Our main projects center on collaborations in Lima, Peru, where we conduct several epidemiologic studies with the following goals:
Within our cohort of MSM and TW treated with antiretroviral therapy (ART) very early after HIV acquisition, we also seek to determine whether timing of ART impacts:
Other important studies of acute and early HIV infection include:
We also evaluate the role of alcohol and substance abuse in HIV, including via a randomized trial of naltrexone as a means of improving ART adherence, mapping alcohol/substance use in phylogenetic clusters, and evaluating the impact of substance abuse on gene transcription and inflammation in HIV
Our newest project is a collaborative effort to prevent and treat HPV-related cancers in women and children living with HIV in Lima, Peru; Rio de Janeiro, Brazil; and Santa Domingo in the Dominican Republic.
The Sabes Study evaluated a treatment-as-prevention intervention among cisgender men who have sex with men (MSM) and transgender women (TW) in Lima, Peru—populations disproportionately affected by the HIV epidemic. The intervention was designed to prevent onward transmission of HIV by identifying HIV-negative high-risk individuals, testing them monthly for the presence of HIV, and then rapidly treating those who became HIV-positive. The main outcome of interest was the development of a model predicting the population-level impact of early detection of HIV infection and immediate initiation of antiretroviral therapy in this population. From July 2013 to September 2015, a total of 3,337 subjects were screened for HIV; 2,685 (80.5%) were negative, and 2,109 began monthly testing. We identified 256 individuals shortly after HIV acquisition, 216 of whom were enrolled in the treatment phase of the study. All participants were followed for 48 weeks (follow-up ended in 2017) and were then referred to the Peruvian Ministry of Health to continue receiving free HIV care and treatment. Initial findings from this intervention demonstrate that it is possible to recruit high-risk individuals, screen them for HIV, continue to test those who are initially HIV-negative in order to identify incident cases shortly after acquisition, and then rapidly link them to health care. The treatment phase of the study randomized participants to immediate vs 24-week deferred ART initiation, stratified by whether diagnosis occurred while seronegative (acute HIV). Ongoing analyses are evaluating immunologic, virologic, and clinical outcomes of this cohort, specifically asking the question whether timing of ART initiation and substance use in early HIV infection impacts these outcomes.
The CNS is a sanctuary and reservoir for HIV, which is known to enter the CNS within days of primary infection. We sought to assess whether early ART would improve neurocognitive performance (NP) in the Sabes study by comparing outcomes for participants who began ART at different times after the estimated date of detectable infection (EDDI), derived from an algorithm compiling test parameters of last negative and first positive HIV tests. We hypothesized that, by limiting CNS infection, ART initiation within 30 days of HIV acquisition would improve NP compared to ART initiation later in early infection.
112 Sabes participants who had neurocognitive assessments were included in this analysis. NP was measured with a 15-test battery covering Gross motor, Attention, Executive, Learning, Memory, Speed of Processing, and Fine Motor domains at weeks 12, 24, 48, 72, 96 and 120 after randomization. Seventy-seven observations came from participants with an EDDI to ART initiation interval of ≤30 days (blue), 190 from participants who started ART after 31-90 days (red), and 262 from those who started ART 91 to 249 days after EDDI (>90 days) (green).
NP did not differ significantly between the EDDI to ART categories over time (p=ns). However, NP significantly improved with ART out to 120 weeks of follow up (p <.0001), across categories (mean total z score at week 0=0.09, week 12=0.28, week 24=0.41, week 48=0.47, week 72 = 0.50, week 96=0.52).
The impact of ART initiated during acute or recent HIV infection is under studied, but failure to effectively intervene with the population of newly infected persons results in ongoing risk of onward transmission. The intervention tested in the Sabes study, which included frequent routine testing for HIV by serology and RNA and rapid linkage to care, was feasible, acceptable, and effective among MSM and transgender women at high risk for HIV acquisition in Lima, Peru.
We assessed the economic impact of implementing the Sabes approach of frequent HIV testing and rapid linkage to HIV care through peer navigators. We estimated the cost-effectiveness of the Sabes program compared to the standard of care from the perspective of the Peruvian Ministry of Health. This approach used a compartmental model we developed which was parameterized with epidemiological data representative of the HIV epidemic among MSM in Lima. Our analysis included estimating the cost of the Sabes intervention (health care costs) and the impact on disease burden and averted health care costs (see Figure). We evaluated the cost of a testing algorithm that incorporates the Sabes testing and linkage strategy and measured the effectiveness of the intervention by estimating the proportion of cases of HIV detected during the acute/recent phase of infection, the number of additional HIV cases averted, and incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB). We found that early intervention (detection of HIV and rapid initiation of ART), especially during acute HIV infection when viral load is high, is cost-effective due to lower health care costs and reduced HIV transmission among MSM and TW in Lima, Peru.
In Lima, Peru, as in the US, the HIV epidemic is concentrated among men who have sex with men (MSM) and transgender women (TW) in whom HIV incidence rates are as high as 4.2 per 100 person-years. In this tudy we investigate the risks for onward HIV transmission for MSM and TW in Lima using phylogenetic and molecular epidemiologic methods.
The study began with 13 transgender women (TW) who acted as seeds participants, selected to begin enrollment (red dots). TW see participants completed a survey and invited up to 3 sexual partners using a WhatsApp referral system. In each wave of forward partner referral, invited partners could complete the survey and were provided referral coupons. In total, 470 eligible respondents completed the survey. The study found that almost all partners invited by TW were cisgender men who almost always invited only TW sexual partners in the next wave.
Recent studies suggest that very early initiation of ART (prior to seroconversion) does not prevent the establishment of HIV reservoirs, which eventually expand when ART is discontinued. Early ART initiation is, however, associated with preservation of CD4+ T cells and lower levels of total HIV DNA and cell-associated RNA as well as preservation of gut Th17 cells, thereby averting a major driver of HIV-related immune activation and limiting the size of the HIV reservoir. When, by contrast, ART is initiated after HIV seroconversion (in Fiebig III or later), many HIV-associated changes have already occurred, including seeding of HIV reservoirs, damage to GI mucosa, and initiation of inflammatory cascades. Since ART initiation within weeks of HIV acquisition is not a viable public health strategy, it is important to more completely understand the relative long-term benefits of initiating ART at very early times after infection (FI-II) as opposed to after a short (during FIII-V) or longer delay (at 24 weeks).
Our overarching hypotheses are: 1. Initiation of ART soon after HIV infection will dampen perturbations of GI microbiota, reduce HIV-induced inflammatory changes, and decrease seeding of the reservoir. Initiation of ART in FI-II will have the greatest benefit. We anticipate that CD4 counts and peripheral inflammatory markers in participants who initiate ART during FIII-V and the group treated at 24 weeks will approach those in the FI-II group at 1.5 and 3.5 years; in contrast, we expect changes in the GI microbiome and the HIV reservoir over time will be more modest. 2. Irrespective of the time of ART initiation, alcohol use will compound the negative effects of HIV to generate greater levels of dysbiosis, microbial translocation, up-regulation of inflammatory pathways, and seeding of the HIV reservoir. To investigate these hypotheses, we will study outcomes after 1.5 and 3.5 years after extended follow-up of Sabes study participants with acute (Ab-, HIV RNA+) or recent (≤3 months) HIV infection.
Because the incidence of HIV in unacceptably high in MSM and TW, and this population is considered difficult to reach, we partnered with several groups in Lima, Peru to conduct mobile HIV screening in social venues, including gay clubs, saunas, and plazas. HIV infections identified were then mapped using phylogentics and geospacial analysis and added to a database of samples from Sabes to attempt to identify HIV transmission “hot spots.” The goal is to target HIV testing and prevention interventions to these hot spots with less intensive resource utilization.
Adolescent girls and young women experience among the highest rates of HIV infection in the world. This project uses data from HIV-prevention programs and clinical trials, as well as mathematical modeling, to study how best to combine different prevention approaches to achieve maximum benefit for this population.
This novel viral serosurvey developed in the Elledge Lab (HHMI, Harvard University) is hosted at the FHCRC in collaboration with the Boeckh lab. Dr. Bender Ignacio is leading several initiatives to test the predictive power of this assay in the hematopoietic transplant population and in prediction of risk of HIV acquisition.
This was a double-blinded randomized trial of 159 HIV positive MSM and transgender women with alcohol use disorder in Lima, Peru. The goal of the study was to determine whether oral daily naltrexone (vs placebo) improves adherence to antiretroviral therapy. While oral Naltrexone was safe and well tolerated in this study population, adherence to daily oral Naltrexone was low and participants randomized to Naltrexone did not show a significant increase in adherence to ART.
This is a collaborative study to advance screening, prevention, and treatment of HPV-related cancers in women and children living with HIV. The study will have 3 trials. Trial 1 called OPTIMO, focuses on optimizing the dosage and timing of HPV vaccine in children living with HIV in Peru and Brazil. The schematic shows the different arms of the study.