Antiretroviral drug resistance in KwaZulu Natal

夸祖鲁纳塔尔省的抗逆转录病毒耐药性

• 批准号: 9463184
• 负责人: Daniel R. Kuritzkes
• 金额: $ 22.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9463184
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adherence; Affect; African Traditional Medicine; Alleles; Anti-Retroviral Agents; Antiretroviral drug resistance; Blood; CD4 Lymphocyte Count; Caring; Case-Control Studies; Clinic; Clinical; Cohort Effect; Conflict (Psychology); Country; Data; Death Rate; Dose; Drug resistance; Enrollment; Erythrocytes; European; Failure; Frequencies; Generations; Genotype; Government; HIV; HIV drug resistance; HIV-1; HIV-1 drug resistance; Hair; Hospitals; Interview; Laboratories; Lamivudine; Logistic Regressions; Measures; Medical Records; Minority; Modeling; Monitor; Morbidity - disease rate; Mother-to-child HIV transmission; Mutation; NNRTI-resistance; National Health Services; Neurocognitive; Nevirapine; Outcome; PHEMX gene; Participant; Patient Self-Report; Patients; Pattern; Persons; Pharmaceutical Preparations; Pharmacy facility; Plasma; Population; Population Genetics; Prevalence; Prevalence Study; Prevention; Probability; Province; Questionnaires; Regimen; Regression Analysis; Reporting; Resistance; Resistance development; Resources; Risk; Risk Factors; Rural; Sampling; Source; South Africa; Southern Africa; Spottings; Structure; Tenofovir; Testing; Time; Treatment Failure; Validation; Variant; Viral; Virus; Woman; antiretroviral therapy; base; case control; clinically significant; cohort; cost; deep sequencing; design; experience; fitness; follow-up; interest; mortality; mutant; next generation sequencing; non-nucleoside reverse transcriptase inhibitors; novel; peri-urban; pill; prevent; public health relevance; resistance mutation; response; rural setting; success; theories; therapy adherence; transmission process; treatment adherence; treatment duration; virology

DESCRIPTION (provided by applicant): Since the introduction in 2002 of government-sponsored antiretroviral therapy (ART) in South Africa in 2002, nearly 1 million patients have received ART, and the death rate from HIV/AIDS has declined. Although early accounts of treatment success reported high rates of adherence and viral suppression, rates of virologic failure (VF) have begun to approximate those observed in resource-rich countries. Because virologic monitoring is less frequent than in the US, there is more opportunity for resistance mutations to accumulate before VF is detected and ART switched to a 2nd-line regimen. As a result, the efficacy of 2nd-line therapy may be compromised. To date, there has not been a comprehensive study of the prevalence and risk factors associated with drug resistance in persons failing 1st-line ART in South Africa. Likewise, the effect of minority drug-resistant variants on the efficacy of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens has not been studied except in women who received single-dose nevirapine (NVP) for prevention of mother-to-child transmission of HIV-1. Because transmitted resistance remains rare in South Africa, drug- resistant minority variants detected in this population may be assumed to reflect the spontaneous generation of such mutants by the error-prone HIV-1 RT. We propose to study the patterns and predictors of HIV-1 drug resistance after VF of 1st-line ART and the clinical significance of minority drug-resistant minority variants in peri-urban and rural settings in KwaZulu-Natal (KZN), South Africa. Specific aims of this proposal are as follows: 1) To determine the red blood cell ARV levels associated with VF and HIV-1 drug resistance at the time of 1st-line ART failure in KZN; 2) To determine the risk factors for VF and HIV-1 drug resistance in rural and peri-urban settings in the KZN province, South Africa; 3) To determine the effect of spontaneously arising drug- resistant minority variants on the risk of VF in patients receiving 1st-line ART. Subjects starting ART will be enrolled from clinics in two settings in KZN-peri-urban and rural. The number and patterns of HIV drug resistance mutations for patients who experience virologic failure of a 1st-line regimen of TDF plus lamivudine and EFV or NVP will be compared to resistance patterns reported for subtype B virus. A case-control design will be used to identify risk factors for suboptimal adherence and virologic failure with or without drug resistance in different settings in KZN province. The prevalence of minority drug resistant variants in the virus population will be determined in pre-treatment samples using allele-specific PCR and next-generation sequencing using the Illumina Solexa platform; the effect of these resistance mutations on the risk of virologic failure will be determined. Exploratory analyses will compare the frequency distribution of minority drug resistance mutations with the frequency predicted from population genetic theory to estimate the fitness cost of these mutations compared to the wildtype in the absence of drugs. The probability that a minority variant becomes fixed in the population and leads to resistance and VF will also be determined.

描述（由申请人提供）：自2002年南非引入政府资助的抗逆转录病毒疗法以来，已有近100万患者接受了抗逆转录病毒疗法，艾滋病毒/艾滋病死亡率有所下降。尽管早期治疗成功报告了高依从性和病毒抑制率，但病毒学失败率（VF）已开始接近资源丰富国家的观察结果。由于病毒学监测的频率低于美国，在检测到VF和ART转为二线治疗方案之前，耐药突变积累的机会更多。因此，二线治疗的疗效可能会受到损害。迄今为止，尚未对南非一线抗逆转录病毒治疗失败者的流行情况和与耐药相关的风险因素进行全面研究。同样，除了在接受单剂量奈韦拉平（NVP）预防HIV-1母婴传播的妇女中，尚未研究少数耐药变异对基于非核苷逆转录酶抑制剂（NNRTI）的方案疗效的影响。由于传播性耐药在南非仍然很少见，在这一人群中检测到的耐药少数变异可能反映了容易发生错误的HIV-1 rt自发产生的这种突变体。我们建议研究一线抗逆转录病毒治疗VF后HIV-1耐药性的模式和预测因素，以及在南非夸祖鲁-纳塔尔省（KZN）的城市周边和农村环境中少数耐药少数变异的临床意义。本提案的具体目的如下：1)确定KZN一线抗逆转录病毒治疗失败时与VF和HIV-1耐药性相关的红细胞抗逆转录病毒水平；2)确定南非KZN省农村和城市周边地区VF和HIV-1耐药的危险因素；3)确定自发产生的耐药少数变异对接受一线抗逆转录病毒治疗的患者发生VF风险的影响。开始抗逆转录病毒治疗的受试者将从kzn -城郊和农村两种环境的诊所招募。在TDF +拉米夫定和EFV或NVP一线治疗方案中经历病毒学失败的患者中，HIV耐药突变的数量和模式将与B亚型病毒报告的耐药模式进行比较。病例对照设计将用于确定次优依从性和病毒学失败的危险因素

项目成果

Concurrent use of traditional medicine and ART: Perspectives of patients, providers and traditional healers in Durban, South Africa.

同时使用传统医学和艺术：南非德班的患者，提供者和传统治疗师的观点。

• DOI: 10.1080/17441692.2014.967709
• 发表时间: 2015-01
• 期刊: Global public health
• 影响因子: 3.3
• 作者: Appelbaum Belisle H;Hennink M;Ordóñez CE;John S;Ngubane-Joye E;Hampton J;Sunpath H;Preston-Whyte E;Marconi VC
• 通讯作者: Marconi VC