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  • 1
    Online Resource
    Online Resource
    SAGE Publications ; 2016
    In:  Statistical Methods in Medical Research Vol. 25, No. 2 ( 2016-04), p. 917-935
    In: Statistical Methods in Medical Research, SAGE Publications, Vol. 25, No. 2 ( 2016-04), p. 917-935
    Abstract: In many resource-poor countries, hiv-infected patients receive a standardized antiretroviral cocktail. In these settings, population-level surveillance of drug resistance is needed to characterize the prevalence of resistance mutations and to enable antiretroviral therapy programs to select the optimal regimen for their local population. The surveillance strategy currently recommended by the World Health Organization is prohibitively expensive in some settings and may not provide a sufficiently precise rendering of the emergence of drug resistance. By using a novel assay on pooled sera samples, we decrease surveillance costs while simultaneously increasing the accuracy of drug resistance prevalence estimates for an important mutation that impacts first-line antiretroviral therapy. We present a Bayesian model for pooled-testing data that garners more information from each resistance assay conducted, compared with individual testing. We expand on previous pooling methods to account for uncertainty about the population distribution of within-subject resistance levels. In addition, our model accounts for measurement error of the resistance assay, and this added uncertainty naturally propagates through the Bayesian model to our inference on the prevalence parameter. We conduct a simulation study that informs our pool size recommendations and that shows that this model renders the prevalence parameter identifiable in instances when an existing non-model-based estimator fails.
    Type of Medium: Online Resource
    ISSN: 0962-2802 , 1477-0334
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2016
    detail.hit.zdb_id: 2001539-2
    detail.hit.zdb_id: 1136948-6
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  • 2
    In: Antiviral Chemistry and Chemotherapy, SAGE Publications, Vol. 15, No. 4 ( 2004-08), p. 189-200
    Abstract: To detect and characterize polymerase gene ( pol) polymorphisms and mutation patterns in HIV-1C-infected Batswana patients treated with reverse transcriptase inhibitors, samples from AIDS patients treated with highly active antiretroviral therapy (HAART) were sequenced for the region encompassing the entire HIV-1 protease (PR) and the first 335 amino acids of reverse transcriptase (RT). Amongst the 16 patients treated with antiretroviral (ARV) drugs, eight started HAART regimens containing didanosine, stavudine and nevirapine (ddI/d4T/NVP) or efavirenz (EFV) (arm A) while the others started with zidovudine (AZT) and lamivudine (3TC) given together as combivir (CBV) with either NVP or EFV as arm B. Arm B is the first line regimen currently provided by the Botswana ARV national programme. Greater efficacy, in terms of treatment duration, was observed in patients in arm B (14 months) as compared with patients in arm A (9 months); P 〈 0.05, n=8. Appearance of the M184V mutation in the arm B patients coincided with a rebound of viral load (VL) (4.3 +0.1 log 10 RNA copies/ml) and a significantly improved immunological parameter (ΔCD4=207.0 +48.1 cells/μl; P 〈 0.05). Interestingly, patients developing the M184V mutation preferentially harboured polymorphisms Q174K and/or I178L located in close proximity to pol position 184. The M184V mutation occurred following a clear clinical benefit consisting of increased CD4 cell counts and lower plasma viral loads. Primary mutations known to be associated with NNRTI and NRTI resistance for HIV-1B were observed in 10 of the 16 treated patients.
    Type of Medium: Online Resource
    ISSN: 2040-2066 , 2040-2066
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2004
    detail.hit.zdb_id: 2130088-4
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  • 3
    In: Antiviral Therapy, SAGE Publications, Vol. 18, No. 4 ( 2013-05), p. 1-6
    Abstract: Pharmacokinetic data for lopinavir in late pregnancy and in breastfeeding are limited, and no data for abacavir in breast milk are available. Methods Women in the Mma Bana Study initiated HAART from 18 to 34 weeks of gestation. We determined trough plasma and whole breast milk concentrations of lopinavir (LPV), abacavir (ABC), nevirapine (NVP), lamivudine (3TC) and zidovudine (ZDV) among separate subsets of pregnant and breastfeeding women, and in plasma of exposed infants. Lopinavir was measured 1 month after starting HAART or 1 month postpartum, and other drugs were measured 1 month postpartum. Results Sampling occurred a median of 14 h (range 11–17) from last maternal drug ingestion. Although 50% higher median LPV levels were seen in postpartum than antepartum plasma (8.29 μg/ml versus 5.51 μg/ml; P=0.02), antepartum levels with standard LPV dosing were therapeutic for all women ( 〉 1.0 μg/ml). Very low LPV levels ( 〈 0.25 μg/ml) were detected in breast milk. Median ABC levels in breast milk were 85% of those in plasma (0.057 μg/ml versus 0.067 μg/ml). Breast milk concentrations of NVP and 3TC were 27% and 74% of plasma levels, respectively. At these trough maternal time points, only NVP was detectable in potentially inhibitory levels in breastfeeding infants, and most infants had non-detectable levels of LPV, ABC, ZDV and 3TC via maternal breast milk. Conclusions Standard LPV dosing achieved therapeutic levels in pregnancy and no appreciable concentrations in breast milk. ABC is detectable in breast milk at similar concentrations to plasma, but does not result in appreciable infant exposure.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2013
    detail.hit.zdb_id: 2118396-X
    SSG: 15,3
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  • 4
    In: Antiviral Chemistry and Chemotherapy, SAGE Publications, Vol. 16, No. 2 ( 2005-04), p. 103-115
    Abstract: Current HIV-1 antiretroviral (ARV) drug resistance knowledge is limited to HIV-1 subtype B (HIV-1B). We addressed whether unique genetic and phenotypic properties of HIV-1 subtype C (HIV-1C), southern Africa's most prevalent subtype, may foment earlier and/or distinct resistance mutations. Population-level HIV-1C genotypes were evaluated with respect to drug resistance prevalence before Botswana's public ARV treatment programme began. Viruses were genotyped from 11 representative districts of northern and southern Botswana, and consensus sequences from these 71 individuals and 51 previously reported sequences from HIV-positive blood donors were constructed. Phylogenetic analysis classified all 71 sequences but one, which exhibited pol gene mosaicism, as HIV-1C. The protease and reverse transcriptase coding region had no detectable known primary mutations associated with HIV-1B protease inhibitor (PI) drug resistance. Secondary mutations associated with PI drug resistance were found in all sequences. Several HIV-1C—specific polymorphic sites were found across the pol gene. Northern and southern Botswana viral sequences showed no significant differences from each other. Population genotyping shows that, without countrywide ARV treatment, HIV-1C—infected Batswana harbour virtually no primary mutations known to confer resistance to the three major HIV-1B ARV drug classes. Some secondary PI mutations and polymorphic sites in the protease enzyme necessitate continuous population monitoring, particularly after introduction of countrywide ARV treatment in Botswana. Although its PI resistance development rate and kinetics are not known, our data may suggest increased susceptibility and readiness of HIV-1C to develop resistance under drug pressure when the PI class of drugs is used.
    Type of Medium: Online Resource
    ISSN: 2040-2066 , 2040-2066
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2005
    detail.hit.zdb_id: 2130088-4
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