Browsing by Author "Violari A."

Now showing 1 - 9 of 9
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    Antiretroviral treatment for children with peripartum nevirapine exposure
    (2010) Palumbo, P.; Lindsey, J. C.; Hughes, M. D.; Cotton, M. F.; Bobat, R.; Meyers, T.; Bwakura-Dangarembizi, M.; Chi, B. H.; Musoke, P.; Kamthunzi, P.; Schimana, W.; Purdue, L.; Eshleman, S. H.; Abrams, E. J.; Millar, L.; Petzold, E.; Mofenson, L. M.; Jean-Philippe, P.; Violari A.
    Background: Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown. Methods: We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. Results: A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P = 0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events. Conclusions: Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. Copyright © 2010 Massachusetts Medical Society.
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    Early antiretroviral therapy and mortality among HIV-infected infants
    (2008) Violari A.; Cotton M.F.; Gibb D.M.; Babiker A.G.; Steyn J.; Madhi S.A.; Jean-Philippe P.; McIntyre J.A.
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    Early antiretroviral treatment reduces risk of bacille Calmette- Guérin immune reconstitution adenitis
    (2011) Rabie H.; Violari A.; Duong T.; Madhi S.A.; Josipovic D.; Innes S.; Dobbels, Els; Lazarus E.; Panchia R.; Babiker A.G.; Gibb D.M.; Cotton M.F.
    SETTING: Two centres in Soweto and Cape Town, South Africa. OBJECTIVE: To assess the effects of timing of initiation of antiretroviral treatment (ART) and other factors on the risk of bacille Calmette-Guérin (BCG) related regional adenitis due to immune reconstitution infl ammatory syndrome (BCG-IRIS) in human immunodefi ciency virus (HIV) infected infants. DESIGN: HIV-infected infants aged 6-12 weeks with CD4 count ≥25% enrolled in the Children with HIV Early Antiretroviral Therapy (CHER) Trial received early (before 12 weeks) or deferred (after immunological or clinical progression) ART; infants with CD4 count <25% all received early ART. All received BCG vaccination after birth. Reactogenicity to BCG was assessed prospectively during routine study follow-up. RESULTS: Of 369 infants, 32 (8.7%) developed BCGIRIS within 6 months of starting ART, 28 (88%) within 2 months after ART initiation. Of the 32 cases, 30 (93.8%) had HIV-1 RNA > 750 000 copies/ml at initiation. Incidence of BCG-IRIS was 10.9 and 54.3 per 100 personyears (py) among infants with CD4 count ≥25% at enrolment receiving early (at median age 7.4 weeks) vs. deferred (23.2 weeks) ART, respectively (HR 0.24, 95%CI 0.11-0.53, P < 0.001). Infants with CD4 count <25% receiving early ART had intermediate incidence (41.7/ 100 py). Low CD4 counts and high HIV-1 RNA at initiation were the strongest independent risk factors for BCG-IRIS. CONCLUSIONS: Early ART initiation before immunological and/or clinical progression substantially reduces the risk of BCG-IRIS regional adenitis. © 2011 The Union.
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    Effect of HIV infection status and Anti-retroviral treatment on quantitative and qualitative antibody responses to pneumococcal conjugate vaccine in infants
    (2010) Madhi S.A.; Adrian P.; Cotton M.F.; McIntyre J.A.; Jean-Philippe P.; Meadows S.; Nachman S.; Kayhty H.; Klugman K.P.; Violari A.
    Serotype-specific antibody concentration and opsonophagocytic activity (OPA) were evaluated after 3 doses of pneumococcal conjugate vaccine. Groups included human immunodeficiency virus (HIV)-positive infants with CD4+ cell percentages ≥25% who initiated immediate antiretroviral treatment (the HIV+/ART+ group) or whose antiretroviral treatment was deferred until clinically or immunologically indicated (the HIV+/ART+ group). Immune responses were also evaluated in HIV-noninfected infants born to HIV-seronegative (M+/I+) or HIV-positive mothers (M+/I+). Antibody concentrations were similar between HIV+/ART+ and HIV+/ART+ infants. However, antibody concentrations were lowerin M+/I+ infants than in M+/I+ infants. Nevertheless, M+/I+ infants had superior OPA responses, compared with those in HIV+/ART+ infants, who in turn had better OPA responses, compared with those in HIV+/ART+ infants. © 2010 by the Infectious Diseases Society of America.
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    HAART and risk of tuberculosis in HIV-infected South African children: A multi-site retrospective cohort
    (2009) Martinson N.A.; Moultrie H.; Van Niekerk R.; Barry G.; Coovadia A.; Cotton M.; Violari A.; Gray G.E.; Chaisson R.E.; McIntyre J.A.; Meyers T.
    SETTING: Four human immunodeficiency virus (HIV) clinics located at South African tertiary hospitals. OBJECTIVE: To assess the effectiveness of highly active antiretroviral therapy (HAART) in reducing incident tuberculosis (TB) in HIV-infected children. DESIGN: Retrospective cohort. RESULTS: A total of 1132 children's records were included in the study. At entry to the cohort, the median (interquartile range [IQR]) age, CD4%, CD4 count and viral load of all children was respectively 6.3 years (4.1-8.8), 15% (9.0-22.2), 576 cells/mm 3 (287-960) and 160 000 copies/ml (54941.5-449683); 75.9% were started on HAART. The male:female ratio was 1:1, and median follow-up time was 1.7 years. In children whose follow-up included both pre-HAART and on-HAART periods, the incidence of clinically diagnosed TB was respectively 21.1 per 100 person-years (py; 95%CI 18.2-24.4) and 6.4/100 py (95%CI 4.8-8.1), and when restricted to confirmed cases, respectively 3.1/100 py (95%CI 2.2-4.2) and 0.8/100 py (95%CI 0.5-1.4). Only 23% of all cases of TB were microbiologically confirmed. Multivariate analyses showed that HAART reduced incident TB by approximately 70%, both for confirmed and all TB cases. CONCLUSIONS: In this high TB burden country, the incidence of diagnosis of TB in HIV-infected children is at least as high as that of adults. HAART reduces incident TB, but further prospective TB preventive and diagnostic studies are urgently needed in children. © 2009 The Union.
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    High prevalence of drug resistance amongst HIV-exposed and -infected children in a tuberculosis prevention trial
    (2012) Hesseling A.C.; Kim S.; Madhi S.; Nachman S.; Schaaf H.S.; Violari A.; Victor T.C.; McSherry G.; Mitchell C.; Cotton M.F.
    An emergence of drug-resistant tuberculosis (DR-TB) in settings affected by human immunodeficiency virus (HIV) and tuberculosis (TB) has been observed. We investigated the prevalence of DR-TB in P1041, a multicentred, randomised, double-blind trial which compared the administration of isoniazid (INH) to placebo, in HIV-exposed, non-infected and -infected African infants in the absence of any documented TB exposure. The prevalence of multidrug-resistant TB (MDR-TB) was 22.2% (95%CI 8.5-45.8) and INH monoresistance 5.6% (95%CI 0.1-27.6) among culture-confirmed cases, with all MDR-TB occurring in a single site. There was no association between INH treatment or placebo group, or between HIV infection status, and DR-TB prevalence. There was a high prevalence of DR-TB among HIV-exposed and -infected children. Surveillance of DR-TB among children in high-burden TB-HIV settings should be routine. © 2012 The Union.
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    Increased microbial translocation in ≤180 days old perinatally human immunodeficiency virus-positive infants as compared with human immunodeficiency virus-exposed uninfected infants of similar age
    (2011) Papasavvas E.; Azzoni L.; Foulkes A.; Violari A.; Cotton M.F.; Pistilli M.; Reynolds G.; Yin X.; Glencross D.K.; Stevens W.S.; McIntyre J.A.; Montaner L.J.
    BACKGROUND: The effect of early versus deferred antiretroviral treatment (ART) on plasma concentration of lipopolysaccharide (LPS) and host LPS-binding molecules in human immunodeficiency virus (HIV)-infected infants up to 1 year of age was investigated. METHODS: We evaluated 54 perinatally HIV-infected and 22 HIV-exposed uninfected infants (controls) at the first and second semester of life. All HIV-infected infants had a baseline CD4 of ≥25%, participated in the Comprehensive International Program of Research on AIDS Children with HIV Early Antiretroviral Therapy trial in South Africa, and were randomized in the following groups: group 1 (n = 20), ART deferred until CD4 <25% or severe HIV disease; and group 2 (n = 34), ART initiation within 6 to 12 weeks of age. LPS, endotoxin-core antibodies, soluble CD14 (sCD14), and LPS-binding protein (LBP) were measured in cryopreserved plasma. T-cell activation was measured in fresh whole blood. RESULTS: At the first semester, LPS concentration was higher in HIV-infected infants than in controls; sCD14, LBP, and T-cell activation were higher in group 1 than in group 2 and controls. Although LPS was not correlated with study variables, viral load was positively associated with sCD14, LBP, or endotoxin-core antibodies. At the second semester, LPS was not detectable and elevated host LPS-control molecules values were sustained in all groups and in conjunction with ART in all HIV-infected infants. CONCLUSIONS: Although plasma concentration of LPS was higher in perinatally HIV-infected infants 0 to 6 months of age than in controls independent of ART initiation strategy, concentration of LPS-control molecules was higher in infants with deferred ART, suggesting the presence of increased microbial translocation in HIV-infected infants with sustained early viral replication. Copyright © 2011 by Lippincott Williams & Wilkins.
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    Inferior quantitative and qualitative immune responses to pneumococcal conjugate vaccine in infants with nasopharyngeal colonization by Streptococcus pneumoniae during the primary series of immunization
    (2011) Madhi S.A.; Violari A.; Klugman K.P.; Lin G.; McIntyre J.A.; von Gottberg A.; Jean-Philippe P.; Cotton M.F.; Adrian P.
    Background: Heightened immunogenicity, measured one month after the primary series of pneumococcal conjugate vaccine (PCV), in African children was previously hypothesized to be due to increased rates of nasopharyngeal pneumococcal colonization during early infancy. Methods: We analyzed the effect of selected vaccine-serotype (6B, 19F and 23F) nasopharyngeal colonization prior to the first PCV dose or when colonized for the first time prior to the second or third (2nd/3rd) PCV dose on serotype quantitative and qualitative antibody responses. Results: Colonization prior to receiving the first PCV was associated with lower geometric mean antibody concentrations (GMCs) one month after the third dose of PCV and six months later to the colonizing-serotype. Colonized infants also had lower geometric mean titers (GMTs) on opsonophagocytosis activity assay (OPA) and a lower proportion had titers ≥8 against the colonizing serotypes (19F and 23F) post vaccination. Colonization occurring only prior to the 2nd/3rdPCV dose was also associated with lower GMCs and OPA GMTs to the colonizing-serotype. The effect of colonization with serotypes 19F and 23F prior to PCV vaccination had a greater effect on a lower proportion of colonized infants having OPA titers ≥8 than the effect of colonization on the lower proportion with antibody ≥0.35 μg/ml. Conclusion: Infant nasopharyngeal colonization at any stage before completing the primary series of PCV vaccination was associated with inferior quantitative and qualitative antibody responses to the colonizing-serotype. © 2011 Elsevier Ltd.
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    Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children
    (2011) Madhi S.A.; Nachman S.; Violari A.; Kim S.; Cotton M.F.; Bobat R.; Jean-Philippe P.; McSherry G.; Mitchell C.
    BACKGROUND: The dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infected children and uninfected children exposed to HIV during the perinatal period. METHODS: We randomly assigned 548 HIV-infected and 804 HIV-uninfected infants (91 to 120 days of age) to isoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infected children had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infected children and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfected children within 96 to 108 weeks after randomization. RESULTS: Antiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P = 0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P = 0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups. CONCLUSIONS: Primary isoniazid prophylaxis did not improve tuberculosis-disease- free survival among HIV-infected children or tuberculosis-infection-free survival among HIV-uninfected children immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infected children. (Funded by the National Institutes of Health and Secure the Future; ClinicalTrials.gov number, NCT00080119.) Copyright © 2011 Massachusetts Medical Society.