Two Generations Explore HIV Drug Resistance in Trans Women, MSM

While many in the field of infectious disease research and medicine have noted the decline in new investigators and practitioners entering the workforce, the HIV Medicine Association and the Infectious Diseases Society of America Foundation have teamed up to do something about it. In Summer 2018, they announced a program to fund 15 medical students in the U.S. for clinical learning and research projects, each to be paired with an experienced mentor to support the student's research area of interest. This is one of a series of interviews with a mentor/mentee pair.

We spoke with Rachel Bender Ignacio, M.D., M.P.H., assistant professor (acting) in the Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington and an associate in the Division of Vaccine and Infectious Diseases at the Fred Hutchinson Cancer Research Center. We also spoke with her mentee, William Trebelcock, who is a second-year medical student at the University of Washington School of Medicine and hopes to pursue a career as a board-certified infectious diseases physician specializing in LGBTQ HIV care.

Jeanine Barone: Is HIV drug resistance (HIVDR) more likely to occur with certain antiretroviral drugs?

Rachel Bender Ignacio: Certain classes of drugs have different barriers to resistance -- the lower the barrier, the easier it is for HIV to develop resistance while on that medication. With NNRTIs, resistance can happen easily when people have interruptions in therapy, because some of these drugs have a long half-life compared to NRTIs. This means that if a PLWH (person living with HIV) takes their three-drug combination ART (often two NRTI + NNRTI) intermittently, or they have problems getting refills due to access, stigma, or stockouts of medication, the two NRTIs wash out of their body quickly, and the NNRTI stays at higher blood levels for about a week. As a result, the virus is seeing monotherapy with that one NNRTI during that time. We have learned that early therapies (before combination three-drug ART [antiretroviral therapy]) quickly resulted in the development of resistance if the virus kept replicating while "seeing" the medication. Newer regimens anchored on integrase strand transfer inhibitor (INSTI) have a much higher barrier to resistance, as do modern protease-inhibitor anchored regimens.

JB: How can HIVDR be prevented?

RBI: Preventing HIVDR requires a multi-pronged approach. We need to make sure that the ART being provided as first-line treatment is effective, meaning that when a PLWH [person living with HIV] starts ART for the first time, their regimen will suppress their virus. If they have pre-treatment or transmitted drug resistance (TDR), which is what Bill and I are studying together, then even if they take their ART well, they may develop virologic failure. (TDR is when a person becomes infected with an HIV strain that already developed mutations while in someone else's body, whether that was the person from whom the infection came, or somewhere long ago in the sexual network who themselves built up acquired resistance and then passed it along.) Options to prevent problems arising from TDR include performing genotyping on all newly diagnosed infections and then selecting appropriate regimens for that PLWH, or else using a first-line regimen based on dolutegravir [Tivicay, DTG], for example, which has a very high barrier to resistance and almost nonexistent TDR.

JB: Why are we seeing an increase in resistance in certain parts of the world?

RBI: For a long time, in low-and middle-income countries (LMIC), ART monitoring had been, and still is, being done with CD4 testing. There is a long lag before the CD4 T-cell count drops after virologic failure occurs, and not all virologic failure is due to resistance. We need to increase monitoring with viral load testing and drug-resistance testing. Most of these tests require electricity, fancy lab machinery, and transport of specimens from the patient to this specialized lab. Many scientists, including some of my colleagues at the University of Washington, are working hard to develop point-of-care tests to make these tests affordable and available in places that can't currently access them routinely and promptly. In addition, single-dose prevention of mother-to-child transmission with nevirapine has led to higher rates of NNRTI resistance in especially sub-Saharan Africa. LMIC are also disproportionately affected by systems-based issues that result in interruption in provision of ART to PLWH. Also, the longer a population has been on ART, the more likely HIVDR will occur.

JB: What new drugs are being tested that are less likely to be associated with resistance?

Of currently available regimens, INSTI is the favored drug class to prevent and treat HIVDR. Of drugs in development that I am aware of, none are being proposed as monotherapy, meaning that unless there is a complete paradigm change, we always recommend at least two highly active drugs. There is a bit of a paradigm change happening already, in that prior regimens always contained three active drugs. The FDA just approved the first two-drug regimen, which is considered to have a high enough barrier to resistance so that a third agent isn't needed. These new INSTIs and INSTI combinations will still need to be handled carefully.

RBI: Why are you specifically working with transgender women and cisgender men who have sex with men (MSM) in Peru?

In Peru, the epidemic is largely isolated in this population (>20% prevalence of HIV in MSM and >30% in trans women versus 0.4% in the general population), so this is why we focus on research that could improve detection of new infections, reduce transmission, and improve treatment and access in this population. We hypothesized that because trans women are at higher risk of HIV and likely have different sexual networks from cis MSM, including probably partners who don't identify as LGBTQ or access the clinics that serve LGBTQ PLWH, they might have a higher risk for having acquired TDR. Therefore, we wanted to find a large enough group of samples from cis MSM and trans women so that we could answer this question.

Jeanine Barone: What intrigues you about working with Dr. Rachel Bender Ignacio on this project?

William Trebelcock: After starting this project, I was fortunate to be able to see patients with Dr. Bender Ignacio at the Madison Clinic at Harborview, a clinic that is focused on providing care for individuals with HIV/AIDS. I saw firsthand how her passion for serving those with HIV/AIDS translated into patient care. Her candidness and compassion for her patients was truly admirable. My time with her at the clinic fueled my desire to specialize in this area and further the science necessary to ensure that HIV remains a treatable and hopefully curable disease in the future.

JB: Are there any findings that you can share on this research project?

WT: Although we are still working on producing the final analyses, our preliminary results show higher levels of resistance than we expected to certain drugs. These data follow an alarming trend of increasing HIV-transmitted drug resistance. It highlights the importance of using DNA molecular methods (genotyping) to look for drug resistance before initiating antiretroviral therapy in newly diagnosed individuals. One of the most striking findings for me was an individual who recently acquired HIV and was found to have multiple transmitted drug-resistant mutations. This individual had ultimately failed first-line therapy and was switched to third-line containing an integrase strand transfer inhibitor. It emphasized the reality of transmitted drug resistance and how detrimental it can be to the treatment of HIV.

JB: What kind of an impact do you hope to make by specializing in LGBTQ HIV care?

WT: I hope to bring a level of expertise, compassion, and empathy to my patients and the community. Like Dr. Bender Ignacio, I will treat my patients with the highest level of aptitude and scientific knowledge to achieve long-term health. I also hope to contribute to a decrease in HIV-related stigma, and therefore the spread of HIV, by having honest discussions around treatment as prevention and PrEP [pre-exposure prophylaxis] use -- another important lesson I have learned from Dr. Bender Ignacio. As a member of the LGBTQ community, my shared experiences will help me better identify with my patients. I think that with this insight, I can help create a health care setting where all are welcome without judgment or preconceived notions. Additionally, I hope to take my passion for HIV/AIDS research into the lab and clinical trials.