‘No need to reduce number of drugs for triple-drug therapy to treat HIV’

Kim Yun-mi  Published 2019.04.18  15:20  Updated 2019.04.18 17:50


- US expert stresses importance of customized treatment based on patient-reported outcome

In the past, HIV and AIDS were known as deadly diseases that could take away a patient’s life. Thanks to advancement in treatment, however, patients can lead a regular life into their seniorhood if they take anti-retroviral drugs regularly.

The pharmaceutical companies developing HIV treatments are now focusing on not only inhibiting HIV viruses but also improving the lives of the patients.

This means that they are trying to propose new treatments and products for patients who have to take drugs for the rest of their lives by decreasing the number of medications taken from the existing triple-drug therapy, which has been used as HIV treatment, so that drug toxicity can be minimized, or by developing a simple tablet of the same dosage so as to make it more convenient for the patients, which would improve a patient’s drug compliance.

Against this backdrop, The Korean Doctors Weekly met with Dr. Sorana Segal-Maurer, professor of Clinical Medicine at Weill Cornell Medical College and board-certified internal medicine physician specializing in infectious disease at New York-Presbyterian Medical Group Queens, to discuss changing trends in HIV/AIDS treatment and the potential for customized treatment based on patient-reported outcome (PRO).

Dr. Sorana Segal-Maurer of Internal Medicine at New York-Presbyterian Queens

Question: How are the recent trends in HIV treatment changing, and what should people look out for?

Answer: The approach toward HIV and AIDS has completely changed compared to how it was in the past. The patients nowadays can live well past their 70s, so it is crucial for the patients to receive treatment at the right time. For example, if they start treatment after being diagnosed in their 20s, then they can continue their treatment for 50-60 years and survive. That is why the safety and the effectiveness, as well as the tolerability of the treatment, are essential.

One of the significant changes in the HIV/AIDS treatment is that the patients receive their treatment as early on as possible. Nowadays, if a diagnosis is given for HIV, just like an STD, the patient can receive treatment right away. There is no waiting until the results of additional blood tests come out. This change in approach to treatment is based on the concept of “U=U,” meaning “undetectable = untransmittable.” This means that if the virus is subdued to the point that it is not detectable, it will not be transmittable to others. The purpose of this kind of approach is to prevent the infection as much as possible.

Pre-exposure prophylaxis (PrEP) is also used for HIV infection. Furthermore, physicians are choosing a single tablet that can be taken once a day or a drug with low drug interaction and food interaction. Also, treatments that are proven safe against the lowering of bone density and kidney functions are being used as well. HIV/AIDS treatment guidelines are also being revised to reflect these changes.

One of the most important drugs for HIV/AIDS treatment these days is integrase strand transfer inhibitor (InSTI). The reason this is so important is that InSTIs are highly safe, effective and tolerable and have a high barrier to resistance. In other words, InSTIs would check off all the items in a checklist for HIV/AIDS treatment, if there were any.

Also, with the treatment starting early on, the most challenging patients to treat – those with low CD4+ T cell count and high viral load – need to start on a drug that can start working right away. That is why it is important to use InSTIs that can cover a wide range of patients from the beginning.

In addition, this is also why the guidelines by the International Antiviral Society (IAS) and the Department of Health and Human Services (DHHS) also recommend the use of the second generation InSTIs before trying other treatments.

Q: Recently, double-drug therapy, wherein the number of drugs used HIV/AIDS is reduced from three to two, is resurfacing.

A: It would be helpful to trace back the history of anti-retroviral treatment. In my case, I started treating patients with HIV/AIDS in 1986. Back then, we used azidothymidine (AZT). However, the problem with this drug was that the viral load would decrease when it is first used but would return to its initial level soon after. As such, the average survival of the patients was only about six months.

Since then, a double-drug therapy, wherein another drug was added to nucleotide reverse transcriptase inhibitors (NRTI), was used. However, the same problem resurfaced with this therapy as well. A significant difference emerged when we started using triple-drug therapy. The viral load dropped significantly, and it remained low for a relatively long period. As such, the survival of the patients increased. However, there was a serious toxicity issue with this triple-drug therapy.

Double-drug therapy is nothing new. In the past, when opinavir/ritonavir or efavirenz/NRTI were used, the number of drugs taken was reduced, and they were effective. However, tolerability of the drugs was rather low.

Looking at the clinical research for recently developed dolutegravir (DTG) and lamivudine (3TC), we can see that the patient group was carefully structured so that it would be composed of those with not-so-high viral load and not-so-low T cell count. So far, the outcomes are positive. However, we need to wait and see whether the patients continue to show positive results well after five years because it is possible that drug compliance issue may arise.

In the case of triple-drug therapy, the probability is very low that a patient’s body would resist all three drugs, so it is relatively safe. Besides, the main active ingredient in this therapy is a drug with the same proven effectiveness and safety as tenofovir alafenamide fumarate (TAF). In the past, drug toxicity was a serious problem, as such, reducing the number of drugs was considered. Now, however, there is almost no drug toxicity issue, so I don’t think anyone would choose double-drug therapy when they can go with triple-drug.

Q: Are there any difference among second-generation InSTIs?

A: We can compare raltegravir and dolutegravir, the two significant InSTIs that can be used as a treatment, as an example. Both are excellent drugs, but there are slight differences.

Biochemically speaking, bictegravir is a substance that can remain much longer in the pocket that can inhibit any action in the integrase compared to dolutegravir. This means that bictegravir stays in the active pocket, which can inhibit any activity well, twice as long as dolutegravir. Moreover, the decaying process, wherein the substance goes in and out of the active pocket, takes twice as long as dolutegravir. As such, the barrier to resistance is higher for bictegravir than for dolutegravir.

When comparing the effectiveness of the two drugs against multiple drug resistant (MDR) viruses, the probability that a patient would be susceptible to dolutegravir is 25 percent whereas the likelihood of developing a susceptibility to bictegravir is 75 percent. That is why when raltegravir is used as a treatment, the patient can rest assured that he or she is well protected even if he/she did not take the drug at a specific time. In short, one can safely assume that bictegravir is the treatment that best fits the current HIV/AIDS treatment trend, wherein the treatment begins right away after a diagnosis is given.

Q: As one of the researchers who participated in the development and clinical test of bictegravir, you stressed the importance of PRO. Why is PRO for bictegravir important?

A: Patient-reported outcome, also known as PRO, has been used for a long time in areas such as anticancer and rheumatism treatment. A patient would use a given drug and report his/her experience with the drug. So PRO is excellent in that any adverse effect that was not fully observed through clinical study can be detected. In a clinical study, a participating physician interprets a patient’s reaction and reports it as an adverse effect; in the case of PRO, however, it is possible to accurately pinpoint what the problem is that the patient is facing.

Based on this outcome, more practical and accurate advice can be given to the patients in the future. This is also possible because the number of good treatment options that a patient can choose has increased.

In the clinical study, both bictegravir and dolutegravir displayed no serious adverse effects. According to PRO, however, the patients’ reaction to these drugs are different. When comparing adverse effects on the active site, patients showed more statistically-significant adverse effects to dolutegravir at week 4, week 12 and week 48. Furthermore, patients who took dolutegravir suffered from sleep disorder when checked in at week 4, week 12 and week 48.

The more adverse effects and discomfort a patient feels in his/her daily life, the more likely he/she is to stop taking the drug. If drug compliance is lowered, then it’ll be difficult for the patient to receive proper treatment, and it will end up increasing healthcare costs, which will be bad for society. That is why it is becoming increasingly important to find out using PRO how the patients feel and what they experience with the drugs they are taking.

Besides, the clinical study for bictegravir showed that there is no resistance to the drug during the initial treatment. In the SWITCH trial, two patients developed M184V resistance, but they were not in the patient group that received bictegravir. So from the clinical study outcomes, we can safely say that bictegravir has a strong barrier to resistance.

Basic science research data also shows that bictegravir has a strong barrier to resistance. Using MDR viruses to decide on resistance threshold, the standard is those with more than 10 times in change. In this test, only 2 percent of the viruses showed resistance to bictegravir whereas 17 percent of the viruses developed resistance to dolutegravir.

These study outcomes show that bictegravir is stronger against resistance compared to dolutegravir.

Q: This sounds like the era of customized treatment is finally here for HIV/AIDS treatment thanks to PRO. Does that mean that if a patient experiences discomfort in his/her treatment, it is possible to switch drugs even if he/she has not developed resistance to the drug he/she was using?

A: Changing a drug when the patient has not developed resistance to it would depend significantly on the physician’s judgment because the physician needs to figure out what this discomfort may be in advance and intervene so that the patient wouldn’t stop taking the drugs amid treatment. This is to prevent patients from feeling discomfort caused by adverse effects and to prevent a situation where they are put at a higher risk of infection due to lower drug compliance.

Actually, in the past, there was no other treatment option even if a patient was suffering from adverse effects. So it was difficult to figure out how important it is to understand a patient’s experience to a particular drug. Now, however, there are many treatment options, and the range of adverse effects that a patient can deal with is different from patient to patient. That is why it has becoming crucial to try to understand a patient’s experience using PRO data.

In short, for patients receiving initial treatment, it is essential to explain to them various treatment options and help them choose the treatment they want. Also, for patients switching to a different drug, it is crucial to figure out what adverse effects they are experience in advance and change the medications.

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