Scale-up of antiretroviral treatment in sub-Saharan Africa is accompanied by increasing HIV-1 drug resistance mutations in drug-naive patients

Most patients failing antiretroviral treatment in Uganda continue to fail their treatment regimen even if a dominant drug-resistant HIV-1 genotype is not detected. In a recent retrospective study, we observed that approximately 30% of HIV-infected individuals in the Joint Clinical Research Centre (Kampala, Uganda) experienced virologic failure with a susceptible HIV-1 genotype based on standard Sanger sequencing. Selection of minority drug-resistant HIV-1 variants (not detectable by Sanger sequencing) under antiretroviral therapy pressure can lead to a shift in the viral quasispecies distribution, becoming dominant members of the virus population and eventually causing treatment failure. Here, we used a novel HIV-1 genotyping assay based on deep sequencing (DeepGen) to quantify low-level drug-resistant HIV-1 variants in 33 patients failing a first-line antiretroviral treatment regimen in the absence of drug-resistant mutations, as screened by standard population-based Sanger sequencing. Using this sensitive assay, we observed that 64% (21/33) of these individuals had low-frequency (or minority) drug-resistant variants in the intrapatient HIV-1 population, which correlated with treatment failure. Moreover, the presence of these minority HIV-1 variants was associated with higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading of drug-resistant HIV-1 variants from the viral quasispecies in the presence or absence of drug pressure, respectively. This study identified low-frequency HIV drug resistance mutations by deep sequencing in Ugandan patients failing antiretroviral treatment but lacking dominant drug resistance mutations as determined by Sanger sequencing methods. We showed that these low-abundance drug-resistant viruses could have significant consequences for clinical outcomes, especially if treatment is not modified based on a susceptible HIV-1 genotype by Sanger sequencing. Therefore, we propose to make clinical decisions using more sensitive methods to detect minority HIV-1 variants.

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Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study

The Lancet Infectious Diseases ◽

10.1016/s1473-3099(11)70255-9 ◽

2012 ◽

Vol 12 (4) ◽

pp. 307-317 ◽

Cited By ~ 127

Author(s):

Raph L Hamers ◽

Rob Schuurman ◽

Kim CE Sigaloff ◽

Carole L Wallis ◽

Cissy Kityo ◽

...

Keyword(s):

Drug Resistance ◽

Cohort Study ◽

Antiretroviral Treatment ◽

Sub Saharan Africa ◽

First Line ◽

Multicentre Cohort Study ◽

Sub Saharan ◽

Hiv 1 ◽

Multicentre Cohort

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HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0000000000001285 ◽

2017 ◽

Vol 75 (2) ◽

pp. e45-e54 ◽

Cited By ~ 17

Author(s):

Cissy Kityo ◽

Jennifer Thompson ◽

Immaculate Nankya ◽

Anne Hoppe ◽

Emmanuel Ndashimye ◽

...

Keyword(s):

Drug Resistance ◽

Virological Failure ◽

Sub Saharan Africa ◽

Resistance Mutations ◽

First Line ◽

Hiv Drug Resistance ◽

Drug Resistance Mutations ◽

Sub Saharan

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Low-Frequency HIV-1 Drug Resistance Mutations and Risk of NNRTI-Based Antiretroviral Treatment Failure

JAMA ◽

10.1001/jama.2011.375 ◽

2011 ◽

Vol 305 (13) ◽

pp. 1327 ◽

Cited By ~ 260

Author(s):

Jonathan Z. Li

Keyword(s):

Drug Resistance ◽

Treatment Failure ◽

Antiretroviral Treatment ◽

Low Frequency ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Hiv 1 ◽

Antiretroviral Treatment Failure

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Genetic Diversity and Drug Resistance Mutations in HIV-1 from Untreated Patients in Niamey, Niger

ISRN Microbiology ◽

10.5402/2011/797463 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Saïdou Mamadou ◽

Yahayé Hanki ◽

Amadou Roufaï Ali Maazou ◽

Balki Aoula ◽

Sanata Diallo

Keyword(s):

Drug Resistance ◽

Genetic Variants ◽

Care Center ◽

Rna Extraction ◽

Resistance Mutation ◽

Capital City ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Drug Naïve ◽

Hiv 1

The objective of the study was to estimate the prevalence of transmitted resistance to antiretroviral of HIV-1 circulating in Niger. We collected plasmas from 96 drug-naive patients followed up in the main HIV/AIDS Care Center of Niamey, the capital city of Niger. After RNA extraction and retrotranscription to proviral DNA, nested PCR was performed to amplify PR (codons 1–99) and RT (codons 1–240) fragments for sequencing. Sequences were analysed for phylogeny, then for resistance-associated mutations according to IAS-USA and Stanford's lists of mutations. We characterized six HIV-1 genetic variants: CRF02-AG (56.3%), CRF30_0206 (15.6%), subtype G (15.6%), CRF06_cpx (9.4%), CRF11_cpx (2.1%), and CRF01_AE (1%). About 8.3% of HIV strains had at least 1 resistance mutation: 4 strains with at least 1 mutation to NRTI, 5 for NNRTI, and 1 for PI, respectiveley 4.2%, 5.2%, and 1.0%. These preliminary results gave enough information for the need of instauring HIV drug resistance national surveillance.

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Immediate pools of malaria infections at diagnosis combined with targeted deep sequencing accurately quantifies frequency of drug resistance mutations

PeerJ ◽

10.7717/peerj.11794 ◽

2021 ◽

Vol 9 ◽

pp. e11794

Author(s):

Ozkan Aydemir ◽

Benedicta Mensah ◽

Patrick W. Marsh ◽

Benjamin Abuaku ◽

James Leslie Myers-Hansen ◽

...

Keyword(s):

Drug Resistance ◽

Diagnostic Testing ◽

Resistance Mutation ◽

Drug Resistance Mutation ◽

Sub Saharan Africa ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Antimalarial Resistance ◽

Sample Pooling ◽

Sub Saharan

Antimalarial resistance surveillance in sub-Saharan Africa is often constrained by logistical and financial challenges limiting its breadth and frequency. At two sites in Ghana, we have piloted a streamlined sample pooling process created immediately by sequential addition of positive malaria cases at the time of diagnostic testing. This streamlined process involving a single tube minimized clinical and laboratory work and provided accurate frequencies of all known drug resistance mutations after high-throughput targeted sequencing using molecular inversion probes. Our study validates this method as a cost-efficient, accurate and highly-scalable approach for drug resistance mutation monitoring that can potentially be applied to other infectious diseases such as tuberculosis.

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