Beyond Viral Suppression: Expert Strategies to Improve Patient Outcomes

[00:36:29]

WHO Global Health Sector Strategy on HIV: 2022-2030

So really the WHO global health sector strategy on HIV really calls for a more precise focus to reach individuals most affected by HIV and to address inequities. Certainly a very difficult time currently, with the US funding cuts. And more holistic, people-centered approach to HIV prevention and care to address multimorbidity and quality of life, but importantly, stigma.

And we have here in San Francisco a 3-pronged approach to the getting to zero, to the end of the HIV epidemic, which is no new HIV infections, no new AIDS related deaths, and importantly, no stigma to get to zero with stigma, given its impact on HIV care and treatment outcomes.

[00:37:20]

5 Pillars to Support the Vision for Long-term Success for People Living With HIV

So really 5 pillars to support the vision for people living with HIV in their long-term success. And 1 is really getting HIV RNA to undetectable for everyone. The goal of the entire planet is to get everyone to virologic suppression. We're only at a 73% rate of virologic suppression according to the UNAIDS latest data that was presented in Kigali, Rwanda, at the International AIDS meeting from July 13th through 17th.

And here in this country, in the United States, the CDC latest data is that we're only at 67.2% of people living with HIV in this country virologically suppressed. So a very long way to go.

Treatment-related factors and excessive clinic visits were identified as the most notable version. So we want to decrease the number of visits and minimal impact of treatment and clinical monitoring. We'll talk about this when we talk about long-acting vs oral ART. Certainly maintaining optional health-related quality of life. And then consistency of care as among different healthcare providers.

And at Ward 86, we try to develop a model that there's a 1-stop shopping, that everyone comes into the clinic and has as much a possible services provided in 1 place. We actually just recently hired an endocrinologist because we talk about weight gain in case number 3, that's 1 of our biggest concerns with HIV. And we try to get specialists on site that help with people living with HIV as the needs arise.

And the last 1 is to really improve stigma and discrimination.

[00:39:03]

Case 1: Individualizing Initial ART While Supporting Overall Wellness

So let's talk about case number 1, which is really individualizing initial ART.

[00:39:08]

Pretest 1

So this leads to our pre-test question, which is, I prioritize discussing and offering mental health treatment at all HIV care appointments. And please vote, which is:

1. Strongly disagree;
2. Disagree;
3. Neither agree or disagree;
4. Agree; or
5. Strongly agree.

Speaker: Poll is open. Five more seconds. All right. Thank you. We'll close the poll and share the results.

Dr Gandhi: So majority 76% either agree or strongly agree. I think mental health is incredibly important. And we actually just recently got a psychiatrist at Ward 86 after having a gap in that and it was incredibly important, especially right now.

[00:40:16]

Case 1: Background

So we'll talk about this. This is a 24-year-old man with new HIV diagnosis. He started pre-exposure prophylaxis with TDF/FTC-based PrEP at the age of 21 after graduating from college. But there was intermittent adherence to that daily oral pill and there were no labs clinic follow up in the past 3 months. His last refill was 5 months ago for that 3-month supply.

And when you see him in the office, unfortunately, his HIV fourth-generation antigen antibody test was reactive. So new diagnosis of HIV infection with past medical history of being diagnosed with depression at age 18 and is on treatment. He works in an office. It's been remote since the pandemic, and most weekends there is a history of substance use with heavy alcohol, methamphetamine, cocaine, MDMA, unprotected sex and he doesn't recall anything beyond HIV on his problem list, except for that history of depression and substance use and that new diagnosis of HIV.

[00:41:27]

ART Management Options Until HIV Status is Confirmed

So this was an antigen antibody test. He will be repeated with that and also tested with a qualitative or quantitative HIV RNA test. And at this point, essentially the immediate management would be, given the risk factors, given the fact that he was inconsistent with PrEP, that this is very likely a real diagnosis to intensify to a complete antiretroviral therapy regimen. Assume it's a real infection. This can worry people, but - and can have a psychologic toll. But I think that this is unfortunately really very likely that he has a new HIV infection.

I don't think the second one is indicated in this particular case. And certainly, stopping PrEP to clarify diagnosis without drug pressure is not what we're usually doing while we're waiting for HIV resistance testing, but to really intensify to that complete ART regimen. That really would be the most indicated option here.

[00:42:39]

Case 1: Single Positive HIV Test During/Following Inconsistent FTC/TDF PrEP Use

So, in this case, he actually was not started on ART, and was awaiting results of confirmatory HIV testing. But the HIV RNA level did reveal a positive test. It was low level. In fact, it was so low level that it couldn't be genotyped. But having a positive test, certainly, really confirms the diagnosis. And his further history really revealed multiple STIs at ages 16 to 18 years, really difficult time with family stress and shame and that internal stigma that he's experiencing.

So starting ART would have been the indicated option. And it certainly needs to start ART now. We're really in the era of rapid HIV treatment. This is a new HIV infection with a low level RNA level. He may have been intermittently taking the TDF/FTC, and certainly there is a concern about drug resistance in that setting on PrEP.

[00:43:47]

Recommended Initial ART If HIV Acquired While Taking PrEP

So what are the recommended initial ART options? Essentially, at this point, even if he was taking FTC/TDF intermittently, we're really in the era of integrase inhibitor-based therapy, and are very unlikely to have acquired a K65R or a more high-level resistance pattern, very low level possibility of having an M184V. But in that case, an integrase-based inhibitor regimen will still work. And really, it's either bictegravir/FTC/TDF or dolutegravir/FTC/TAF. And those are really first-line regimens.

Now, if he had seroconverted on cabotegravir-based PrEP, even though, again, there is a low chance of this, there are, at least in the HPTN 083 study, which was the study that looked at cabotegravir-based PrEP every 8 weeks compared to daily oral TDF/FTC. In that trial, 18 out of 34 seroconversions did have integrase inhibitor mutations. And because of that, the recommendation on cabotegravir-based PrEP seroconversion is to start with a derivative-based regimen and not an integrase inhibitor while you're waiting for that resistance testing.

So in this case, he did not seroconvert on cabotegravir-based PrEP, but that would be indicated because INSTI resistance is possible for those who acquire HIV while taking long-acting cabotegravir.

[00:45:23]

Case 1: HIV Infection During/Following Inconsistent FTC/TDF PrEP Use

So in his case, he was using FTC/TDF-based PrEP inconsistently. So started on BIC/TAF/FTC, and on diagnosis he did, like we just considered, did have an M184V mutation that selective drug pressure from 3TC most likely made this an emergent M184V mutation on intermittent FTC/TAF as he acquired HIV, high CD4 cell count, negative for STIs on this particular encounter and no other laboratory abnormalities.

So the next question is if he has an M184V, would you change ART from the BIC/TAF/FTC?

[00:46:14]

No Effect of Baseline M184V/I on BIC/FTC/TAF Efficacy

So this was actually a relatively recent update to the BIC/TAF/FTC package insert, which is that, having an M184V is not a contraindication to using BIC/TAF/FTC that TDF with combination with bictegravir even in the face of M184V bringing down susceptibility considerably to 3TC does not mean that a switch is necessary. This was really the results of those initial pooled trials of looking at BIC/TAF/FTC efficacy that even though those trials in among 2,034 participants were performed in those supposedly who were virologically suppressed at baseline. So that a baseline HIV genotype could not be done.

Looking back in M184V was present in 10% of individuals, among the participants in those trials. And among those who had an M184V at baseline, there was still a persistently high level virologic suppression, 98% in those with an M184V vs 99% in those without. And so this really led to a package insert, change to the BIC/TAF/FTC use by the FDA that it is okay to use BIC/TAC/FTC in the presence of an M184V.

There's also been a number of trials with dolutegravir in the face of an M184V, the NADIA trial, DAWNING, 2SD, VISENSE. These are using dolutegravir in the setting of baseline M184V mutations and dolutegravir is also indicated in that setting.

[00:48:03]

Mental Health Conditions Often Precede HIV Infection

So in the case of this particular individual, there are mental health concerns and mental health conditions often precede HIV infection as opposed to accompanies the new diagnosis. This can include depressive symptoms just like in our patient, heavy alcohol use, stimulant use or polydrug use.

And so if you look at the number of psychosocial conditions here among this large study of over 4200 men who have sex with men from 6 US cities, having more than 1 condition is common. So that 4-plus conditions, it's really more likely to acquire HIV infection in the face of multiple mental health conditions, unfortunately, just like our patient here in this case.

[00:48:56]

Mental Wellness vs Mental Illness

And really, the idea of the question of mental wellness vs mental illness. We really want to regularly screen for mental illness, in this case, not only also look at treatments, most likely in substance use for opioid infection or opiate addiction, because that's where we have the strongest evidence for pharmacologic therapies, prescription of antidepressants, and certainly as much as possible, integrating mental healthcare with HIV care and getting that collaborative care.

So mental wellness is really our responsibility as the primary care physician, because of its link to patients ability to engage in care and adhere to HIV treatment.

[00:49:45]

Posttest 1

So this is really leads us to the post-test of the same question, where a lot of you actually had said agree or strongly disagree, but the same question. I prioritize discussing and offering mental health treatment at all HIV care appointments. And this is:

1. Strongly disagree;
2. Disagree;
3. Neither disagree or agree;
4. Agree; or
5. Strongly agree.

Speaker: The poll is open. Five more seconds. All right. Thank you. Close the poll and share the results.

Dr Gandhi: Thank you. So we actually did shift it to strongly dis - strongly agree with this integration of mental health.

[00:50:46]

Case 1: Addressing Overall Wellness

Okay. So this particular patient is definitely open to conversations about wellness. He joins a bike club that goes on weekend rides. And because of his number of sexual risk factors for other STDs, he's already acquired HIV infection, you offer doxycycline postexposure prophylaxis to really massively lower his risk of chlamydia and syphilis infection. Increasingly, we're not seeing effects on gonorrhea with increasing tetracycline resistance in gonorrhea. But this will really prevent the other STDs and also agrees to begin to see a counselor.

And after starting counseling and initiating an antidepressant, he really does want to reduce his use of recreational drugs and is linked with a substance use support group.

[00:51:40]

Case 1: Key Points

So the key point is that he was diagnosed with HIV while intermittently on oral PrEP, which led to that lower HIV viral load on his diagnosis because there is partial activity, of course, of TDF/FTC, but it also led to selective drug pressure for the development of an M184V mutation, which really confers 3TC resistance.

Mental health diagnoses are a common barrier to taking that pre-exposure prophylaxis consistently, which is why there was such a high suspicion of HIV infection. Most common resistance mutation, which develops as an M184V and with 3-drug regimens with an integrase inhibitor as the backbone. Really, dolutegravir and bictegravir can be used even in the setting of M184V mutation. I wouldn't use those much more with any other NRTI resistance.

[00:52:43]

Case 2: Addressing Internalized Stigma With LA ART

Okay, great. Let's turn to case number 2, which is really addressing internalized stigma.

[00:52:48]

Case 2: Background

In this case, this is a 47-year-old man who was diagnosed with HIV 1 year ago. And he has been taking BIC/TAF/FTC since diagnosis. He's adherent to ART, but putting that pill in his mouth, taking that pill every day reminds him internally that he has HIV, really internalized stigma. No other past medical history or other medication use.

And when you see him with this discussion that you're having about his stigma about taking daily oral ART, he has a baseline CD4 cell count of 406, and it had risen to 515. He is virologically suppressed on that daily oral TDF/FTC. He had actually acquired HIV with a transmitted NNRTI mutation of a K103N, the most common NNRTI mutation that is acquired—still rare, but acquired, not emergent—HIV subtype B. And importantly, he is immune to hepatitis B infection, negative hepatitis C.

So normal creatinine, normal BMI and LDL.

[00:54:09]

Pretest 2

So the question is, should an ART switch be:

1. Considered from that oral BIC/TAF/FTC to long-acting cabotegravir and rilpivirine-based ART; or
2. Should you consider switching him from 3 drug to 2-drug therapy; or
3. No, he's virologically suppressed. He's fine; or
4. No, he's not experiencing any adverse events.

So please do vote.

Speaker: Poll is open. Five more seconds. All right. Thank you. We'll close the poll and share the results.

Dr Gandhi: Okay, great. So actually 50% of you said considering long-acting cab/ril and I would really want to discuss that next. And that's absolutely what I would do.

[00:55:21]

Reasons to Consider Regimen Optimization in Setting of Viral Suppression

So essentially, this individual is experiencing internalized stigma from taking an oral ART regimen. And at this setting, certainly he's virologically suppressed at present. But you do want to consider switching because he is essentially having internalized stigma of taking that daily oral pill.

And so the idea of regimen switching even in the setting of virologic suppression, is to simplify the regimen, is to enhance tolerability. And in this case, really switching to relieve that stigma, that pill fatigue that he's having with concern about disclosure. Really he's telling you that every time he puts this pill in his mouth, he's feeling that stigma. And this is an absolutely perfect reason to switch over to long-acting cabotegravir and rilpivirine.

We would do this even in the setting in our clinic at Ward 86, with a very low barrier to switching over to long-acting.

[00:56:33]

Evidence That LA ART May Reduce Internalized Stigma

There is evidence that long-acting ART reduces internalized stigma. It takes you away from that daily pill taking. It's administered in the clinic. You can sort of forget about the need of administration in between. I will say that beyond this study, which we'll talk about in a minute, the SOLAR study actually looked at participants who were on BIC/TAF/FTC and then got switched over to long-acting cabotegravir and rilpivirine.

And in the case of the SOLAR study, 47% said at baseline that they wanted that switch to long-acting cab/ril really for internalized or externalized stigma. In this case, this was a survey study that looked of 688 people living with HIV across Europe, and they were surveyed even before long-acting ART was available because long-acting cabotegravir and rilpivirine came out in 2021, and the interest in trying it even before we got to these therapies was really highest among people with perceived stigma from their daily oral ART, and people stress that by daily dosing that really increase their feeling of stigma.

So in the phase III trials, people really describe freedom as their main benefit. But that freedom, not just logistically from having to take a daily oral pill, but psychologic freedom from internalized stigma, a really important reason for switching to long-acting.

[00:58:04]

BEYOND: Perspectives After Switch to LA CAB + RPV

The BEYOND study. Actually, the data was updated on the BEYOND study at International AIDS meeting in Kigali, Rwanda from July 13th through 17th. But this was the initial presentation of the BEYOND study.

And the BEYOND study was a prospective observational study across 27 US sites after switching to long-acting cabotegravir and rilpivirine from daily oral ART. And the most common primary reason across US sites was pill fatigue and convenience, or having anxiety about taking that pill every day.

[00:58:41]

Case 2: Background

So the proportion of patients also at Month 12 after being on long-acting cabotegravir and rilpivirine, you can see that there was a high number of patients who felt uncomfortably reminded of their HIV status, 28% always often, or even more with some times in there that just taking that daily pill reminded them of their HIV status. And feeling stigmatized by HIV treatment. So that really reduced in the setting after months 12 of being on long-acting cabotegravir and rilpivirine, much higher numbers of not feeling that way.

I do think that stigma is a major reason to switch to long-acting cab/ril. And in this case, you have a perfect example of someone who's telling you that taking a pill every day reminds them of HIV infection.

[00:59:38]

Posttest 2

So the post-test is really, should an ART switch be considered for this person? And the - still the same options. But really after we've talked about this, yes, considering a long-acting cabotegravir and rilpivirine-based regimen. And please vote.

Sorry, actually, we're not voting here. But - oh, it looks like we are, but - so. Yeah, please do vote.

Speaker: Poll is open. Five more seconds. All right. Thank you. Close the poll and share the results.

Dr Gandhi: So this really led to 95% of us saying that we would switch.

[01:00:38]

Posttest 2: Rationale

I absolutely agree. And in fact, a 2-drug regimen I would be more concerned about with someone with intermittent adherence.

[01:00:48]

Approved Use of LA CAB + RPV

Okay. So, you know, there is essentially a disparity right now between the approved use of long-acting cabotegravir and rilpivirine on the FDA guidance and what people are doing in clinical practice and the US-based guidelines.

So really because the initial trials of long-acting cabotegravir and rilpivirine, FLAIR, ATLAS and ATLAS 2M were performed in those who are virologically suppressed. The FDA package insert, at least for these drugs, really say use in the context of virologic suppression. FLAIR was done in treatment-naive individuals who were switched first from their oral—they were naive. They were first put on dolutegravir/abacavir/3TC first virologically suppressed and then switched over to long-acting cab/ril.

And ATLAS and ATLAS 2M, with the ATLAS 2M regimen being every 8 weeks as opposed to every 4 weeks with cabotegravir and rilpivirine were performed in those who were virologically suppressed on whatever oral ART they were on and then switched over to long-acting cab/ril.

So those are the virologically suppressed individuals like this person, and our patient in case number 2, who are virologically suppressed.

However, there is absolutely data emerging from observational studies, including data that we presented from Ward 86 to support the use of long-acting cabotegravir in this setting of viremia. And these observational studies at University of Mississippi, which is the Brock article below; Ward 86, which is the clinic I directed in San Francisco, has really shown the benefit of using long-acting cabotegravir and rilpivirine in these demonstration projects and those with viremia, especially to combat stigma, and especially in those with concomitant challenges to taking daily oral ART like housing insecurity, substance use, mental health concerns.

And so, this is really led last year for the IAS-USA guidelines in March of 2024 in this country, to permit the use of long-acting ART in those with viremia. And the DHHS guidelines were updated in September of 2024 to also permit the use of long-acting antiretroviral therapy in the context of those with adherence challenges in viremia.

So both IAS and USA guidelines and the DHHS guidelines have now changed, which is great news for those who are viremic because I think it's an incredibly important strategy to use long-acting to achieve virologic suppression.

Certainly, we don't - cannot use long-acting CAB in the face of prior INSTI or NNRTI resistance that affects rilpivirine susceptibility, but a K103N has no impact on rilpivirine susceptibility, and chronic hepatitis B infection is also a contraindication to using cab/ril because neither component has hepatitis B activity.

[01:03:59]

Confirmed VF and Emergent Resistance With LA CAB + RPV in 5 Clinical Trials

So these were those 5 trials that I talked about. But it was really LATTE-2 was the phase II trial. So it's the ATLAS, FLAIR and ATLAS 2M trial that showed the efficacy of the use of long-acting cabotegravir and rilpivirine in those with virologic suppression.

[01:04:14]

Systematic Review and Meta-analysis of LA CAB + RPV vs Standard Oral ART

But this is really the data, which was from a series of observational studies looking at long-acting ART and the setting of viremia. This has been looked at in a number of observational studies. And this particular CID paper put this data together in a systematic review and meta-analysis of long-acting cabotegravir and rilpivirine.

I'm sorry to say that the—that particular—there is an updated reference for this in CID, and it was looking at then that AAC article and we'll get that to you. But it was in December 2024 in CID, which is a systematic review looking at long-acting cab/ril vs standard oral ART among these 6 RCTs. And essentially in those who started with viremia, there was a high rate of still maintenance of virologic suppression, compared to even those who started with virologic suppression.

This has been really looked at in—not in randomized controlled trials, but in observational settings. And even those who started with viremia again have a high rate of virologic suppression. In our setting, which we published this paper in JAMA in March of 2025, we found that 129 people who started with viremia at Ward 86 on long-acting cab/ril, out of 370 individuals who started long-acting ART but up to October 2024 at Ward 86, of those 129 individuals who started with viremia, there was a 98% virologic suppression rate at 48 weeks, and that published data that was performed after the systematic review.

So again, the DHHS guidelines permit the use of long-acting cab/ril in those with viremia. And if you fail—and this is important—if you fail on long-acting ART, there is a high rate, unfortunately, of INSTI resistance that does develop. So we have to watch very carefully for those who fail.

[01:06:31]

Systematic Review of Observational and Interventional Studies of LA CAB + RPV

This is a deeper dive on those 33 studies. This was 9,224 participants, who had virologic failure data. And the meta-analysis divided these groups into those who are ART naive, like in the FLAIR study, and started long-acting cab/ril after virologic suppression.

The second group that was looked at followed the ATLAS and ATLAS 2M design, where ART was started in those with virologic suppression. And then started ART with viremia. And in those 3 cases, looking at virologic failure rate, the virologic failure rate was higher in those who started with viremia at 5% vs 1% in the 2 other categories, but it was still rare. But in all 3 categories, if there was failure that occurred on long-acting cabotegravir and rilpivirine, unfortunately, there was a high rate of the emergence of INSTI resistance.

[01:07:36]

Real-world Analyses of VF With Switch to LA CAB + RPV

Okay, so there are a number of sort of real-world analyses of virologic failure with switch to long-acting cabotegravir and rilpivirine. The OPERA study is the 1 that I would really look at as kind of the largest electronic medical review of those living with HIV infection. The OPERA study represents about 14% of people on—it's an EMR-based cohort, living with HIV state.

And there was an updated analysis that was presented at CROI 2025 and actually even more of an updated analysis presented of the OPERA study at IAS, International AIDS meeting in Rwanda in July.

But essentially, clinicians are starting long-acting cabotegravir and rilpivirine in those with viremia. And in the case of those who were started with viremia in the OPERA study, there was a low rate of confirmed virologic failure. There are other real-world studies, TRIO, BEYOND, CARLOS. And these other studies all again, really looking at the setting of switching to long-acting cabotegravir and rilpivirine in those with confirmed virologic suppression.

And importantly, there wasn't any difference in confirmed virologic failure in the OPERA study in those with high BMIs vs low BMIs. Our patient had a BMI that was low. But there is a concern of reduced cabotegravir levels and those with high BMIs, unless you administer the long-acting cab/ril with a longer needle.

[01:09:24]

Risk Factors for Virologic Failure With LA CAB + RPV

What are the risk factors that emerge from ATLAS, FLAIR, and ATLAS 2M of developing confirmed virologic failure on long-acting cabotegravir and rilpivirine? There were really 3 factors that came out in the pooled analyses in - in multivariate logistic regression in those 3 trials.

One was having rilpivirine resistance-associated mutations in the past. In this case, this was looked at in DNA genotyping, but even having rilpivirine mutations in the past. Of course, K103N like in our—and our patient does not matter. Rilpivirine has full activity against a K103N mutation.

And then the second most important was that having a high BMI of greater than 30 kg/m², in which case we actually use a longer needle to administer the cabotegravir to get it into the intramuscular space. HIV subtype A1 has completely been eliminated as a risk factor for developing resistance.

The CARES study, which was the study performed in low and middle income studies, warrants 57% of participants with an HIV subtype A1, so not a concern. HIV subtype A6 still being examined.

[01:10:41]

DHHS Recommendations on Proviral DNA Genotyping

So in terms of our particular patient case number 2, he was virologically suppressed before switching over—before your consideration to switch over to long-acting cab/ril. And there really is not a recommendation to perform DNA genotyping. The DHHS guidelines do not recommend DNA genotyping in that deep reservoir to see if there's any mutations in his past. And I agree with that. We have found that that is unlikely to provide any valuable information.

So what we do instead look at back is if we can get any historical genotypes in the RNA in chart review.

[01:11:25]

Case 2: HIV Care Optimization

So in this case, we didn't perform any proviral DNA genotyping. He was switched to long-acting cabotegravir and rilpivirine every 2 months and monitored for maintenance of virologic suppression. No hepatitis B infection. He was hepatitis B immune and perform follow-up with mental health evaluation and follow-up.

[01:11:52]

Case 2: Key Points

So in this case, we really do want to assess patient satisfaction with HIV management at every visit, regularly assess whether that is the regimen that's working for them. And data really, at this point, is accumulating that long-acting ART can really reduce stigma and can safely be used in those with viremia. Maybe not this particular patient, but we have used very commonly at Ward 86, long-acting ART in the case of - to increase virologic suppression in those with viremia. And now our joint US guidelines in this country really permit the use of long-acting ART in those with viremia.

[01:12:30]

Case 3: Considering Weight Gain on ART

Okay. Our final case is to consider weight gain on ART.

[01:12:36]

Pretest 3

So this leads to our pretest question for us with a patient with stable virologic suppression and a good CD4 cell count. What is your most common reason that you would discuss switching, is that the best ART regimen for them? Is it because of:

1. Laboratory or health status changes;
2. The patient's dissatisfied with their regimen;
3. Newer regimens as they become available; or
4. Just part of routine discussion at every visit.

So please vote.

Speaker: Poll is open. Five more seconds. All right. Thank you. We'll close the poll and share the results. So just answers really across all 4 categories. And I think that all of them are indicated essentially. Certainly if a patient is satisfied with their regimen, which is the most common answer in this case.

[01:13:52]

Case 3: Background

So this is a case of a 63-year old woman who was diagnosed with HIV infection in 2010. She has been treated with ART continuously since her diagnosis, and her current regimen is an integrase inhibitor-based regimen with dolutegravir, FTC and TAF. She was fine with the 2 single small pills. Didn't want that single pill combination of BIC/TAF/FTC last year.

She has been persistently undetectable. And her last regimen prior to this was a single pill combination, but with elvitegravir and cobicistat.

Her weight has increased over the last 4 years and has increased from a BMI of 28 to 32 kg/m². And her LDL is up. And her HDL is also mildly up as well, which is a good thing. And she does have also chronic hypertension, which needs 2 antihypertensives at this point.

And a recent right upper quadrant ultrasound in this face of slightly elevated AST and ALT elevation showed hepatic steatosis.

[01:14:59]

Poll 2

So the second question is, following weight gain on dolutegravir/FTC/TAF and a new diagnosis of hepatic steatosis, would you change this patient's ART regimen?

1. Yes, he would switch to a 2-drug regimen taking away that TAF;
2. Switch to dolutegravir/FTC/TDF instead of TAF;
3. Switch to an NNRTI or PI-based regimen, essentially an NRTI sparing regimen; or
4. No, the available evidence wouldn't switch.

Please vote.

Speaker: The poll is open. Five more seconds. All right. Thank you. We'll close the poll and share the results.

Dr Gandhi: So here, the available evidence doesn't support ART switches to reduce weight, 25%; or 31% want to get off that TAF and replace it with TDF. So this is a really good to discuss that, essentially, at this point, we don't have great data that shows that switching ART is going to make that difference in weight loss.

[01:16:25]

Weight Gain Following ART Initiation and Switch

But what we do know is that TDF and efavirenz, at least both attenuate weight gain with ART. But and there's really theoretical reasons for that that have to do with brown fat and estrogen. People living with HIV do often gain weight, especially in that return to health phenomenon if the CD4 cell count is low.

However, there just hasn't been great data, including the DO-IT study that was just presented at the International AIDS meeting in July, that switching over from an INSTI/TAF-based regimen, which is the regimen in which weight gain is most prominent, either with BIC/TAF/FTC, or dolutegravir/TAF in this case that switching over to doravirine-based regimens did not result in significant weight loss in the DO-IT study that was just presented.

So it does happen. It is more prominent in the case of an INSTI and TAF. The ADVANCE study really showed us that—the ADVANCE study was a South Africa based study that looked at dolutegravir/TAF/FTC vs dolutegravir/TDF/FTC vs efavirenz/TDF/FTC and the weight gain was most, especially among African women on dolutegravir/TAF/FTC like this woman. But switching ART unfortunately in multiple studies does not seem to result in weight loss.

[01:17:59]

Switch From Suppressive BIC/FTC/TAF to 2-Drug Oral ART (No Previous VF)

And so this was a study that looked from suppress - switching over from suppressed - suppressive BIC/TAF/FTC to a 2-drug oral ART regimen, which is 1 of your options on the poll. And the DYAD study really looked at switching vs continuing BIC/TAF/FTC. And you can see by these p values here on the right that there was really no difference in weight loss in switching over in the small study to dolutegravir 3TC to that 2-drug regimen, no significant difference in weight change.

And then switching to doravirine/islatravir vs continuing BIC/TAF/FTC. This was the doravirine/islatravir phase III studies that were presented at CROI 2025. Again, no difference in weight change. Even though you're getting away from the INSTI, getting away from the TAF, at least at 48 weeks, no difference in weight loss.

[01:18:57]

PASO-DOBLE: Switch From Suppressive ART (No Previous VF) to DTG/3TC vs BIC/FTC/TAF

The PASO-DOBLE study looked at switching from suppressive ART to dolutegravir 3TC vs continuing that BIC/TAF/FTC. And this was a larger study where the weight change did not seem to decrease. There was no weight loss, not significant switching over to that 2-drug regimen. By the way, it really is prior use of abacavir and TDF in this case that predisposed to greater weight gain. So it's that switch from TDF to TAF that seems to lead to that increased weight gain. But again, switching to the 2-drug therapy did not lead to significant weight loss.

[01:19:42]

Additional Separate Studies of Switches to 2-Drug Regimens: Weight Changes

And in separate studies, switching over to 2-drug regimens that take away that TAF that excludes TAF, again doesn't consistently lead to clinically important reversal of weight gain. SALSA, TANGO, SOLAR and the P018 study no significant weight loss.

[01:20:03]

ACTG A5391/DO-IT Trial: Switch to DOR ± TDF vs Continuing INSTI + TAF/FTC in People With Obesity

Again the study that was presented most recently was the DO-IT study at the International AIDS meeting just this July. And this was the A5391 study. And the design of the DO-IT study was to switch over from that INSTI and TAF-based regimen, like our particular patient in this study, over to a doravirine-based regimen either with TAF/FTC in 47 individuals or doravirine/TDF/FTC or continuing that INSTI-based regimen.

And those 3 arms of the trial, the primary outcome was to look at weight change at 48 weeks.

ACTG A5391/DO-IT Trial: Weight Change and Safety at Wk 48

And the results were presented just 2 months ago, that in all 3 arms actually lost weight, even continuing the INSTI/TAF-based regimen, but no significant difference in weight change associated with switching over to the doravirine-based regimen, whether it be with TDF or TAF.

So at least at 48 weeks, a long-awaited trial, but no significant weight change with doravirine-based regimen.

[01:21:14]

IAS-USA Guidelines: Recommendations for Weight Gain and Cardiometabolic Comorbidities

So the recommendations at this point for weight gain, and especially in the case of cardiometabolic comorbidities, this particular patient in our case number 3 has hypertension and is getting into hepatic steatosis, and slightly elevated cholesterol that ART-related weight gain, hypertension or insulin resistance regimen changes at least have not shown a significant weight loss. And what we really want to do is work on potential cardiometabolic complications and the importance of lifestyle changes, exercise, diet, look at weight loss with GLP-1 agonists. There's data with GLP-1 agonists in the face of hepatic steatosis in the context of HIV and really controlling those cardiovascular risk factors. So optimizing health beyond the ART switch.

Optimizing Health Beyond ART

Case 3: Lipid Level Increases

In this case, this patient has LDL had increased, and did have that hypertension. So we want to look at that lipid level increase.

[01:22:24]

REPRIEVE: Statins for Cardiovascular Disease Prevention in People Living With HIV

So what the REPRIEVE study looked at was statins for cardiovascular disease prevention in people living with HIV. The results were published in The New England Journal in 2023. And the design of this study was essentially looking at people living with HIV 40 to 75 years old on stable ART, who had a low to moderate risk ASCVD risk score.

Now, this is a moderate risk individual and the placebo vs putting on a statin, pitavastatin in this case, was the design of this study. And the outcome was looking at major adverse cardiovascular events, MACE in this case is the abbreviation.

And you can see that there was a 35% reduction in major adverse cardiovascular events in the statin arm compared to the placebo arm in those with moderate risk. Actually, the number needed to treat was so low in the low risk that it's really the moderate risk category of cardiovascular disease that had the most effect. And at least here in this country, we really recommend starting a statin on those who have moderate ASCVD risk scores at baseline.

[01:23:35]

IAS-USA Guidelines: Statin Recommendations for Persons With HIV Based on 10-Yr ASCVD Risk

Now, in Britain, for example, the UK guidelines actually say start a statin in everyone 40 years and older living with HIV. So just go straight to the chase there. But here in the US, our guidelines are saying those at moderate risk like our particular patient.

So the IAS-USA guidelines are ASCVD risk score, of course that's high. High-intensity statin. But in our case, age 40 to 75. This is the REPRIEVE trial and ASCVD risk score of 5 to less than 20% to use a moderate intensity statin like pitavastatin 4 mg in the trial. But really, atorvastatin 20 mg would be most commonly used.

In those with a low ASCVD risk score, really a statin can be considered. But it's really at that point working on other cardiovascular risk factors like stopping smoking, and cholesterol and hypertension optimization.

[01:24:36]

Semaglutide: Potential Benefits in People Living With HIV

Now, I alluded to this trial that looked at semaglutide or GLP-1 agonist in people living with HIV, especially in the case of hepatic steatosis. This was published in Annals of Internal Medicine in 2024 by Jordan Lake. And the question was in the SLIM-LIVER trial as so-called, 51 people with essentially NASH or metabolic-associated liver disease receiving a GLP-1 agonist and what that did in terms of effects on hepatic steatosis.

And the outcome of this study did show a decrease in inflammatory markers and a 25% reduced risk of metabolic syndrome in those who received the GLP-1 agonist, compared to those who maintained therapy. So there were some benefits of GLP-1 agonists in the face of hepatic steatosis, like in our particular patient.

And at least in terms of improving cognition, significant improvement in visuospatial scores seen with GLP-1 agonists.

So in the CNICS cohort—and there have been effects of GLP-1 agonists on addiction-related outcomes in the CNICS cohort looking at alcohol abstinence in those with alcohol use, there was a decrease in alcohol use with GLP-1 agonists. And I think there's increasing data on GLP-1 agonists in the case of addiction use disorders.

[01:26:16]

CNICS Cohort: Innovation Lag in Semaglutide Prescribing

In this CNICS cohort, there was kind of an innovation or a lag in prescribing semaglutide. This was an analysis of people with HIV who were eligible for semaglutide therapy because of BMI being greater than 30 kg or having diagnosed diabetes. And in 2019 to 2013, even though there were 11,617 individuals with indication for GLP-1 agonist, there was a lag in prescription of GLP-1 agonists, especially among those who are Black or Latino. So we really want to be aggressive about the use of GLP-1 agonists in those indications.

Having high BMI, having diabetes and those racial ethnicity differences means that we have to be really vigilant to prescribing semaglutide when it's indicated.

[01:27:14]

Mediterranean Diet

In terms of dietary changes for weight loss, at least US News and World Report call the Mediterranean diet the best diet for 2025. But flexitarian diets and DASH diets were took second and third place. So that kind of Mediterranean diet with fruits and vegetables, as indicated here below and in moderation, or in higher amounts of fruits, legumes and vegetables, really placed highest in the diet rankings.

[01:27:50]

Weight Loss Interventions to Prevent Obesity-Related Morbidity and Mortality in Adults

So other weight loss interventions to prevent obesity-related morbidity and mortality in terms of the US Preventive Services Task Force recommendations, really behavioral interventions is kind of rated as a grade B recommendation for systematic review - in this systematic review of evidence for behavioral and pharmacotherapy weight loss, behavioral weight loss plus weight loss medications were really associated with more weight loss.

So hard to change behavior and also hard to achieve kind of sustained change with behavioral modifications. So to really look at GLP-1 agonists in terms of that weight loss medications as part of our counseling on weight loss in the case of HIV.

[01:28:41]

Prospective Study of At-Home Exercise Program for Older Adults to Reduce Frailty

This was a prospective study of at-home exercise program for older adults to reduce frailty over 12 weeks doing at-home exercises with resistance, endurance, balance and flexibility. And those who were sedentary above 50 years old, with and without HIV. And with HIV really reduction essentially, at least in the pre-frailty indication. So at-home exercises, weight-based training, really important.

[01:29:14]

DHHS Recommendations: Weight Gain

So in terms of weight gain, the DHHS guidelines as of September 2024 really do not, at least at this point recommend changing off therapy. We've kind of gone over that data, and at least clinicians should really consider GLP-1 agonists, and behavioral changes like exercise and nutrition.

[01:29:38]

Case 3: Key Points

So weight gain is common, appears to be greater in those on TAF and INSTIs, especially those in combination. Little evidence to support changing that ART. But really what works is optimizing overall health, including pharmacologic and other interventions for weight management and control of other cardiovascular risk factors.

[01:30:03]

[END OF TRANSCRIPT]