Browsing by Author "Richardson, Paul"

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    The Association Between the Ratio of Monocytes: Lymphocytes and Risk of Tuberculosis Among HIV-Infected Postpartum Women
    (BMC medicine, 2014) Naranbhai, Vivek; Moodley, Dhayendre; Chipato, Tsungai; Chibanda, Lynda Stranix; Nakabaiito, Clemensia; Kamateeka, Moreen; Musoke, Philippa; Manji, Karim; George, Kathleen; Emel, Lynda M.; Richardson, Paul; Andrew, Philip; Fowler, MaryGlenn; Fletcher, Helen; McShane, Helen; Coovadia, Hoosen M.; Hill, Adrian V. S.; for the HPTN 046 Protocol Team
    Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV.We tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious.Increasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%).Elevated ML ratio at three- to four-months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease.
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    Feasibility and Safety of ALVAC-HIV vCP1521 Vaccine in HIVexposed Infants in Uganda: Results from the First HIV Vaccine Trial in Infants in Africa
    (Journal of acquired immune deficiency syndromes, 2013) Kintu, Kenneth Guay; Andrew, Philip; Musoke, Philippa; Richardson, Paul; Asiimwe- Kateera, Brenda; Nakyanzi, Teopista; Wang, Lei; Glenn Fowler, Mary; Emel, Lynda; Ou, San-San; Baglyos, Lynn; Gurunathan, Sanjay; Zwerski, Sheryl; Jackson, J. Brooks; Guay, Laura
    The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) for prevention mother-to-child transmission of HIV would significantly advance the goal of eliminating HIV infection in children. Safety and feasibility results from Phase I, randomized, double blind, placebo-controlled trial of ALVACHIV vCP1521 in infants born to HIV-1-infected women in Uganda are reported. Methods—HIV exposed infants were enrolled at birth and randomized (4:1) to receive vaccine or saline placebo intramuscular injections at birth, 4, 8 and 12 weeks of age. Vaccine reactogenicity was assessed at vaccination, and days 1 and 2 post-vaccination. Infants were followed until 24 months of age. HIV infection status was determined by HIV DNA PCR. Findings—From October 2006 to May 2007, 60 infants (48 vaccine, 12 placebo) were enrolled with 98% retention at 24 months. One infant was withdrawn, but there were no missed visits or vaccinations among the 59 infants retained. Immune responses elicited by Diptheria, Polio, Hepatitis B and Heamophilus influenzae type B and measles vaccination were similar in the two arms. The vaccine was well tolerated with no severe or life-threatening reactogenicity events. Adverse events were equally distributed across both study arms. Four infants were diagnosed as HIV infected [3 at birth (2 vaccine, 1 placebo) and one in vaccine arm at 2 weeks of age]. Interpretation—The ALVAC-HIV vCP1521 vaccination was feasible and safe in infants born to HIV-infected women in Uganda. The conduct of high quality infant HIV vaccine trials is achievable in Africa.