May 10, 2011
I recently returned from a wonderful meeting in Baltimore sponsored by Project Inform, Treatment Action Group (TAG), the AIDS Policy Project and amfAR that gathered top researchers in immune-based approaches that may lead to a cure for HIV. It was certainly an eye-opener for me to foresee the emerging challenges in this important research. One of these challenges will be how future studies will be enrolled.
These studies may ask people who have undetectable HIV viral loads to stop their HIV medications after they are exposed to different approaches that will attempt to strengthen their immune system or purge latent HIV reservoirs. Most of these studies will present no personal benefit to patients enrolling in them, but they will hopefully appeal to those altruistic enough to take a risk for the greater good and advancement of this important research. Many question themselves as to whether it is ethical to ask patients to take risks when we now have so many ways to control viral replication in the blood.
Current antiretrovirals (ARVs) are very effective in reducing viral load in 60 to 80 percent of people who take them. However, HIV remains dormant in different reservoirs of the body even after years of successful HIV treatment. When people stop taking their HIV medication, this hidden virus quickly infects newly produced CD4 cells as it resumes replication.
All current ARVs need to be taken daily for life, and only 30 percent of people in the world who need HIV treatments have access to them, even after 30 years of the AIDS pandemic. Most combinations of ARVs cost a minimum of $19,000 a year in the United States, and we have at least 50,000 new infections per year in this country alone. 2.6 million new infections occurred in 2009 in the world. But only 1.2 million people started HIV medications that year, which means that there are two new infections for every person we have put on treatment. So far, there are no totally effective prevention methods that have slowed down the infection rates.
So, obviously, pretending that ARVs alone will stop the pandemic is not only naive but impossible to justify. We need a cure. A cure that will be accessible to all around the world and that does not follow the tragic trajectory of HIV medication access in the past 17 years of effective ARVs.
The perception that HIV could not be cured shifted in the past four years since the cured "Berlin patient" report. Cure is not longer a four-letter word in the research world. Although this reported cure was a great wake-up call for many of us, it is an expensive and risky one. So, only patients with HIV and leukemia may have access to studies that will try to duplicate what happened to this patient. For the rest of us who do not have leukemia, researchers are finding ways to mimic that case without having to go through the extremes of chemotherapy, radiation and bone marrow transplant.
Different approaches are being investigated to cure HIV. Strengthening the immune system with stem or CD4 cell manipulation with compounds that may make CD4 cells resistant to HIV infection has generated a lot of excitement, after proof-of-concept data on the use of zinc finger nucleases was presented at CROI this past February.
Another approach is to use compounds to shrink or purge the reservoir of virus-infected CD4 cells not accessible to (ARV) drugs. Commercially available ARVs can't reach HIV inside this reservoir of infected cells, notably long-lived "memory" CD4 cells. This is because the cells are inactive; most ARVs only work in cells that are actively reproducing. Once HIV is purged, it can be treated successfully by ARVs present in the blood. Hopefully, the combination of immune-based manipulations and these purging compounds can lead to a cure that is not toxic or exorbitant in cost. There is only one way to find out: exposing patients to them.
Both of the approaches described will most likely be given first to people who have had an undetectable viral load for a few months. But then ARVs would have to be stopped to assess the effect of these interventions on HIV viral load. We are now calling these treatment interruptions ATIs (analytical treatment interruptions) since they will be following people very closely with frequent analytical tests to measure viral rebound. But how can we ask people to get off their medications and take risks? We know from the SMART trial that those who interrupt treatment may have higher cardiovascular risks, and also potential for resistance if the drugs in their ARV combination have different half-lives that may expose them to functional monotherapy*.
These studies will also be asking people to agree to get biopsies to measure HIV in different reservoirs like the rectal mucosa, bone marrow, central nervous system and others. These additional tests can be cumbersome to many patients who may want to enroll for altruistic purposes. Should patients be compensated monetarily for their trouble and time? Most of us think they should, but some fear that this compensation will induce people with low incomes to enroll in these studies to make ends meet. I think there will still be a lot of discussion on this issue in the coming months.
As an activist, there is something that I fear the most when it comes to HIV cure research. I fear that if we find one or a combination of approaches that may lead to a cure, access to this breakthrough will be limited if a pharmaceutical company owns the rights to the patent. We have seen how ineffective it has been for access when companies cannot let go of their profits to make ARVs available to all who need them around the world. Should the cure of AIDS belong to a pharmaceutical company or should governments get involved now so that we prevent greediness from blocking future access?
This is the elephant in the room in most meeting I have attended in the past few months. Only one company in the present has a commercial patent in this field: Sangamo Biosciences. They own the rights to the use of zinc finger nucleases to induce mutations on the CD4 CCR5 receptor that render them resistant to HIV infection. Discouraging pharmaceutical and biotech companies from owning rights of products that may lead to a cure may be counterproductive to the development of these products. So, there lies another ethical dilemma.
Researchers are afraid that studies asking people to go through ATIs will not be attractive to people living with HIV, which can cause a halt or slow down of the development process. No one really knows the degree of altruism in the community and their willingness to accept risks for the good of all.
Will we be heroes in this fight and enroll in these future studies; or will we be afraid to join studies that can expose us to risks?
We will soon find out. Would you be a hero?
* To treat HIV, it is required to combine three antiretrovirals (ARVs) that disrupt different stages of the life cycle of HIV. Due to lack of adherence to medications and other factors, HIV can mutate, rendering ARVs ineffective to control its replication (this is called drug resistance). This causes HIV viral load to rebound. The ARV combination to which HIV develops resistance is then called a "failing regimen. " Adding a new ARV to a failing regimen is called virtual or functional monotherapy since only one drug is really active against HIV. Functional monotherapy eventually leads to resistance of the new added ARV and viral load rebounds again, causing a vicious cycle of added resistance. So, the goal for achieving long-term HIV replication control is to avoid functional monotherapy while constructing an effective ARV combination with two to three active drugs to which the virus has not developed resistance.