Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia

Context  The Zambian Ministry of Health provides pediatric antiretroviral therapy (ART) at primary care clinics in Lusaka, where, despite scale-up of perinatal prevention efforts, many children are already infected with the human immunodeficiency virus (HIV). Objective  To report early clinical and immunologic outcomes of children enrolled in the pediatric treatment program. Design, Setting, and Patients  Open cohort assessment using routinely collected clinical and outcome data from an electronic medical record system in use at 18 government primary health facilities in Lusaka, Zambia. Care was provided primarily by nurses and clinical officers ("physician extenders" akin to physician assistants in the United States). Patients were children (<16 years of age) presenting for HIV care between May 1, 2004, and June 29, 2007. Intervention  Three-drug ART (zidovudine or stavudine plus lamivudine plus nevirapine or efavirenz) for children who met national treatment criteria. Main Outcome Measures  Survival, weight gain, CD4 cell count, and hemoglobin response. Results  After enrollment of 4975 children into HIV care, 2938 (59.1%) started ART. Of those initiating ART, the median age was 81 months (interquartile range, 36-125), 1531 (52.1%) were female, and 2087 (72.4%) with World Health Organization stage information were in stage III or IV. At the time of analysis, 158 children (5.4%) had withdrawn from care and 382 (13.0%) were at least 30 days late for follow-up. Of the remaining 2398 children receiving ART, 198 (8.3%) died over 3018 child-years of follow-up (mortality rate, 6.6 deaths per 100 child-years; 95% confidence interval [CI], 5.7-7.5); of these deaths, 112 (56.6%) occurred within 90 days of therapy initiation (early mortality rate, 17.4/100 child-years; post–90-day mortality rate, 2.9/100 child-years). Mortality was associated with CD4 cell depletion, lower weight-for-age, younger age, and anemia in multivariate analysis. The mean CD4 cell percentage at ART initiation among the 1561 children who had at least 1 repeat measurement was 12.9% (95% CI, 12.5%-13.3%) and increased to 23.7% (95% CI, 23.1%-24.3%) at 6 months, 27.0% (95% CI, 26.3%-27.6%) at 12 months, 28.0% (95% CI, 27.2%-28.8%) at 18 months, and 28.4% (95% CI, 27.4%-29.4%) at 24 months. Conclusions  Care provided by clinicians such as nurses and clinical officers can result in good outcomes for HIV-infected children in primary health care settings in sub-Saharan Africa. Mortality during the first 90 days of therapy is high, pointing to a need for earlier intervention.      

Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial

Context  A 2-dose intrapartum/newborn nevirapine regimen reduced perinatal humanimmunodeficiency virus (HIV) transmission in Ugandan women not receiving antenatalantiretroviral therapy (ART). However, it is unknown whether the additionof the 2-dose nevirapine regimen to standard ART would further reduce perinatalHIV transmission. Objective  To determine whether a 2-dose nevirapine regimen can decrease perinataltransmission of HIV in nonbreastfeeding women receiving standard ART. Design and Setting  International, blinded, placebo-controlled, phase 3 trial enrollingwomen between May 1997 and June 2000 at clinical sites providing care forHIV infection throughout the United States, Europe, Brazil, and the Bahamas. Participants  A total of 1270 women received nevirapine (n = 642) or placebo (n =628). Infants were followed up for 6 months to determine HIV-infection status,which was available for 1248 deliveries. Intervention  A 200-mg dose of oral nevirapine to women after onset of labor and a2-mg/kg dose of oral nevirapine to newborns between 48 and 72 hours afterbirth. Main Outcome Measures  Detection of HIV infection in infants and grade 3 and 4 toxic effectsin women and newborns. Results  After review by the data and safety monitoring board, the trial wasstopped early because the overall transmission rates were significantly lowerthan assumed for the study design. Antenatal ART included zidovudine alonein 23%; combinations without protease inhibitors in 36%; and combinationswith protease inhibitors in 41%. Thirty-four percent of women had electivecesarean delivery. No significant safety concerns were identified for womenor infants. Detection of HIV infection occurred in 9 (1.4%; 95% confidenceinterval [CI], 0.6%-2.7%) of 631 nevirapine group deliveries and 10 (1.6%;95% CI, 0.8%-2.9%) of 617 placebo group deliveries. The 95% CI for the differencein transmission rate (-0.2) between the 2 study arms ranged from -1.5%in favor of nevirapine to 1.2% in favor of placebo (P= .82, Fisher exact test). The transmission rate was higher in women withlower baseline CD4 cell counts and higher delivery HIV RNA levels, but therewas no significant difference between treatment arms in any subgroup. Conclusion  Risk of perinatal HIV transmission was low and no benefit from additionalintrapartum/newborn nevirapine was demonstrated when women received prenatalcare and antenatal ART, and elective cesarean section was made available.      

Lack of Long-term Effects of In Utero Exposure to Zidovudine Among Uninfected Children Born to HIV-Infected Women

Context  With the success of zidovudine chemoprophylaxis for prevention of perinatal transmission of the human immunodeficiency virus (HIV), an increasing number of HIV-exposed but uninfected children will have in utero exposure to zidovudine and other antiretroviral drugs. Objective  To evaluate the long-term effects of in utero exposure to zidovudine vs placebo among a randomized cohort of uninfected children. Design  Prospective cohort study based on data collected during Pediatric AIDS Clinical Trials Group Protocol 076, a perinatal zidovudine HIV prevention trial, and Protocol 219, a long-term observational protocol. Setting  Pediatric research clinics in the United States. Patients  Two hundred thirty-four uninfected children born to 230 HIV-infected women enrolled in Protocol 076 and followed up through February 28, 1997, in Protocol 219 (122 in the zidovudine group and 112 in the placebo group). Main Outcome Measures  Physical growth measurements, immunologic parameters, cognitive/developmental function, occurrence of neoplasms, and mortality data assessed every 6 months for children younger than 24 months and yearly thereafter or as clinically indicated. Baseline echocardiogram and funduscopic evaluations were collected before 36 months of age. Results  Median age of children at time of last follow-up visit was 4.2 years (range, 3.2-5.6 years). There were no significant differences between children exposed to zidovudine and those who received placebo in terms of sequential data on lymphocyte subsets; weight, height, and head circumference z scores; and cognitive/developmental function. No deaths or malignancies occurred. Two children (both exposed to zidovudine) are being followed up for abnormal, unexplained ophthalmic findings. One child exposed to zidovudine had a mild cardiomyopathy on echocardiogram at the age of 48 months; the child is clinically asymptomatic. Conclusions  No adverse effects were observed in HIV-uninfected children with in utero and neonatal exposure to zidovudine followed up for as long as 5.6 years. Continued prospective evaluations of children born to HIV-infected women who are exposed to antiretroviral or immunotherapeutic agents are critical to assess the long-term safety of interventions that prevent perinatal HIV transmission.      

Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes

Context  The Zambian Ministry of Health has scaled-up human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) care and treatment services at primary care clinics in Lusaka, using predominately nonphysician clinicians. Objective  To report on the feasibility and early outcomes of the program. Design, Setting, and Patients  Open cohort evaluation of antiretroviral-naive adults treated at 18 primary care facilities between April 26, 2004, and November 5, 2005. Data were entered in real time into an electronic patient tracking system. Intervention  Those meeting criteria for antiretroviral therapy (ART) received drugs according to Zambian national guidelines. Main Outcome Measures  Survival, regimen failure rates, and CD4 cell response. Results  We enrolled 21 755 adults into HIV care, and 16 198 (75%) started ART. Among those starting ART, 9864 (61%) were women. Of 15 866 patients with documented World Health Organization (WHO) staging, 11 573 (73%) were stage III or IV, and the mean (SD) entry CD4 cell count among the 15 336 patients with a baseline result was 143/µL (123/µL). Of 1142 patients receiving ART who died, 1120 had a reliable date of death. Of these patients, 792 (71%) died within 90 days of starting therapy (early mortality rate: 26 per 100 patient-years), and 328 (29%) died after 90 days (post-90-day mortality rate: 5.0 per 100 patient-years). In multivariable analysis, mortality was strongly associated with CD4 cell count between 50/µL and 199/µL (adjusted hazard ratio [AHR], 1.4; 95% confidence interval [CI], 1.0-2.0), CD4 cell count less than 50/µL (AHR, 2.2; 95% CI, 1.5-3.1), WHO stage III disease (AHR, 1.8; 95% CI, 1.3-2.4), WHO stage IV disease (AHR, 2.9; 95% CI, 2.0-4.3), low body mass index (<16; AHR,2.4; 95% CI, 1.8-3.2), severe anemia (<8.0 g/dL; AHR, 3.1; 95% CI, 2.3-4.0), and poor adherence to therapy (AHR, 2.9; 95% CI, 2.2-3.9). Of 11 714 patients at risk, 861 failed therapy by clinical criteria (rate, 13 per 100 patient-years). The mean (SD) CD4 cell count increase was 175/µL (174/µL) in 1361 of 1519 patients (90%) receiving treatment long enough to have a 12-month repeat. Conclusion  Massive scale-up of HIV and AIDS treatment services with good clinical outcomes is feasible in primary care settings in sub-Saharan Africa. Most mortality occurs early, suggesting that earlier diagnosis and treatment may improve outcomes.      

Risk factors for pediatric human immunodeficiency virus-related malignancy

Context  Although cancers occur with increased frequency in children with human immunodeficiency virus (HIV) infection, the specific clinical, immunological, and viral risk factors for malignancy have not been identified. Objective  To identify risk factors for malignancy among HIV-infected children. Design, Setting, and Patients  A multicenter case-control study of children with HIV at 26 institutions participating in the Pediatric Oncology Group. Forty-three case patients with a new malignancy and 74 control patients without a malignancy were matched based on the duration of their infection. Patients were enrolled between January 1992 and July 1998. Main Outcome Measures  Clinical and laboratory factors assessed as putative risk factors included demographic characteristics, HIV characteristics, prior antiretroviral treatment, and CD4 cell count. Coviral infections with Epstein-Barr virus (EBV), cytomegalovirus, and human herpesvirus 6 were assessed by semiquantitative polymerase chain reaction assays and serological testing. Results  Case malignancy diagnoses included 28 non-Hodgkin lymphoma, 4 B-cell acute lymphoblastic leukemia, 1 Hodgkin disease, 8 leiomyosarcoma, 1 hepatoblastoma, and 1 schwannoma. Epstein-Barr virus viral load of more than 50 viral genome copies per 10⁵ peripheral blood mononuclear cells was strongly associated with cancer risk but only for children with CD4 cell counts of at least 200/µL (odds ratio [OR], 11.33; 95% confidence interval [CI], 2.09-65.66, P<.001). High EBV viral load was not associated with cancer for children with CD4 cell counts of less than 200/µL (OR, 1.12; 95% CI, 0.13-9.62; P = .99). Zidovudine antiretroviral therapy did not confer a significant protective effect for either the high (OR, 0.81; 95% CI, 0.22-3.09; P = .77) or the low CD4 cell count groups (OR, 0.27; 95% CI, 0.04-1.46; P = .16). The route of HIV infection was not associated with increased cancer risk. Conclusions  Route of infection, demographic characteristics, and zidovudine use were not associated with the development of malignancy in HIV-infected children. High viral burden with EBV was associated with the development of malignancy in HIV-infected children although the effect was modified by CD4 cell count. The pathogenesis of HIV-related pediatric malignancies remains unclear and other contributing risk factors can be elucidated only through further study.      

Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial

Context  Peripheral lipoatrophy may complicate antiretroviral therapy of humanimmunodeficiency virus (HIV) infection, often related to duration and typeof nucleoside analog therapy, and may have a mitochondrial pathogenesis. Noproven therapy exists for lipoatrophy, but abacavir is a nucleoside analogthat may be less toxic to mitochondria. Objective  To determine if substitution of stavudine or zidovudine with abacavirimproves HIV lipoatrophy without affecting control of HIV replication. Design  Randomized, open-label 24-week study. Setting  Seventeen hospital HIV outpatient clinics and primary care centers inAustralia and England, with randomization from June 2000 through January 2001. Participants  A total of 111 adults (109 men) with moderate or severe lipoatrophywho were receiving stavudine (n = 85) or zidovudine (n = 26) and had stableplasma HIV RNA levels below 400 copies/mL and no prior abacavir therapy. Intervention  Patients were randomly assigned to switch from stavudine or zidovudineto abacavir, 300 mg twice per day, while continuing all other antiretroviraltherapy (n = 54) or to continue all antiretroviral therapy (n = 57). Main Outcome Measures  The primary end point was limb fat mass, measured by dual-energy x-rayabsorptiometry; key secondary end points were plasma HIV RNA levels, adverseevents, physician-assessed (via subjective measures) lipodystrophy severity,total and central fat mass, and fasting metabolic (lipid, glycemic, and lactate)levels. Results  There was a significant increase in limb fat in the abacavir group relativeto the stavudine/zidovudine group (0.39 vs 0.08 kg; mean difference, 0.31;95% confidence interval [CI], 0.06-0.57 kg), as well as significant relativeincreases in subcutaneous thigh (P = .01), arm (P<.001), and abdominal (P =.001) fat areas on computed tomography. Switching had no significant effecton secondary end points, including plasma HIV RNA (for unadjusted comparisonbetween groups at week 24, odds ratio, 1.38; 95% CI, 0.48-3.96). Change inlimb fat mass at week 24 did not correlate with change in subjectively determinedperceived lipoatrophy severity (r = -0.06; P = .53 by Spearman correlation). Hypersensitivity to abacavirwas seen in 5 patients (10%). Conclusions  In this sample of lipoatrophic HIV-infected adults, switching from stavudineor zidovudine to abacavir for 24 weeks led to significant, albeit modest,objectively measured increases in limb fat. Clinical lipoatrophy, as assessedsubjectively, did not resolve, however, and at the rate of increase observedmay take years to resolve with use of this strategy. Longer-term follow-upis needed.      

Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial

Context  Children with familial hypercholesterolemia have endothelial dysfunction and increased carotid intima-media thickness (IMT), which herald the premature atherosclerotic disease they develop later in life. Although intervention therapy in the causal pathway of this disorder has been available for more than a decade, the long-term efficacy and safety of cholesterol-lowering medication have not been evaluated in children. Objective  To determine the 2-year efficacy and safety of pravastatin therapy in children with familial hypercholesterolemia. Design  Randomized, double-blind, placebo-controlled trial that recruited children between December 7, 1997, and October 4, 1999, and followed them up for 2 years. Setting and Participants  Two hundred fourteen children with familial hypercholesterolemia, aged 8 to 18 years and recruited from an academic medical referral center in the Netherlands. Intervention  After initiation of a fat-restricted diet and encouragement of regular physical activity, children were randomly assigned to receive treatment with pravastatin, 20 to 40 mg/d (n = 106), or a placebo tablet (n = 108). Main Outcome Measures  The primary efficacy outcome was the change from baseline in mean carotid IMT compared between the 2 groups over 2 years; the principal safety outcomes were growth, maturation, and hormone level measurements over 2 years as well as changes in muscle and liver enzyme levels. Results  Compared with baseline, carotid IMT showed a trend toward regression with pravastatin (mean [SD], –0.010 [0.048] mm; P = .049), whereas a trend toward progression was observed in the placebo group (mean [SD], +0.005 [0.044] mm; P = .28). The mean (SD) change in IMT compared between the 2 groups (0.014 [0.046] mm) was significant (P = .02). Also, pravastatin significantly reduced mean low-density lipoprotein cholesterol levels compared with placebo (–24.1% vs +0.3%, respectively; P<.001). No differences were observed for growth, muscle or liver enzymes, endocrine function parameters, Tanner staging scores, onset of menses, or testicular volume between the 2 groups. Conclusion  Two years of pravastatin therapy induced a significant regression of carotid atherosclerosis in children with familial hypercholesterolemia, with no adverse effects on growth, sexual maturation, hormone levels, or liver or muscle tissue.      

Circumcision status and risk of HIV and sexually transmitted infections among men who have sex with men: a meta-analysis

Gregorio A. Millett, MPH; Stephen A. Flores, PhD; Gary Marks, PhD; J. Bailey Reed, MD, MPH; Jeffrey H. Herbst, PhD

JAMA. 2008;300(14):1674-1684.

Context  Randomized controlled trials and meta-analyses have demonstrated that male circumcision reduces men's risk of contracting human immunodeficiency virus (HIV) infection during heterosexual intercourse. Less is known about whether male circumcision provides protection against HIV infection among men who have sex with men (MSM).

Objectives  To quantitatively summarize the strength of the association between male circumcision and HIV infection and other sexually transmitted infections (STIs) across observational studies of MSM.

Data Sources  Comprehensive search of databases, including MEDLINE, EMBASE, ERIC, Sociofile, PsycINFO, Web of Science, and Google Scholar, and correspondence with researchers, to find published articles, conference proceedings, and unpublished reports through February 2008.

Study Selection  Of 18 studies that quantitatively examined the association between male circumcision and HIV/STI among MSM, 15 (83%) met the selection criteria for the meta-analysis.

Data Extraction  Independent abstraction was conducted by pairs of reviewers using a standardized abstraction form. Study quality was assessed using the Newcastle-Ottawa Scale.

Data Synthesis  A total of 53 567 MSM participants (52% circumcised) were included in the meta-analysis. The odds of being HIV-positive were nonsignificantly lower among MSM who were circumcised than uncircumcised (odds ratio, 0.86; 95% confidence interval, 0.65-1.13; number of independent effect sizes [k] = 15). Higher study quality was associated with a reduced odds of HIV infection among circumcised MSM (β, –0.415; P = .01). Among MSM who primarily engaged in insertive anal sex, the association between male circumcision and HIV was protective but not statistically significant (odds ratio, 0.71; 95% confidence interval, 0.23-2.22; k = 4). Male circumcision had a protective association with HIV in studies of MSM conducted before the introduction of highly active antiretroviral therapy (odds ratio, 0.47; 95% confidence interval, 0.32-0.69; k = 3). Neither the association between male circumcision and other STIs (odds ratio, 1.02; 95% confidence interval, 0.83-1.26; k = 8), nor its relationship with study quality was statistically significant (β, 0.265; P = .47).

Conclusions  Pooled analyses of available observational studies of MSM revealed insufficient evidence that male circumcision protects against HIV infection or other STIs. However, the comparable protective effect of male circumcision in MSM studies conducted before the era of highly active antiretroviral therapy, as in the recent male circumcision trials of heterosexual African men, supports further investigation of male circumcision for HIV prevention among MSM.

     

Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial

Context  Acute otitis media (AOM) frequently complicates influenza infection. Previous studies have found influenza vaccine effective in reducing the occurrence of AOM in children mainly older than 2 years. Objective  To evaluate the effectiveness of inactivated influenza vaccine in preventing AOM in children aged 6 to 24 months. Design, Setting, and Patients  Randomized, double-blind, placebo-controlled trial of 786 children aged 6 to 24 months enrolled at Children's Hospital of Pittsburgh before the 1999-2000 (411 children) and 2000-2001 (375 children) respiratory seasons (defined as December 1 through March 31 of the respective following year). Children received influenza vaccine or placebo in a 2:1 ratio. The first cohort was observed for 1 year and the second cohort until the end of the ensuing respiratory season. Intervention  Two doses (0.25 mL each) of inactivated trivalent subvirion influenza vaccine or placebo were administered intramuscularly approximately 4 weeks apart. Main Outcome Measures  Proportion of children who developed AOM, monthly occurrence rate of AOM, estimated proportion of time with middle ear effusion, and utilization of selected health care and related resources. Results  Of the 66 children in the vaccine group from whom serum samples were collected, seroconversion against strains in the vaccine formulations developed in 88.6% to 96.8%, depending on the specific strain. The efficacy of the vaccine against culture-confirmed influenza was 66% (95% confidence interval [CI], 34%-82%) in 1999-2000 and -7% (95% CI, -247% to 67%) in 2000-2001; however, influenza attack rates differed between these 2 periods (in the placebo group, 15.9% and 3.3%, respectively). Compared with placebo, influenza vaccine did not reduce the proportion of children who had at least 1 episode of AOM during the respiratory season (in the first cohort: vaccine, 49.2% vs placebo, 52.2%; P = .56 ]; in the second cohort: vaccine, 55.8% vs placebo, 48.3%; P = .17). The vaccine also did not reduce the monthly rate of AOM; the estimated proportion of time with middle ear effusion; or the utilization of selected health care and related resources. There were also no differences between the vaccine and placebo groups regarding any of these outcomes during peak influenza periods. The vaccines administered to both cohorts of children were well tolerated. Conclusion  Administration of inactivated trivalent influenza vaccine to children aged 6 to 24 months did not reduce their burden of AOM or their utilization of selected health care and related resources.      

Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection

Context  Plasma human immunodeficiency virus (HIV) RNA level predicts HIV disease progression, but the extent to which it explains the variability in rate of CD4 cell depletion is poorly characterized. Objective  To estimate the proportion of variability in rate of CD4 cell loss predicted by presenting plasma HIV RNA levels in untreated HIV-infected persons. Design  Repeated-measures analyses of 2 multicenter cohorts, comprising observations beginning on May 12, 1984, and ending on August 26, 2004. Analyses were conducted between August 2004 and March 2006. Setting  Two cohorts of HIV-infected persons: patients followed up at 4 US teaching medical institutions or participating in either the Research in Access to Care for the Homeless Cohort (REACH) or the San Francisco Men's Health Study (SFMHS) cohorts and participants in the Multicenter AIDS Cohort Study (MACS) cohort. Participants  Antiretroviral treatment–naive, chronically HIV-infected persons (n = 1289 and n = 1512 for each of the 2 cohorts) untreated during the observation period (6 months) and with at least 1 HIV RNA level and 2 CD4 cell counts available. Approximately 35% were nonwhite, and 35% had risk factors other than male-to-male sexual contact. Main Outcome Measures  The extent to which presenting plasma HIV RNA level could explain the rate of model-derived yearly CD4 cell loss, as estimated by the coefficient of determination (R²). Results  In both cohorts, higher presenting HIV RNA levels were associated with greater subsequent CD4 cell decline. In the study cohort, median model–estimated CD4 cell decrease among participants with HIV RNA levels of 500 or less, 501 to 2000, 2001 to 10 000, 10 001 to 40 000, and more than 40 000 copies/mL were 20, 39, 48, 56, and 78 cells/µL, respectively. Despite this trend across broad categories of HIV RNA levels, only a small proportion of CD4 cell loss variability (4%-6%) could be explained by presenting plasma HIV RNA level. Analyses using multiple HIV RNA measurements or restricting to participants with high HIV RNA levels improved this correlation minimally (R², 0.09), and measurement error was estimated to attenuate these associations only marginally (deattenuated R² in the 2 cohorts, 0.05 and 0.08, respectively). Conclusions  Presenting HIV RNA level predicts the rate of CD4 cell decline only minimally in untreated persons. Other factors, as yet undefined, likely drive CD4 cell losses in HIV infection. These findings have implications for treatment decisions in HIV infection and for understanding the pathogenesis of progressive immune deficiency.      

Incidence of opportunistic and other infections in HIV-infected children in the HAART era

Context  Combination anti-retroviral therapy or highly active antiretroviral therapy (HAART) has resulted in a dramatic decline in the incidence of opportunistic and other infections in human immunodeficiency virus (HIV)–infected adults and children. Objectives  To estimate the incidence of 29 targeted opportunistic and other infections occurring in the era of HAART—between January 1, 2001, and December 31, 2004—in HIV-infected infants, children, and adolescents followed up in Pediatric AIDS Clinical Trials Group (PACTG) 219C; to compare incidence rates in the HAART era to those of the pre-HAART era; and to test for linear trends over time in the HAART era. Design, Setting, and Participants  Ongoing, multicenter, prospective cohort study designed to examine long-term outcomes in HIV-infected children. The study population included 2767 children enrolled between September 15, 2000, and December 31, 2004, with information entered in the database up to August 1, 2005, when data analysis was conducted. The pre-HAART era comparison population included 3331 children enrolled in 13 PACTG protocols from October 1988 to August 1998. Main Outcome Measures  First occurrence of each of the 29 targeted infections. Results  Seventy-five percent of the children were enrolled in 2000 and 2001, 90% acquired HIV perinatally, 52% were girls, and 59% were black. The median age was 8.2 years (range, 6-13 years). The median duration of follow-up was 3.4 years. Overall, 553 first episodes of a specific infection occurred among 395 (14%) of the study participants. The number of events for the 4 most common first-time infections and their incidence rates (IRs) per 100 person-years were 123 bacterial pneumonia (IR, 2.15; 95% confidence interval [CI], 1.79-2.56), 77 herpes zoster (IR, 1.11; 95% CI, 0.88-1.39), 57 dermatophyte infections (IR, 0.88; 0.67-1.14), and 52 oral candidiasis (IR, 0.93; 95% CI, 0.70-1.22). Incidence rates of first bacteremia, Pneumocystis jeroveci pneumonia, disseminated Mycobacterium avium complex, lymphoid interstitial pneumonitis, systemic fungal infection, cytomegalovirus retinitis, and tuberculosis were all less than 0.50 per 100 person-years. There were no statistically significant linear trends in incidence for any of the 29 infections over the 4 calendar years. However, infection rates were significantly lower than those reported in the PACTG in the pre-HAART era. The pre-HAART IRs were as follows: for bacterial pneumonia, IR, 11.1; 95% CI, 10.3-12.0; bacteremia, IR, 3.3; 95% CI, 2.9-3.8; herpes zoster, IR, 2.9; 95% CI, 2.6-3.3; disseminated M avium complex, IR, 1.8; 95% CI, 1.5-2.1; P jeroveci, IR, 1.3; 95% CI, 1.1-1.6; oral candidiasis, IR, 1.2; 95% CI, 1.0-1.5; cytomegalovirus retinitis, IR, 0.5; 95% CI, 0.3-0.6; and tuberculosis, IR, 0.2; 95% CI, 0.1-0.4. Conclusions  Opportunistic infections and other related infections are uncommon in children in the HAART era, and infection rates continue to be lower than those reported in the pre-HAART era. Continued surveillance is important to assess the long-term effect of HAART on the occurrence of opportunistic and other related infections in children.      

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      

Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial

Context  The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. Objective  To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. Design, Setting, and Participants  Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). Interventions  Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. Main Outcome Measures  The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. Results  Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. Conclusions  Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.      

Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration

Context  Studies have reported that single-nucleotide polymorphisms in the genes CFH and LOC387715 are associated with age-related macular degeneration (AMD). Objective  To assess whether these genetic variants have prognostic importance for progression to advanced AMD and related visual loss. Design, Setting, and Participants  Prospective analysis of 1466 white participants in the Age-Related Eye Disease Study (AREDS), a US multicenter clinical trial conducted from 1990 to 2001 with a mean follow-up time of 6.3 years. Age-related macular degeneration status was determined by grading of fundus photographs. Progression (n = 281) was defined as newly diagnosed advanced AMD (geographic atrophy, exudative disease, or AMD causing visual loss) in one or both eyes during the course of the study. Genotypic analysis was conducted in 2006. Main Outcome Measure  Incidence rates of dry and neovascular advanced AMD. Results  The CFH Y402H and LOC387115 A69S polymorphisms were each independently related to progression from early or intermediate stages to advanced stages of AMD, controlling for demographic factors, smoking, body mass index, and AREDS vitamin-mineral treatment assignment, with odds ratios (ORs) of 2.6 (95% confidence interval [CI], 1.7-3.9) for CFH and 4.1 (95% CI, 2.7-6.3) for LOC387715 for the homozygous risk genotypes (P<.001 for trend for each additional risk allele for both genes). The effect of LOC387715 was stronger for progression to neovascular disease (OR, 6.1; 95% CI, 3.3-11.2) compared with geographic atrophy (OR, 3.0; 95% CI, 1.4-6.5) relative to no progression for the homozygous risk state. The presence of all adverse factors (both risk genotypes, smoking, and body mass index 25) increased risk 19-fold. Smoking and high body mass index increased odds of progression within each risk genotype. Genetic plus nongenetic risk scores provided an area under the receiver operating characteristic curve of up to 0.78. Conclusions  Common polymorphisms in the genes CFH and LOC387715 are independently related to AMD progression after adjustment for other known AMD risk factors. Presence of these polymorphisms plus AREDS vitamin-mineral treatment, smoking, and body mass index of 25 or higher identify patients who are highly susceptible to developing advanced stages of this visually disabling disease.      

Cognitive therapy for the prevention of suicide attempts: a randomized controlled trial

Context  Suicide attempts constitute a major risk factor for completed suicide, yet few interventions specifically designed to prevent suicide attempts have been evaluated. Objective  To determine the effectiveness of a 10-session cognitive therapy intervention designed to prevent repeat suicide attempts in adults who recently attempted suicide. Design, Setting, and Participants  Randomized controlled trial of adults (N = 120) who attempted suicide and were evaluated at a hospital emergency department within 48 hours of the attempt. Potential participants (N = 350) were consecutively recruited from October 1999 to September 2002; 66 refused to participate and 164 were ineligible. Participants were followed up for 18 months. Intervention  Cognitive therapy or enhanced usual care with tracking and referral services. Main Outcome Measures  Incidence of repeat suicide attempts and number of days until a repeat suicide attempt. Suicide ideation (dichotomized), hopelessness, and depression severity at 1, 3, 6, 12, and 18 months. Results  From baseline to the 18-month assessment, 13 participants (24.1%) in the cognitive therapy group and 23 participants (41.6%) in the usual care group made at least 1 subsequent suicide attempt (asymptotic z score, 1.97; P = .049). Using the Kaplan-Meier method, the estimated 18-month reattempt-free probability in the cognitive therapy group was 0.76 (95% confidence interval [CI], 0.62-0.85) and in the usual care group was 0.58 (95% CI, 0.44-0.70). Participants in the cognitive therapy group had a significantly lower reattempt rate (Wald ²₁ = 3.9; P = .049) and were 50% less likely to reattempt suicide than participants in the usual care group (hazard ratio, 0.51; 95% CI, 0.26-0.997). The severity of self-reported depression was significantly lower for the cognitive therapy group than for the usual care group at 6 months (P= .02), 12 months (P = .009), and 18 months (P = .046). The cognitive therapy group reported significantly less hopelessness than the usual care group at 6 months (P = .045). There were no significant differences between groups based on rates of suicide ideation at any assessment point. Conclusion  Cognitive therapy was effective in preventing suicide attempts for adults who recently attempted suicide.      

Effects of antibiotic therapy on outcomes of patients with coronary artery disease: a meta-analysis of randomized controlled trials

Context  Although Chlamydia pneumoniae infection has been associated with the initiation and progression of atherosclerosis, results of clinical trials investigating antichlamydial antibiotics as adjuncts to standard therapy in patients with coronary artery disease (CAD) have been inconsistent. Objective  To conduct a meta-analysis of clinical trials of antichlamydial antibiotic therapy in patients with CAD. Data Sources  The MEDLINE and Cochrane Central Register of Controlled Trials databases were searched from 1966 to April 2005 for English-language trials of antibiotic therapy in patients with CAD. Bibliographies of retrieved articles were searched for further studies. Presentations at major scientific meetings (2003-2004) were also reviewed. Search terms included antibacterial agents, myocardial infarction, unstable angina, and coronary arteriosclerosis. Study Selection  Eligible studies were prospective, randomized, placebo-controlled trials of antichlamydial antibiotic therapy in patients with CAD that reported all-cause mortality, myocardial infarction, or unstable angina. Of the 110 potentially relevant articles identified, 11 reports enrolling 19 217 patients were included. Data Extraction  Included studies were reviewed to determine the number of patients randomized, mean duration of follow-up, and end points. End points of interest included all-cause mortality, myocardial infarction (MI), and a combined end point of MI and unstable angina. Data Synthesis  Event rates were combined using a random-effects model. Antibiotic therapy had no impact on all-cause mortality among treated vs untreated patients (4.7% vs 4.6%; odds ratio [OR], 1.02; 95% confidence interval [CI], 0.89-1.16; P = .83), on the rates of MI (5.0% vs 5.4%; OR, 0.92; 95% CI, 0.81-1.04; P = .19), or on the combined end point of MI and unstable angina (9.2% vs 9.6%; OR, 0.91; 95% CI, 0.76-1.07; P = .25). Conclusion  Evidence available to date does not demonstrate an overall benefit of antibiotic therapy in reducing mortality or cardiovascular events in patients with CAD.      

Repetitive bilateral arm training and motor cortex activation in chronic stroke: a randomized controlled trial

Context  Reorganization in central motor networks occurs during early recovery from hemiparetic stroke. In chronic stroke survivors, specific rehabilitation therapy can improve upper extremity function. Objective  To test the hypothesis that in patients who have chronic motor impairment following stroke, specific rehabilitation therapy that improves arm function is associated with reorganization of cortical networks. Design, Setting, and Patients  A randomized controlled clinical trial conducted in a US ambulatory rehabilitation program with 21 patients (median [IQR], 50.3 [34.8-77.3] months after unilateral stroke). Data were collected between 2001 and 2004. Interventions  Patients were randomly assigned to bilateral arm training with rhythmic auditory cueing (BATRAC) (n = 9) or standardized dose-matched therapeutic exercises (DMTE) (n = 12). Both were conducted for 1 hour, 3 times a week, for 6 weeks. Main Outcome Measures  Within 2 weeks before and after the intervention, brain activation during elbow movement assessed by functional magnetic resonance imaging (fMRI) and functional outcome assessed using arm function scores. Results  Patients in the BATRAC group but not in the DMTE group increased hemispheric activation during paretic arm movement (P = .03). Changes in activation were observed in the contralesional cerebrum and ipsilesional cerebellum (P = .009). BATRAC was associated with significant increases in activation in precentral (P<.001) and postcentral gyri (P = .03) and the cerebellum (P<.001), although 3 BATRAC patients showed no fMRI changes. Considering all patients, there were no differences in functional outcome between groups. When only BATRAC patients with fMRI response were included (n = 6), BATRAC improved arm function more than DMTE did (P = .02). Conclusions  These preliminary findings suggest that BATRAC induces reorganization in contralesional motor networks and provide biological plausibility for repetitive bilateral training as a potential therapy for upper extremity rehabilitation in hemiparetic stroke.      

Results of therapy for acute lymphoblastic leukemia in black and white children

Context  Treatment results for acute lymphoblastic leukemia (ALL) clearly have improved over the past decade, but black children have not fared as well as white children in large national trials. Objective  To compare the clinical outcomes of therapy for black and white children with ALL treated at a single institution. Design, Setting, and Patients  A retrospective analysis of 412 children and adolescents (68 black, 338 white, and 6 other race) with newly diagnosed ALL who were treated consecutively at a pediatric cancer center in Memphis, Tenn. Patients were enrolled from December 1991 to July 1998 in successive Total Therapy studies regardless of race, ethnicity, or ability to pay and received risk-directed therapy according to stringent criteria. Interventions  All patients received the same intensive, remission-induction therapy followed by 120 weeks of risk-assigned postremission therapy that included reinduction treatment, pulses of high-dose methotrexate, and early intensification of intrathecal chemotherapy. Main Outcome Measures  Event-free and overall survival rates for black and white children were estimated by the method of Kaplan and Meier and compared with the Mantel-Haenszel test and by Cox proportional hazards regression analysis, adjusting for known prognostic factors. Results  The 68 black children were significantly more likely than the 338 white children to have higher-risk prognostic features, including an initial leukocyte count greater than 100 x 10³/µL, a T-cell immunophenotype, and the t(1;19) chromosomal translocation with E2A-PBX1 fusion, and were less likely to have hyperdiploid blast cells, a favorable prognostic factor in childhood ALL. However, the clinical outcomes for these 2 cohorts were not significantly different: 5-year event-free and overall survival rates were 80.7% (95% confidence interval [CI], 70.3%-91.1%) and 86.2% (95% CI, 77.2%-95.2%) for black children vs 79.4% (95% CI, 74.7%-84.1%) and 85.0% (95% CI, 80.9%-89.1%) for white children. Ten-year results also were comparable, but the CIs were wide because of the small numbers of patients who had been followed up for 10 years or more. The lack of a racial effect on the long-term outcome of therapy was still apparent in a multivariate Cox regression analysis, adjusting for sex, age, presenting leukocyte count, leukemic cell DNA index, immunophenotype, and central nervous system status. Conclusion  With equal access to effective antileukemic therapy, black and white children with ALL can expect the same high rate of cure.      

Thrombolytic therapy vs primary percutaneous coronary intervention for myocardial infarction in patients presenting to hospitals without on-site cardiac surgery: a randomized controlled trial

Context  Trials comparing primary percutaneous coronary intervention (PCI) and thrombolytic therapy for treatment of acute myocardial infarction (MI) suggest primary PCI is the superior therapy, although they differ with respect to the durability of benefit. Because PCI is often limited to hospitals that have on-site cardiac surgery programs, most acute MI patients do not have access to this therapy. Objective  To determine whether treatment of acute MI with primary PCI is superior to thrombolytic therapy at hospitals without on-site cardiac surgery and, if so, whether superiority is durable. Design  The Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) trial, a prospective, randomized trial conducted from July 1996 through December 1999. Setting  Eleven community hospitals in Massachusetts and Maryland without on-site cardiac surgery or extant PCI programs. Patients  Four hundred fifty-one thrombolytic-eligible patients with acute MI of less than 12 hours' duration associated with ST-segment elevation on electrocardiogram. Interventions  After a formal primary PCI development program was completed at all sites, patients were randomly assigned to receive primary PCI (n = 225) or accelerated tissue plasminogen activator (bolus dose of 15 mg and an infusion of 0.75 mg/kg for 30 minutes followed by 0.5 mg/kg for 60 minutes; n = 226). After initiation of assigned treatment, all care was determined by treating physicians. Main Outcome Measures  Six-month composite incidence of death, recurrent MI, and stroke; median hospital length of stay. Results  The incidence of the composite end point was reduced in the primary PCI group at 6 weeks (10.7% vs 17.7%; P = .03) and 6 months (12.4% vs 19.9%; P = .03) after index MI. Six-month rates for individual outcomes were 6.2% vs 7.1% for death (P = .72), 5.3% vs 10.6% for recurrent MI (P = .04), and 2.2% vs 4.0% for stroke (P = .28) for primary PCI vs thrombolytic therapy, respectively. Median length of stay was also reduced in the primary PCI group (4.5 vs 6.0 days; P = .02). Conclusions  Compared with thrombolytic therapy, treatment of patients with primary PCI at hospitals without on-site cardiac surgery is associated with better clinical outcomes for 6 months after index MI and a shorter hospital stay.      

Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease

Context  Recent reports suggest an increasing occurrence and severity of Clostridium difficile–associated disease. We assessed whether the use of gastric acid–suppressive agents is associated with an increased risk in the community. Objective  To determine whether the use of gastric acid–suppressive agents increases the risk of C difficile–associated disease in a community population. Design, Setting, and Patients  We conducted 2 population-based case-control studies using the United Kingdom General Practice Research Database (GPRD). In the first study, we identified all 1672 cases of C difficile recorded between 1994 and 2004 among all patients registered for at least 2 years in each practice. Each case was matched to 10 controls on calendar time and the general practice. In the second study, a subset of these cases defined as community-acquired, that is, not hospitalized in the prior year, were matched on practice and age with controls also not hospitalized in the prior year. Main Outcome Measures  The incidence of C difficile and risk associated with gastric acid–suppressive agent use. Results  The incidence of C difficile in patients diagnosed by their general practitioners in the General Practice Research Database increased from less than 1 case per 100 000 in 1994 to 22 per 100 000 in 2004. The adjusted rate ratio of C difficile–associated disease with current use of proton pump inhibitors was 2.9 (95% confidence interval [CI], 2.4-3.4) and with H₂-receptor antagonists the rate ratio was 2.0 (95% CI, 1.6-2.7). An elevated rate was also found with the use of nonsteroidal anti-inflammatory drugs (rate ratio, 1.3; 95% CI, 1.2-1.5). Conclusions  The use of acid-suppressive therapy, particularly proton pump inhibitors, is associated with an increased risk of community-acquired C difficile. The unexpected increase in risk with nonsteroidal anti-inflammatory drug use should be investigated further.