Drug resistance testing through remote genotyping and predicted treatment options in human immunodeficiency virus type 1 infected Tanzanian subjects failing first or second line antiretroviral therapy

被引:11
作者
Svard, Jenny [1 ]
Mugusi, Sabina [2 ]
Mloka, Doreen [3 ]
Neogi, Ujjwal [1 ]
Meini, Genny [4 ]
Mugusi, Ferdinand [5 ]
Incardona, Francesca [6 ]
Zazzi, Maurizio [4 ]
Sonnerborg, Anders [1 ,7 ]
机构
[1] Karolinska Inst, Karolinska Univ Hosp, Div Clin Microbiol, Dept Lab Med, Stockholm, Sweden
[2] Muhimbili Univ Hlth & Allied Sci, Dept Clin Pharmacol, Sch Med, Dar Es Salaam, Tanzania
[3] Muhimbili Univ Hlth & Allied Sci, Dept Pharmaceut Microbiol, Dar Es Salaam, Tanzania
[4] Univ Siena, Dept Med Biotechnol, Siena, Italy
[5] Muhimbili Univ Hlth & Allied Sci, Dept Internal Med, Dar Es Salaam, Tanzania
[6] EuResist Network GEIE, Rome, Italy
[7] Karolinska Inst, Karolinska Univ Hosp, Infect Dis Unit, Dept Med Huddinge, Stockholm, Sweden
基金
瑞典研究理事会;
关键词
VIROLOGICAL FAILURE; VIRAL LOAD; CHILDREN; PERFORMANCE; AFRICA; ADULTS; SWITCH;
D O I
10.1371/journal.pone.0178942
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Introduction Antiretroviral therapy (ART) has been successfully introduced in low-middle income countries. However an increasing rate of ART failure with resistant virus is reported. We therefore described the pattern of drug resistance mutations at antiretroviral treatment (ART) failure in a real-life Tanzanian setting using the remote genotyping procedure and thereafter predicted future treatment options using rule-based algorithm and the EuResist bioinformatics predictive engine. According to national guidelines, the default first-line regimen is tenofovir + lamivudine + efavirenz, but variations including nevirapine, stavudine or emtricitabine can be considered. If failure on first-line ART occurs, a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and boosted lopinavir or atazanavir is recommended. Materials and methods Plasma was obtained from subjects with first (n = 174) or second-line (n = 99) treatment failure, as defined by clinical or immunological criteria, as well as from a control group of ART naive subjects (n = 17) in Dar es Salaam, Tanzania. Amplification of the pol region was performed locally and the amplified DNA fragment was sent to Sweden for sequencing (split genotyping procedure). The therapeutic options after failure were assessed by the genotypic sensitivity score and the EuResist predictive engine. Viral load was quantified in a subset of subjects with second-line failure (n = 52). Results The HIV-1 pol region was successfully amplified from 55/174 (32%) and 28/99 (28%) subjects with first- or second-line failure, respectively, and 14/17 (82%) ART-naive individuals. HIV-1 pol sequence was obtained in 82 of these 97 cases (84.5%). Undetectable or very low (<2.6 log(10) copies/10(-3) L) viral load explained 19 out of 25 (76%) amplification failures in subjects at second-line ART failure. At first and second line failure, extensive accumulation of NRTI (88% and 73%, respectively) and NNRTI (93% and 73%, respectively) DRMs but a limited number of PI DRMs (11% at second line failure) was observed. First line failure subjects displayed a high degree of cross-resistance to second-generation NNRTIs etravirine (ETR; 51% intermediate and 9% resistant) and rilpivirine (RPV; 12% intermediate and 58% resistant), and to abacavir (ABC; 49% resistant) which is reserved for second line therapy in Tanzania. The predicted probability of success with the best salvage regimen at second-line failure decreased from 93.9% to 78.7% when restricting access to the NRTIs, NNRTIs and PIs currently available in Tanzania compared to when including all approved drugs. Discussion The split genotyping procedure is potential tool to analyse drug resistance in Tanzania but the sensitivity should be evaluated further. The lack of viral load monitoring likely results in a high false positive rate of treatment failures, unnecessary therapy switches and massive accumulation of NRTI and NNRTI mutations. The introduction of regular virological monitoring should be prioritized and integrated with drug resistance studies in resource limited settings.
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