Dreaming of the Cells We Had
We Need to Bring Immune-Based Therapies Off of the Sidelines
by Jeannie Wraight
For most people living with HIV, antiretrovirals (ARVs) will suppress viral load to undetectable levels. CD4 counts will increase with a quick escalation, usually followed by a slower climb to the normal or near normal range of 500–1,500 cells. Studies show that this can take as long as five years after beginning initial therapy, if the original CD4 count was below 500. However, for some, despite maintaining a suppressed viral load, their CD4 count may never fully recuperate.
PLWHAs whose CD4 counts fail to rebound are called immunological non-responders (INRs). Approximately 5-33% of HIV-positive people, after treatment, fail to see CD4 counts and other important immunological markers (CD4, CD8 cells ) return to normal levels.
The mechanisms involved in this immunological failure are multi-faceted and still remain mysterious to scientists in many ways. This summer’s 2019 IAS HIV Science Conference saw a renewed sense of interest from immunologists and several studies attempting to discover more about this occurrence and investigate biomarkers to identify who will become an INR.
An immune non-responder is loosely described as one whose CD4 count plateaus around 350 cells or fewer, despite viral suppression. Research suggests that this most often occurs in people who start therapy when their CD4 counts were already low (exactly how low, we don’t know) and those of older age. INR is linked to both an increased risk of serious co-morbidities as well as a greater risk of morbidity and mortality (sickness and death) when compared to individuals who have greater CD4 count gains.
Options for INRs are currently limited and more research is needed to find the best treatment strategies. From the beginning of the HIV pandemic, the focus of HIV treatment and research has always been virologic (focused on the virus itself) and not immune restoration after HIV has destroyed important populations of CD4s. With ARVs suppressing the viral load and, for many, CD4s increasing as the virus is suppressed, the growing number of immune non-responders has not been a priority for discovering treatment options to strengthen the immune system. Neither has a full understanding of the exact clinical impact resulting from this lack of CD4s.
In published study of immune non-responders, “Immuno-Virological Discordance and the Risk of Non-AIDS and AIDS Events in a Large Observational Cohort of HIV-Patients in Europe,” lead researcher Dr. Alexander Zoufaly stated, “Compared to CD4 responders, patients with immuno-virological discordance [immune non-responders] may be at increased risk of developing non-AIDS events. Further studies are warranted to establish whether in patients with ID [immuno-virological discordance], strategies to directly modify CD4 count response may be needed besides the use of ART.”
Immune therapies studied in the past were not very successful as most were conducted at a time when we had much less understanding of both the nuances of the life cycle of HIV and the broader effect HIV has on the immune system. With the diverse ARVs now available, options to strengthen the immune system should be prioritized by research networks like the NIH’s AIDS Clinical Trials Groups (ACTGs). But funding is in short supply for these approaches. There’s a lot of reasons for this gap in treatment priorities, the most prominent of which include the cost and length of immune reconstitution studies and the complexity of commercialization of these therapies in comparison to ARVs, all of which discourages both drug developers and research programs like the ACTGs, despite the clinical promise. Research studies to identify traits of immune non-responders, strategies to study drugs that would allow for FDA approval, and research into therapeutics and strategies to boost immune responses in the context of HIV infection are essential.
In 2016, a coalition of HIV advocates including TAG, AIDS Treatment Activists Coalition and AIDS Action Baltimore led a conference call with the FDA to propose strategies to confront the issue of HIV immune non-responders and discuss ways to advance the evaluation and development of drugs demonstrating promise for immune non-responders. According to treatment activists involved in this effort, as cited in the conference call’s minutes: “There is not current research specifically aimed at this population due to real and perceived concerns by industry. Due to the the relatively small size of this at-risk population and complexities in proving clinical benefit of potential immune-enhancing therapies, the advocacy community initiated efforts to creatively stimulate industry’s interest by reviewing with the FDA specific approaches to development paths for indications aimed at this population.”
Further work in this area by HIV activists has been slow in advancing any research on immune non-responders. HIV activists and advocates are spread thin on issues of PrEP, global funding, healthcare and Ryan White and, let’s face it, advocacy around immune restoration takes much more dedication than fighting for access to ARVs. Anti-inflammatory medications like Lodonal, a low dose form of naltrexone, and JAK inhbitors, which are being studied as a treatment for HAND (HIV-associated dementia), and, as part of a functional cure, therapeutic vaccines like Vacc4, HIV-MAG pDNA, rVSV HIV gag and VRC01, as well as adoptive cellular therapy (harnessing a person’s t-cells, cloning them in a lab and re-infusing them) do not send busloads of activists to Capitol Hill to demand funding from the NIH. Therapies like these to help the immune system better respond to and control HIV, as well as inflammation that contributes to co-morbidities like heart disease, liver and kidney disease, bone deficiencies and cancers are greatly needed. Research should be supported by the NIH to help ensure they are studied and developed. Some of these drugs like Lodonol and certain JAK inhibitors are already being used to treat other illnesses and have been shown to be safe.
Currently, the HIV community has a potential opportunity for immune-based therapies in INRs to get the attention they deserve in the current End the Epidemic (EtE) funding…if the HIV advocacy organizations around the country supporting EtE don’t forget that the growing number of immune non-responders need drugs too.
Jeannie Wraight is the former editor-in-chief and co-founder of HIV and HCV Haven and a blogger and writer for TheBody.com. She is a member of the Board of Directors of Health People, a community-based organization in the South Bronx and an advisor to TRW (Teach me to Read and Write), a community-based organization in Kampala, Uganda. She lives with her husband in New York City.