Antiretroviral Therapy for HIV-2 Infection in Senegal

描述（由申请人提供）：我们续期申请的总体目标是开发一个综合项目，以进一步提高我们为HIV-2感染患者提供基于证据的有效抗逆转录病毒治疗（ART）的能力。与HIV-1相比，HIV-2感染的特点是无症状期较长，血浆病毒载量较低，CD4计数下降较慢，艾滋病死亡率较低，母婴传播率较低，生殖器脱落和性传播率较低。在艾滋病毒-1和艾滋病毒-2共同传播的西非，有100万至200万人感染了艾滋病毒-2，很大一部分人同时感染了艾滋病毒-1和艾滋病毒-2。尽管艾滋病毒-2的病程相对较短，但有相当少数未经治疗的个体在没有抗逆转录病毒治疗的情况下会发展为临床艾滋病或死亡，大多数双重感染艾滋病毒-1和艾滋病毒-2的人也是如此。通过地方和全球行动，在资源有限的西非，抗逆转录病毒治疗越来越容易获得。由于HIV-2本质上对非核苷类逆转录酶抑制剂具有耐药性，并且可能对某些蛋白酶抑制剂（PI）具有部分耐药性，因此治疗HIV-2和HIV-1/HIV-2双重感染提出了不同的挑战。在资源有限的情况下，这尤其成问题，因为基于NRTI-PI的一线方案的选择和可用性有限，对于那些有临床进展、免疫病毒学失败或抗逆转录病毒（ARV）毒性的个体，随后的二线和挽救方案也有限。在我们的拨款提案的最初阶段，我们（和其他人）在进一步了解抗逆转录病毒药物治疗HIV-2的成人以及HIV-2抗逆转录病毒药物耐药性方面取得了实质性进展。然而，到目前为止，我们对抗逆转录病毒治疗HIV-2感染者的长期结果仍然知之甚少，我们迫切需要评估治疗HIV-2的新型抗逆转录病毒药物，我们甚至缺乏治疗HIV-1/HIV-2双重感染的抗逆转录病毒治疗方案的基本研究，或者使用基于NRTI-PI的方案的抗逆转录病毒治疗结果是否与HIV-2单一感染不同。我们的更新提案有以下具体目标：目标1：在塞内加尔抗逆转录病毒治疗HIV-2感染的长期结果：确定接受抗逆转录病毒治疗的HIV-2感染者的长期艾滋病毒/艾滋病相关结果和抗逆转录病毒相关并发症。对HIV-2感染改用二线和挽救性抗逆转录病毒治疗方案的频率、原因和结果进行评估。目的2：确定HIV-2对新型抗逆转录病毒药物的潜在效用和易感性：整合酶抑制剂和CCR5共受体进入抑制剂。目的3：在50名HIV-1/HIV-2双重感染的arv - nav患者和50名HIV-2单一感染的arv - nav患者的纵向前瞻性队列中，比较使用NRTI+PI方案与ART相关的临床、病毒学和免疫学结果。我们的更新建议将以华盛顿大学和塞内加尔达喀尔谢赫·安塔·迪奥普大学之间正在进行的强有力合作为基础，进一步增进我们的了解，并为2型艾滋病毒感染者提供循证抗逆转录病毒治疗和护理。

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.