIV patients on antiretroviral therapy who have achieved immune-reconstitution are limited. Studies to address these questions are ongoing or planned, and the results should provide the evidence base required to guide the prevention and treatment of malaria in HIV-infected patients.
antimalarial treatment; antiretroviral therapy; HIV infection; malaria; malaria prevention
The burden of malaria has decreased in parts of Africa following the scaling up of control interventions. However, similar data are limited from high transmission settings.
A cohort of 100 children, aged six weeks to 10 months of age, were enrolled in an area of high malaria transmission intensity and followed through 48 months of age. Children were given a long-lasting insecticide-treated bed net (LLIN) at enrolment and received all care, including monthly blood smears and treatment with artemisinin-based combination therapy (ACT) for uncomplicated malaria, at a dedicated clinic. The incidence of malaria was estimated by passive surveillance and associations between malaria incidence and age, calendar time and season were measured using generalized estimating equations.
Reported compliance with LLINs was 98% based on monthly routine evaluations. A total of 1,633 episodes of malaria were observed, with a median incidence of 5.3 per person-year (PPY). There were only six cases of complicated malaria, all single convulsions. Malaria incidence peaked at 6.5 PPY at 23 months of age before declining to 3.5 PPY at 48 months. After adjusting for age and season, the risk of malaria increased by 52% from 2008 to 2011 (RR 1.52, 95% CI 1.10-2.09). Asymptomatic parasitaemia was uncommon (monthly prevalence <10%) and rarely observed prior to 24 months of age.
In Tororo, despite provision of LLINs and prompt treatment with ACT, the incidence of malaria is very high and appears to be rising. Additional malaria control interventions in high transmission settings are likely needed.
Current Controlled Trials Identifier NCT00527800
Malaria; Plasmodium falciparum; Immunity; Epidemiology
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children in the United States. Although changes in diet are often recommended to improve NAFLD, little is known regarding diet influence on histologic features of the disease.
This was a prospective, cross-sectional registry based study. Children (n=149) enrolled in the multi-center NASH Clinical Research Network had demographic, anthropometric, clinical, laboratory and histology data obtained, including the Block Brief Food Questionnaire. Subjects were grouped by presence or absence of steatohepatitis and grades of histologic features according to NASH-CRN criteria.
No significant differences were found between children with steatosis compared to steatohepatitis for fraction of calories from fat, carbohydrates, and protein. Sugar sweetened beverage consumption was low and did not correlate with histologic features, although uric acid, a surrogate marker for fructose intake, was significantly increased in those with definite NASH (p=.008). For all groups, vitamin E consumption was insufficient compared to the recommended daily allowance. Median consumption of vitamin E was lower in children with higher grade of steatosis (8.4 vs 6.1 vs 6.9 for grade I, II and III respectively, p = .05). Those consuming less vitamin C had increased ballooning degeneration (p = 0.05).
Children with NAFLD have a diet that is insufficient in vitamin E and this may contribute to the pathophysiology of NAFLD. In children with NAFLD, reported sugar sweetened beverage consumption is low; however uric acid, which may reflect total fructose consumption, was significantly associated with NASH and should be further evaluated.
NASH; Nutrition; Vitamin C; Sugar Sweetened Beverages
Antibodies are important in the control of blood stage Plasmodium falciparum infection. It is unclear which antibody responses are responsible for, or even associated with protection, partly due to confounding by heterogeneous exposure. Assessment of response to partially effective antimalarial therapy, which requires the host to assist in clearing parasites, offers an opportunity to measure protection independent of exposure.
A cohort of children aged 1–10 years in Kampala, Uganda were treated with amodiaquine+sulfadoxine-pyrimethamine for uncomplicated malaria. Serum samples from the time of malaria diagnosis and 14 days later were analyzed for total IgG to 8 P. falciparum antigens using a quantitative indirect ELISA. Associations between antibody levels and risk of treatment failure were estimated using Cox proportional hazard regression.
Higher levels of antibodies to apical membrane antigen 1 (AMA-1), but to none of the other 7 antigens were significantly associated with protection against treatment failure (HR 0.57 per 10-fold increase in antibody level, CI 0.41–0.79, p = 0.001). Protection increased consistently across the entire range of antibody levels.
Measurement of antibody levels to AMA-1 at the time of malaria may offer a quantitative biomarker of blood stage immunity to P. falciparum, a tool which is currently lacking.
Discovering new lead compounds against malaria parasites is a crucial step to ensuring a sustainable global pipeline for effective anti-malarial drugs. As far as we know, no previous phytochemical or pharmacological investigations have been carried out on Sorindeia juglandifolia. This paper describes the results of an anti-malarial activity-driven investigation of the fruits of this Cameroonian plant.
Air-dried fruits were extracted by maceration using methanol. The extract was fractionated by flash chromatography followed by column chromatography over silica gel, eluting with gradients of hexane-ethyl acetate mixtures. Resulting fractions and compounds were tested in vitro against the Plasmodium falciparum chloroquine-resistant strain W2, against field isolates of P. falciparum, and against the P. falciparum recombinant cysteine protease falcipain-2. Promising fractions were assessed for acute toxicity after oral administration in mice. One of the promising isolated compounds was assessed in vivo against the rodent malaria parasite Plasmodium berghei.
The main end-products of the activity-guided fractionation were 2,3,6-trihydroxy benzoic acid (1) and 2,3,6-trihydroxy methyl benzoate (2). Overall, nine fractions tested against P. falciparum W2 and falcipain-2 were active, with IC50 values of 2.3-11.6 μg/ml for W2, and 1.1-21.9 μg/ml for falcipain-2. Purified compounds (1) and (2) also showed inhibitory effects against P. falciparum W2 (IC50s 16.5 μM and 13.0 μM) and falcipain-2 (IC50s 35.4 and 6.1 μM). In studies of P. falciparum isolates from Cameroon, the plant fractions demonstrated IC50 values of 0.14-19.4 μg/ml and compounds (1) and (2) values of 6.3 and 36.1 μM. In vivo assessment of compound (1) showed activity against P. berghei strain B, with mean parasitaemia suppressive dose and curative dose of 44.9 mg/kg and 42.2 mg/kg, respectively. Active fractions were found to be safe in mice after oral administration of 7 g/kg body weight.
Fractions of Sorindeia juglandifolia and two compounds isolated from these fractions were active against cultured malaria parasites, the P. falciparum protease falcipain-2, and in a rodent malaria model. These results suggest that further investigation of the anti-malarial activities of natural products from S. juglandifolia will be appropriate.
Malaria; Drug discovery; Sorindeia juglandifolia; Plasmodium falciparum; Plasmodium berghei
We compared the prevalence of key pfmdr1 alleles between pretreatment Plasmodium falciparum parasite isolates and parasites that emerged after treatment of uncomplicated malaria in a longitudinal cohort of Ugandan children. The pfmdr1 86N, 184F, and 1246D alleles were selected after treatment with artemether-lumefantrine, but not after artesunate-amodiaquine or amodiaquine-sulfadoxine-pyrimethamine. Remarkably, selection persisted in infections presenting up to about 60 days after treatment with artemether-lumefantrine. Thus, parasites selected for decreased drug sensitivity can appear long after predicted exposure to antimalarial drugs. Continued surveillance of the clinical efficacy and in vitro activity of new combination therapies is warranted.
Novel conjugates of the antimalarial drug primaquine (compound 1) with ferrocene, named primacenes, have been synthesized and screened for their activities against blood stage and liver stage malaria in vitro and host-vector transmission in vivo. Both transmission-blocking and blood-schizontocidal activities of the parent drug were conserved only in primacenes bearing a basic aliphatic amine group. Liver stage activity did not require this structural feature, and all metallocenes tested were comparable to or better than primaquine in this regard. Remarkably, the replacement of primaquine's aliphatic chain by hexylferrocene, as in compound 7, led to a ∼45-fold-higher level activity against liver stage parasitemia than that of primaquine.
Progressive familial intrahepatic cholestasis, type 2 (PFIC2), characterized by cholestasis in infancy that may progress to cirrhosis, is caused by mutation in ABCB11, which encodes bile salt export pump (BSEP). We correlated histopathologic, immunohistochemical, and ultrastructural features in PFIC2 with specific mutations and clinical course. Twelve patients with clinical PFIC2 and ABCB11 mutations were identified, and 22 liver biopsy and explant specimens were assessed. All had hepatocellular cholestasis; most had canalicular bile plugs. At least 1 specimen from every patient had centrizonal/sinusoidal fibrosis, often with periportal fibrosis. Neonatal hepatitis-like features (inflammation, giant cells, necrosis) varied. In 2 of the 5 patients with paired specimens obtained > 6 months apart, lobular and portal fibrosis worsened. Transmission electron microscopy (EM) in all 9 patients studied showed canalicular dilatation, microvilli loss, abnormal mitochondrial internal structure, and varying intra-canalicular accumulation of finely granular bile. Canalicular staining for BSEP was absent in 10 patients and present in 2 patients, 1 of whom had intermittent symptoms. ABCB11 sequencing of all patients identified 6 novel and 10 previously described mutations, with nonsense, missense, and/or noncoding mutations in the 10 patients without immunohistochemically demonstrable BSEP. Missense and/or noncoding mutations were identified in the 2 patients with demonstrable BSEP, whose clinical course was more indolent. Mutations ending ABCB11 transcription appear linked, through hepatocellular necrosis and fibrosis, to worse outcome. In conclusion, light microscopy and electron microscopy findings in clinical PFIC2 can support diagnosis, but are variable and nonspecific. Therefore, no correlation between specific mutations and histopathology is yet possible.
PFIC2; progressive familial intrahepatic cholestasis; bile salt export pump; BSEP; ABCB11; neonatal hepatitis
(See the article by Bejon et al, on pages 9–18, and Bousema et al, on pages 1–3.)
Background. Associations between antibody responses to Plasmodium falciparum antigens and protection against symptomatic malaria have been difficult to ascertain, in part because antibodies are potential markers of both exposure to P. falciparum and protection against disease.
Methods. We measured IgG responses to P. falciparum circumsporozoite protein, liver-stage antigen 1, apical-membrane antigen 1 (AMA-1), and merozoite surface proteins (MSP) 1 and 3, in children in Kampala, Uganda, and measured incidence of malaria before and after antibody measurement.
Results. Stronger responses to all 5 antigens were associated with an increased risk of clinical malaria (P < .01) because of confounding with prior exposure to P. falciparum. However, with use of another assessment, risk of clinical malaria once parasitemic, stronger responses to AMA-1, MSP-1, and MSP-3 were associated with protection (odds ratios, 0.34, 0.36, and 0.31, respectively, per 10-fold increase; P < .01). Analyses assessing antibodies in combination suggested that any protective effect of antibodies was overestimated by associations between individual responses and protection.
Conclusions. Using the risk of symptomatic malaria once parasitemic as an outcome may improve detection of associations between immune responses and protection from disease. Immunoepidemiology studies designed to detect mechanisms of immune protection should integrate prior exposure into the analysis and evaluate multiple immune responses.
Analogs of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogs, particularly at low pH; they retained acceptable predicted permeability properties, but were predicted to be susceptible to hepatic metabolism. These analogs were synthesized and found to exhibit notable in vitro antimalarial activity. Compounds 25 and 27 were the most active of the analogs. In vitro metabolism studies indicated susceptibility of the analogs to hepatic metabolism. There was also evidence of primary glucuronidation for analogs 24 – 27. Presumed cis - trans isomerism of 12, 22 and 23 under in vitro metabolism assay conditions was also observed, with differences in the nature and rates of metabolism observed between isomers. Biochemical studies strongly suggested that inhibition of hemozoin formation is the primary mechanism of action of these analogs.
The malaria burden remains a major public health concern, especially in sub-Saharan Africa. The complex biology of Plasmodium, the apicomplexan parasite responsible for this disease, challenges efforts to develop new strategies to control the disease. Proteolysis is a fundamental process in the metabolism of malaria parasites, but roles for proteases in generating vasoactive peptides have not previously been explored.
In the present work, it was demonstrated by mass spectrometry analysis that Plasmodium parasites (Plasmodium chabaudi and Plasmodium falciparum) internalize and process plasma kininogen, thereby releasing vasoactive kinins (Lys-BK, BK and des-Arg9-BK) that may mediate haemodynamic alterations during acute malaria. In addition, it was demonstrated that the P. falciparum cysteine proteases falcipain-2 and falcipain-3 generated kinins after incubation with human kininogen, suggesting that these enzymes have an important role in this process. The biologic activity of peptides released by Plasmodium parasites was observed by measuring ileum contraction and activation of kinin receptors (B1 and B2) in HUVEC cells; the peptides elicited an increase in intracellular calcium, measured by Fluo-3 AM fluorescence. This effect was suppressed by the specific receptor antagonists Des-Arg9[Leu8]-BK and HOE-140.
In previously undescribed means of modulating host physiology, it was demonstrated that malaria parasites can generate active kinins by proteolysis of plasma kininogen.
The aim of this study was to prospectively assess the quality of life (QOL), behavioral/emotional functioning, and cognitive status of children undergoing treatment for hepatitis C virus (HCV) infection. One hundred fourteen children (5 to 18 years old) enrolled in a multi-site randomized clinical trial (Peds-C) to evaluate peginterferon alpha 2a (PEG 2a) with ribavirin (RV) or with placebo (PL) completed several standardized measures prior to treatment and at 24 weeks, 48 weeks, 6 months following treatment, and at two annual follow-up visits. After 24 weeks of treatment, mean physical QOL scores declined significantly for both groups from baseline to 24 weeks of treatment (F = 5.8, p = 0.004), although scores remained in the average range. There were no significant time or group effects for behavioral/emotional or cognitive functioning. Three children (5%) in the PEG 2a + RV group and no children in the PEG 2a + PL group had a clinically significant increase in depression symptoms. For those children who received 48 weeks of treatment, there were no significant time or group effects on any of the outcome measures (p's > 0.05). A majority of children in both the PEG 2a + RV and PEG 2a + PL groups experienced no clinically significant change in physical QOL, behavioral adjustment, depression, or cognitive functioning during or after treatment.
Overall QOL and psychosocial functioning are not deleteriously impacted by PEG 2a + RV or PL treatment of children with HCV.
pediatrics; HCV; parents; clinical trial; quality of life
Malaria and HIV infection are both very common in many developing countries. With the increasing availability of therapy for HIV infection, it was of interest to determine whether antiretroviral drugs exert antimalarial effects. We therefore tested the in vitro activity of 19 antiretroviral drugs against the W2 and 3D7 strains of Plasmodium falciparum at concentrations up to 50 μM. None of 5 tested nucleoside reverse transcriptase inhibitors demonstrated activity. Two nonnucleoside reverse transcriptase inhibitors, efavirenz (mean 50% inhibitory concentration [IC50] of 22 to 30 μM against the two strains) and etravirine (3.1 to 3.4 μM), were active; nevirapine was not active. Also active were the fusion inhibitor enfuvirtide (6.2 to 7.9 μM) and the entry inhibitor maraviroc (15 to 21 μM). Raltegravir was not active. However, for all active drugs mentioned above, the IC50s were considerably greater than the concentrations achieved with standard dosing. The effects most likely to be clinically relevant were with HIV protease inhibitors. Of the tested compounds, activity was seen with lopinavir (2.7 to 2.9 μM), atazanavir (3.3 to 13.0 μM), saquinavir (5.0 to 12.1 μM), nelfinavir (6.5 to 12.1 μM), ritonavir (9.5 to 10.9 μM), tipranavir (15.5 to 22.3 μM), and amprenavir (28.1 to 40.8) but not darunavir. Lopinavir was active at levels well below those achieved with standard dosing of coformulated lopinavir-ritonavir. Lopinavir also demonstrated modest synergy with the antimalarial lumefantrine (mean fractional inhibitory concentration index of 0.66 for W2 and 0.53 for 3D7). Prior data showed that lopinavir-ritonavir also extends the pharmacokinetic exposure of lumefantrine. Thus, when used to treat HIV infection, lopinavir-ritonavir may have clinically relevant antimalarial activity and also enhance the activity of antimalarials.
It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The “magic bullet” thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC50], ∼10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.
To examine the clinical significance of elevated conjugated bilirubin (CB) levels in newborns.
This retrospective study evaluated a birth cohort of 271,186 full-term newborns born within a Northern California hospital network from 1995–2004. All CB and direct bilirubin (DB) levels were available in a database and were correlated with the patients’ in and out patient ICD-9 diagnoses.
The 99th percentile for CB is 0.5 mg/dL, and the 99th percentile for DB is 2.1 mg/dL. CB levels between 0.5–1.9 mg/dL can be associated with infection, but most often remain unexplained. Liver and biliary disease become increasingly likely as CB levels increase, for CB ≥5 mg/dL 47% have biliary disease and 43% have liver disease.
CB and DB levels are not interchangeable. In newborns with CB levels ≥0.5 mg/dL and <2 mg/dL, infection must be ruled out and the newborn should be followed. In newborns with levels ≥2 mg/dL, a more in-depth assessment of the hepatobiliary system is indicated.
conjugated bilirubin; epidemiology; newborn; cholestasis; diagnostic test
We conducted a study among pediatric renal (RTRs) and liver transplant recipients (LTRs) to determine: a) the overall burden of oral disease; and b) the frequency with which this population utilizes dental care services in relation to sociodemographic factors and oral disease burden.
In this cross-sectional survey, study procedures included the completion of a standardized questionnaire (by parents/guardians), oral mucosal examination, assessment of caries, gingival enlargement, and plaque index.
The 142 children (82 RTRs and 60 LTRs) enrolled from April 2002 to November 2005 were predominantly Latino (41 percent) and Caucasian (34 percent). Forty-three percent had at least one carious surface (in either a deciduous or permanent tooth), 19 percent had five or more carious surfaces, and 25 percent had gingival enlargement. We found only one case of oral candidiasis. Even though 72 percent of parents/guardians reported their child had a regular source of dental care, only 49 percent had a dental cleaning and 44 percent had dental radiographs in the past year, reflecting a low prevalence of preventive dental care. Among children with no regular source of dental care, there were statistically significantly higher proportions of Latinos, younger children, and families with an annual household income <$35,000.
While the prevalence of oral mucosal disease and gingival enlargement was low, the prevalence of children with caries was high, and there was low use of preventive dental care. Strategies to improve this population's utilization of preventive dental care are needed.
organ transplantation; pediatric dentistry; caries; dental care utilization
Portal hypertension can be caused by a wide variety of conditions. It frequently presents with bleeding from esophageal varices. The approach to acute variceal hemorrhage in children is a stepwise progression from least invasive to most invasive. Management of acute variceal bleeding is straightforward. But data on primary prophylaxis and long term management prevention of recurrent variceal bleeding in children is scarce, therefore prospective multicenter trials are needed to establish best practices.
Portal hypertension; Variceal hemorrhage; Children
Intrahepatic cholestasis of pregnancy (ICP) has important fetal implications. There is increased risk for poor fetal outcomes, including preterm delivery, meconium staining of amniotic fluid, respiratory distress, fetal distress and demise.
One hundred and one women diagnosed with ICP between January 2005 and March 2009 at San Francisco General Hospital were included in this study. Single predictor logistic regression models were used to assess the associations of maternal clinical and biochemical predictors with fetal complications. Clinical predictors analyzed included age, race/ethnicity, gravidity, parity, history of liver or biliary disease, history of ICP in previous pregnancies, and induction. Biochemical predictors analyzed included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total protein, and total bile acids (TBA).
The prevalence of ICP was 1.9%. Most were Latina (90%). Labor was induced in the majority (87%) and most were delivered by normal spontaneous vaginal delivery (84%). Fetal complications occurred in 33% of the deliveries, with respiratory distress accounting for the majority of complications. There were no statistically significant clinical or biochemical predictors associated with an increased risk of fetal complications. Elevated TBA had little association with fetal complications until reaching greater than 100 µmoL/L, with 3 out of 5 having reported complications. ICP in previous pregnancies was associated with decreased risk of fetal complications (OR 0.21, p = 0.046). There were no cases of late term fetal demise.
Maternal clinical and laboratory features, including elevated TBA, did not appear to be substantial predictors of fetal complications in ICP.
Background & Aims
Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized, controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5–17 years old with chronic hepatitis C.
HCV RNA-positive children from 11 university medical centers were randomly groups assigned to receive either the combination of peginterferon alfa-2a (PEG 2a; 180 μg/1.73 m2 body surface area, subcutaneously each week; n=59) and ribavirin (15 mg per kilogram orally in 2 doses daily) or PEG2a and placebo for 48 weeks (n=55). The primary endpoint was sustained virologic response (SVR, lack of detectable HCV RNA at least 24 weeks after stopping therapy).
An SVR was achieved in 53% of children treated with PEG 2a and ribavirin, compared with 21% of children who received PEG 2a and placebo (P<0.001). Early virologic response (> 2 log10 IU reduction in HCV RNA at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year-2 follow-up visit; the durability of virologic response was 100% in both groups.
The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.
antiviral therapy; pediatric liver disease; multi-center pediatric trial
Without virologic testing, HIV-infected African children starting antiretroviral (ARV)-therapy are at risk for undetected virological failure and the development of ARV-resistance. We sought to determine the prevalence of early virologic failure (EVF), to characterize the evolution of ARV-resistance mutations, and to predict the impact on second-line therapy.
The prevalence of EVF (HIV-RNA >400 copies/mL on sequential visits after 6 months of therapy) was identified among 120 HIV-infected Ugandan children starting ARV-therapy. ARV-mutations were identified by population sequencing of HIV-1 pol in sequential archived specimens. Composite discrete genotypic susceptibility scores (dGSS) were determined for second-line ARV-regimens.
EVF occurred in 16 (13%) children and persisted throughout a median (IQR) 938 (760-1066) days of follow-up. M184V and non-nucleoside-reverse-transcriptase-inhibitor-associated mutations emerged within 6 months of EVF; thymidine-analog-mutations arose after 12 months. Worse dGSS scores correlated with increasing duration of failure (Spearman R = −0.47, p=0.001). Only 1 child met World Health Organization CD4 criteria for ARV-failure at the time of EVF or during the follow-up period.
A significant portion of HIV-infected African children experience EVF that would be undetected using CD4/clinical monitoring and resulted in the accumulation of ARV-mutations that could compromise second line therapy options.
Resistance; Antiretroviral therapy; HIV; children; Africa
Increasing numbers of HIV-infected children not yet eligible for antiretroviral therapy (ART) are entering health care in Africa. We sought to characterize the risk of short-term disease progression in this population.
In a cohort of HIV-infected ART-naive and -ineligible Ugandan children >1 year old, the rates of clinical/immunologic progression within 2 years were assessed using Kaplan–Meier survival analysis and multivariate Cox proportional-hazards modeling.
Among 192 children (mean age: 6.4 years, CD4%:25), 19% progressed within 2 years by WHO-stage 3/4 event(n=22), death (n=3), or WHO-defined CD4 threshold for ART-initiation(n=12). Significant univariate predictors were CD4%(HR=2.0 per 10% decrease, p=0.005), HIV-RNA level(HR=2.4 per log10 increase, p=0.002), male gender (HR:2.0, p=0.04), age < 3 years (HR=3.7, p=0.001), CD4-activation [%CD4+CD38+HLADR+] (HR=1.6 per 10% increase, p=0.05) and CD8-activation [%CD8+CD38+HLADR+](HR=1.3 per 10% increase, p=0.05] (HR=1.3, p=0.5). In multivariate analysis, CD4%(HR=2.0, p=0.034), HIV-RNA level(HR=1.8, p=0.013) and age < 3 years (HR:3.0, p=0.008) were independently predictive. Children with HIV-RNA >105 copies/ml and CD4% <25 had progression rates of 29% (1 year) and 34% (2 years).
Even with frequent CD4 monitoring, HIV-infected Ugandan children experienced significant clinical events while ineligible for ART. Alternate strategies for monitoring or ART-initiation may be needed to improve outcomes.
HIV; children; progression; monitoring; resource-limited