Prevalence of HIV type-1 drug-associated mutations in pre-therapy patients in the Free State, South Africa

Huang, Kuan-Hsiang Gary; Goedhals, Dominique; Fryer, Helen; Vuuren, C.V. van; Oliveira, Túlio de; Brown, Helen; Cassol, Sharon; Seebregts, Christopher J.; McLean, Angela R.; Klenerman, Paul; Phillips, Rodney E.; Frater, John

doi:10.3851/imp1416

Cited by 25 publications

(22 citation statements)

References 26 publications

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“…We studied 2,126 chronically HIV-1 subtype C-infected, antiretroviral-naïve adults from five established African cohorts, including subjects in (i) Durban, South Africa (n ϭ 1,218) (49,56), (ii) Bloemfontein, South Africa (n ϭ 261) (38), (iii) Kimberley, South Africa (n ϭ 31) (55), and (iv) Gaborone, Botswana (n ϭ 514) (69), and (v) southern African subjects attending outpatient HIV clinics in the Thames Valley area of the United Kingdom (n ϭ 102), originating from Botswana, Malawi, South Africa, and Zimbabwe (55 High-resolution sequence-based HLA typing was performed as previously described (55). For the present study, all HLA alleles that could not be resolved to the subtype level were considered missing (2,919 of 14,486; 20.2%).…”

Section: Methodsmentioning

confidence: 99%

Widespread Impact of HLA Restriction on Immune Control and Escape Pathways of HIV-1

Carlson

Listgarten

Pfeifer

et al. 2012

J Virol

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jThe promiscuous presentation of epitopes by similar HLA class I alleles holds promise for a universal T-cell-based HIV-1 vaccine. However, in some instances, cytotoxic T lymphocytes (CTL) restricted by HLA alleles with similar or identical binding motifs are known to target epitopes at different frequencies, with different functional avidities and with different apparent clinical outcomes. Such differences may be illuminated by the association of similar HLA alleles with distinctive escape pathways. Using a novel computational method featuring phylogenetically corrected odds ratios, we systematically analyzed differential patterns of immune escape across all optimally defined epitopes in Gag, Pol, and Nef in 2,126 HIV-1 clade C-infected adults. Overall, we identified 301 polymorphisms in 90 epitopes associated with HLA alleles belonging to shared supertypes. We detected differential escape in 37 of 38 epitopes restricted by more than one allele, which included 278 instances of differential escape at the polymorphism level. The majority (66 to 97%) of these resulted from the selection of unique HLA-specific polymorphisms rather than differential epitope targeting rates, as confirmed by gamma interferon (IFN-␥) enzyme-linked immunosorbent spot assay (ELISPOT) data. Discordant associations between HLA alleles and viral load were frequently observed between allele pairs that selected for differential escape. Furthermore, the total number of associated polymorphisms strongly correlated with average viral load. These studies confirm that differential escape is a widespread phenomenon and may be the norm when two alleles present the same epitope. Given the clinical correlates of immune escape, such heterogeneity suggests that certain epitopes will lead to discordant outcomes if applied universally in a vaccine.

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Section: Methodsmentioning

confidence: 99%

Widespread Impact of HLA Restriction on Immune Control and Escape Pathways of HIV-1

Carlson

Listgarten

Pfeifer

et al. 2012

J Virol

Self Cite

120

223

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“…One sequence had drug resistance mutations associated with nucleosides and nonnucleoside RT inhibitors (M184V and Y181C, respectively). Another five sequences had multiple resistance mutations associated with NNRTI resistance 35,41 (Fig. 3).…”

Section: Changes In Prevalence Of Tdr Mutations Over the Past 20 Yearsmentioning

confidence: 99%

“…Eight of these published datasets [34][35][36][37][38][39][40][41] contained sequences derived from HIV-1-infected, ART-naive individuals. Additional HIV-1 pol sequences 42 amplified from untreated patients were retrieved from GenBank and included in the analysis.…”

Section: Changes In Prevalence Of Tdr Mutations Over the Past 20 Yearsmentioning

confidence: 99%

Primary Drug Resistance in South Africa: Data from 10 Years of Surveys

Manasa

Katzenstein²,

Cassol³

et al. 2012

AIDS Research and Human Retroviruses

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HIV-1 transmitted drug resistance (TDR) could reverse the gains of antiretroviral rollout. To ensure that current first-line therapies remain effective, TDR levels in recently infected treatment-naive patients need to be monitored. A literature review and data mining exercise was carried out to determine the temporal trends in TDR in South Africa. In addition, 72 sequences from seroconvertors identified from Africa Centre's 2010 HIV surveillance round were also examined for TDR. Publicly available data on TDR were retrieved from GenBank, curated in RegaDB, and analyzed using the Calibrated Population Resistance Program. There was no evidence of TDR from the 2010 rural KwaZulu Natal samples. Ten datasets with a total of 1618 sequences collected between 2000 and 2010 were pooled to provide a temporal analysis of TDR. The year with the highest TDR rate was 2002 [6.67%, 95% confidence interval (CI): 3.09-13.79%; n = 6/90]. After 2002, TDR levels returned to < 5% (WHO low-level threshold) and showed no statistically significant increase in the interval between 2002 and 2010. The most common mutations were associated with NNRTI resistance, K103N, followed by Y181C and Y188C/L. Five sequences had multiple resistance mutations associated with NNRTI resistance. There is no evidence of TDR in rural KwaZulu-Natal. TDR levels in South Africa have remained low following a downward trend since 2003. Continuous vigilance in monitoring of TDR is needed as more patients are initiated and maintained onto antiretroviral therapy.

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“…First, primary viral resistance could, of course, have resulted in treatment failure in perfectly adhering patients. [37][38][39] But, according both to results from modeling studies 40 and local empirical evidence 41,42 primary resistance was very rare in South Africa during the time of this study. Hence, we would not expect primary resistance to have affected our results.…”

Section: Discussionmentioning

confidence: 47%

Validating Five Questions of Antiretroviral Nonadherence in a Public-Sector Treatment Program in Rural South Africa

Chaiyachati

Hirschhorn

Tanser

et al. 2011

AIDS Patient Care and STDs

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Simple questions are the most commonly used measures of antiretroviral treatment (ART) adherence in subSaharan Africa (SSA), but rarely validated. We administered five adherence questions in a public-sector primary care clinic in rural South Africa: 7-day recall of missed doses, 7-day recall of late doses, a six-level Likert item, a 30-day visual analogue scale of the proportion of doses missed, and recall of the time when an ART dose was last missed. We estimated question sensitivity and specificity in detecting immunologic (or virologic) failure assessed within 45 days of the adherence question date. Of 165 individuals, 7% had immunologic failure; 137 individuals had viral loads with 9% failure detected. The Likert item performed best for immunologic failure with sensitivity/specificity of 100%/5% (when defining nonadherence as self-reported adherence less than ''excellent''), 42%/55% (less than ''very good''), and 25%/95% (less than ''good''). The remaining questions had sensitivities 17%, even when the least strict cutoffs defined nonadherence. When we stratified the analysis by gender, age, or education, question performance was not substantially better in any of the subsamples in comparison to the total sample. Five commonly used adherence questions performed poorly in identifying patients with treatment failure in a public-sector ART program in SSA. Valid adherence measurement instruments are urgently required to identify patients needing treatment support and those most at risk of treatment failure. Available estimates of ART adherence in SSA are mostly based on studies using adherence questions. It is thus unlikely that our understanding of ART adherence in the region is correct.

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Prevalence of HIV type-1 drug-associated mutations in pre-therapy patients in the Free State, South Africa

Cited by 25 publications

References 26 publications

Widespread Impact of HLA Restriction on Immune Control and Escape Pathways of HIV-1

Widespread Impact of HLA Restriction on Immune Control and Escape Pathways of HIV-1

Primary Drug Resistance in South Africa: Data from 10 Years of Surveys

Validating Five Questions of Antiretroviral Nonadherence in a Public-Sector Treatment Program in Rural South Africa

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