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Shifting from daily to infrequent dosing will advance HIV treatment
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Judith Feinberg, MD, chair of HIV Medicine Association and professor in the department of medicine/infectious diseases at West Virginia University School of Medicine, spoke with Healio about important FDA approvals in HIV, the burden of drug resistance, threats to HIV control and the future of HIV treatment.
What are the most important FDA approvals in HIV in recent years?
Integrase strand transfer inhibitors are the most powerful class of drugs in HIV treatment. They are “wonder drugs” and we’ve had them for several years. The first drug in this class, raltegravir (Isentress, Merck), was approved in 2007. While this isn’t a brand-new class of drugs, we now have long-acting versions of these drugs in both pill and injection form, which is a big step forward.
Combining these integrase inhibitors with long-acting forms of drugs in other classes as combination therapy in a once-daily, single tablet has changed the landscape of HIV treatment. We are beginning to see the promise of moving away from daily dosing to less frequent dosing, which will be an important advance for many patients, especially those with adherence issues.
We are continuing to make incremental changes in enhancing HIV therapy in recent years. We have seen the approval of newer integrase inhibitors that are more advantageous in terms of effectiveness, dosing frequency and/or side effects, such as bictegravir (in combination with emtricitabine/tenofovir alafenamide (Biktarvy, Gilead) and the investigational cabotegravir (ViiV Healthcare) that can be taken as a pill or as an injection every two months. We now have the first monoclonal antibody, ibalizumab (Trogarzo, THERA) given intravenously once every 2 weeks for patients with resistant HIV.
There are also some drugs in development that are promising because they target different mechanisms than existing drugs, but they are not close to FDA approval.
What factors should be considered when choosing therapeutic regimens for patients?
HIV treatments should always be individualized. Physicians need to consider what coexisting medical problems might be present and what potential side effects would be more problematic to a given patient.
I don’t think now, and I have never thought, that there is a one-size-fits-all approach. Physicians need to make the best decision for each individual patient.
What is the burden of drug resistance on HIV treatment?
These days, the burden of drug resistance is significantly less than it used to be. A great deal of resistance in the 1990s and early 2000s was driven by the fact that our earlier medicines were not that potent and before 1995-1996, we didn’t really have a solid triple therapy combination. We were mostly using one new drug at a time and as they were all fairly related chemically, if a patient developed resistance to one, they would likely have at least partial resistance to another. As we moved into the protease inhibitor era in 1996, everyone wanted to give those potent drugs to every patient. But, if we give one new good solid drug to patients who already have resistance or partial resistance to the other two drugs in the regimen, then they can develop resistance to that new third drug — the protease inhibitor — too. So, for quite a while in the 90s and even the first decade of this century, there was a fair amount of drug resistance because of those issues of prior inadequate therapy.
In the late 2000s, all of a sudden, we had a number of new potent drugs, some of which were in new chemical classes. We could now offer new combinations of potent drugs to patients who had accumulated resistance to the older drugs, and these patients responded very well. Now, of course, these more potent drugs are the basis of our current standard-of-care.
Resistance is not the same kind of issue that it once was. Remember that in 1987, we started with just AZT and people would do okay for a couple of months, but by the time the year was over, they were failing AZT because they developed resistance to it. However, it was the only drug we had, so it’s not like we had a choice. It took about 4 years to develop the second HIV drug, DDI. AZT and DDI were in the same chemical class of nucleoside reverse transcriptase inhibitors, so there was some potential for overlapping resistance.
There was a period where drug resistance was a very significant problem and new drug development was driven by having to overcome existing resistance patterns. For almost a decade now, we’ve had really solid potent drugs in new classes and some in existing classes, such as protease inhibitors, that are not as susceptible to resistance development. The concept of resistance driving drug development as it once did is much less the case now. What we are trying to accomplish now is treatment that is better tolerated with fewer side effects, longer intervals between doses, and the possibility of being able to deliver drugs as long-lasting injections instead of in pill form.
What are the greatest threats to HIV control?
The greatest threat always is that the patient won’t take the medicine as he or she is supposed to. Patients can certainly begin to develop resistance to medication if they do that and then develop progressive clinical disease. That has been the greatest threat all along and it hasn’t entirely gone away. HIV medicines only work if patients swallow them and swallowing is the key, especially if it is preventive medication, such as pre-exposure prophylaxis (PrEP).
We are now seeing a surge of HIV infections among people who are struggling with the disease of addiction. Individuals who acquire HIV through injecting drugs pose a threat to their ability to do well on HIV medicine. In general, the instability and chaos of dealing with the disease of addiction threatens the control of all other medical problems whether it’s HIV, hepatitis C or diabetes.
Where do you see the treatment of HIV going in the future?
We would like to dream that we will be able to cure HIV like we’ve been able to cure hepatitis C with multidrug therapy. There are some baby steps in that direction, but there is no near-term promise of an HIV cure.
Short of a cure, if we could move toward infrequent dosing with HIV drugs that could conceivably stay in the patient’s system for months or even a year, that would be pretty amazing. If we had a combination that you only had to give once or twice a year, that would be fantastic. The fact that a patient might be tired and forget to take their pills wouldn’t even be an issue. That’s the direction I see us going in. Of course, if we can come up with a combination that would effect a cure that would be like winning the golden ring.
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