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.
In West Africa, two distinct AIDS viruses (HIV-1 and HIV-2) are found, and some people become infected by both types. Because HIV-1 and HIV-2 infection have different natural histories (with HIV-2 being less aggressive) and different antiretroviral drug susceptibilities (with HIV-2 being more drug resistant), treatment for HIV-2 and dual HIV-1/HIV-2 infection is clinically challenging. Understanding how to better treat HIV-2 and dual HIV-1/HIV-2 infection is an import public health priority in West Africa.
|Gottlieb, Geoffrey S (2013) Changing HIV epidemics: what HIV-2 can teach us about ending HIV-1. AIDS 27:135-7|
|Smith, Robert A; Raugi, Dana N; Kiviat, Nancy B et al. (2011) Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance. AIDS 25:2235-41|
|Gottlieb, Geoffrey S; Smith, Robert A; Dia Badiane, Ndeye Mery et al. (2011) HIV-2 integrase variation in integrase inhibitor-naive adults in Senegal, West Africa. PLoS One 6:e22204|
|Smith, Robert A; Gottlieb, Geoffrey S; Miller, A Dusty (2010) Susceptibility of the human retrovirus XMRV to antiretroviral inhibitors. Retrovirology 7:70|
|Smith, Robert A; Anderson, Donovan J; Pyrak, Crystal L et al. (2009) Antiretroviral drug resistance in HIV-2: three amino acid changes are sufficient for classwide nucleoside analogue resistance. J Infect Dis 199:1323-6|
|Gottlieb, Geoffrey S; Eholie, Serge-Paul; Nkengasong, John N et al. (2008) A call for randomized controlled trials of antiretroviral therapy for HIV-2 infection in West Africa. AIDS 22:2069-72;discussion 2073-4|
|Smith, Robert A; Gottlieb, Geoffrey S; Anderson, Donovan J et al. (2008) Human immunodeficiency virus types 1 and 2 exhibit comparable sensitivities to Zidovudine and other nucleoside analog inhibitors in vitro. Antimicrob Agents Chemother 52:329-32|