A Proposal to Refer to Four Coronaviruses of Limited Human Virulence "Common Cold Coronaviruses".

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.

Treatment Failure in HIV-Infected Children on Second-line Protease Inhibitor-Based Antiretroviral Therapy.

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.

Switching HIV treatment in adults based on CD4 count versus viral load monitoring: a randomized, non-inferiority trial in Thailand.

BACKGROUND: Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand. METHODS AND FINDINGS: The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm(3). The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6-11.4) in VL versus 7.4% (5.1-10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2-8.4) in VL versus 7.5% (5.0-11.1) in CD4 (p=0.097). Median time from treatment initiation to switch was 11.7 months (7.7-19.4) in VL and 24.7 months (15.9-35.0) in CD4 (p=0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported. CONCLUSIONS: The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings. TRIAL REGISTRATION: ClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary.

Efficacy and safety of 1-month postpartum zidovudine-didanosine to prevent HIV-resistance mutations after intrapartum single-dose nevirapine.

BACKGROUND: Intrapartum single-dose nevirapine plus third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings. The persistence of nevirapine in the plasma for 3 weeks postpartum risks selection of resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). We hypothesized that a 1-month zidovudine-didanosine course initiated at the same time as single-dose nevirapine (sdNVP) would prevent the selection of nevirapine-resistance mutations. METHODS: HIV-infected pregnant women in the PHPT-4 cohort with CD4 cell counts >250 cells/mm3 received antepartum zidovudine from the third trimester until delivery, sdNVP during labor, and a 1-month zidovudine-didanosine course after delivery. These women were matched on the basis of baseline HIV load, CD4 cell count, and duration of antepartum zidovudine to women who received sdNVP in the PHPT-2 trial (control subjects). Consensus sequencing and the more sensitive oligonucleotide ligation assay were performed on samples obtained on postpartum days 7-10, 37-45, and 120 (if the HIV load was >500 copies/mL) to detect K103N/Y181C/G190A mutations. RESULTS: The 222 PHPT-4 subjects did not differ from matched control subjects in baseline characteristics except for age. The combined group median CD4 cell count was 421 cells/mm3 (interquartile range [IQR], 322-549 cells/mm3), the median HIV load was 3.45 log10 copies/mL (IQR, 2.79-4.00 log10 copies/mL), and the median duration of zidovudine prophylaxis was 10.4 weeks (IQR, 9.1-11.4 weeks). Using consensus sequencing, major NNRTI resistance mutations were detected after delivery in 0% of PHPT-4 subjects and 10.4% of PHPT-2 controls. The oligonucleotide ligation assay detected resistance in 1.8% of PHPT-4 subjects and 18.9% of controls. Major NNRTI resistance mutations were detected by either method in 1.8% of PHPT-4 subjects and 20.7% of controls (P < .001). CONCLUSIONS: A 1-month postpartum course of zidovudine plus didanosine prevented the selection of the vast majority of NNRTI resistance mutations.

Early immunological predictors of neurodevelopmental outcomes in HIV-infected children.

BACKGROUND: A previous analysis of children infected with human immunodeficiency virus (HIV) in the Women and Infants Transmission Study showed a strong correlation between low activated CD8(+) T lymphocytes in the first 2 months of life and good immunological prognosis. We sought to extend these observations to neurodevelopmental prognosis. METHODS: Ninety-eight HIV-infected children born before 1994 with flow cytometric data from the first 2 months of life and adequate neurodevelopmental testing through age 30 months were studied. Children were divided into those with low (5% CD8(+)HLA-DR(+) cells or >25% CD8(+)CD38(+) cells) immune activation at 1 and/or 2 months of age. Analysis was performed using survival analysis, Cox's proportional hazard regression, and longitudinal regression models. RESULTS: Absence of immune activation, measured as

Development of dual-class antiretroviral drug resistance in a child coinfected with HIV and tuberculosis: a case report from KwaZulu-Natal, South Africa.

The treatment of concurrent HIV and tuberculosis (TB) in children <3 years of age has not been well-studied and is complicated by potential drug-drug interactions. The recommended antiretroviral therapy (ART) in coinfected children in South Africa consists of full-strength ritonavir, lamivudine and stavudine. We report on a child initiated on this regimen, during concurrent TB treatment, who promptly developed an adverse reaction, virologic failure and dual-class antiretroviral drug resistance, compromising subsequent salvage ART.

Increased incidence of asthma in HIV-infected children treated with highly active antiretroviral therapy in the National Institutes of Health Women and Infants Transmission Study.

BACKGROUND: Immunoreconstitution of HIV(+) patients after treatment with highly active antiretroviral therapy (HAART) appears to provoke inflammatory diseases. OBJECTIVE: We sought to determine whether HIV(+) children receiving HAART (HIV(+) HAART(+)) have a higher incidence of asthma than HIV(+) children not receiving HAART (HIV(+) HAART(-)). METHODS: Two thousand six hundred sixty-four children (193 HIV(+) and 2471 HIV(-) children) born to HIV(+) women were evaluated for the incidence and prevalence of asthma (ie, asthma medication use) and change of CD4(+) T-cell percentage with time. RESULTS: The HIV(+) HAART(+) children had higher CD4(+) T-cell percentages, lower CD8(+) T-cell percentages, and lower viral burdens than the HIV(+) HAART(-) children (P < or = .05 to P < or = .01). The cumulative incidence of asthma medication use in HIV(+) HAART(+) children at 13.5 years increased to 33.5% versus 11.5% in HIV(+) HAART(-) children (hazard ratio, 3.34; P = .01) and was equal to that in the HIV(-) children. In children born before the HAART era, the prevalence of asthma medication use for HIV(+) HAART(+) children at 11 years of age was 10.4% versus 3.8% for HIV(+) HAART(-) children (odds ratio, 3.38; P = .02) and was equal to that of the HIV(-) children. The rate of change of CD4(+) T cells around the time of first asthma medication for HIV(+) HAART(+) versus HIV(+) HAART(-) children was 0.81%/y versus -1.43%/y (P = .01). CONCLUSION: The increased incidence of asthma in HIV(+) HAART(+) children might be driven by immunoreconstitution of CD4(+) T cells.

Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study.

BACKGROUND: Previous observational studies found highly active antiretroviral therapy (HAART) to be associated with improved survival among human immunodeficiency virus (HIV)-infected children and adolescents. However, these studies had limited follow-up of HIV-infected children undergoing HAART. Given that HIV infection is chronic and that exposure to HAART is likely to be life-long, there is a need to evaluate the long-term effect of HAART on survival in this population. METHODS: The study included 1236 children and adolescents who were perinatally infected with HIV, who were on study or enrolled after January 1996 in a United States-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C), and who were not receiving HAART at baseline; subjects were observed for a maximum of 10 years through June 2006. A weighted Cox regression model was used to estimate the effect of HAART on survival, appropriately adjusted for time-varying confounding by severity. RESULTS: At the end of the 10-year follow-up period (median duration of follow-up, 6.3 years; interquartile range, 4.3-9.8 years), 70% of participants had initiated HAART. Lower CD4 cell percentages, total lymphocyte counts, and albumin levels were associated with an increased probability of initiating HAART. Eighty-five deaths were observed, and the mortality hazard ratio associated with HAART, compared with non-HAART regimens, was 0.24 after adjusting for measured confounding by severity (95% confidence interval, 0.11-0.51). CONCLUSIONS: The use of HAART was highly effective in reducing mortality during the period 1996-2006 among children and adolescents infected with HIV. With improved long-term survival, continued follow-up is necessary to evaluate the effects of prolonged use of HAART on potential adverse events, immune function, growth, sexual maturation, and quality of life in this population.

Long-term effects of highly active antiretroviral therapy on CD4+ cell evolution among children and adolescents infected with HIV: 5 years and counting.

BACKGROUND: Lower percentages of CD4(+) T lymphocytes are associated with adverse clinical outcomes among children and adolescents infected with human immunodeficiency virus (HIV). CD4(+) lymphocyte percentage generally increases with receipt of highly active antiretroviral therapy (HAART), but long-term follow-up is required to assess whether these increases in CD4(+) cell percentage are maintained and whether they lead to normal CD4(+) cell percentages in children with severe immunosuppression. METHODS: The study population included 1236 children and adolescents perinatally infected with HIV who were enrolled in a US-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C) and who were not receiving HAART at study initiation. We estimated the effects of HAART, HAART with protease inhibitors, and HAART with nonnucleoside reverse-transcriptase inhibitors on CD4(+) cell percentage, using marginal structural models to account for confounding by severity. RESULTS: Initiation of any type of HAART increased CD4(+) cell percentage by 2.34% (95% confidence interval, 1.35%-3.33%) in the first year, relative to noninitiation of HAART. The substantial increases in CD4(+) cell percentage observed after the first year of experience with these combination therapies were followed by relatively smaller increases that continued for 5 years after initiation. Although larger increases in CD4(+) cell percentage were observed among children with a greater degree of immunosuppression at baseline, the mean CD4(+) cell percentage after 5 years of HAART did not reach normal levels. CONCLUSIONS: Our study supports the initiation of HAART in children before severe immunosuppression occurs for long-term maintenance of normal CD4(+) cell percentages. This beneficial result must be weighed against the evidence of potential adverse events associated with the prolonged use of such therapy.

Similar HIV protection from four weeks of zidovudine versus nevirapine prophylaxis among formula-fed infants in Botswana.

BACKGROUND: The World Health Organization HIV guidelines recommend either infant zidovudine (ZDV) or nevirapine (NVP) prophylaxis for the prevention of intrapartum mother-to-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.

Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand.

BACKGROUND: Although zidovudine prophylaxis decreases the rate of transmission of the human immunodeficiency virus (HIV) type 1 substantially, a large number of infants still become infected. We hypothesized that the administration, in addition to zidovudine, of a single dose of oral nevirapine to mothers during labor and to neonates would further reduce transmission of HIV. METHODS: We conducted a randomized, double-blind trial of three treatment regimens in Thai women who were receiving zidovudine therapy during the third trimester of pregnancy. In one group, mothers and infants received a single dose of nevirapine (nevirapine-nevirapine regimen); in another, mothers and infants received nevirapine and placebo, respectively (nevirapine-placebo regimen); and in the last, mothers and infants received placebo (placebo-placebo regimen). The infants also received one week of zidovudine therapy and were formula-fed. The end point of the study was infection with HIV in the infants, established by virologic testing. RESULTS: Between January 15, 2001, and February 28, 2003, a total of 1844 Thai women were enrolled. At the first interim analysis, the independent data monitoring committee stopped enrollment in the placebo-placebo group. Among women who delivered before the interim analysis, the as-randomized Kaplan-Meier estimates of the transmission rates were 1.1 percent (95 percent confidence interval, 0.3 to 2.2) in the nevirapine-nevirapine group and 6.3 percent (95 percent confidence interval, 3.8 to 8.9) in the placebo-placebo group (P<0.001). The final per-protocol transmission rate in the nevirapine-nevirapine group, 1.9 percent (95 percent confidence interval, 0.9 to 3.0), was not significantly inferior to the rate in the nevirapine-placebo group (2.8 percent; 95 percent confidence interval, 1.5 to 4.1). Nevirapine had an effect within subgroups defined by known risk factors such as viral load and CD4 count. No serious adverse effects were associated with nevirapine therapy. CONCLUSIONS: A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to oral zidovudine prophylaxis starting at 28 weeks' gestation, is highly effective in reducing mother-to-child transmission of HIV.

Baseline resistance to nucleoside reverse transcriptase inhibitors fails to predict virologic response to combination therapy in children (PACTG 338).

BACKGROUND: The association between baseline drug resistance mutations and subsequent increase in viral failure has not been established for HIV-infected children. We evaluated drug resistance mutations at 39 codon sites (21 protease inhibitor (PI) resistant codons and 18 nucleoside reverse transcriptase inhibitor (NRTI) resistant codons) for 92 clinically stable NRTI-experienced, PI-naive HIV-infected children 2 to 17 years of age who were initiating new therapy with ritonavir plus zidovudine (ZDV) and lamivudine or plus stavudine. The association between baseline drug resistance mutations and subsequent viral failure after 12 and 24 weeks of highly active antiretroviral therapy (HAART) was studied. RESULTS: There were few primary PI associated mutations in this PI-naïve population, but 84% had NRTI mutations--codons 215 (66%), 41 (42%), 67 (37%), 210 (33%) and 70 (32%). None of the specific baseline drug resistance mutations were associated with a higher rate of virologic failure after 12 or 24 weeks of HAART. Median week 12 viral load decreased as the total number of NRTI mutations at baseline increased (P = 0.006). Specifically, a higher level of baseline ZDV resistance mutation was associated with a decrease in viral failure after 12 weeks on a ZDV-containing HAART regimen (P = 0.017). CONCLUSION: No increase was seen in the rate of viral failure after HAART associated with the presence of resistance mutations at baseline. This paradoxical result may be due to adherence, replicative capacity, or ZDV hypersusceptibility to the new regimen.

Maternal HIV-1 DNA load and mother-to-child transmission.

While many factors contribute to mother-to-child transmission (MTCT) of HIV-1, maternal plasma HIV-1 RNA viral load (RNA-VL) has been consistently found as the main risk factor, including when antiretroviral prophylaxis was used to prevent MTCT. However the predictive value of RNA-VL is poor. A recent study of HIV-1-positive pregnant women who did not receive antiretroviral prophylaxis reported an association between HIV-1 DNA viral load (DNA-VL) and MTCT that was stronger than the association between RNA-VL and MTCT. We sought to determine if HIV-1 DNA-VL was independently associated with MTCT of HIV in a population of women who received zidovudine prophylaxis during pregnancy and whose infants received zidovudine after birth. Patients were 33 non-breastfeeding transmitting (TR) and 33 nontransmitting mothers (NTR) from Perinatal HIV Prevention Trial (PHPT-1), a multicenter clinical trial conducted in Thailand comparing zidovudine prophylaxis durations to prevent MTCT. TR and NTR mothers were matched according to baseline RNA-VL. Maternal peripheral blood mononuclear cell (PBMC)-associated HIV-1 DNA was extracted from whole blood, and DNA-VL was established by quantitative real-time polymerase chain reaction. We found that TR had a significantly higher cell-associated HIV-1 DNA viral load than did NTR. Median TR DNA-VL was 2.54 log(10) copies per microgram PBMC DNA, while it was 2.28 log(10) copies per microgram PBMC DNA in NTR (Wilcoxon p = 0.02). In summary, HIV-1 DNA viral load was associated with MTCT in a population of women who received antiretroviral prophylaxis during pregnancy, independently from RNA viral load.

Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial.

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.

Incidence of Tuberculosis and Associated Mortality in a Cohort of Human Immunodeficiency Virus-Infected Children Initiating Antiretroviral Therapy.

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 <15 years of age initiating first-line antiretroviral therapy (ART) between 1999 and 2012 in Thailand, one of the 22 high tuberculosis burden countries. METHODS.: A physician reviewed and classified tuberculosis cases. Incidence was the number of children with incident tuberculosis, defined as a first or recurrent tuberculosis diagnosis >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.

Growth of human immunodeficiency virus-uninfected children exposed to perinatal zidovudine for the prevention of mother-to-child human immunodeficiency virus transmission.

BACKGROUND: Perinatal human immunodeficiency virus (HIV) prevention programs have been implemented in several countries, and many children have been or will be exposed to antiretrovirals in utero and during their first weeks of life. Although reducing substantially the number of infected children, the potential adverse consequences of these treatments on the health of HIV-uninfected children need to be assessed. OBJECTIVE: To investigate the impact of in utero and postnatal zidovudine exposure on the growth of HIV-uninfected children born to HIV-infected women. METHODS: We used data prospectively collected in 1408 live born children participating in a clinical trial comparing zidovudine regimens of different durations to prevent perinatal transmission in Thailand (PHPT-1). We used a linear mixed model to analyze the anthropometric measurements (weight for age, height for age and weight for height Z-scores) until 18 months of age according to zidovudine treatment duration (mothers, <7.5 weeks versus more; infants, 3 days versus >4 weeks). RESULTS: Children exposed in utero for >7.5 weeks had a slightly lower birth weight (Z-score difference, 0.08; P = 0.003). However, zidovudine exposure had no effect on the evolution of Z-scores from 6 weeks to 18 months of age. CONCLUSIONS: Although a longer in utero zidovudine exposure may have had a negative impact on birth weight, the magnitude of this effect was small and faded over time. Neither the total nor the postnatal duration of exposure was associated with changes in infant Z-scores from 6 weeks to 18 months of age.

Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study.

CONTEXT: Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. OBJECTIVE: To compare the efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. DESIGN, SETTING, AND PATIENTS: A 2 x 2 factorial randomized clinical trial with peripartum (single-dose nevirapine vs placebo) and postpartum infant feeding (formula vs breastfeeding with infant zidovudine prophylaxis) interventions. In Botswana between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomized from 4 district hospitals. Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month through age 18 months. INTERVENTION: All of the mothers received zidovudine 300 mg orally twice daily from 34 weeks' gestation and during labor. Mothers and infants were randomized to receive single-dose nevirapine or placebo. Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). MAIN OUTCOME MEASURES: Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. RESULTS: The 7-month HIV infection rates were 5.6% (32 infants in the formula-fed group) vs 9.0% (51 infants in the breastfed plus zidovudine group) (P = .04; 95% confidence interval for difference, -6.4% to -0.4%). Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed) vs 86 infants (15.1% breastfed plus zidovudine) (P = .60; 95% confidence interval for difference, -5.3% to 2.9%). Cumulative infant mortality at 7 months was significantly higher for the formula-fed group than for the breastfed plus zidovudine group (9.3% vs 4.9%; P = .003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P = .21). CONCLUSIONS: Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIV-free survival at 18 months. These results demonstrate the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00197587.