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Estimating HIV-1 fitness characteristics from cross-sectional genotype data.

ABSTRACT: Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing in vivo viral fitness is a challenging task and yet one that has significant clinical relevance. Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure.

SUBMITTER: Gopalakrishnan S

PROVIDER: S-EPMC4222584 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Estimating HIV-1 fitness characteristics from cross-sectional genotype data.

Gopalakrishnan Sathej S Montazeri Hesam H Menz Stephan S Beerenwinkel Niko N Huisinga Wilhelm W

PLoS computational biology 20141106 11

Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and in ...[more]

PMID: 25375675

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Project description:BACKGROUND:Sero- prevalence studies often have a problem of missing data. Few studies report the proportion of missing data and even fewer describe the methods used to adjust the results for missing data. The objective of this review was to determine the analytical methods used for analysis in HIV surveys with missing data. METHODS:We searched for population, demographic and cross-sectional surveys of HIV published from January 2000 to April 2018 in Pub Med/Medline, Web of Science core collection, Latin American and Caribbean Sciences Literature, Africa-Wide Information and Scopus, and by reviewing references of included articles. All potential abstracts were imported into Covidence and abstracts screened by two independent reviewers using pre-specified criteria. Disagreements were resolved through discussion. A piloted data extraction tool was used to extract data and assess the risk of bias of the eligible studies. Data were analysed through a quantitative approach; variables were presented and summarised using figures and tables. RESULTS:A total of 3426 citations where identified, 194 duplicates removed, 3232 screened and 69 full articles were obtained. Twenty-four studies were included. The response rate for an HIV test of the included studies ranged from 32 to 96% with the major reason for the missing data being refusal to consent for an HIV test. Complete case analysis was the primary method of analysis used, multiple imputations 11(46%) was the most advanced method used, followed by the Heckman's selection model 9(38%). Single Imputation and Instrumental variables method were used in only two studies each, with 13(54%) other different methods used in several studies. Forty-two percent of the studies applied more than two methods in the analysis, with a maximum of 4 methods per study. Only 6(25%) studies conducted a sensitivity analysis, while 11(46%) studies had a significant change of estimates after adjusting for missing data. CONCLUSION:Missing data in survey studies is still a problem in disease estimation. Our review outlined a number of methods that can be used to adjust for missing data on HIV studies; however, more information and awareness are needed to allow informed choices on which method to be applied for the estimates to be more reliable and representative.

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Dataset Information

Estimating HIV-1 fitness characteristics from cross-sectional genotype data.

Publications

Estimating HIV-1 fitness characteristics from cross-sectional genotype data.

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