Research

Overview

Our main projects center on collaborations in Lima, Peru, where we conduct several epidemiologic studies with the following goals:

  1. Identify risk factors for incident HIV infection in men who have sex with men (MSM) and transwomen (TW)
  2. Describe HIV transmitted drug resistance in Lima
  3. Map the HIV epidemic and sexual networks in MSM and TW using phylogenetics and respondent driven sampling, and evaluation of concurrency in different risk subpopulations
  4. Identify predictors of linkage to HIV care, such as stigma and coping

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:

  1. Short and long-term clinical course of HIV infection, including neurocognitive outcomes and metabolic syndrome
  2. Risk of acute retroviral syndrome (ARS)
  3. Inflammation and immunologic changes associated with early treatment

Other important studies of acute and early HIV infection include:

  1. Size and kinetics of the latent HIV reservoir after treatment
  2. The gastrointestinal microbiome
  3. Examining the role of viral co-infections on HIV outcomes

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.  


Sabes Study

HIV Testing and Treatment to Prevent Onward HIV Transmission among MSM and Transgender Women in Lima, Peru

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.

Sabes Early timepoints paper Fig 2
HIV-1 RNA and CD4 T-cell count in participants randomized to initiate ART immediately or 24 weeks after diagnosis of early human immunodeficiency virus (HIV) in the Sabes Study. Quantitative HIV-1 RNA and CD4 + T-cells measurements were performed cross-sectionally with blood from within-visit windows at each analysis point (intent to treat analyses with all participants randomized to that arm included). A, Change in HIV-1 RNA viral load (VL) by arm, throughout 48 weeks of the Sabes Study. Box plots represent median and interquartile ranges. Equivalent time-under-ART comparisons for 24-weeks on ART lie at study week 24 in the Immediate arm and at 48 weeks in the Deferred arm, as outlined per-protocol. Virologic suppression was calculated as a single-failure model. B, Proportion of participants with suppressed VL, defined as <40 copies/mL, by analysis week. After 48 weeks on study, the difference in cumulative proportion with virologic suppression was 84.8 vs 70.3% in Immediate vs Deferred arms. C, Box plots demonstrating median and interquartile range in absolute CD4 count by arm at each analysis point. D, CD4+/CD8 + ratio at each analysis point. In (A), (C), and (D), the P value from Kruskal-Wallis test is shown in black for the week 48 between-arm comparison, and the blue bar shows the comparison between arms 24 weeks after intended ART initiation visit (week 24 for Immediate arm, week 48 for Deferred arm). https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa167/5763087
Flowchart of Sabes study steps
CONSORT diagram (Consolidated Standards of Reporting Trials) for participants in the SABES study, Lima, Peru, 2013-2017 “Design Strategy of the Sabes Study: Diagnosis and Treatment of Early HIV Infection Among Men Who Have Sex With Men and Transgender Women in Lima, Peru, 2013-2017.” Lama JR, Brezak A, Dobbins JG, Sanchez H, Cabello R, Rios J, Bain C, Ulrich A, De la Grecca R, Sanchez J, Duerr A Am J Epidemiol. 2018 Mar 7. doi: 10.1093/aje/kwy030. [Epub ahead of print] High-res version
Sabes Early timepoints paper Fig 3
CD4+/CD8 + T-cell ratio at ART initiation and 24 weeks after ART initiation, analyzed as treated by interval between estimated date of detectable HIV infection (EDDI) and ART initiation. Overall, the median CD4+/CD8 + T-cell ratio was different across all 3 groups (1.03 vs 0.96 vs 0.88, respectively, P = .0001 by Kruskal-Wallis test) at time of ART start, and the ratio of those starting ART after 90 days (CD4+/CD8 + T-cell ratio of 0.52) and within 90 days (0.37) differed from those starting ART within 30 days (0.76). After 24 weeks of ART, the CD4+/CD8 + T-cell ratio was not different (P = .09) overall, but those treated > 90 days from EDDI had a significantly lower ratio than those treated within 30 days (0.88 vs 1.03). https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa167/5763087

Sabes Neurologic Sub-study

Effect of time of ART initiation on neurocognitive performance in Sabes study participants

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).

Scatter chart of early infection cohort
In this unique early infection cohort although time between primary infection and ART initiation was not associated with neurocognitive performance, neurocognitive functioning improved over time on ART regardless of timing of ART initiation. High-res version

Sabes Cost-effectiveness Sub-study

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.

Flowchart showing the effects of the Sabes intervention
Flowchart showing the effects of the Sabes intervention (frequent HIV testing with rapid linkage to care including ART initiation). Upper panel shows projected effects on health care costs and lower panel shows projected effect on disease burden.

Investigating the Role of Sexual Networks and Alcohol Use in HIV Transmission Networks 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. 

Investigating the role of sexual networks and alcohol use in HIV transmission networks in Lima, Peru
Network diagram of recruitment into the respondent driven sampling study categorized by gender (TW: transgender women; TM: transgender men; Cis-:cisgender) High-res version

MERLIN Study

Modulating the Impact of Critical Events in Early HIV Infection: Effect of ART Initiation and Alcohol Use

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. 

Bar chart depicting the results of the MERLIN study
The frequency of cells harboring total HIV DNA decays significantly faster in acutely treated individuals compared to recently and deferred groups. There is a faster decay in the integrated HIV DNA in the acute group compared to the deferred Inducible reservoir decay significantly faster in acutely treated participants compared to recently and deferred groups. "Rapid decay of HIV persistence markers in acutely ART-treated individuals in Peru” Marta Massanella, Rachel Bender Ignacio, Javier R. Lama, Sayan Dasgupta, Amélie Pagliuzza, Ricardo Alfaro, Jessica Rios, Carmela Ganoza, Delia Pinto-Santini, Trupti Gilada, Ann Duerr, Nicolas Chomont on behalf of the MERLIN study group. Poster presented at CROI 2018, Boston, MA High-res version

Microepidemics

Spatial and Phylogenetic Clusters of HIV Microepidemics Among MSM in Lima, Peru

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.

Phylogentics and geospacial analysis
Phylogenetic clusters containing HIV sequences from recently HIV infected SABES participants are shown in color. These are thought to represent high risk sexual networks; participants with sequences in these clusters were more likely to have reported attendance at specific social venues. “HIV Transmission Hotspots Among Men Who Have Sex With Men and Transgender Women in Lima, Peru” Audrey Brezak, Manuel Villaran, Samia Ahmed, Angela Ulrich, Joshua Herbeck, Edmund Seto, James Mullins, Ann Duerr AIDS International Conference 2016, Durban, South Africa High-res version

AGYW

Predicting PrEP Uptake and Adherence among Adolescent Girls and Young Women in Sub-Saharan Africa: Leveraging Programmatic and Clinical Trials Data

A collaboration with the Ying Chen Group

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.


VirScan

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.

Heatmap of peptide enrichment for individual profiles
VirScan, a comprehensive serologic profile against the human antivirome, was performed on hematopoietic cell transplant (HCT) donor/recipient pairs. This heatmap depicts number of epitopes detected for each of 58 viruses with public epitopes. Each pair, designated Px includes 5 samples from the donor and then from the recipient pre-HCT, and then 30, 100, and 365 days after HCT. High-res version

AHORA-L

Randomized Placebo-Controlled Clinical Trial to Assess the Impact of Oral Naltrexone on HIV Treatment Outcomes Among HIV-1 Infected MSM and TW with Alcohol Use Disorders in Lima, Peru

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.

Bar chart showing results of AHORA-L AEs
In a RCT of Naltrexone vs placebo among heavy alcohol users on ART, adverse events were uncommon in both treatment and control arms, regardless of adherence to study drugs.

HIV and HPV in Latin America (U54)

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.

Graphic explaining 4 trials and dosage levels
In trial 1 (OPTIMO), 100 children in Peru and Brazil will be enrolled and randomized to receive 1, 2, or 3 doses of 9-valent HPV vaccine. The primary goal of this clinical trial is to compare the longer term immune (anamnestic) responses among the participants living with HIV (arms 1-3) and those who are HIV uninfected (arm 4).