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Summary We propose the term “common cold coronaviruses,” or ccCoV, to describe the four human coronaviruses commonly associated with upper respiratory tract disease – coronaviruses 229E, OC43, NL63, and HKU1. This will differentiate these previously described coronaviruses from those causing more severe disease in humans – including the viruses severe acute respiraotry syndrome coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2.

Background. We assessed the incidence of tuberculosis, risk factors for tuberculosis, and the contribution of tuberculosis on mortality in a large cohort of human immunodeficiency virus (HIV)-infected children 30 days after ART initiation, divided by the total person-years of follow-up (PYFU). Risk factors for incident tuberculosis were identified using Fine and Gray’s competing risks models, with death from other causes treated as a competing event, and risk factors for death were identified using Cox models. Results. At ART initiation, 670 children (55% female) had a median age of 6.4 years (interquartile range, 2.0–9.6), body mass index-for-age z-score −0.8 (−1.9 to 0.0), HIV ribonucleic acid viral load 5.1 log10 copies/mL (4.6–5.6), and CD4 9% (3–17). Median duration of follow-up was 7.7 years. Tuberculosis incidence was 7 per 1000 PYFU (95% confidence interval [CI], 5–11) and decreased with ART duration. Lower age-adjusted hemoglobin, hematocrit, and CD4 at ART initiation were associated with a higher risk of incident tuberculosis. Of the 30 incident tuberculosis cases, 9 died. Diagnosis of incident tuberculosis was associated with mortality (unadjusted hazard ratio = 10.2, 95% CI = 4.8–21.5, P < .001 and adjusted hazard ratio = 5.4, 95% CI = 2.5–11.7, P < .001). Conclusions. Incident tuberculosis was strongly associated with mortality. CD4 counts or hemoglobin or hematocrit levels may prompt clinicians to consider a possible tuberculosis infection.

Background: The World Health Organization HIV guidelines recommend either infant zidovudine (ZDV) or nevirapine (NVP) prophylaxis for the prevention of intrapartum motherto-child HIV transmission (MTCT) among formula-fed infants. No study has evaluated the comparative efficacy of infant prophylaxis with twice daily ZDV versus once daily NVP in exclusively formula-fed HIV-exposed infants. Methods: Using data from the Mpepu Study, a Botswana-based clinical trial investigating whether prophylactic co-trimoxazole could improve infant survival, retrospective analyses of MTCT events and Division of AIDS (DAIDS) Grade 3 or Grade 4 occurrences of anaemia or neutropenia were performed among infants born full-term (≥ 37 weeks gestation), with a birth weight ≥ 2500 g and who were formula-fed from birth. ZDV infant prophylaxis was used from Mpepu Study inception. A protocol modification mid-way through the study led to the subsequent use of NVP infant prophylaxis. Results: Among infants qualifying for this secondary retrospective analysis, a total of 695 (52%) infants received ZDV, while 646 (48%) received NVP from birth for at least 25 days but no more than 35 days. Confirmed intrapartum HIV infection occurred in two (0.29%) ZDV recipients and three (0.46%) NVP recipients (p = 0.68). Anaemia occurred in 19 (2.7%) ZDV versus 12 (1.9%) NVP (p = 0.36) recipients. Neutropenia occurred in 28 (4.0%) ZDV versus 21 (3.3%) NVP recipients (p = 0.47). Conclusions: Both ZDV and NVP resulted in low intrapartum transmission rates and no significant differences in severe infant haematologic toxicity (DAIDS Grade 3 or Grade 4) among formula-fed full-term infants with a birthweight ≥ 2500 g.

Background. Human immunodeficiency virus (HIV)-infected children failing second-line antiretroviral therapy (ART) have no access to third-line antiretroviral drugs in many resource-limited settings. It is important to identify risk factors for second-line regimen failure. Methods. HIV-infected children initiating protease inhibitor (PI)-containing second-line ART within the Program for HIV Prevention and Treatment observational cohort study in Thailand between 2002 and 2010 were included. Treatment failure was defined as confirmed HIV type 1 RNA load >400 copies/mL after at least 6 months on second-line regimen or death. Adherence was assessed by drug plasma levels and patient self-report. Cox proportional hazards regression analyses were used to identify risk factors for failure. Results. A total of 111 children started a PI-based second-line regimen, including 59 girls (53%). Median first-line ART duration was 1.9 years (interquartile range [IQR], 1.4-3.3 years), and median age at second-line initiation was 10.7 years (IQR, 6.3-13.4 years). Fifty-four children (49%) experienced virologic failure, and 2 (2%) died. The risk of treatment failure 24 months after second-line initiation was 41%. In multivariate analyses, failure was independently associated with exposure to first-line ART for >2 years (adjusted hazard ratio [aHR], 1.8; P = .03), age > 13 years (aHR, 2.9; P < .001), body mass index-for-age z score < -2 standard deviations at second-line initiation (aHR, 2.8; P = .03), and undetectable drug levels within 6 months following second-line initiation (aHR, 4.5; P < .001). Conclusions. Children with longer exposure to first-line ART, entry to adolescence, underweight, and/or undetectable drug levels were at higher risk of failing second-line ART and thus should be closely monitored.

Ann Saudi Med 2013 September-October www.annsaudimed.net 427 The emergence of a novel human coronavirus recently renamed the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) from the Arabian Peninsula has created global alarm because it is the causative agent of a severe and frequently fatal acute respiratory illness (SARI) resembling the illness caused by severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV).1-4 The case fatality rate (CFR) in patients infected with MERS-CoV is high—estimated at 43% in 147 patients reported so far by World Health Organization (WHO).3 This rate is higher than that of SARS—estimated at 15%, and is strongly ageand sex-dependent.4 Although the source of virus in patients with sporadic infection remains unknown, it appears likely to be some species of animal.4,5 Clear evidence of limited human-to-human transmission of MERS-CoV has now been documented in several case clusters, including particularly family members and patients in health care facilities,6-8 but all such clusters have, at least thus far, been limited in extent. However, a real concern persists that the virus will adapt to interhuman transmission and switch from an aborted epidemic to a pandemic similar to the SARS-CoV epidemic in 2003–2004. MERS-CoV is transmitted through droplets and contact. In the case of invasive respiratory procedures, MERS-CoV is transmitted through airborne route.2 Early diagnosis and strict implementation of the core components for infection prevention and control programs are crucial for preventing epidemic amplification.2 In the absence of an effective vaccine and a specific antiviral treatment, there is an urgent need to rapidly identify potential therapeutics.

OBJECTIVES: HAART for prevention of mother-to-child HIV transmission (MTCT) may impact long-term survival of women and children. DESIGN: Randomized clinical trial. METHODS: HIV-infected pregnant women with CD4+ cell count at least 200 cells/microl were randomly assigned to abacavir zidovudine lamivudine (arm A) or lopinavir-ritonavir zidovudine-lamivudine (arm B) from week 26 to 34 gestation through planned weaning by 6 months postpartum. Women with baseline CD4+ cell count less than 200 cells/microl received nevirapine-zidovudine-lamivudine indefinitely (Obs arm) as did randomized women later qualifying for treatment. RESULTS: Among 560 randomized and 170 observational women enrolled there were 14 deaths (1.9%) - one antenatally (Obs) three from delivery to 6 months postpartum (1 arm A 2 Obs) and 10 from 6 to 24 months postpartum (5 arm A 3 arm B 2 Obs). Time to death or CD4+ cell count below 200 cells/microl was shorter in arm A vs. B (P = 0.03). Of the 709 live-born children 97% breastfed for a median of 5.8 months. Of 37 (5.2%) deaths by 24 months nine were before breastfeeding initiated (3 arm A 2 arm B 4 Obs); six while breastfeeding (1 arm A 2 arm B 3 Obs); and 22 after weaning (9 arm A 11 arm B 2 Obs). Only eight children (1.1%) were HIV-infected at 24 months (6 arm A 1 arm B 1 Obs) all before 6 months. CONCLUSION: Low MTCT was maintained through extended follow-up in all arms. Disease progression appeared slower after discontinuing protease inhibitor-based HAART but a concerning number of maternal deaths occurred after stopping either regimen. Strategies to improve maternal and child survival in the postintervention period are required.

Diarrhoea and pneumonia are common causes of childhood death in sub-Saharan Africa but there are few studies describing specific pathogens.The study aimed to describe the pathogens associated with diarrhoea, pneumonia and oropharyngeal colonization in children born to HIV-infected women (HIV-exposed infants).The Mashi Study randomized 1200 HIV-infected women and their infants to breastfeed for 6 months with ZDV prophylaxis or formula-feed with 4 weeks of ZDV. Children were tested for HIV by PCR at 1, 4, 7, 9 and 12 months and by ELISA at 18 months. Pre-defined subsets of children were sampled during episodes of diarrhoea (n = 300) and pneumonia (n = 85). Stool was tested for bacterial pathogens, rotavirus and parasites. Children with pneumonia underwent bacterial blood culture, and testing of nasopharyngeal aspirates for viral pathogens by PCR. Oropharyngeal swabs were collected from a consecutive subset of 561 infants at the routine 3-month visit for bacterial culture.The median age (range) at sampling was 181 days for diarrhoea (0-730) and 140 days for pneumonia (2-551). Pathogens were identified in 55 (18%) children with diarrhoea and 32 (38%) with pneumonia. No differences in pathogens by child HIV status (HIV-infected vs HIV-uninfected) or feeding strategy were identified. Campylobacter was the most common diarrhoeal pathogen (7%). Adenovirus (22%) and other viruses (19%) were the primary pathogens isolated during pneumonias. More formula-fed infants had oropharyngeal colonization by pathogenic Gram-negative bacteria (16.8% vs 6.2%, P = 0.003), which was associated with a non-significant increased risk of pneumonia (OR 2.2, 95% CI 0.8-5.7).A trend toward oropharyngeal bacterial colonization was observed in formula-fed infants. Although viruses were most commonly detected during pneumonia, respiratory colonization by Gram-negative bacteria may have contributed to pneumonia in formula-fed infants.

Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother-child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection. In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression. In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design.

Cytotoxic T lymphocytes (CTL) play a central role in containment of HIV infection. Evasion of the immune response by CTL escape is associated with progression to disease. It is therefore hypothesised that transmitted viruses encode escape mutations within epitopes that are required for successful control of viraemia. In order to test this hypothesis, escape through the dominant HLA-A2-restricted CTL epitope SLYNTVATL (p17 Gag residues 77–85 SL9) in the setting of mother-to-child-transmission (MTCT) was investigated. Initial data from two families in which the HIV-infected mother expressed HLA-A*0201 and had transmitted the virus to other family members were consistent with this hypothesis. In addition, analysis of the gag sequence phylogeny in one family demonstrated that CTL escape variants can be successfully transmitted both horizontally and vertically. To test the hypothesis further, a larger cohort of transmitting mothers (n=8) and non-transmitters (n=14) were studied. Variation within the SL9 epitope was associated with expression of HLA-A2 (P=0.04) but overall no clear link between variation from the SL9 consensus sequence and MTCT was established. However, the high level of background diversity within p17 Gag served to obscure any possible association between escape and MTCT. In conclusion, these studies highlighted the obstacles to demonstrating CTL escape arising at this particular epitope. Alternative strategies likely to be more definitive are discussed.

Advances in antiviral therapy have dramatically shifted the demographics of pediatric human immunodeficiency virus type 1 (HIV-1) infection in the developed world, and a growing proportion of perinatally HIV-1-infected children are now entering their second or even third decade of life. Although cellular immune responses to HIV are known to be weak in early infancy, the magnitude, breadth, and specificity of responses later in childhood have not been characterized in detail. We performed a comprehensive characterization of HIV-1-specific CD8 responses in 18 perinatally infected children (age range, 6 to 17 years), most of whom were on antiviral therapy, using both previously defined HIV-1 epitopes and overlapping peptides spanning all HIV-1 proteins. Multispecific responses were detected in all subjects and accounted for a median of 0.25 to 0.3% of all peripheral blood mononuclear cells that was similar to the magnitude seen in HIV-infected adults. CD8 responses were broadly directed at an average of 11 epitopes (range, 2 to 27 epitopes) and targeted nearly all HIV-1 proteins, with the highest proportion in Gag. Responses were readily detected even in those children with suppressed viremia on highly active antiretroviral therapy, although the breadth (P= 0.037) and the magnitude (P= 0.021) were significantly lower in these subjects. Each child recognized only a small minority of the HIV-1 optimal epitopes defined for his or her class I HLA alleles. Together, these data indicate that perinatally infected children who survive infancy mount a robust HIV-1-specific CD8 response that is much stronger than previously thought and is comparable in magnitude and breadth to that of adults. Moreover, this response has the potential to be broadened to target more epitopes, making these children attractive candidates for immunotherapeutic interventions.

Summary Background Co-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear. Methods HEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14–34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761. Findings From June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference −0·2%, 95% CI −1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the co-trimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3–4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3–4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3–4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21). Interpretation Prophylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV. Funding US National Institutes of Health.

Background Alternatives to the available stavudine-containing paediatric fixed-dose combination (FDC) tablets are rapidly needed due to concerns regarding the cumulative toxicity of long-term stavudine exposure. We report the bioavailability and short-term safety of a novel paediatric FDC tablet of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP; 30/15/28 mg) in HIV-infected children. Methods In this Phase I/II open-label pharmacokinetic study, 42 children weighing 6–30 kg treated with NVP-based HAART for ≥4 weeks were randomized to receive the FDC tablets (GPO-VIR Z30) or the liquid formulations. Dosing was weight-based. Intensive 12-h blood sampling was performed after 2 weeks; subjects then crossed-over to the alternate formulation at equal doses and sampling repeated 2 weeks later. Pharmacokinetic parameters were determined by non-compartmental analysis. Buccal-swab samples were collected for cytochrome P450 ( CYP)2B6 polymorphism analysis. Results With the FDC tablet, the geometric mean (90% CI) area under the curve (AUC) for ZDV, 3TC and NVP was 1.58 (1.49-1.68), 7.78 (7.38-8.19) and 68.88 (62.13-76.36) μg•h/ml, respectively. Rules for NVP therapeutic inadequacy were defined a priori, and despite lower NVP exposure with the tablet ( P Conclusions Disparities in drug exposure between formulations were observed; however, the FDC tablet delivered therapeutically adequate exposures of each drug and could well play an important role in simplifying antiretroviral treatment for children.

While post-exposure prophylaxis (PEP) is commonly prescribed in the setting of occupational and non-occupational HIV-1 exposures [1,2], there is limited evidence documenting efficacy in the setting of transfusion with infected blood. Furthermore, there are a paucity of data regarding blood-borne exposures that lead to passive transfer of antibodies against HIV [3,4]. We describe the efficacy of PEP in such a situation using highly-sensitive assays for HIV-1 DNA and low-level residual viremia. We report the case of a 12 year old girl with sickle-cell disease admitted for management of a vaso-occlusive crisis who inadvertently received HIV-infected packed red blood cells (PRBCs). She required intermittent PRBC transfusions since the age of 2, with the last transfusion 5 years ago. Her white blood cell count was 10,100 per uL, and hemoglobin 9.6 g/dL. Hemoglobin electrophoresis revealed 57% hemoglobin S. During her admission, she was transfused with one PRBC unit that was collected 32 hours prior to administration. Despite the standard practice of pre-screening blood products, the laboratory at the public hospital in the Kingdom of Saudi Arabia became aware that the PRBCs were contaminated with HIV-1 within hours of her transfusion as a result of human error involving mixing an unscreened bag with screened bags. The donor blood was discovered to be HIV-1 antibody positive and subsequently determined to have a viral load of 9740 copies/mL (subtype C); the donor was not receiving antiretroviral therapy (ART). The Ministry of Health conducted an in-depth investigation and halted blood transfusions at the responsible blood blank. Approximately 24 hours after transfusion, the patient was started on tenofovir, emtricitabine, ritonavir-boosted darunavir (subsequently changed to lopinavir) and raltegravir. Blood tests were positive 24 hours after transfusion for HIV antibodies by ELISA and confirmatory western blot (WB), but negative for HIV-1 DNA and plasma HIV-1 RNA by PCR. The pattern of reactive bands on WB was identical for samples obtained from the donor and patient (gp120, gp41, gp31, p24 and p17). Genotyping revealed that she was CCR5 wild-type. The patient demonstrated no signs or symptoms of acute infection during 13 weeks of ART in a tertiary care center. Testing of donor blood revealed no HIV-1 resistance to the antiretrovirals chosen. Longitudinal testing of the patient’s plasma and peripheral blood mononuclear cells (PBMCs) was performed by both clinical laboratories and by sensitive research assays with thresholds of detection down to 0.06 HIV-1 DNA copies/106 PBMCs and 0.4 RNA copies/mL of plasma during and after ART. All tests were negative prior to and 8 months after ART interruption. She continued to have declining but detectable HIV-1 antibodies with positive confirmatory line immunoassay up to 5 months after transfusion, but confirmatory testing was negative by month 6. Viral load testing 8 months following exposure remained negative. See Table 1. Table 1 HIV-1 DNA, plasma RNA and antibody tests results before and after infected blood transfusion We report the successful use of combination ART PEP following large-volume transfusion of HIV-infected blood from a viremic donor with passive transfer of antibodies to HIV-1. The observation that no HIV was detected in her blood after stopping ART and that antibody levels disappeared over time, strongly suggests that PEP successfully prevented HIV acquisition. The overall transmission rate from HIV-1 antibody positive blood transfusions was 89% in one study with non-transmission attributed to lower viral load and prolonged blood-product storage [5]. HIV-1 transmission from transfusion of PRBCs stored for

Over the last several years a significant effort has been made toward the development of adult fixed-drug combination (FDC) tablets to help simplify highly active antiretroviral therapy and improve long-term drug adherence. Due in part to lack of affordable pediatric formulations, as well as the convenience of FDC tablets, a large number of HIV-infected children in resource-limited settings have received adult FDCs, which often must be broken in pieces to obtain an appropriate dose.1-3 Previous studies in HIV-infected Thai children who were using an adult FDC tablet produced by the Thai Government Pharmaceutical Organization (GPO) composed of stavudine (d4T), lamivudine (3TC), and nevirapine (NVP), named GPO-VIR S-30, (administered as 1/2, 3/4, or 1 tablet to deliver a NVP dose of 120–200 mg/m2 every 12 hours), found satisfactory NVP exposure and good clinical response.4-6 The World Health Organization (WHO) released a report in 2008 from their Pediatric Antiretroviral Working Group that high-lighted the need for affordable, safe, high-quality antiretroviral FDC formulations for pediatric use.7 To this end, the Thai GPO developed an orange-flavored chewable pediatric FDC scored tablet composed of d4T, 3TC, and NVP, named GPO-VIR S7. The choice of antiretroviral drugs to include in this new pediatric FDC follows the current Thai National Antiretroviral Treatment guidelines8 and the d4T:3TC:NVP ratio of 7:30:50 mg was designed to allow for the different maturational rates of the elimination pathways for the individual FDC components. In December 2009, the WHO antiretroviral guidelines for adults and adolescents proposed that countries progressively phase out d4T as the preferred first-line therapy option. However, d4T will remain an important drug in resource limited settings in the immediate future due to its availability, low cost, and good short-term tolerability, especially for children anemic or intolerant to zidovudine and with no immediate access to other nucleoside reverse transcription inhibitors (NRTIs). Pediatric FDCs provide physicians with the option to initiate a simple regimen in children. Our objective was to assess the relative bioavailability, safety, and therapeutic adequacy of this chewable pediatric FDC tablet in comparison to the individual liquid formulations in HIV-infected Thai children.

The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown.We randomly assigned 560 HIV-1-infected pregnant women (CD4+ count,or = 200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir-ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks' gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovudine-lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine.The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group.All regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%. (ClinicalTrials.gov number, NCT00270296.)

The 2009 H1N1 influenza virus (formerly known as swine flu) first appeared in Mexico and the United States in March and April 2009 and has swept the globe with unprecedented speed as a result of airline travel. On June 11, 2009, the World Health Organization raised its pandemic level to the highest level, Phase 6, indicating widespread community transmission on at least two continents. The 2009 H1N1 virus contains a unique combination of gene segments from human, swine and avian influenza A viruses. Children and young adults appear to be the most affected, perhaps reflecting protection in the elderly owing to exposure to H1N1 strains before 1957. Most clinical disease is relatively mild but complications leading to hospitalization, with the need for intensive care, can occur, especially in very young children, during pregnancy, in morbid obesity, and in those with underlying medical conditions such as chronic lung and cardiac diseases, diabetes, and immunosuppression. Bacterial co-infection has played a significant role in fatal cases. The case of fatality has been estimated at around 0.4%. Mathematical modeling suggests that the effect of novel influenza virus can be reduced by immunization, but the question remains: can we produce enough H1N1 vaccine to beat the pandemic?

OBJECTIVE: Concern for potential adverse effects of antiretroviral (ARV) chemotherapy used to prevent mother-to-child HIV transmission has led the US Public Health Service to recommend long-term follow-up of ARV-exposed children. Nucleoside reverse transcriptase inhibitor ARV agents can inhibit DNA polymerase γ, impairing mitochondrial DNA (mtDNA) synthesis and resulting in depletion or dysfunction.METHODS: We measured the mtDNA content of stored peripheral blood mononuclear cells (PBMCs) of 411 healthy children who were born to HIV-uninfected women and 213 uninfected infants who were born to HIV-infected women with or without in utero and neonatal ARV exposure. Cryopreserved PBMC mtDNA was quantified by using the Primagen Retina Mitox assay.RESULTS: Geometric mean PBMC mtDNA levels were lower at birth in infants who were born to HIV-infected women. Among HIV-exposed children, mtDNA levels were lowest in those who were not exposed to ARVs, higher in those with exposure to zidovudine alone, and higher still in those with combination nucleoside reverse transcriptase inhibitor exposure. A similar pattern was observed in the corresponding women. Levels of mtDNA increased during the first 5 years of life in all HIV-exposed children but achieved normal levels only in those with ARV exposure.CONCLUSIONS: Levels of mtDNA are lower than normal in HIV-exposed children. Contrary to expectation, PBMC mtDNA levels are significantly higher in ARV-exposed, HIV-uninfected infants and their infected mothers compared with ARV-unexposed infants and women. By 5 years, levels of PBMC mtDNA rise to normal concentrations in ARV-exposed children but remain depressed in ARV-unexposed children.

Among children and adolescents infected with HIV, low CD4+ T lymphocyte counts have been associated with weight growth failure [1] and mortality [1–5]. CD4+ cells serve as important immunologic markers of HIV disease progression that facilitate both clinical decision-making about when to initiate antiretroviral therapy and clinical monitoring of treatment effectiveness and drug resistance. Use of HAART has been associated with improved clinical outcomes, such as growth [6, 7] and survival of HIV-infected children [8, 9]. These associations are likely to be partly mediated through the effect of HAART on CD4+ cell counts. Numerous studies have found an association between combination antiretroviral therapy and increases in CD4+ cell count in children [10–24]. However, the majority of these studies included only small numbers of children and/or had follow-up periods of 200 children for >1 year [22, 23]. These studies compared CD4+ cell percentage before initiation with CD4+ cell percentage after initiation and found substantial improvements in CD4+ cell percentage after the first year of therapy, followed by relatively smaller increases in the subsequent years. These immediate and prolonged effects were particularly observed among younger children (5 years after HAART initiation and whether these increases resulted in a CD4+ cell percentage >25%, a level considered to be the lower limit of normal for children >1 year of age [25]. We further aimed to evaluate separately HAART including a protease inhibitor (PI) and HAART including a nonnucleoside reverse-transcriptase inhibitor (NNRTI). Either PIs or NNRTIs are strongly recommended for inclusion in initial regimens for HIV-infected children [26] and are a basis for the definition of HAART. We investigated the mean change in CD4+ cell percentage after HAART exposure, because CD4+ cell percentage is a more stable measure of CD4+ lymphocytes in children than is absolute CD4+ cell count [25].

BackgroundAntiretroviral treatments decrease HIV mother-to-child transmission through pre/post exposure prophylaxis and reduction of maternal viral load. We modeled in-utero and intra-partum HIV transmissions to investigate the preventive role of various antiretroviral treatments interventions.MethodsWe analysed data from 3,759 women-infant pairs enrolled in 3 randomized clinical trials evaluating (1) zidovudine monotherapy, (2) zidovudine plus perinatal single-dose nevirapine or (3) zidovudine plus lopinavir/ritonavir for the prevention of mother-to-child transmission of HIV in Thailand. All infants were formula-fed. Non-linear mixed effect modeling was used to express the viral load evolution under antiretroviral treatments and the probability of transmission.ResultsMedian viral load was 4 log10 copies/mL (Interquartile range: 3.36-4.56) before antiretroviral treatments initiation. An Emax model described the viral load time-course during pregnancy. Half of the maximum effect of zidovudine (28% decrease) and lopinavir/ritonavir (72% decrease) were achieved after 98 and 12 days, respectively. Adjusted on viral load at baseline (Odds ratio = 1.50 [95% confidence interval: 1.34, 1.68] per log10 copies/mL increment), antiretroviral treatments duration (OR = 0.80 [0.75, 0.84] per week increment) but not the nature of antiretroviral treatments were associated with in-utero transmission. Adjusted on gestational age at delivery (ConclusionThese models determined the respective contributions of various antiretroviral strategies on prevention of mother-to-child transmission. This can help predict the efficacy of new antiretroviral treatments and/or prevention of mother-to-child transmission strategies particularly for women with no or late antenatal care who are at high risk of transmitting HIV to their offspring.Trial registrationThis analysis is based on secondary data obtained from three clinical trials. ClinicalTrials.gov. NCT00386230, NCT00398684, NCT00409591.