Prevalence and patterns of HIV drug resistance in patients with suspected virological failure in North-Western Tanzania

Henerico, Shimba; Mikasi, Sello Given; Kalluvya, Samuel; Brauner, Jan Markus; Abdul, Seif; Lyimo, Eric; Desderius, Bernard; Korn, Klaus; Zyl, Gert van; Jacobs, Graeme Brendon; Preiser, Wolfgang; Kasang, Christa

doi:10.1093/jac/dkab406

Cited by 11 publications

(9 citation statements)

References 22 publications

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“…Consistent with a previous study reporting higher prevalence of TAMs in individuals on long-term ART (>36 months) from Ghana (Nii-Trebi et al, 2013), all the TAMs detected in this study were in individuals receiving ART for a minimum of 40 months. TAMs are reported to be common in individuals failing tenofovir disoproxil fumarate-based regimens in sub-Saharan Africa (Gregson et al, 2017;Henerico et al, 2022). Likewise, in this study, six out of the eight individuals with TAMs were on tenofovir disoproxil fumarate-based regimen.…”

Section: Discussionsupporting

confidence: 54%

High-level resistance to non-nucleos(t)ide reverse transcriptase inhibitor based first-line antiretroviral therapy in Ghana; A 2017 study

Parbie

Abana²,

Kushitor³

et al. 2022

Front. Microbiol.

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Expanding access to effective antiretroviral therapy (ART) is a major tool for management of Human Immunodeficiency Virus (HIV) infection. However, rising levels of HIV drug-resistance have significantly hampered the anticipated success of ART in persons living with HIV (PLWH), particularly those from Africa. Though great strides have been made in Ghana toward achieving the UNAIDS “95-95-95” target, a substantial number of PLWH receiving ART have not attained viral suppression. This study investigated patterns of drug resistance mutations in ART naïve as well as ART-experienced PLWH receiving first-line regimen drugs from Ghana. In a cross-sectional study, blood samples were collected from HIV-1 infected adults (≥18 years) attending HIV/AIDS clinic at the Eastern Regional Hospital, Koforidua, Ghana from September to October 2017. Viral RNA isolated from plasma were subjected to genotypic drug resistance testing for Protease Inhibitors (PI), Reverse Transcriptase Inhibitors (RTI), and Integrase Strand Transfer Inhibitors (INSTI). A total of 95 (84 ART experienced, 11 ART naïve) HIV-1 infected participants were sampled in this study. Sixty percent (50/84) of the ART-experienced participants were controlling viremia (viral load < 1,000 copies/ml). Of the 95 patient samples, 32, 34, and 33 were successfully sequenced for protease, reverse-transcriptase, and integrase regions, respectively. The dominant HIV-1 subtypes detected were CRF02_AG (70%), and A3 (10%). Major drug resistance associated mutations were only detected for reverse transcriptase inhibitors. The predominant drug resistance mutations were against nucleos(t)ide reverse transcriptase inhibitors (NRTI)—M184V/I and non-nucleos(t)ide reverse transcriptase inhibitors (NNRTI)—K103N. In the ART-experienced group, M184V/I and K103N were detected in 54% (15/28) and 46% (13/28) of individuals, respectively. Both mutations were each detected in 33% (2/6) of ART naïve individuals. Multiclass resistance to NRTI and NNRTI was detected in 57% of ART-experienced individuals and two ART naïve individuals. This study reports high-level resistance to NNRTI-based antiretroviral therapy in PLWH in Ghana. However, the absence of major PI and INSTI associated-mutations is a good signal that the current WHO recommendation of Dolutegravir in combination with an NRTI backbone will yield maximum benefits as first-line regimen for PLWH in Ghana.

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Section: Discussionsupporting

confidence: 54%

High-level resistance to non-nucleos(t)ide reverse transcriptase inhibitor based first-line antiretroviral therapy in Ghana; A 2017 study

Parbie

Abana²,

Kushitor³

et al. 2022

Front. Microbiol.

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“…The high rates of HIVDR among adolescents are most likely due to prolonged NNRTIs and NRTIs exposure since childhood and ART adherence challenges. The most frequent NNRTI mutations found in the current study (K103N, Y181C/Y, G190A and A98G) are comparable to other studies, which included children <14 years and young adolescents 10–14 years [ 39 , 41 ]. The low genetic barrier to resistance of most NNRTIs [ 13 ] explain the study findings.…”

Section: Discussionsupporting

confidence: 88%

“…Moreover, in SSA, the PI DRMs frequencies are below 10% (21, 35, 44). Moreover, in SSA, the PI DRMs frequencies are below 10% [ 31 , 40 , 41 , 49 ], suggesting that ART failure is most likely due to suboptimal adherence. However, it was surprising that more than 85% of resistance mutations to PIs occurred in Brazilian children and adolescents who had a vertical transmission of HIV for unexplained reasons [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

HIV virologic response, patterns of drug resistance mutations and correlates among adolescents and young adults: A cross-sectional study in Tanzania

et al. 2023

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Background The emergence of HIV drug resistance mutations (DRMs) is of significant threat to achieving viral suppression (VS) in the quest to achieve global elimination targets. We hereby report virologic outcomes and patterns of acquired DRMs and its associated factors among adolescents and young adults (AYA) from a broader HIV drug resistance surveillance conducted in Tanzania. Methods Data of AYA was extracted from a cross-sectional study conducted in 36 selected facilities using a two-stage cluster sampling design. Dried blood spot (DBS) samples were collected and samples with a viral load (VL) ≥1000 copies/mL underwent genotyping for the HIV-1 pol gene. Stanford HIV database algorithm predicted acquired DRMs, Fisher’s exact test and multivariable logistic regression assessed factors associated with DRMs and VS, respectively. Findings We analyzed data of 578 AYA on antiretroviral therapy (ART) for 9–15 and ≥ 36 months; among them, 91.5% and 88.2% had VS (VL<1000copies/mL) at early and late time points, respectively. Genotyping of 64 participants (11.2%) who had VL ≥1000 copies/ml detected 71.9% of any DRM. Clinically relevant DRMs were K103N, M184V, M41L, T215Y/F, L210W/L, K70R, D67N, L89V/T, G118R, E138K, T66A, T97A and unexpectedly absent K65R. Participants on a protease inhibitor (PI) based regimen were twice as likely to not achieve VS compared to those on integrase strand transfer inhibitors (INSTI). The initial VL done 6 months after ART initiation of ≥1000copies/mL was the primary factor associated with detecting DRMs (p = .019). Conclusions VS amongst AYA is lower than the third UNAIDs target. Additionally, a high prevalence of ADR and high levels of circulating clinically relevant DRMs may compromise the long-term VS in AYA. Furthermore, the first VL result of ≥1000copies/ml after ART initiation is a significant risk factor for developing DRMs. Thus, strict VL monitoring for early identification of treatment failure and genotypic testing during any ART switch is recommended to improve treatment outcomes for AYA.

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“… 33 In addition, it has also been documented that the T97A accessory mutation is associated with increased dolutegravir resistance in conjunction with other DRMs in INSTI-experienced patients. 34 Our study has shown that DRMs against dolutegravir in INSTI-naive patients are rare. However, it is possible to occur, as shown in a study conducted in Uganda, which detected major INSTI-associated mutations (E138T, E138K and T66I) in the sequences of 6/511 (1.2%) ART-naive individuals, and accessory mutations were observed in 145 sequences, which accounted for 24% of the 511 sequences.…”

Section: Discussionmentioning

confidence: 75%

“…These possibilities have also been described in some case reports in South Africa, Botswana and Uganda. 34 , 37 , 38 The inevitability of some emergent drug resistance against dolutegravir has also been explained by mutations outside the integrase gene, arising in patients receiving dolutegravir-containing regimens with no mutations in the integrase gene, 39 as well as by the role of natural polymorphisms. 33 , 40 …”

Section: Discussionmentioning

confidence: 99%

Primary resistance against integrase strand transfer inhibitors in integrase strand transfer inhibitor-naive patients failing first- and second-line ART in Tanzania

Henerico

Lyimo

Makubi

et al. 2022

Journal of Antimicrobial Chemotherapy

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Introduction Sub-Saharan African countries are introducing integrase strand transfer inhibitors (INSTIs) in their ART programmes as the preferred first-line regimen, and dolutegravir is the INSTI of choice due to its potency, tolerability and high genetic barrier to resistance. Dolutegravir was introduced into the first-line ART regimen in Tanzania in 2019. However, there is a paucity of data on the occurrence of mutations in HIV lineages circulating in Tanzania. This study aimed to determine the prevalence of INSTI primary resistance mutations in Tanzanian patients exposed to ART but not INSTIs. Methods Plasma samples from 50 INSTI-naive patients failing first- or second-line ART [median (IQR) age: 40 (21.93–46.41) years; 68% women] were subjected to Sanger sequencing of the HIV integrase gene. Participants had been on ART for a median (IQR) duration of 7.32 (4.73–9.29) years, with 80% and 20% failing first- and second-line ART, respectively. Results No major INSTI mutations were found, but 2 (4%) participants had the accessory mutation T97A. Using the REGA HIV-1 subtyping tool, HIV subtype A1 (53.1%) was found to be dominant, followed by subtypes C (30.6%) and D (16.3%). Conclusions This study found no current evidence for transmitted resistance against INSTIs among unexposed patients failing ART and supports the scale-up of INSTI-based regimens. However, the presence of accessory mutations calls for the surveillance of INSTI resistance mutations to ensure that the anticipated long-term desired outcomes are achieved.

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Prevalence and patterns of HIV drug resistance in patients with suspected virological failure in North-Western Tanzania

Cited by 11 publications

References 22 publications

High-level resistance to non-nucleos(t)ide reverse transcriptase inhibitor based first-line antiretroviral therapy in Ghana; A 2017 study

High-level resistance to non-nucleos(t)ide reverse transcriptase inhibitor based first-line antiretroviral therapy in Ghana; A 2017 study

HIV virologic response, patterns of drug resistance mutations and correlates among adolescents and young adults: A cross-sectional study in Tanzania

Primary resistance against integrase strand transfer inhibitors in integrase strand transfer inhibitor-naive patients failing first- and second-line ART in Tanzania

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