Disclosures: Hardy reports being on advisory boards for Gilead, Merck, and ViiV/GSK , and serving as a consultant for Enochian Biosciences.
August 26, 2020
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HIV not linked to COVID-19 risk, other highlights from AIDS 2020

Disclosures: Hardy reports being on advisory boards for Gilead, Merck, and ViiV/GSK , and serving as a consultant for Enochian Biosciences.
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W. David Hardy, MD, scientific and medical consultant, and adjunct professor of medicine in the division of infectious diseases at Johns Hopkins University School of Medicine, shared some important take-aways for clinicians from this year’s International AIDS Conference with Healio.

Hardy discussed COVID-19-related highlights, advancements in HIV prevention and treatment, research that will impact patient care and what he hopes to see at next year’s meeting.

Healio: Was there a focus on COVID-19 at AIDS 2020?

W. David Hardy, MD

Hardy: There was. This conference is one that is always very topical and tries to respond to things that are happening throughout the world. In the past, when Ebola and H1N1 influenza hit, there was some information about those, but not nearly as much as there was about COVID-19 at this conference. In fact, the entire last day of the conference was devoted to COVID-19.

There were at least four very good, but still somewhat small and limited, examinations of whether or not persons living with HIV are either more susceptible to getting COVID-19 or, if they do get it, are they more likely to have a severe disease and die.

Most – I would say 85% to 90% – of the reports from around the world demonstrated that persons with HIV do not seem to be at higher risk for getting COVID-19 and except for one report from New York City, there was no evidence that persons with HIV had a higher risk for having severe disease and perhaps dying of COVID. There was one report from the Bronx that showed increased mortality in persons living with HIV, but it was only nine patients, so it wasn’t very robust in terms of numbers.

Another way that COVID-19 has impacted HIV has been the effect the pandemic has had on HIV testing and also the starting or continuation of antiretroviral therapy.

Some of the most concerning new information was that every study from the United States, Africa and Europe reported that the number of people being tested for HIV has dropped dramatically simply because many of the clinics and test sites are closed. Since March of this year, there has been dramatic decreases in the number of new positive tests simply because the tests are not being done. That is a problem because if someone does not get tested, then they do not find out that they need treatment.

So, that has been a bad thing. Another report from sub-Saharan Africa that was really sobering was that there may be as many as 500,000 additional deaths due to HIV throughout this region because people who were on medications already or who were going to start medications have not been able to either continue or start their medications. Therefore, they are anticipating that this is going to result in a half-million additional people dying from HIV over the next year or so.

Another story that is also important to point out is that early on in the COVID-19 pandemic, there was a hypothesis that because the drug remdesivir (Gilead) and the commonly-used HIV drug tenofovir, one of the components of Truvada (emtricitabine/tenofovir disoproxil fumarate; Gilead), share the same mechanism of action and are in the same drug class NRTIs) that there would be some protection against COVID-19 for persons taking Truvada as part of their HIV cocktail. Most researchers who have examined this question have shown that in persons receiving antiretroviral therapy including Truvada or tenofovir, they were still getting COVID at the same rate as persons who were not HIV-positive.

So, the idea that Truvada would protect HIV-positive people does not seem to be the case either. There is no increased susceptibility nor is there protection because of HIV medications.

Healio: Please discuss developments in diagnosing HIV that were presented at the meeting.

Hardy: That’s one of the areas that I did not see a lot of new information in terms of diagnostic strategies.

One thing that is tangential to that and is interesting was that some of the sites that were providing PrEP as HIV protection have also been negatively impacted by COVID-19. So many clinics have shut down and patients have been afraid to go to clinics because they may be exposed to COVID-19. When a patient is on PrEP, they need to have an HIV test every 3 months to ensure that they are staying HIV-negative. A clinic in Los Angeles has used free COVID-19 testing as an incentive to get their patients to come in for their serial blood tests.

In many past conferences, there’s frequently been a new strategy or test that was described and I can’t say that I saw anything like that this year. Not that there is not always room for improvement, but the state-of-the-art technology for HIV, like rapid tests that are getting more and more accurate and fourth generation tests that are being widely used, is already very good.

In general, what was being touted was many countries have already tested over 90% of their inhabitants for HIV. This has not happened in the U.S. yet – only about 80% to 85% of people who are positive know that they’re positive – but Botswana, Kenya, Norway and Sweden have already gotten to the point where they can now say that they have identified 90% or more of the persons in their countries who are HIV positive. This is good news to know that the first 90 of the 90/90/90 UNAIDS goal has been reached by several countries already.

Healio: Please discuss developments in prevention that were presented.

Hardy: One of the major highlights of the conference was the presentation of the results of HPTN 083, an international PrEP study, which enrolled over 4,500 men and transgender women who have sex with men at higher risk for HIV. Participants were randomized to receive either daily, oral Truvada (TDF/FTC) or every 2 monthly injections of long-acting cabotegravir. Sixty-seven percent of the persons enrolled in the study were younger than 30 years-old and 50% of those enrolled in the U.S. identified as African American or Black – which was the first time a clinical trial looking at prevention or treatment had successfully enrolled populations at higher risk for HIV – persons < 30 years-old and persons of color.

HPTN 083 compared the current standard of care for PrEP for HIV, Truvada, given as one tablet, once-a-day vs. the first long-acting medication, cabotegravir, which is given by intramuscular injection every 2 months.

At the first scheduled look at the data (after 25% of the endpoints had occurred), there were 52 new HIV infections reported – 39 in the Truvada arm and 13 in the cabotegravir arm. This difference (a 66% reduction in the risk of acquiring HIV) was statistically significant and demonstrated that the once-every-2-month, injectable cabotegravir was superior to daily Truvada.

Another study, called the DISCOVER trial, which enrolled this same group of persons at higher risk for HIV, compared Truvada to Descovy (emtricitabine/tenofovir alafenamide; Gilead) and showed that the two drugs were similarly effective at preventing HIV. What HPTN 083 showed was that a new drug, cabotegravir, an integrase inhibitor, given by intramuscular injection once every 2 months or six times a year was not just as good as, but was better than the current gold standard - daily, oral Truvada.

These results are important because long-acting cabotegravir will allow people at higher risk for HIV to get an injection six times a year and be better protected from HIV than with daily Truvada. HPTN 083 was one of the most clinically relevant new studies that came out of the conference. A new treatment or prevention intervention that is superior to the current standard-of-care does not occur very often. These studies have to be very big to be able to detect that kind of difference, but in this case, it detected it at the first time they looked at the data, which was at an early point in the study.

There is a companion study to HPTN 083 going on now, called HPTN 084, which enrolled cisgender women in Africa. This study has enrolled all of its participants but has not followed them long enough to know what’s going to happen. So, there is good news for cabotegravir in MSM and transgender women, but we do not know about how it will perform among cisgender women who have sex with men. We must wait and see what this study will show.

Healio: What major advances in HIV treatment were presented?

Hardy: A few years ago, there was a large prospective cohort study of following HIV-positive women taking different HIV medications at the time that they were conceiving a pregnancy (Tsepamo Study) and there was an unexpected result – dolutegravir, which had just come on to the recommended ART guidelines for many parts around the world – was shown to have an association with neural tube defects (NTDs), severe birth defects that affects the brain and spinal cord and oftentimes are fatal.

In 2018, with the first report from this cohort study, we saw a concerning prevalence of this birth defect associated with dolutegravir (0.94%) when taken by HIV-positive women during or near conception. This initial prevalence rate was statistically significantly greater than those seen with non-dolutegravir regimens. When more women were enrolled in the study in Botswana, the prevalence fell from 0.94% to 0.3% in 2019 at the second presentation of the study. The 2020 update demonstrated further decrease in the prevalence of these birth defects from 0.3% down to 0.19% and now not statistically different than the prevalence of NTDs in HIV-positive women who received other ART regimens at conception.

The good news that came out about treatment was that in 2018 and even 2019, most of the ART guidelines around the world recommended that HIV-positive women who were trying to get pregnant or who could get pregnant (meaning sexually active and not on birth control) should not receive dolutegravir, which was taking a very well-tolerated and potent drug away from women.

What this study now is saying, is that risk for neural tube defects is no different than taking any other ART regimen. With longer follow-up and more women being observed during pregnancy, that adverse signal is going away and is now no different now than with other ART regimens.

Other news regarding ART was focused on weight gain associated with certain antiretroviral agents. One of the concerns that has been demonstrated internationally and in the U.S. is increased weight gain occurring in association with integrase inhibitors, dolutegravir and bictegravir, and with tenofovir alafenamide (TAF).

We first saw a signal about two years ago from the ADVANCE study in South Africa that the combination of dolutegravir plus TAF/FTC caused a statically significant greater amount of weight gain compared to either a dolutegravir plus TDF/FTC or an efavirenz/TDF/FTC regimen, particularly in African women. At the end of two years of treatment with this combination, women had gained almost 25 pounds of additional weight, which was noted to be primarily central and peripheral fat not lean body mass. Because of this, many cohorts around the world have been looking at the changes in weight occurring in their study participants.

Using clinical data from the OPERA cohort in the U.S., which has more than 115,000 people living with HIV enrolled from 65 cities, 19 states and Puerto Rico, an analysis to see what happened when patients were switched from tenofovir- to TAF-containing regimens. The study found that no matter what other ARV medications that the patient was taking in addition to the TAF, patients gained as much on average 2 to 4.5 kilograms within the first 9 months after the switch. This occurred to the greatest extant with integrase inhibitors and to a lesser extent with NNRTI- and then PI-containing regimens.

Although this wasn’t a clinical trial — it was a observational clinical cohort — it brought home to treaters in the U.S. that the signal that was seen first in South Africa, among both African men and women, is occurring in the U.S. as well. Clearly, there is more weight gain when a patient either starts or switches to an integrase inhibitor and if TAF is part of that regimen, there is even more weight gain.

At first, HIV treating clinicians were not concerned about people living with HIV starting ART gaining weight – patients with untreated HIV can be emaciated and may need to gain weight. But weight gain is also associated with more serious health conditions, such as diabetes, cardiovascular disease, high lipid levels and the metabolic syndrome. When it gets to a certain point, the weight gain is no longer a cosmetic or personal preference issue and can have significant health risks.

In the ADVANCE study from South Africa, which is a randomized, controlled trial comparing patients who assigned to different types of antiretroviral therapy, women who received dolutegravir plus TAF were found to have a statistically significantly greater risk of developing the metabolic syndrome, which is a harbinger for diabetes and heart disease. Currently, the mechanism for this weight gain is unknown and hypotheses are under investigation.

Healio: What information from AIDS 2020 do you think will have the most immediate impact on patient care?

Hardy: Whenever a study, such as HPTN 083 shows superiority of a new medication over the current standard of care, the drive to put more patients on the superior intervention is extraordinarily strong. I’ve heard that the company (ViiV Healthcare) that is developing injectable cabotegravir is not going to apply for FDA approval of this new form of PrEP until the women’s study (HPTN 084) that is currently ongoing is complete. When they do apply for approval of this new PrEP intervention, they will include MSM, transgender women and cisgender women.

What will have the most immediate impact from the conference is that women who are in their childbearing years, aged 15 to 50, can now be started on dolutegravir regardless of whether they plan to become pregnant or if they are sexually active and don’t take birth control. That signal for increased neural tube defects occurring in their babies is gone – that’s good news.

Another bit of news is that the discussion between doctors and their patients about weight gain with either starting or changing antiretroviral medications is going to start happening more and more.

Healio: What do you hope to see at next year’s meeting?

Hardy: I hope to see the results of HPTN 084. I hope to see it before then, but the study is not very mature yet so it may be another year before we get to see that.

The other thing I would like to see is more research on other long-acting medications. There is one called lenacapavir, which is both an oral and injectable medication. At this year’s conference we saw a study in HIV-negative persons, that showed that after either a single or two subcutaneous injections, the medication levels persisted at levels anticipated to suppress HIV for as long as 6 months. I hope to see more data on the development of lenacapavir to translate these promising results into HIV suppression in PLWH. In addition, further development of long-acting medications, both oral as well as injectable ones, will be of high interest.

The medication closest to FDA approval, cabotegravir, given alone for PrEP and with long-acting rilpivirine for treatment, are given by intramuscular injections, which can be painful, are infrequently a reason to stop the medications, but can’t be easily self-administered. Lenacapavir is being developed as a subcutaneous injection, so it will probably be less painful, and a person can give the injection to themselves at home. An attribute which makes delivering the medication even easier.

A potential downside about lenacapavir is that we’ve never been successful in treating HIV with a single drug, so lenacapavir will most likely need to have at least one partner drug to create an effective, antiviral regimen and it’s not clear what that’s going to be yet.

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