Protease Inhibitor Resistance in the First 3 Years of Second-Line Antiretroviral Therapy for HIV-1 in Sub-Saharan Africa

Boender, T. Sonia; Hamers, Raph L; Ondoa, Pascale; Wellington, Maureen; Chimbetete, Cleophas; Siwale, Margaret; Maksimos, Eman E. F. Labib; Balinda, Sheila N.; Kityo, Cissy; Adeyemo, Titilope A.; Akanmu, Alani S; Mandaliya, Kishor; Botes, Mariëtte E.; Stevens, Wendy; Wit, Tobias F. Rinke de; Sigaloff, Kim C.E.

doi:10.1093/infdis/jiw219

Cited by 44 publications

(47 citation statements)

References 33 publications

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“…In a previous cross‐sectional study conducted in Uganda that assessed 36 patients failing second‐line ART, HIV subtype distribution was similar to that in our study, major PI mutation was observed in 19.4% of cases (18.5% in our study) and the three most prevalent DRM were the same: V82A, I54V and M46I/L . The reported rate of major PI mutations at second‐line failure is very variable: 3% and 21.9% in two clinical trials and 64% in one observational study . There is no evidence that subtype would have an impact on the rate, but it may have an impact on spectra of PI mutations.…”

Section: Discussionsupporting

confidence: 80%

“…In other words, without DRT, more than 60% of patients with VF included would have been unnecessarily switched to third‐line ART. Recent studies also reported a significant proportion of second‐line failure without major resistance to the current regimen and poor adherence was indicated as a major factor underlying VF .…”

Section: Discussionmentioning

confidence: 99%

“…As of June 2017, approximately 20.9 million people living with HIV were on antiretroviral therapy (ART) worldwide , and up to 25 million are expected to receive ART in 2020, of whom 0.5–3 million would be on a second‐line regimen . Prevalence of boosted protease inhibitor‐based second‐line virological failure in observational studies in sub‐Saharan Africa ranges from 10% to 38% and was 19% and 14% at 48 and 144 weeks respectively in two experimental studies . Factors commonly associated with second‐line failure are low CD4 count, high viral load and high genotypic sensitivity score (GSS) for nucleoside/nucleotide reverse transcriptase inhibitors (NRTI GSS) at first‐line failure, tuberculosis treatment while on second‐line and poor adherence of adults and children .…”

Section: Introductionmentioning

confidence: 99%

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HIV‐1 drug resistance testing at second‐line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third‐line

Fily

Ayikobua

Ssemwanga

et al. 2018

Tropical Med Int Health

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HIV‐1 drug resistance testing at second‐line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third‐line

Fily

Ayikobua

Ssemwanga

et al. 2018

Tropical Med Int Health

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“…In a study among adults in 12 Asian countries, the failure rate was 8.8 per 100 patientyears [20]. A large cohort study in six African countries among adults on second-line ART found that 15% experienced virologic failure after two years [30]. When only looking at the subgroup of younger children in our study, outcomes are even better than adult results, as the failure rate was 4.5 per 100 patient-years and 9.1% failed after two years.…”

Section: Discussionmentioning

confidence: 99%

Multicentre analysis of second‐line antiretroviral treatment in HIV‐infected children: adolescents at high risk of failure

Boerma

Bunupuradah

Dow

et al. 2017

Journal of the International AIDS Society

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Introduction: The number of HIV-infected children and adolescents requiring second-line antiretroviral treatment (ART) is increasing in low- and middle-income countries (LMIC). However, the effectiveness of paediatric second-line ART and potential risk factors for virologic failure are poorly characterized. We performed an aggregate analysis of second-line ART outcomes for children and assessed the need for paediatric third-line ART. Methods: We performed a multicentre analysis by systematically reviewing the literature to identify cohorts of children and adolescents receiving second-line ART in LMIC, contacting the corresponding study groups and including patient-level data on virologic and clinical outcomes. Kaplan–Meier survival estimates and Cox proportional hazard models were used to describe cumulative rates and predictors of virologic failure. Virologic failure was defined as two consecutive viral load measurements >1000 copies/ml after at least six months of second-line treatment. Results: We included 12 cohorts representing 928 children on second-line protease inhibitor (PI)-based ART in 14 countries in Asia and sub-Saharan Africa. After 24 months, 16.4% (95% confidence interval (CI): 13.9–19.4) of children experienced virologic failure. Adolescents (10–18 years) had failure rates of 14.5 (95% CI 11.9–17.6) per 100 person-years compared to 4.5 (95% CI 3.4–5.8) for younger children (3–9 years). Risk factors for virologic failure were adolescence (adjusted hazard ratio [aHR] 3.93, p < 0.001) and short duration of first-line ART before treatment switch (aHR 0.64 and 0.53, p = 0.008, for 24–48 months and >48 months, respectively, compared to <24 months). Conclusions: In LMIC, paediatric PI-based second-line ART was associated with relatively low virologic failure rates. However, adolescents showed exceptionally poor virologic outcomes in LMIC, and optimizing their HIV care requires urgent attention. In addition, 16% of children and adolescents failed PI-based treatment and will require integrase inhibitors to construct salvage regimens. These drugs are currently not available in LMIC.

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“…At second-line viral load (VL) failure, patients commonly have no PI resistance mutations [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries: An Observational Analysis Within the EARNEST Randomized Trial

Thompson

Kityo

Dunn

et al. 2018

Clinical Infectious Diseases

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Background Limited viral load (VL) testing in HIV-infected individuals on treatment in low-income countries often results in late detection of treatment failure. The impact of remaining on failing second-line, protease inhibitor (PI) containing regimens is unclear. Methods We retrospectively tested VL from 2,164 stored plasma samples from 386 patients randomised to receive PI-monotherapy (ritonavir-boosted lopinavir, after initial PI+raltegravir induction) in the EARNEST trial. Protease genotypic resistance testing was performed in samples with VL>1000 copies/ml. We assessed evolution of drug resistance mutations from virological failure (confirmed VL>1000 copies/ml) until discontinuation of PI-monotherapy and examined associations using Poisson and linear mixed-effects models. Results 118 patients had a median 68(IQR 48-88) weeks on PI-monotherapy post-failure. At failure, 21/107(20%) had intermediate/high resistance to lopinavir. 40-48 weeks post-failure, 49/72(68%) and 36/71(51%) had intermediate/high-level resistance to lopinavir and atazanavir. Most remained susceptible to darunavir (12/72[17%] intermediate, no high resistance). Common PI mutations were

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Protease Inhibitor Resistance in the First 3 Years of Second-Line Antiretroviral Therapy for HIV-1 in Sub-Saharan Africa

Abstract: Although VL suppression rates were high, PI resistance was detected in 22% of participants with VLs ≥1000 cps/mL. To ensure long-term ART success, intensified support for adherence, VL and drug resistance testing, and third-line drugs will be necessary.

Cited by 44 publications

References 33 publications

HIV‐1 drug resistance testing at second‐line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third‐line

HIV‐1 drug resistance testing at second‐line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third‐line

Multicentre analysis of second‐line antiretroviral treatment in HIV‐infected children: adolescents at high risk of failure

Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries: An Observational Analysis Within the EARNEST Randomized Trial

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