Immune marker predictors of HIV acquisition

Prior studies attempting to link biomarkers of immune activation with risk of acquiring HIV have relied on cross sectional samples, most without proximity to HIV acquisition. We created a nested case-control study within the Sabes study in Peru, and assessed a panel of plasma immune biomarkers at enrollment and longitudinally, including within a month of diagnosis of primary HIV or matched timepoint in controls. We used machine learning to select biomarkers and sociobehavioral covariates predictive of HIV acquisition. Most biomarkers were indistinguishable between cases and controls one month before HIV diagnosis. However, levels differed between cases and controls at study entry, months to years earlier. Dynamic changes in IL-2, IL-7, IL-10, IP-10 and IL-12, rather than absolute levels, jointly predicted HIV risk when added to traditional risk factors, and there was modest effect modification of biomarkers on association between sociobehavioral risk factors and HIV acquisition. 

These findings were published at:

Bender Ignacio RA, Dasgupta S, Valdez R, Pandey U, Pasalar S, Alfaro R, Hladik F, Gornalusse G, Lama JR, Duerr A.  Dynamic immune markers predict HIV acquisition and augment associations with sociobehavioral factors for HIV exposure.  iScience. 2022 Nov 19;25(12):105632. doi: 10.1016/j.isci.2022.105632. eCollection 2022 Dec 22.PMID: 36483014 

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.

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. 

Investigating risk profiles in sexual and gender minority populations

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. 

These results have been published:

Long JE, Sanchez H, Dasgupta S, Huerta L, Calderón Garcia D, Lama JR, Duerr A. Exploring HIV risk behavior and sexual/gender identities among transgender women and their sexual partners in Peru using respondent-driven sampling. AIDS Care. 2021 Aug 23;:1-9. doi: 10.1080/09540121.2021.1967855. [Epub ahead of print] PubMed PMID: 34424782; NIHMSID:NIHMS1733123.

Long JE, Tordoff DM, Reisner SL, Dasgupta S, Mayer KH, Mullins J, Lama JR, Herbeck JT, Duerr A. HIV transmission patterns among transgender women, their cisgender male partners, and cisgender MSM in Lima, Peru: a molecular epidemiologic and phylodynamic analysis. Lancet Reg Health Am . 2022 Feb;6:100121. doi: 10.1016/j.lana.2021.100121

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

Collaboration with Dr. Ying Chen (Currently at Stanford: https://profiles.stanford.edu/ying-qing-chen)

• We studied persistence and adherence to oral PrEP among 336 AGYW ages 18 to 24 enrolled in the PEPFAR-funded DREAMS PrEP program and residing in Kisumu and Homa Bay Counties, Kenya.
• We interviewed girls at 2 time points, capturing self-reported information about PrEP use. We collected dried blood spots (DBS) for measurement of a PrEP metabolite (TFV-DP).
• A total of 176 AGYW persisted in the PrEP program, that is, they attended the follow-up and PrEP refill visits and stated that they were continuing PrEP. However, most were not adherent. Only 28/176 (16%) had detectable TFV-DP levels at Interview 2, with only 7 (4%) having levels consistent with protection (≥700 fmol/punch).
• Compared to AGYW who discontinued PrEP altogether, this persistent but non-adherent group (N = 144) was older (twice as likely to be ≥22 years), 4 times more likely to be active in the DREAMS program, 10 times more likely to think they would be at moderate-to-high risk for HIV if not taking PrEP, and 3 times more likely to use injectable contraceptives.

These results have been published at:

Tapsoba JD, Cover J, Obong'o C, Brady M, Cressey TR, Mori K, Okomo G, Kariithi E, Obanda R, Oluoch-Madiang D, Chen YQ, Drain P, Duerr A. Continued attendance in a PrEP program despite low adherence and non-protective drug levels among adolescent girls and young women in Kenya: Results from a prospective cohort study. PLoS Med. 2022 Sep 12;19(9):e1004097. doi: 10.1371/journal.pmed.1004097. PMID: 36095005; PMCID: PMC9521917.

HIV and HPV in Latin America

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.

OBJECTIVES

1. Compare HPV16 and HPV18 antibody responses one month after a single dose of 9-valent HPV vaccine in children with HIV (CWH) vs. uninfected children

2. Compare HPV16 and HPV18 antibody responses one month (peak) and 18 months (durability) after 1, 2 or 3 doses in CWH vs. after 1 dose in HIV-uninfected children.

LAB METHODS

HPV16 and HPV18 IgG concentrations in plasma determined by L1 VLP ELISA (Pinto Laboratory).