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      Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa

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          Abstract

          Objective:

          To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs).

          Design:

          Prospective cohort.

          Methods:

          Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3–6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-to-event endpoints: CD4 + cell count 350 cells/μl or less, viral load measurement at least 1 × 10 5 copies/ml, and clinical AIDS.

          Results:

          From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4 + hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09).

          Conclusion:

          Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials.

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          Most cited references29

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          Global and regional distribution of HIV-1 genetic subtypes and recombinants in 2004.

          To estimate the global and regional distribution of HIV-1 subtypes and recombinants in 2004. A study was conducted in which molecular epidemiological data on HIV-1 subtype distribution in individual countries were combined with country-specific estimates of the number of people living with HIV. HIV-1 subtype data were collected for 23 874 HIV-1 samples from 70 countries, which together accounted for 89% of all people living with HIV worldwide in 2004. The proportions of HIV-1 infections due to various subtypes detected in each country were combined with the number of HIV infected people in the respective countries to generate regional and global HIV-1 subtype distribution estimates. Subtype C accounted for 50% of all infections worldwide in 2004. Subtypes A, B, D and G accounted for 12%, 10%, 3% and 6%, respectively. The subtypes F, H, J and K together accounted for 0.94% of infections. The circulating recombinant forms CRF01_AE and CRF02_AG each were responsible for 5% of cases, and CRF03_AB for 0.1%. Other recombinants accounted for the remaining 8% of infections. All recombinant forms taken together were responsible for 18% of infections worldwide. Combining data on HIV-1 subtype distribution in individual countries with country-specific estimates of the number of people living with HIV provided a good method to generate estimates of the global and regional HIV-1 genetic diversity in 2004. The results could serve as an important resource for HIV scientists, public health officials and HIV vaccine developers.
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            Effect of human immunodeficiency virus Type 1 (HIV-1) subtype on disease progression in persons from Rakai, Uganda, with incident HIV-1 infection.

            Human immunodeficiency virus type 1 (HIV-1) subtypes differ in biological characteristics that may affect pathogenicity. We determined the HIV-1 subtype-specific rates of disease progression among 350 HIV-1 seroconverters. Subtype, viral load, and CD4(+) cell count were determined. Cox proportional hazards regression modeling was used to estimate adjusted hazard ratios (HRs) of progression to acquired immunodeficiency syndrome (AIDS) (defined as a CD4(+) cell count of < or =250 cells/mm(3)) and to AIDS-associated death. A total of 59.1% of study subjects had subtype D strains, 15.1% had subtype A, 21.1% had intersubtype recombinant subtypes, 4.3% had multiple subtypes, and 0.3% had subtype C. Of the 350 subjects, 129 (37%) progressed to AIDS, and 68 (19.5%) died of AIDS. The median time to AIDS onset was shorter for persons with subtype D (6.5 years), recombinant subtypes (5.6 years), or multiple subtypes (5.8 years), compared with persons with subtype A (8.0 years; P = .022). Relative to subtype A, adjusted HRs of progression to AIDS were 2.13 [95% confidence interval {CI}, 1.10-4.11] for subtype D, 2.16 [95% CI, 1.05-4.45] for recombinant subtypes, and 4.40 [95% CI, 1.71-11.3] for multiple subtypes. The risk of progression to death was significantly higher for subtype D (adjusted HR, 5.65; 95% CI, 1.37-23.4), recombinant subtypes (adjusted HR, 6.70; 95% CI, 1.56-28.8), and multiple subtypes (adjusted HR, 7.67; 95% CI, 1.27-46.3), compared with subtype A. HIV disease progression is affected by HIV-1 subtype. This finding may impact decisions on when to initiate antiretroviral therapy and may have implications for future trials of HIV-1 vaccines aimed at slowing disease progression.
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              CLSI-Derived Hematology and Biochemistry Reference Intervals for Healthy Adults in Eastern and Southern Africa

              Background Clinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial. Methods and Findings Equal proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S.-derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials. Conclusions To accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa.
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                Author and article information

                Journal
                AIDS
                AIDS
                AIDS
                AIDS (London, England)
                Lippincott Williams & Wilkins
                0269-9370
                1473-5571
                13 November 2013
                06 November 2013
                : 27
                : 17
                : 2775-2786
                Affiliations
                [a ]International AIDS Vaccine Initiative, New York, New York, USA
                [b ]Project San Francisco, Kigali, Rwanda
                [c ]Medical Research Council/Uganda Virus Research Unit, Research Unit on AIDS, Entebbe, Uganda
                [d ]Biostatistics Consultant, Arlington, Virginia, USA
                [e ]Centre for Geographic Medicine-Coast/Kenya Medical Research Institute, Kilifi, Kenya
                [f ]University of Oxford, Oxford, UK
                [g ]Zambia-Emory HIV Research Project, Lusaka, Zambia
                [h ]Kenya AIDS Vaccine Initiative, University of Nairobi, Nairobi, Kenya
                [i ]Aurum Institute, Rustenburg
                [j ]Desmond Tutu HIV Centre, University of Cape Town, Cape Town, Republic of South Africa
                [k ]Emory University, Atlanta, Georgia, USA
                [l ]IAVI Human Immunology Laboratory, Imperial College, London, UK.
                Article
                10.1097/QAD.0000000000000012
                3815107
                24113395
                40fa95ce-4b21-4fb5-bae7-9d131c9bd692
                © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                : 4 April 2013
                : 12 July 2013
                : 17 July 2013
                Categories
                Epidemiology and Social
                Custom metadata
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                africa,aids,cd4+ cell count,hiv disease progression,hiv-1 subtype,hiv-serodiscordant couples,men who have sex with men,viral load

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