Joseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; and Ian Frank, MD provide an overview of the current HIV landscape, with a discussion on the impact demographics, location, and sexual orientation have on prevalence and rate of infection.

 titled “HIV Screening, Prevention, and Treatment Advances.” The treatment of HIV has a long history. There are currently over 40 individual and combination drugs approved for the treatment of HIV, and the life expectancy of a person with HIV nears that of a person not living with HIV. Challenges still remain regarding therapy, including tolerability, long-term adverse effects, and drug-drug interactions.

 panel discussion, I am joined by infectious disease specialists who are experts in managing HIV infection. We will review HIV treatment guideline updates and discuss important considerations that will help differentiate the current therapies. Emerging agents and novel management approaches will also be discussed.

I am Joseph Eron, a professor of medicine at the University of North Carolina School of Medicine in Chapel Hill.

Dr. W. David Hardy. He’s an adjunct professor of medicine at Johns Hopkins University in Baltimore, Maryland.

Dr. Paul Sax. He’s the clinical director of the Division of Infectious Disease at the Brigham & Women’s Hospital in Boston, Massachusetts, and a professor of medicine at the Harvard Medical School.

Dr. Ian Frank, a professor of medicine at the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania.

And Dr. Eric S. Daar, the interim chair of the Department of Medicine and chief of the Division of HIV Medicine at Harbor-UCLA Medical Center and a professor of medicine at the David Geffen School of Medicine at UCLA in Los Angeles, California.

Thank you so much for joining us. Let’s begin.

So we’re going to start talking about screening and prevention. So Eric, give us a little sense of where we are in terms of infections in the United States—incidence and prevalence and where are we now?

 Yeah. So the recent estimates are that there’s about 1.2 million people living with HIV in the United States, and I think more importantly, people have been carefully tracking incident of infections, challenging as it is to do, and this is where there has actually been some progress. And some of the progress may be linked to what we’re going to talk about during the course of this discussion when we talk about treatment and prevention, but after really decades of estimated 50,000 new infections per year, we now believe that it’s closer to around 40 or maybe even less than 40,000 per year. And there may be a lot of factors that are driving that, but it continues to be a really important metric to follow for our progress in trying to curb the epidemic in the United States. I think the other big challenge is recognizing where these infections are coming from and what are the things driving the epidemic?

Because if you look by group, it’s not everybody kind of going down. There’s a difference by risk group.

Yeah. Predominantly it has been infections involving men who have sex with men in the United States as the leading risk category. And for that group, especially in the 20 to 30 age group, it’s actually increasing a little bit. And everywhere else it’s decreasing. So the second-largest category is heterosexual transmission among women, men to women, and in that group it’s declining. And aside from a few very well-recognized outbreaks, among injection drug users, the new infections are very rare.

You can break that down even further. Among the MSM [men who have sex with men], it’s not even all MSMs; it’s primarily black and Hispanic MSMs, because transmission among white MSMs has actually come down pretty well.

So, Ian, so what about different areas of the country in terms of new infections?

So there are major regional differences. The CDC divides the country into 4 different groups. They’re Northeast. Infection rates are actually going down. They’re also going down in the Midwest. The Southeast, which is actually the largest group, that includes all of the territory basically south of Pennsylvania down to Florida, and west to Texas. The rates of new infections there are stable, although in some areas they’re actually increasing a little bit. And in the far West, the infection rates are stable.

I want to though point out, because we often emphasize infections among young individuals, about 15% to 20% of new diagnoses are made in individuals ages 55 and above. And I just want to remind people of that fact because we need to remember to continue to test people if they’re at-risk or if they come in certainly with any indicator disease that could be associated with HIV. I want us to not overlook that.

I want to mention 1 other thing about testing, which is that there’s progress, when you look at the incidence of HIV in the United States, and this progress that Eric alluded to, it starts to improve back in around 2006, 2007 when the testing laws started getting more relaxed.

So right now the proportion of people unaware that they have HIV infection in the United States is only about 12% to 15%. Whereas in 2004, 2005, it was about 30%. So we made a lot of progress in getting the people who were undiagnosed diagnosed.

We also made it easier to get diagnosed with this rapid test that requires saliva and no longer blood drawing, which has actually helped a lot as well.

And I think we have to remember before we abandon our concerns about injection drug users, there is an opioid epidemic and there is reason to be concerned that we may see an uptake in the number of new infections.

We’ve had an outbreak in the Boston area over the past year in that it’s just been quite surprising to see a new HIV diagnosis in a young person who uses injection drugs. It’s the first time we’ve seen that in over a decade so it’s really.

We’ve had some very high-profile outbreaks over the last 5 years or so.

And needle sharing is happening because young people who are injecting are getting hepatitis C infections.

So we know that that’s happening, but virologic suppression rates are surprisingly high among injection drug users. That’s probably the reason why infection rates are low. But I think the hepatitis C data is a warning sign, because it really means that if a few cases get introduced there’s the potential for rapid spread among intravenous drug users is relatively high.

Right. The half-life of some of the opiates of choice now, fentanyl in particular is so short, that in certain situations people who inject drugs are injecting 5, 10, 20 times a day. And so in that context there’s really a chance for explosive spread of HIV.

Yeah. And I think also that, at least in North Carolina, and I don’t know about, the 2 epidemics just haven’t overlapped yet. So it’s poor, White, and rural for injection drug use in hepatitis C, and it’s poor Black and some a little bit also in the cities, and it just hasn’t intersected yet. So I don’t, I’m not sure that, that suppression in our injection drug users is the answer in North Carolina, but it might be.

The HIV Treatment Landscape

 Joseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; and Ian Frank, MD provide recommendations for proper screening and diagnostic protocol and considerations of the stages of HIV infection in presenting patients.

: So let’s move on and talk a little bit about the kinds of stages of infection, Paul. And you can actually, I think, talk about diagnosis here and also maybe remind people that new diagnosis doesn’t necessarily mean a recent infection.

Sure. Correct. But since we’re talking about stages, why not start at the beginning and realize that people who get infected with HIV can have a clinical syndrome that we call acute HIV infection, which is a lot like infectious mononucleosis. And it’s about estimates: It’s hard to know, but about half the people who require HIV are symptomatic. And then the severity of that illness is really incredibly variable. Everything from a very mild mono-like illness to, you know, I’ve seen someone with very fulminant meningoencephalitis who got admitted to our ICU [intensive care unit] with very severe encephalitis from acute HIV. Interestingly, it was an individual over the age of 50 who was from sub-Saharan Africa, and it was really interesting.

But anyway, the diagnosis during those symptomatic periods early on is actually the HIV viral load test. In most contexts, though, that’s not the test we’re going to be sending when we want to screen for HIV. We’re going to be sending this fourth-generation antigen antibody combination assay, and that has really improved our ability to diagnose HIV after recent acquisition. It’s not quite as sensitive as the viral load test, but it’s almost as good. So that’s our screening test.

And its crisis is more expandable. And its turnaround time is also easier to do because it’s ELISA [enzyme-linked immunosorbent assay] as opposed to a PCR [polymerase chain reaction] test so that it can be done more quickly as well.

I mean, if you’re going to screen someone for HIV who doesn’t have acute HIV infection, someone who you know maybe had risk behaviors a couple of years before, who has never been tested before, is asymptomatic. It’s that fourth-generation antigen antibody test that they’re going to be sending.

But it is important. Paul, as you said, it’s a great test for routine screening. If you encounter someone in whom you have a high index of suspicion, and the fourth generation is negative, they really do need to have an RNA test done.

It’s amazing that the quantitative HIV RNA test, the viral load test that we use for all our patients—nobody has ever gone to the trouble to get it FDA approved for diagnosis.

Which is annoying, but it’s just not—you can’t use it for diagnosis. One thing that I just also mentioned just clinically because it’s important, is if that antigen antibody test comes back positive, it doesn’t have enough specificity for you to sort of say that’s conclusively the diagnosis, so it has to be confirmed with the second test, which is now called differentiation assay. And in our hospital where we have a large obstetric service and a lot of women who are pretty low risk are getting screened, it’s actually just as common for their screening test once positive to be not confirmed as it is for it to be confirmed. So there is a false-positive rate in that, in that screening assay.

So that’s like the kind of acute infection. In Los Angeles, what, how are people presenting now?

Yeah. So I mean, obviously we occasionally see people with acute infection, but the majority of people are coming in for routine screening, or increasingly because of guidelines, like CDC guidelines, people are—even without obvious risk factors&mdash;just getting a test. So a lot of people admit to the hospital, people who are going to certainly STD [sexually transmitted disease] clinics and urgent cares are getting screened and getting diagnosed. And I think anecdotally&mdash;and I think there are data in other centers&mdash;that we are catching people earlier because our threshold screen is now, you know, if you’re a warm body, and we think of it, we should do it.

And I think the other thing that Paul just mentioned, taking away the obstacles of getting tested make a huge difference. Taking out the consent form, taking out the counseling before and after has really helped. And then also the other thing we’ve noticed in Washington, DC is that if you take the test out of the testing center into the community, people will come and get tested. For many years, they tested people at the DMV [Department of Motor Vehicles] in DC because the incidence was so high. And after you got your driver’s license, you got a chance, you know, to go get tested as well. They stopped doing it because the pickup rate was so small, but it really normalized HIV testing, which is so important.

And what about advanced disease? Do you guys see that, people presenting with advanced disease still?

We see fewer cases in Philadelphia, people coming in with AIDS defining clinical events. And in the outpatient setting we see fewer people with CD4 counts—fewer than 200 at presentation than we have. But occasionally those people still surface.

We still see a lot of people who slipped through the cracks.

It really is very dependent on the region in which you practice, and whether you do inpatient medicine, because really, the only context I see it now is someone who gets admitted to the hospital with an opportunistic infection, or gets admitted with a mysterious wasting illness that turns out to be not so mysterious after all.

In DC it’s really interesting because there’s a real dichotomy between who’s giving chronic infection and who’s not. So in my experience African-Americans are the ones who are coming in very late in large part because of the fact that even though they may know they’re positive, they’re not accessing treatment because of the stigma of taking the treatment, and what that means in their community. So I saw several cases working in DC of individuals who came in with T cells less than 50 and minor opportunistic infections.

In North Carolina we still see—you know, we probably have 2 or 3 cryptococcal meningitis. Sometimes there are people who are actually seen in an outside hospital. They’re perceived at being lower risk; they might be a little bit older, like an older woman, for example. They’re perceived to be at lower risk, so the diagnosis isn’t necessarily considered. And the other thing you see is a lot of them have had an opportunity to be tested but they’re not tested.

Yes. There’s actually quite a bit of literature on this. And every infectious disease specialist has many, many anecdotes of people who bounced from clinician to clinician to clinician getting unexplained symptoms and laboratory abnormalities worked up. You know, the classic example is the bone marrow biopsy that’s done before the HIV test because of leukopenia. I mean that’s just completely crazy these days.

Sometimes it’s not so subtle either. Sometimes it’s, you know, it’s an oral candida that may be seen in a dental office or herpes zoster or where there’s been no HIV test or new cirrhosis. An HIV provider would say, “Hmm, I think this person needs to be HIV tested,” but it doesn’t always happen in a general practice, or another subspecialist’s care.

One last group of people who don’t get diagnosed. There are some patients who do still refuse testing. And the anecdotal—again, there was a patient I saw from rural Vermont who had been seen by multiple clinicians and several had recommended that he get HIV testing; he kept refusing. And then he insisted on getting a, quote, second opinion at the Boston Medical Center in Boston, Massachusetts, poor guy, and the first thing I said to him was, get an HIV test.

But he ultimately did it, but I mean there are some of those people who are so stigmatized by the diagnosis, and also are so afraid, that they just refused to get tested.

I’ll tell you, using the opportunity when you encounter somebody to explain to them how good treatment really is and how everybody has access to the best of treatment. Those are often what drive people away. They can’t access, the treatment isn’t good, the treatment’s toxic, and even if it is good, they can’t get it.

HIV Screening and Diagnosis

Joseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; and Ian Frank, MD, discuss the effectiveness of pre-exposure prophylaxis (PrEP) therapy.

: So let’s shift a little bit and talk about PrEP, pre-exposure prophylaxis. I think we have a pretty experienced audience, but maybe, Ian, you could take a shot at describing PrEP and how we should be using it—in 2 minutes.

The use of antiretrovirals [ARTs] to prevent individuals from becoming HIV infected is really 1 of the major advances in our field over the last few years. Studies have shown that if individuals take daily tenofovir and emtricitabine, 1 pill a day on a daily basis, you can prevent nearly 100% of HIV transmissions. It’s that effective.

There are some data with intermittent strategies: 2 pills before sex, 1 a day after, 1 the day after that. A study called the IPERGAY study that was done in France. In the US, the recommendation is still daily tenofovir and emtricitabine, 1 pill a day. It works in men, it works in women, and it works in intravenous drug users, and the CDC has clear guidelines for who should be offered PrEP, and it’s basically individuals who are sexually active in nonmonogamous relationships with partners who are either known to have HIV or whose HIV status is not known.

I think we should be talking about PrEP with anybody who has had a sexually transmitted infection. We should be talking about the use of PrEP in men who have sex with men who are not in monogamous relationships. And it’s really an easy conversation to have. The combination is very safe. There are very few serious toxicities. We should be aware of hepatitis B status in individuals before starting, because tenofovir and emtricitabine is active against hepatitis B, and if you initiate the combination in people with chronic hepatitis B and then ultimately stop, there’s a risk of hepatitis B reactivating and causing acute liver injury.

You want to make sure that somebody doesn’t have acute HIV before starting on PrEP. So if there are symptoms, you may want to do a viral load in addition to a serological assay, because individuals with acute HIV won’t be on totally effective antiretroviral therapy if they get only 2 drugs. And so the risk of resistance is relatively high.

There are a handful of cases of individuals that seemed to have been well adherent to their PrEP combination but still became HIV infected. Sometimes they’ve gotten infected with very resistant virus, and in some cases we don’t really have a good explanation of why they’ve gotten infected. But this is a strategy that is highly effective.

I guess the big issue, though, is that if the use of it doesn’t overlap with the parts of the country where the risk is the highest.

Exactly. So there’s way more prescribing of PrEP among white individuals than there is among black individuals. A lot of the people we have prescribed PrEP to would fall into the category really of the worry—well, they may be in a monogamous relationship with an HIV-infected partner, but that person is taking [ARTs] already, so their risk is actually really low, if not 0, but they still want to take PrEP just because. I mean, those are not the people at highest risk of getting HIV, and really that’s where PrEP needs to be rolled out.

So it’s estimated based on the people who are candidates for it. There are maybe 1.2 million—that is the number that’s sort of floating around. And only about 10% of those people are on PrEP. And as you say, it’s mostly the people who aren’t in the traditional high-risk group that we really need to be targeting. And in order to do a better job, we need to do better marketing for sure. But I think we also have to, as Ian said, remind everybody that this is simple. We have to stop making this sound as difficult as treating somebody with HIV. It’s simple, easy to take, the screening is very straightforward, and it’s what we need to do. As long as we don’t give it to someone who has HIV, we’re probably going to do mostly good.

I think 1 of the problems is we’ve medicalized this. If you look at the PrEP guidelines, you’re monitoring patients more often than we’re monitoring people with HIV infections.  

When you think about it, what thing has made the PrEP rollout difficult is because of that medicalization. In most cases, the only sort of medical interactions many people who are on PrEP have is with their PrEP provider. So why make that more complex, more difficult, more time-consuming for a prevention of the disease. I mean innovative ways of, for example, having people being seen every 3 months—not by a care provider but by a talented pharmacist&mdash;to get the test done and then have them interpreted, because those tests are very easy to interpret. You know the way that PrEP is going to work best, especially for individuals at highest risk, is No 1, to market it directly to them and to take it out of medicalization, so people can get it easily and quickly.

Yeah, but I still think, and 1 thing that Eric said, you know there might be 100,000 people who have been prescribed PrEP, because that’s the other thing, right, that is sustaining. I mean, you can look at the data, especially in younger people, and maybe it has to do with the medicalization, David, as you just pointed out, but sustaining PrEP is a challenge.

You’re not supposed to refill it until you get that next negative HIV test, and it’s been 3 months and then. But I think we have to be a little looser with our follow-ups, allowing people to stay on PrEP without necessarily doing everything that is in the guidelines every 3 months like clockwork.

Because another thing we have to realize also is that PrEP is not taken like HIV medications, meaning continually for a lifetime.

PrEP can be taken in fact on and off and on and off, depending upon someone’s sexual activity, depending upon what’s going on in their life, depending on what’s going on in their partner’s life. Now we have to be aware of that and also be flexible to let people say, “I’m going to be off for the next 3 months, so don’t expect to see me. But when I’m ready to go back on, I’ll go back on.”

It’s worth reminding everybody that, as Ian said, it’s tenofovir and emtricitabine. But right now at least, pending more data, tenofovir, disoproxil fumarate, and emtricitabine. So we’re not yet using the new form of tenofovir that we’ve integrated extensively into our treatment strategies. We’re not yet using that for prevention, although there is a study that’s actually looking at that. So hopefully we’ll find out soon.

HIV Pre-Exposure Prophylaxis Therapy

Joseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; Ian Frank,  MD, partake in a conversation on the importance of rapid treatment initiation, the difficulties of adherence, and accessibility.

So I’m going to move to talking about treatment. And I just want to bookmark that, we’ll talk about U=U sometime during this treatment thing. Because I think it makes sense to now kind of talk a little bit more about the treatment landscape. Maybe, Eric, you could, like, set the picture. And then we’ll go through some more specific things. But maybe you could set up where we are.

Yeah. When I think about the treatment landscape, I still think it starts at the beginning, and it’s worth reminding everybody that after decades of debate as to when to start, I think everybody completely agrees that everybody diagnosed with HIV—regardless of their CD4 count, regardless of symptoms, regardless of comorbidities&mdash;should be offered and encouraged to initiate after antiviral therapy. And that’s because we now have convincing data showing that it prevents disease progression. In addition, we know, and we’ll talk about U=U, that it prevents transmission. But probably as important is that it’s just so darn easy to do. The treatment now, you know most people we start on 1 or 2 relatively small pills often in a day with virtually no adverse effects for the majority of them.

So the decision about when to start is very straightforward. Obviously we need to help people get prepared to take their meds consistently if they’re dealing with psychiatric disease and substance abuse and that. But so we should start everybody. And when we start the guidelines, there’s increasingly a consensus in the guidelines, both in the United States and in Europe, that most recommended regimens are 2 nucleosides and a third drug, and the third drug is essentially always an integrase inhibitor.

And the most recent guidelines, and we may go over this in more detail, have really focused on 2 of the more recently approved integrase inhibitors that are small pills and don’t require boosting, so you don’t have to worry about drug-drug interactions. They are generally very well tolerated and happen to have a high barrier to resistance. So even if things don’t go right, resistance is very unlikely to occur.

And in many ways, as the guidelines become more and more small in terms of the number of recommended regimens, it’s getting easier for people who, unlike us, may not have been doing this all their lives and have always been put off by it. Because the guidelines used to have so many different options that it looked too confusing, and the guidelines were so expansive. You know, in younger providers now who are thinking about getting into HIV, the treatment has become simpler. And I think it’s all become good. The downside on all those regimens is really pretty small.

That’s true. And 1 thing about treatment initiation is, how quickly should we do it? We’ve talked about this. It’s a thing.

It’s a thing, right. Historically there was this whole idea that before people started on ART [antiretroviral therapy], they needed to like go through a little educational course, an HIV 101 course, to learn about the importance of adherence and what viral loads CD4 mean and all this stuff. But it turns out that was all garbage. You know?

You know 1 of the most remarkable moments I’ve experienced recently at a major meeting was watching my colleague, Serena Koenig, present a study that they did in Haiti where they basically took people who were newly diagnosed and randomized them to start that same day they got their diagnosis. Or to go through this little HIV 101 course and then start, and it turns out that the 

 stopped the study early because the people who started the same day did clinically better.

Clinically they do better, right—better survival.

Survived better. And it turns out we can do that with our treatments now. If people want to start treatment right away, and there is no reason to delay, in the vast majority of people we see now, we give them a prescription for ART that first day.

One thing I will mention is that transmitted resistance, which is a big fear, is significant enough to impair the activity of a bictegravir- or dolutegravir-containing regimen, which is vanishingly rare.

So go ahead and start, and you can just don’t give them HIV 101 course, but after they’re on ART, so.

So there is certainly paternalism or maternalism in our readiness to prescribe therapy early on. But I would say that still counseling people about the importance of adherence is crucial. And I would also say that there’s no urgent need to start everybody on therapy the day that they’re HIV diagnosed. I think for the studies that are done in Haiti, or other developing-world scenarios, there’s a high loss to follow-up rate, folks are presenting very late in the course of their disease. And they often travel a long distance to get to the HIV clinic.

So some of these issues are less important. We’re going to come back to U=U and as treatment as prevention. We want to get people on therapy quickly to get their viral load undetectable as rapidly as possible. But if somebody comes in and says, “I don’t think I’m ready to start this,” I don’t think we should be twisting their arm to get them to start on therapy.

I agree with you that we shouldn’t twist their arm.

Yes, we should be talking them into it, but, you know, it’s OK for people to walk out of the office without a prescription.

What other STI [sexually transmitted infection] do we ever say, come back in 3 weeks and we’ll see if it’s still there; until it gets really bad. Do we do that with hypertension, diabetes, hypercholesterolemia?

We don’t start people on antihypertensive therapy when their first diastolic blood pressure is 92; they come back.

Right, and diabetes might not also be the best example here.

But if it’s discovered, and it is diabetic. Then you don’t wait and say let’s wait till it gets worse.

Sure, we don’t wait to start the adventure.

Yes, there are challenges, but most of the time they can be overcome. I know in some regions we don’t have them and we don’t need them. In some places there are starter packs that people have access to 10 days of therapy. It does make people feel better to start sooner rather than later.

Yeah. I think my point was kind of like, you do have to have your clinic or office set up to do that. And if you can do it, it’s great. If it’s a few days later, that’s OK, you know? But it’s this idea of it’s an important problem.

One thing just to mention about San Francisco’s experience, because you know they didn’t do a randomized study, but they have this historical data. And what they’ve shown, importantly, is that this process of starting ART right away has led to a much faster decline in HIV RNA and a faster time to undetectable; but importantly, there was no increased risk of resistance. That’s over time looking at their historical data. It’s not as if they lost anything by doing this.       

But also they were using, they were using 2 very potent regimens, though: boosted darunavir or dolutegravir exclusively for that study though too. And you wouldn’t expect resistance if they weren't.

That’s why we can do this, and we don’t have to worry about hepatitis B. We can wait for that test to come back and that sort of thing.

HIV Treatment: Initiation, Adherence, and Accessibility

 So David, talk about the guidelines. Talk about what we’re supposed to be doing in terms of screening people.

The good news is the US Preventive Services Task Force many years ago gave HIV testing a very high recommendation, the highest recommendation, Grade A, and it’s been confirmed. So there’s really no scientific doubt that this was a good thing to do in terms of preventing longer-term HIV-related complications. And I think that’s what really makes it very clear. We’ve talked a little bit about how testing has been made better in many ways by taking over the consent form and the other things like that that used to get in the way.

But I think the thing that is tough is the stigma, because although we can persuade physicians to test people, and I think that’s great because it follows that guideline, whether or not people will consent to it is not always great. But the opt out, I think, has really helped when people get tested, are asked to be tested, or will be tested, and the wording can be as simple as, “I test all my patients for HIV. I’m going to test you today too, unless you say no.” So it assumes that it’s a good thing, and if presented in that light, it then goes on from there. Because, you know, for many years the CDC even recommended it, as the first with this epidemic, that we test people based upon their risk activities, or their risk factors, their percent, their perceived risk activities. And when you say that’s shown it’s not a good idea that everyone should be tested at least once after they become sexually active, after the age of 14 or so, up to the age of 65 at least, and that we do this on a regular basis if we detect that there are continuing risk factors going on. And the risk factors are very simple, including drugs.

And so are there different recommendations for pregnant women?

Definitely, because we can now prevent HIV infection and transmission of HIV infection from mother to child. Every woman should be tested at any time that she is going to get pregnant, if that’s a good idea, or after she’s pregnant. And certainly even up to the point of time of delivery. Because there are interventions that can be done all along that full continuum to be able to stop the transmission from mother to child. So testing there is really important.

Exactly. The very few cases of HIV transmission in newborns; when you look back they often had a negative test early in pregnancy and then a positive one later on.

Absolutely. Which gets back to that acute infection thing in which there are super-high viral loads with no antibody present. Which you know.

HIV US Preventive Task Force Screening Recommendations

 Joseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; Ian Frank, MD, have a discussion on the undetectable equals untransmittable concept (U=U) and its effectiveness in preventing the transmission of HIV.

David, this is an opportunity that maybe we should talk about U=U now, before we get into specifics about choosing a regimen.

You know U=U is simply a new term that basically just stands for “undetectable equals untransmissible” or “untransmittable.” And it’s 1 that actually in many ways was generated in the community, and then it was actually the scientific individuals like [Anthony Fauci, MD, of the National Institute of Allergy and Infectious Diseases, part of National Institutes of Health], and Robert Redfield, MD, at the CDC, also approved it because there are great data behind it that say that it’s all very true. I think some of the most powerful data are the PARTNER 1 and 2 studies that really show how hard you can stress an undetectable person’s ability to transmit by having them have unprotected, condomless sex with their partner on repeated occasions with ejaculation and have no transmission. Both heterosexual and homosexual. And I think that’s really very powerful.

And Eric, whom is this important for, do you think?

I’d personally think it’s mostly for people who are in a discordant relationship, a stable relationship. You know the message is important for everybody. There’s no reason to withhold the message, but the practicality is that if you have lots of people you’re exposed to, it’s impossible to know what their status is.

So I mean, I think it’s for people in stable relationships. They can feel comfortable that they don’t need to use condoms, as long as the partner is stably suppressed on antiretrovirals.

I think it’s for the person who’s infected.

Regardless of the relationship, because it’s so stigmatizing to think; you know you hear these stories about people who are transmitting HIV all over the place. On the other hand, most of my patients.

Terrified that they might give this to someone else. And to me, there’s the public health message.

So our social workers describe patients who start crying when they hear that this is a scientifically proved fact, that they can go on treatment and become uncontagious to others.

The stigma lowering—you know I think that’s why it’s so important. Because this actually came from the community in many ways, what we see in terms of biologic stopping transmissions and treatment equals prevention is interpreted very differently in the community in terms of how it makes people who are HIV positive feel. For years, I know in the gay community there has been a very strong prejudice against HIV-positive individuals within their own community because they’re HIV positive. And this really sends that away because they can’t transmit the virus anymore, so they no longer can be stigmatized. I think it’s a little more difficult in some other communities, but you know the message should really be continued to be put out there.

 The other place that I think it has value is when you’re counseling that newly infected person. The whole discussion about trying to engage them and get them on care. Now we can tell them that not only will they be able to initiate therapy that is simple to take, is well tolerated, and will always suppress their virus to undetectable levels, and that they’ll presumably live forever from an HIV perspective on treatment. But they also don’t have to worry about transmitting to their partners.

Yeah, I know, I think that’s exactly right.

We have cities like New York and San Francisco that have “Getting to Zero” programs in which they hope to at least level off the number of new infections.

That’s right. So there’s a huge public health benefit to this. This is a major component of ever “Getting to Zero” urban campaign or rural campaign.

And you have to assume any reduction in which we’re going to see an incidence. You know, we think we’ve seen a reduction. Any further reduction is going to be completely driven by getting people diagnosed on treatment and getting high-risk people on PrEP [pre-exposure prophylaxis].

And doing it in areas where we know there’s transmission. Recently, the CDC presented data that 50% of new infections in 2016 were in 46 counties.

There are, like, thousands of counties in the United States. And again, yeah, I think that there are hot spots where we can really focus this.

HIV: Undetectable Equals Untransmittable

Key opinion leaders consider the best treatment options for the general HIV population.

Let’s get back to kind of choosing a therapy. So all kinds of benefits getting people on rapidly, decreasing transmissions, making people less stigmatized and untransmissible, as David said. What about selecting therapy, Ian? What goes into your thinking about how to select therapy? Or is it now so easy, we don’t really have to think that much?

Well, I think there has been a convergence of therapies in a lot of ways, and we don’t really need to think quite as much. I’ll go through some of the factors we used to consider, and we’re going to talk about maybe some people who don’t fit into the general category, who are the exceptional patients where we really need to focus our thoughts a little bit harder. But we used to worry about CD4 count and viral load. I think it’s certainly true that even with the newest therapies, maybe people with CD4 counts that are on the lower side may not do as well as people with CD4 counts higher. But it’s difficult to distinguish between 1 combination and another, even in people whose CD4 counts are low and whose viral loads are high. When we’re choosing a next-generation integrase inhibitor, bictegravir or dolutegravir, and when we’re using the kind of active nucleoside combinations that we most commonly do, generally tenofovir alafenamide, maybe abacavir when needed in some situations.

We used to worry about cardiovascular disease. We don’t have to worry so much about that with the next-generation integrase inhibitors. We may not want to use abacavir or lamivudine. There may be a signal of an increased risk of MIs [myocardial infarctions] in people who are on abacavir regimens. We used to worry about tenofovir and renal effects and effects on bone density with tenofovir alafenamide. We probably don’t need to worry about that complication so much.

If individuals have chronic hepatitis C infection, you may want to have avoided an efavirenz-based combination or boosted protease inhibitor combination in the past because of drug-drug interactions with the directly acting anti—hepatitis C drugs. If you use an integrase inhibitor, you don’t have to worry about those interactions.

If somebody has chronic hepatitis B, you want to start them on a tenofovir-based regimen, so that’s a coinfection for which you want to make sure you choose a particular nuke combination. But we don’t have to worry about lipid effects so much. We don’t have to worry about other metabolic complications the way we used to. So I think it’s really become a lot simpler.

You just made the case for why we can do rapid initiation.

Because all those labs that we used to have to draw and wait for to come back, we don’t really need to wait for them anymore, other than the positive HIV test, the confirmation test.

Pregnant women and women who are electing to become pregnant would probably be the largest group who would maybe fall outside the general guideline.

HIV Therapy Selection for the General Population

Joseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; Ian Frank, MD, discuss the updated US HHS guidelines regarding antiretroviral agents and rapid initiation, as compared with the IAS-USA Guidelines.

Eric, tell us, what are the HHS [US Department of Health and Human Services] guidelines right now?

OK, before I say that though, let me just say there’s 1 other branch point that actually was very relevant in my practice in which we take care of lot of very difficult patients—not difficult patients but patients with difficult problems. They’re homeless, they’re dealing with substance abuse, alcoholism, psychiatric disease.

I don’t have a lot of adolescents, but they have similar issues. The group of people that I really worry about when I start them on a therapy that they wouldn’t the medications, right? Or maybe never even come back. And for me that used to be a big branch point. It sort of boosted PI [protease inhibitors] versus other. But now with the data on dolutegravir as a barrier to resistance, I’m perfectly comfortable moving forward with that. And I think bictegravir may turn out to be exactly the same way. We don’t have as much data. So suddenly, as you say, all those things that were important before with comorbidities and drug-drug interactions and now barrier to resistance have all gone away, and they are preferred options to really meet all those needs.

And Paul made the point earlier that the prevalence of integrase-associated resistance is very low. I still think that we should be doing resistance, testing at baseline. Paul will argue against it. But I still think that there are a number of reasons why it’s still valuable. But I think it doesn’t influence our treatment decisions very much anymore.

What are the current guidelines? The current guidelines are dolutegravir with abacavir and 3TC lamivudine in a single tablet, dolutegravir with TAF-FTC [tenofovir and emtricitabine], and bictegravir with TAF-FTC. And those are really the US guidelines right now.

You know the HHS still has raltegravir in there.

One addition—and raltegravir remains on the HHS guidelines but not IAS-USA [International Antiviral Society].

Exactly, and that’s 1 place where they differ substantially. And since I’m on the IAS-USA panel with some of my colleagues here, I’m going to say I don’t really see how raltegravir fits when you’re comparing it with bictegravir and dolutegravir. It’s 2 pills; it can’t be co-+formulated. Residence does occur, especially, you know, to class resistance. So it does, yeah, we have a long track record with it, and when it came out in 2007, it transformed HIV therapeutics. But these second-generation integrase inhibitors are better.

Just a resistance difference is one that would make you stop want to use it, despite the pills.

Yeah, I’m not pushing back on that because I agree with you, but the 1 issue that we sort of started to talk about, and maybe we need to talk a little more about is, women of childbearing age potential.

Yeah, we’re going to get to that in literally just a minute.

Can I critique the DHHS guidelines a bit more?

So I actually don’t think there’s much role for abacavir any more. You know abacavir was always a little less well tolerated than tenofovir, even independent of a hypersensitivity. And the signals on cardiovascular risk are concerning enough that I probably wouldn’t use it. Why use it? You know, it really does not seem to have much of a role any longer. And then so both raltegravir and abacavir kind of have fallen down.

It certainly doesn’t, if you read the guidelines. You know, for most people it just—there are too many caveats.

Exactly. You know and you still have to do an HLA-B*57:01 test, which isn’t a big deal, but it is another test.

HHS vs IAS-USA Guidelines for HIV

oseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; Ian Frank, MD, consider the use of dolutegravir with lamivudine and boosted protease inhibitors for women who are pregnant.

Yeah, so I agree, and I think we’ve kind of touched on the safety and efficacy. And these drugs are very safe with a barrier to resistance, and the pill burden is small. So I think we should get to this: who falls outside most patients. And I think we might as well address that—women who are thinking about becoming pregnant or are pregnant. So who wants to&mdash;David, are you going to start?

I think that we know the 1 thing the guidelines did several years ago is that they no longer just had a single box, a single recommendation for first-line therapy. And they qualified it by saying, “for most patients.” And then they went into great detail in other parts of the guidelines and with new and different tables, where the patients were being discussed. Such as those who have comorbidities like renal problems and could not take even TAF [tenofovir alafenamide], for example, and needed perhaps a non-nuke regimen.

For women of child-bearing potential, women who want to have children, 2 of them are recommended. Well, all but 1 of the recommended regimens for everyone could be used in women: the raltegravir. Bictegravir and dolutegravir are not going to be recommended at this point, especially not the dolutegravir at this point in time as more data are accumulated around the 

But I think you know it’s really trying to, again, get back to the individualization of therapy and breaking things down and say, you know, for most patients as we have talked about, the integrase inhibitor regimen with 2 nukes, especially with a TAF [tenofovir alafenamide] component. It works really well for most patients. You know you would have to say probably in 75%, 80%, 85% of patients who we see, and even that idea about having to use a boosted PI [protease inhibitor]—you know that’s gone, that’s gone away as well.

So you know what I struggle with, many times, is trying to find those patients, besides women of childbearing potential, or you know even for a patient with hepatitis B or hepatitis C, the first-line regimens are still oftentimes the best ones.

So Eric, let’s say you have a woman. She comes in, and she says that she wants to have a family and wants to start soon. She realizes she has to suppress first, but she doesn’t want to wait too long. What are you going to give her, and why?

You know, the challenge is that it used to be when we had this discussion is that people would go immediately to the pregnancy guidelines and say that these are the drugs approved in pregnancy. And a lot of the reason why these drugs are recommended in pregnancy was because we had some experience, but mostly we had the PK [pharmacokinetic] data…

Telling us that we were OK in that trimester—second, third trimester&mdash;when there’s the increased volume and distribution. The way I always looked at it was well as long as I’m following her: If she gets pregnant, I’ll worry about that later. I don’t really care what I start her on.

Even efavirenz has sort of fallen off the list as a concern for teratogenicity.

And then came the Botswana cohort that was trying to look more carefully at the relationship with dolutegravir as it was being rolled out. So they were following women prospectively during their pregnancy and there was the signal report about a year ago—of 4 cases, I think. Four cases of neural tube defects, which translated into about a 7- to 10-fold increased risk over other antiretrovirals that are being used. And sort of then what you’d expect in an HIV-negative group, it got a lot of attention and raised concerns appropriately. So now all the guidelines, you know, jumped on the fact that dolutegravir is an issue and particularly where it showed up was in women who were exposed at the time of conception.

Not the first trimester. In general, not beyond the first trimester.

At the time of conception—which makes sense for neural tube defects, so you can’t dismiss it, because most of that happens in the first 6 weeks or so. So it created a problem. It used to be the only time we had to worry about these drugs in pregnancy was for our subset of patients who were pregnant. Now we have to worry about it for all our women of childbearing potential who aren’t reliably using contraception.

Boy, it’s a tricky one because here we’ve been praising the dolutegravir-based regimens. And one could easily say probably the same thing about bictegravir, for which we have no data but very similar drugs. And you don’t want to deprive women of the best possible therapies, and it ends up being a difficult trade-off. Numerically, it’s a trade-off that is not easily answerable because the benefits to a woman of going on the best regimen may exceed the risks of the neural tube defects, which are really right now a big unknown.

It is. I mean, it is conceivable the signal will go away with more follow-up. I think there’s going to be additional analysis next month.

Sure, and it’s going to be very soon, actually. It may be happening right now, literally.

I think when they originally reported it, they said the end of March 2019.

So then we have no data with bictegravir, and then we have raltegravir, which is at least still on 1 of the lists. And when we think about why it might be there, you could argue for women of childbearing potential, because it is 1 of the drugs approved in pregnancy. But it’s not because we know there’s a lot of documented experience for exposures at the time of conception, right? The registry has all sorts of limitations. And even when it breaks it down in the first trimester, you can’t really specifically say how many of them were at the time of conception. So the data are really thin.

Though I guess there is probably enough raltegravir that has been distributed over the last 13 years.

It’s very hard because there’s been nothing like this prospective data collection…

One thing I will say is that boost of protease inhibitors in pregnancy is still widely used, but we haven’t been so enthusiastic. I think part of it has to do with just the GI [gastrointestinal] tolerability, which has always been an issue. Part of it has to be you dose darunavir twice daily -- It’s really kind of difficult. And then also my colleagues who study this think that it is associated with premature birth, and that’s really not a good side effect during pregnancy. One thing I confess, we’re using raltegravir still for the women you described, Eric, and then we’re very comfortable using dolutegravir late in pregnancy.

And I think the other thing that is important to know is we used to say that if a woman was on a stable regimen that they were tolerating, don’t mess with it, even if it’s a drug [for which] we don’t have necessarily data. But cobicistat now is 1 that is out.

So if a woman who’s on a stable cobicistat-containing therapy and becomes pregnant, you should change that therapy.

HIV Treatment Options for Pregnant Women

Segment Description: Joseph Eron, MD; Paul Sax, MD; W. David Hardy, MD; Eric S. Daar, MD; Ian Frank, MD, discuss the efficacy of the INSTI and NNRTI 2-drug regimen dolutegravir-rilpivirine and results of the SWORD-1 and SWORD-2 studies.

Let’s talk quickly about 2 drugs, especially dolutegravir-lamivudine. Maybe Paul. Should we use it?

I think the data are very promising, especially from the GEMINI studies. We anticipated there might be some extra resistance from the ACTG [A5353] pilot study, a single-arm study. But so far, at least at 48 weeks of data, there was no resistance, and it was as good as dolutegravir plus TDF/FDC [a fixed-dose combination of tenofovir disoproxil fumarate], so that is very encouraging. And we are going to see a large study of switching patients who are stably suppressed from TAF [tenofovir alafenamide] regimens and comparing continuing TAF [tenofovir alafenamide] regimens with dolutegravir-lamivudine. So there definitely are some attractive aspects of it. One in particular is pharmacoeconomic. Lamivudine has been available since 1995. It’s been generic a long time. We totally know its safety track record, and our modeling studies suggest that this is really the most cost-effective way to treat people, especially if we can switch stably suppressed patients to dolutegravir-lamivudine. It’s not a good drug for that immediate start, that immediate regimen.

I think we don’t know about its resistance barrier. Transmitted 184V does happen, although it’s not that common. I would not be choosing it for that particular approach. We’ll say 1 other group for whom I’m still not totally comfortable using TAF [tenofovir alafenamide] is people with really moderate to severe renal disease, and these typically are older patients—older patients who have maybe been on tenofovir for years and years in its DF [disoproxil fumarate] formulation. And their creatinine clearance is 30 mL/min. or so, and you want to save those last nephrons. Why not switch them to dolutegravir-lamivudine or even dolutegravir-emtricitabine if you’re concerned about using lamivudine with impaired renal function. So those are 2 settings in which I feel very comfortable using it.

Or dolutegravir plus rilpivirine. Maybe you could mention that.

It works.                                                                  

So there were 2 studies called SWORD-1 and SWORD-2, and really Paul introduced the concept of switching antiretroviral therapy. And I’ll just start by saying this is the most common decision that I’m making in my practice today. We have people who are on older regimens associated with high risk for toxicities or complicated regimens. We can simplify therapies. We can maybe eliminate the use of some drugs entirely or the need to take pills multiple times a day. So the SWORD-1 and SWORD-2 studies looked at people who were on classic 3-drug antiretroviral combinations and compared continuing that regimen with switching to dolutegravir and rilpivirine, which is now available in a single-tablet combination pill. And people did just as well. Virological suppression rates of 95% in people who switched versus continue. They couldn’t have had any baseline resistance to either of their components, which would likely not be the case in most of the clinical scenarios we’re talking about.

But whom would you use this combination in? Well, it could be somebody with some renal insufficiency. I have people who are on historic regimens, complicated regimens with multiple baseline or multiple nuke associated mutations, and this has enabled me to simplify regimens considerably. I’ve had a couple of patients now who have gotten older, who now have moved to Medicare, and so they’ve lost their commercial insurance. And there’s that doughnut hole in which you need to pay for medications potentially out of your pocket. Antiretrovirals are expensive, my friends.

It isn’t cheaper, but I’ve had people who are on complicated boosted protease inhibitor regimens with integrase inhibitors, really 5 individual antiretrovirals, who have been able to switch to this and simplify their regimen and cost saving.

Yeah, just a couple of caveats to this discussion. 1) For the dolutegravir plus 3TC, it is important to remember, Paul already alluded to the resistance issue, which is that everybody enrolled in that study was screened for any resistance. And a lot of people screened out of the study because they had any transmitted resistance.

You have to have their hepatitis B at some point soon because it’s only 1 hepatitis B drug, and it enrolled only people with viral loads of up to 500,000. So we’re going to have to live with that limitation. And then the dolutegravir-rilpivirine, same thing, it’s maintenance therapy for people who…

That’s how it was studied. But interestingly, that’s not on the package insert.

It’s fascinating. I agree with Ian, because I’ve used that combination to simplify some pretty complicated regimens of people with NRTI [nucleoside reverse transcriptase inhibitor] and PI [protease inhibitor] mutations.

And there are some data from that small experience in Spain in which they did switch people who had highly complicated regimens…

To dolutegravir-rilpivirine. It actually came out pretty well. So invoking 2 new classes to which there is now previous resistance.

Dolutegravir + Rilpivirine Combination Therapy for HIV

A discussion on the use of tenofovir alafenamide (TAF) during hemodialysis, and the rationale behind switching antiretroviral (ART) regimens in viral suppression.

I just have a question for our moderator here. You don’t get to ask all the questions. You were involved in a study looking at the TAF [tenofovir alafenamide]—based regimen in hemodialysis. Instinctually, it doesn’t seem right to me to use TAF [tenofovir alafenamide] and emtricitabine in people on hemodialysis. What do you think?

Well, I think that you can come up with other alternatives, though it depends. There are people who have very strong ties to tenofovir. In our clinic, we had people on 1 weekly tenofovir [disoproxil fumarate]—TDF, sorry&mdash;and the levels with TAF [tenofovir alafenamide] daily for people on chronic dialysis, and these were all people who were on chronic dialysis. They weren’t transplant candidates, so it’s kind of a different setting. But I think there are other alternatives. But if you need to, you can use it in that setting.

Right now I’m struggling with a very difficult case—I can get some consults here. A person has chronic hepatitis B and almost certainly has resistance to lamivudine.

Because he’s on TAF [tenofovir alafenamide]—based regimen. But he’s losing his kidney function because of aging and comorbidities, not because of TAF [tenofovir alafenamide]. I don’t think there’s a ready solution to that one.

Sure. Yeah. No, I think that’s right. But in terms of tenofovir exposures, it will be quite low.

It’s good but higher than an estimated GFR [glomerular filtration rate of] 15 mL/min/m

Yeah. But again, depending on his resistance profile, I think actually dolutegravir-rilpivirine.

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HIV Therapy Selection for the General Population

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HIV Treatment Options for Pregnant Women

Dolutegravir + Rilpivirine Combination Therapy for HIV

The Difficulty of Switching ART Regimens in HIV

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