Antiretroviral Therapy for HIV-2 Infection in Senegal

塞内加尔针对 HIV-2 感染的抗逆转录病毒治疗

• 批准号: 8660589
• 负责人: Geoffrey Scott Gottlieb
• 金额: $ 66.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-07 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660589
• 关键词: AIDS-Related Opportunistic Infections; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adherence; Adult; Adverse effects; Affect; Africa; Algorithms; Amprenavir; Anti-Retroviral Agents; Antiretroviral resistance; Applications Grants; Atazanavir; Attenuated; Base Sequence; Biological Assay; CCR1 gene; CCR5 gene; CD3 Antigens; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8B1 gene; CXCR4 gene; CXCR6 gene; Caring; Cell Count; Cell Culture Techniques; Cells; Cessation of life; Characteristics; Clinical; Clinical Management; Collaborations; DNA; Data; Databases; Disease; Dose; Drug resistance; Drug-sensitive; Epidemiology; Event; Exposure to; Failure; Frequencies; Gambia; Genes; Genetic; Genital system; Genotype; Goals; Grant; Growth; HIV; HIV-1; HIV-2; Immune; Immunologics; In Vitro; Indinavir; Individual; Infection; Integrase; Integrase Inhibitors; International; Ivory Coast; Logistic Regressions; Mali; Measures; Methods; Minor; Minority; Molecular Cloning; Mutation; NNRTI-resistance; Natural History; Needs Assessment; Nelfinavir; Nigeria; Outcome; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Plasma; Population; Predisposition; Protease Gene; Protease Inhibitor; RNA; RNA-Directed DNA Polymerase; Randomized Controlled Trials; Regimen; Regression Analysis; Research; Resistance; Resources; Risk; Sampling; Secondary to; Senegal; Sexual Transmission; Site; Site-Directed Mutagenesis; Staging; Survival Analysis; Symptoms; T-20; T-Lymphocyte Subsets; Testing; Time; Toxic effect; Treatment outcome; Universities; Variant; Vertical Disease Transmission; Viral; Viral Load result; Virus; Washington; antiretroviral therapy; base; cohort; cross reactivity; effectiveness measure; evidence base; fitness; follow-up; inhibitor/antagonist; meetings; mortality; non-nucleoside reverse transcriptase inhibitors; population based; pressure; programs; prospective; public health priorities; receptor; reconstitution; resistance mutation; response; tipranavir

DESCRIPTION (provided by applicant): The overarching goals of our renewal proposal are to develop an integrated program to further our ability to provide evidenced-based, potent antiretroviral therapy (ART) to patients with HIV-2 infection. Compared to HIV-1, HIV-2 infection is characterized by a longer asymptomatic stage, lower plasma viral loads, slower decline in CD4 count, decreased mortality rate due to AIDS, lower rates of mother to child transmission, and lower rates genital shedding and sexual transmission. In West Africa, where both HIV-1 and HIV-2 co- circulate, between 1-2 million individuals are infected with HIV-2 and a significant proportion are co-infected with both HIV-1 and HIV-2. Despite the relatively attenuated disease course of HIV-2, a significant minority of untreated individuals will progress to clinical AIDS or death without ART and as will the majority of those dually infected with HIV-1 and HIV-2. Through local and global initiatives, antiretroviral therapy is becoming increasingly available in resource-limited West Africa. Because HIV-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors and may have partial resistance to some protease inhibitors (PI), treating HIV-2 and HIV-1/HIV-2 dual infection presents distinct challenges. This is especially problematic in resource-limited settings where there is limited choice and availability of 1st- line NRTI-PI based regimens as well as subsequent 2nd- line and salvage regimens in those individuals with clinical progression, immuno-virologic failure or antiretroviral (ARV) toxicities. During the initial period of our grant proposal we (and others) have made substantial progress in furthering our understanding ART for HIV-2 in ARV-naove adults as well as HIV-2 ARV-resistance. However, to date, we remain largely ignorant about the long-term outcomes of ART in HIV-2 infected people, we are in urgent need for assessment of new classes antiretrovirals for HIV-2 and we lack even rudimentary studies on ARV-regimens to treat HIV-1/HIV-2 dual infection, or whether ARV treatment outcomes using NRTI-PI based regimens are different than HIV-2 single infection. Our Renewal proposal has the following specific aims: AIM 1: Long-term outcomes of ART for HIV-2 infection in Senegal: Determine long- term HIV/AIDS associated outcomes and ARV-associated complications in HIV-2 infected individuals treated with ART for >2 years. Assessment of the frequency, causes and outcomes of switching to 2nd line and salvage ARV regimens for HIV-2 infection. AIM 2: To determine the potential utility and susceptibility of HIV-2 to new ARV classes: the integrase inhibitors and the CCR5 co-receptor entry inhibitors. AIM 3: To compare the clinical, virologic and immunologic outcomes associated with ART using NRTI+PI based regimens in a longitudinal prospective cohort of 50 HIV-1/HIV-2 dually infected ARV-naove subjects and a longitudinal prospective cohort of 50 HIV-2 ARV-naove singly infected subjects. Our Renewal proposal will build on a strong ongoing collaboration between the University of Washington and the Universite Cheikh Anta Diop de Dakar, Senegal to further our understanding and provide evidence-based ART and care for HIV-2 infected people.

描述（由申请人提供）：我们续签提案的总体目标是制定综合计划，以进一步为HIV-2感染患者提供基于证据的，有效的抗逆转录病毒疗法（ART）的能力。与HIV-1相比，HIV-2感染的特征是较长的无症状阶段，血浆病毒载荷较低，CD4计数较慢降低，由于艾滋病而导致的死亡率降低，母亲对儿童传播的率较低以及降低生殖器脱落和性传播的速度。在HIV-1和HIV-2循环的西非，在1-200万个人之间感染了HIV-2，并且与HIV-1和HIV-2共同感染了HIV-2。尽管HIV-2的疾病病程相对减弱，但少数未经治疗的人将在没有艺术的情况下发展为临床艾滋病或死亡，大多数受HIV-1和HIV-2感染的大多数人也会发展。通过地方和全球倡议，抗逆转录病毒疗法在资源有限的西非越来越多。因为HIV-2在本质上对非核苷逆转录酶抑制剂具有抗性，并且可能对某些蛋白酶抑制剂（PI）具有部分抗性，因此治疗HIV-2和HIV-1/HIV-1/HIV-2双重感染带来了明显的挑战。在资源有限的设置中，这尤其有问题，在这些设置中，基于NRTI-PI的一行有限和可用性，以及随后的临床进展，免疫性衰竭或抗逆转录病毒（ARV）毒性的人的随后的第2行和救助方案。在我们赠款提案的最初阶段，我们（和其他人）在进一步发展了ARV-Naove成年人和HIV-2 ARV ARV抵抗力的HIV-2方面取得了重大进展。但是，迄今为止，我们在很大程度上仍然对HIV-2感染者的艺术的长期结果一无所知，我们迫切需要评估HIV-2的新类抗逆转录病毒，甚至缺乏对HIV-1/HIV-1/HIV-2双重感染的ARV-ERVERMENS的基本研究，或者使用NRTI-PI基于NRTI-PI造成了HOV的hIV hiv and Infftion and Infuntion and Inftimens and Inftimens and Inftimens and Infuntions and Inftimens and Inftimens and Inftimens-niffent HOV。我们的续签提案具有以下具体目的：目标1：塞内加尔HIV-2感染的ART的长期结局：确定与ART治疗的HIV-2感染者中与ART治疗的HIV-2相关结果和ARV相关并发症的长期HIV/AIDS的并发症。评估HIV-2感染的频率，原因和结果。目标2：确定HIV-2对新ARV类的潜在效用和敏感性：整合酶抑制剂和CCR5共受体进入抑制剂。目的3：比较在50 HIV-1/HIV-2的纵向前瞻性队列中，使用基于NRTI+PI的治疗方案比较与ART相关的临床，病毒学和免疫学结果，该临床和免疫结局是50 HIV-1/HIV-2双重感染的ARV-NAOVE受试者和纵向前瞻性群体的纵向前瞻性群体，该纵向均具有50 HIV-2 ARV-2 ARV-NAOVE的受试者。我们的续签提议将基于华盛顿大学与塞内加尔的Cheikh Anta diop de Diop de Diop de Diop de Diop de Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop Diop，并为HIV-2感染的人提供基于证据的艺术和护理。

项目成果

Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens.

• DOI: 10.1371/journal.pone.0045372
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Smith RA;Raugi DN;Pan C;Coyne M;Hernandez A;Church B;Parker K;Mullins JI;Sow PS;Gottlieb GS;University of Washington-Dakar HIV-2 Study Group
• 通讯作者: University of Washington-Dakar HIV-2 Study Group

Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses.

• DOI: 10.1186/1742-4690-7-112
• 发表时间: 2010-12-20
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Smith RA

In vitro activity of dolutegravir against wild-type and integrase inhibitor-resistant HIV-2.

• DOI: 10.1186/s12977-015-0146-8
• 发表时间: 2015-02-05
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Smith RA;Raugi DN;Pan C;Sow PS;Seydi M;Mullins JI;Gottlieb GS;University of Washington-Dakar HIV-2 Study Group
• 通讯作者: University of Washington-Dakar HIV-2 Study Group