Early Virologic Failure and Rescue Therapy of Tenofovir,Abacavir, and Lamivudine for Initial Treatment of HIV-1 Infection: TONUS Study

Abstract

Background: To assess the efficacy and safety of the triple NRTI combination of abacavir (ABC), lamivudine (3TC), and tenofovir (TDF) in a once-daily regimen. Method: 38 HIV-naive patients (pts) were treated in a prospective open-arm study over 48 weeks (W48). Virological failure was defined as never achieving plasma HIV-1 RNA <400 copies/mL or rebound of ≥0.7 log₁₀. Results: 12/36 (33%) pts had virologic failure at W24 and 10 additional pts had HIV RNA >50 copies/mL at W12 or W24. There was a significant association between baseline viral load (VL) and virologic failure in 0%, 29%, and 64% pts with baseline VL levels <4, 4-5, and >5 log₁₀ copies/mL, respectively (p = .014). 76% of pts developed K65R and M184V/I mutations by W24, and 19% developed M184V/I alone. At W4, 86% of pts had adequate plasma C_min for the 3 drugs. 14 pts with K65R and M184V/I were given a rescue therapy with a successful outcome (<50 copies/mL; median follow-up 48 weeks). Conclusion: Convergent genetic pathway to resistance, in conjunction with lower antiretroviral potency, may explain the high rate of selection K65R and M184V mutations. These mutations did not appear to have a negative effect on rescue therapy with a variety of regimens.     

Prevalence and risk factors for developing K65R mutations among HIV-1 infected patients who fail an initial regimen of fixed-dose combination of stavudine, lamivudine, and nevirapine.

BACKGROUND: A fixed-dose combination of stavudine, lamivudine, and nevirapine (d4T/3TC/NVP) is extensively used as initial antiretroviral regimen in developing countries. K65R mutations that occur after failing this regimen prevent the use of tenofovir, didanosine, and abcavir in the second-line regimen. OBJECTIVES: To determine the prevalence and risk factors of K65R mutations after failing d4T/3TC/NVP. STUDY DESIGN: Genotypic resistance testing was conducted among HIV-1 infected patients who experienced virological failure with an initial regimen of d4T/3TC/NVP. RESULTS: There were 122 patients who received antiretroviral therapy (ART) for a median (IQR) duration of 19 (13-27) months. Median (IQR) CD4 cell count and plasma HIV-1 RNA at virological failure was 174 (109-264) cells/mm(3) and 4.0 (3.7-4.6)log copies/mL, respectively. The prevalence of K65R mutations was 7%. Patients with K65R mutations had higher plasma HIV-1 RNA at virological failure compared to patients without K65R mutations (4.9log copies/mL vs. 4.0log copies/mL, p=0.001). By logistic regression analysis only plasma HIV-1 RNA at failure correlated with the occurrence of K65R mutations [OR 4.2 (95% CI, 1.5-11.2) per 0.5log copies/mL increment of HIV-1 RNA]. CONCLUSIONS: Seven percent of patients had K65R mutations after failing an initial d4T/3TC/NVP regimen. Tenofovir, didanosine, and abcavir cannot be used in second-line regimen for these patients. HIV-1 RNA at the time that virological failure was detected correlated with the occurrence of K65R mutations.     

河南省长期接受抗病毒治疗的艾滋病患者耐药横断面分析

目的 阐明河南省长期接受艾滋病抗病毒治疗患者的耐药情况,为这类患者继续有效的治疗提供参考依据.方法 抽取河南省两个艾滋病重点县中2004年左右开始接受一线抗病毒治疗的艾滋病患者,进行CD4+T淋巴细胞、病毒载量和基因型耐药检测.结果 两个县共抽取164例艾滋病患者,这些患者的CD4+T淋巴细胞计数的中位数(四分位数)为398.00(242.00 ～489.50)个/μl,有32.32％的患者体内检测不到病毒.有95例患者的病毒载量大于1000拷贝/ml,其中的77例患者完成了耐药检测.在这77例患者中,有耐药突变(任意一种)发生的患者占到68.83％,其中NNRTIs类突变较高为64.94％,NRTIs类突变为55.84％,无PIs类突变发生.NNRTIs类耐药突变中发生最多的是K103N/S(44.16％),其次为G190A/S(19.48％)和Y181C/V(14.29％).NRTIs类耐药突变中发生最多的是胸苷类似物突变(thymidine analogue mutations,TAMs),≥1TAM占46.75％,TAM-1/TAM-2占24.68％,M184V/I为24.68％.77例患者中,对NRTIs类药物ddI、3TC、AZT、D4T和TDF产生耐药的患者分别占50.65％、33.77％、48.05％、50.65％和46.75％.对NNRTIs类药物EFV、NVP和DLV产生耐药的患者分别占64.94％、64.94％和62.34％.结论 河南省长期接受抗病毒治疗的艾滋病患者的耐药情况严峻,需要对这部分患者重点关注并及时调整治疗方案.