The true measure of UW/Fred Hutch CFAR accomplishment in supporting HIV/AIDS research is the quality and potential clinical impact of the final published research. In this section, we highlight recent examples of CFAR-supported projects that address important questions and point to potential new approaches in improved prevention or management of HIV infection and AIDS.
Earlier Antiretroviral Therapy Improves Survival
Results of this seminal study had an immediate impact on the treatment of HIV-infected individuals—both nationally and internationally. The study, which analyzed data from over 17,000 asymptomatic patients with HIV/AIDS who received ART beween 1996 and 2005, relied on the services of the CFAR Clinical Epidemiology and Health Services Research Core. Results showed that early initiation of antiretroviral therapy—at CD4 cell counts between 500 and 350 cells/ mm3—was associated with a 70% reduction in mortality when compared to the prevailing guideline-directed practice of waiting until counts fell to = 350. A separate analysis showed that patients with CD4 counts above 500 who started therapy within 6 months had a 94% lower mortality rate, compared to those who deferred therapy. Dr. Carl Dieffenbach, Director of the Division of AIDS at NIAID, has referred to these observations as the most important research findings in the HIV/AIDS field during the past year. A recent meeting on ‘ART for HIV Prevention’ convened by the World Health Organization (WHO) in Geneva November 4, 2009 also considered the results of this CFAR-supported study in changing WHO guidelines for initiating ART by raising the threshold from <200 cells/ mm3 to <350 cells/ mm3.
Kitahata MM et al. Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival. N Engl J Med. 2009;360:1815-1826. (PMID 19339714) [View PDF]
Men Seeking Men of Same HIV Status: What’s the Impact on Public Health?
Serosorting, the act of engaging in unprotected anal intercourse with partners of the same HIV status, is increasing among men who have sex with men. But the impact of this practice on HIV reduction is unclear. Using an Emerging Opportunity Grant from the UW/Fred Hutch CFAR Developmental Core, Susie Cassels developed a mathematical model of HIV transmission dynamics that suggests—assuming specific high rates of condom use and HIV testing and a limited number of partners—that serosorting can be an effective harm reduction strategy. The model makes clear that serosorting impacts are highly dependent on testing rates, condom use, and prevalence of acute and chronic HIV cases.
Cassels S et al. HIV serosorting as a harm reduction strategy: evidence from Seattle, Washington. AIDS. 2009;23:2497-2506. (PMID 19834319) [View PDF]
Two Viruses, 14 African Sites, >3000 Assays… and Several Surprising Conclusions
Co-infections with HIV-1 and herpes simplex virus 2 (HSV-2) are common. Preliminary evidence suggests that suppression of HSV-2 with acyclovir may reduce HIV transmission risk. To test this important hypothesis, several researchers affiliated with the CFAR International Core designed a multi-site clinical trial evaluating the effect of acyclovir on HIV-1 transmission and progression in 14 sites in Africa. Among >3,000 heterosexual HIV-1 discordant couples in which HIV-1 infected partners with HSV co-infection were randomized to acyclovir 400 mg vs. placebo, HIV-1 transmission risk did not differ significantly between the study arms during 2-year follow-up. However, acyclovir lowered the risk of HIV-1 disease progression by 16%. In those with CD4 counts >/=350 cells, acyclovir delayed risk of CD4 cell counts falling to <350 cells by 19%. In addition, recent data from the study were presented at CROI 2010 demonstrating significant reduction in HIV-1 transmission following antiretroviral therapy. All told, this ambitious and carefully conducted study led by Dr. Celum contributed important data on sexual HIV-1 transmission, prevention, and progression. This accomplishment demonstrated the timely laboratory service component of the UW CFAR Clinical Retrovirology Core. Building on an earlier demonstration of important genital mucosal interactions of HIV with HSV-2, this group rapidly validated the commercial Roche COBAS AP/COBAS TM real-time HIV-1 PCR assay for genital fluids and provided bulk HIV-1 RNA quantification from blood and the semen of men and endocervical canal of women. The careful and timely work of the CFAR Core helped to show how therapeutic intervention in a large international study (Partners in Prevention: Clinical Core) directed at the genital co-pathogen HSV-2 could influence the relationship between HIV-1 levels in these compartments but—surprisingly—not in the sexual transmission of HIV. Over 3000 assays were performed in three months time, which assisted with the rapid completion and publication of this important clinical trial.
Celum C et al. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010;362:427-439. (PMID 20089951) [View PDF]
Lingappa JR et al. Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial. Lancet. 2010;375:824-833. (PMID 20153888) [View PDF]
Lessons from One Patient’s Seroconversion
Understanding the exact mechanisms underlying altered susceptibility to HIV-1 infection in highly exposed seronegative (ES) individuals can provide insight into strategies to control HIV-1 with an effective vaccine. This study focused on one individual (LSC63) who seroconverted after over 2 years of repeated unprotected sexual contact with his HIV-1-infected partner (P63) and other sexual partners of unknown HIV-1 serostatus. Employing the viral analysis services of the Computational Biology Core, CFAR-affiliated investigators found that the HIV-1 variants infecting LSC63 were genetically unrelated to those sequenced from P63. Broad HIV-1-specific cytotoxic T-lymphocyte (CTL) responses were detected in LSC63 before seroconversion but compared to those detected after seroconversion, these responses were of lower magnitude and half of them targeted different regions of the viral proteome. Strong HLA-B27-restricted CTLs, which have been associated with disease control, were detected in LSC63 after but not before seroconversion. Furthermore, for the majority of the protein-coding regions of the HIV-1 variants in LSC63 (except gp41, nef, and the 3' half of pol), the genetic distances between the infecting viruses and the viruses to which he was exposed through P63 were comparable to the distances between random subtype B HIV-1 sequences and the exposed viruses. These results suggest that broad preinfection immune responses were not able to prevent the acquisition of HIV-1 infection in LSC63, even though the infecting viruses were not particularly distant from the viruses that may have elicited these responses.
Liu, Y et al. 2009. Preinfection human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes failed to prevent HIV type 1 infection from strains genetically unrelated to viruses in long-term exposed partners. J Virol. 2009; 83:10821-10829. (PMID 2753147) [View PDF]
Slightly Higher Rates of Concurrent Partners in African Americans Lead to Greatly Higher Rates of HIV
HIV infection is a concentrated epidemic among African Americans. Tapping into the resources offered by the CFAR Sociobehavioral and Prevention Research Core, Dr Morris analyzed the role that concurrent sexual partnerships may play in explaining the disparities in HIV (and all other STI) prevalence by race in the US. The study reviewed data from four population-based surveys and found consistent evidence that the point prevalence of concurrency was higher for African American men and women than for other racial/ethnic groups. Using newly developed simulation models, the researchers showed that while overall rates of concurrency are quite low, about 4-5%, concurrent partnerships comprise nearly 50% of the links in the reachable path of infection. A relatively small difference in concurrency by race – about 5 percentage points – has the effect of tripling the racial disparity in the reachable path of infection. Reducing the prevalence of concurrency among African Americans could eliminate the racial disparities in HIV and other STI infections.
Morris M et al. Concurrent partnerships and HIV prevalence disparities by race: linking science and public health practice. Am J Public Health. 2009;99:1023-1031. (PMID 19372508) [View PDF]