Experts in infectious diseases provide an overview of the current HIV burden in the country and the potential signs and symptoms of acute HIV infections.

Interview Transcript (modified slightly for readability):

 I am Joseph Eron, MD. I’m a professor of medicine in the Division of Infectious Diseases at the University of North Carolina, Chapel Hill School of Medicine, which is in Chapel Hill, North Carolina.

The treatment of HIV has a long history. The life expectancy of a person with HIV nears that of a person not living with HIV. Yet challenges remain regarding therapy, including tolerability, long-term adverse effects, and drug-drug interaction. In this 

® panel discussion, we will discuss this epidemic with specialists who are experts in managing and understanding HIV infections. We will review available HIV treatments, emerging agents, and novel management approaches.

I am joined by Dr. Allison L. Agwu, an associate professor of pediatric and adult infectious diseases at John Hopkins University School of Medicine in Baltimore, Maryland; Dr. Ian Frank, a professor of medicine at the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania; Dr. Colleen Kelley, an associate professor of medicine in the Division of Infectious Diseases at Emory University School of Medicine in Atlanta, Georgia; and Dr. Julia Marcus, an infectious disease epidemiologist and an assistant professor in the Department of Population Medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute in Boston, Massachusetts.

Let’s begin by talking about the kind of HIV incidence and prevalence. Julia, where are we in the United States?

 The CDC estimates that there are 1.1 million people living with HIV in the United States. In terms of incidence, there are nearly 40,000 new HIV infections each year, and that has basically plateaued since about 2013.

 Yes, the cases are going down, right? And new incidences are becoming flat.

 Pretty flat. There are some groups in which incidences are decreasing, but 70% of the new infections are among men who have sex with men. Within that group HIV rates are declining in white men who have sex with men, but not so much in other groups. And there are increases in some groups, like in Latino MSM (men who have sex with men).

 Yes, it seems that with women, for example, we’re actually seeing a decline. Is that right?

 I think so, and I believe there are differences by age. There are increases in the youngest age groups and either flat lining or declines in other groups.

 Unfortunately, the young people seem to account for about 25% of new infections. Overall we’re not really making a dent in that.

 It’s different in different parts of the country, and where we live it’s a little different. Right, Colleen?

 Yes, the Southeastern United States is really where the epidemic has shifted over the last decade. This is where we are still seeing very high rates of HIV incidence and prevalence. Most notably in urban and rural areas, which could be communities of color and or poverty.

 Just to emphasize that point, the CDC has divided the country into 4 regions: South, Northeast, Midwest, and West Coast. Interestingly, there are as many infections in the South as all the other regions combined. There happen to be many sociological and political reasons for that. It’s really important for us to be aware of and to consider making public health decisions in this country.

 When we’re thinking about people who have HIV with an acute infection, what are we looking for when they present?

 What I think is interesting is that probably about 50% of people or more, when you talk to them after they’ve been diagnosed, you ask them, “Did you have the flu, or something weird, back in July?” And they’ll say, “Oh, yeah, I remember I got this flu-like illness.” They could present with fever, chills, muscle aches, and rashes. They present with the “flu,” but it’s a viral illness, and it’s the acute presentation of HIV. Oftentimes they seek medical care and are treated for the flu, right? Or they’re sent home with symptomatic management, and that’s when they actually could have been tested and diagnosed with HIV. In these cases, it’s an opportunity and important for us to recognize that people can present like that. Many people have no symptoms, and this contingent needs to be educated to become engaged in care.

 In North Carolina, 10 years ago we had our acute HIV infection project, and the most common first diagnosis was Rocky Mountain spotted fever. It’s an issue because it’s an opportunity to test to prevent transmission.

 I oftentimes say, you know when you have the flu, we all look for a little TLC. People have flu sex. It’s a perfect opportunity to transmit because our viral load is very high at that time and at that point. If we identify the infection, we can actually intervene and potentially prevent additional infections.

 Ian, are you still seeing acute infections in Philadelphia?

 I would say we’re seeing more acute infections in Philadelphia than we have historically, and maybe it’s because we have better methodologies to identify individuals coming into the emergency department [ED] as having acute HIV. We’re doing some rapid testing and having our ED physicians do viral load testing in people who are at risk for HIV acquisition. So I think we’ve helped our ED faculty become a little more sensitive to that diagnosis, and we’re seeing about 1 new infection a month.

 Allison, how are patients presenting in your practice? What is involved?

 I see both adults and pediatrics, so I treat the range. I commonly treat people who are detected because somebody has already diagnosed them. These patients are asymptomatic and are already in that stage of infection where they’re not acute, but they’re not at end-stage HIV. These patients may have just gotten a test, part of Job Corps or part of some regular screening, which is why screening is so important.  

And when you ask them, they may have had some sore lymph nodes or mention, “Oh, I just haven’t felt great. I’ve had these rashes. I felt tired.” Women may talk about yeast infections that they may have been having. Just sort of nonspecific things a lot of them may be having. Some night sweats. A lot of times they get asymptomatic, which is why it’s so important to test people. I mean, as people progress with more immunosuppression, they may have opportunities of infections and present that way. Unfortunately, we still do see quite a few number of people who present at the end, where their CD4 is lower than 200, or they may have pneumocystis pneumonia. They may have streptococcus, and we happen to see that again. There are some deficits in our health care system, where the system is not engaged. So we really do see the range.

 Lots of times there are missed opportunities to test those patients, right?

 Yes, I think any time you look at someone who’s diagnosed late in the course of their infection and you look back, you’ll often see that they touched the health care system multiple times. Then there were missed opportunities for diagnosis where we could have intervened early on and preserved their health, as well as reduce their risk of transmission to partners.

Burden of HIV in the USA and Associated Symptoms

Ian Frank, MD, reviews current US Preventive Services Task Force screening recommendations that prompt testing and factors to identify high-risk groups.

Transcript (modified slightly for readability):

 Ian, what about screening? What does the US Preventive Services Task Force [USPSTF] recommend? What are we supposed to be doing? Screening? What would you recommend to the generalists, community physicians, and family medicine physicians?

 Well, the recommendations are that every person aged 15 to 65 be tested for HIV at least once in their life. It doesn’t mean you shouldn’t be testing younger individuals who may be sexually active. It doesn’t mean you shouldn’t be testing older individuals, older than 65, who are sexually active. Maybe they’re divorced or their partners have died, or they have new sexual partners. Everybody should be tested at least once.

Pregnant women should be tested during their pregnancy at least once. And then individuals should be tested again, depending upon their risk group. For men who have sex with men, individuals with a sexually transmitted illness, or individuals who are injecting drugs, they should be tested at least on an annual basis if not more often. Pregnant women who may come in contact with HIV because of sexual risk should be tested during their third trimester if they’ve been tested earlier. Because women who acquire acute HIV infection during their pregnancy are at more likely risk of transmitting their infection to their fetus or the newborn. Those are the general recommendations.

 Julia, you’ve really thought about this, in part identifying people for pre-exposure prophylaxis. But really it’s about identifying people who are at high risk and probably should be tested more frequently. We can use this as a way to start talking about PrEP [pre-exposure prophylaxis]. But talk a little about treatment in a general practice or in any kind of practice. How do we find these high-risk people?

 It’s a challenge, and it’s 1 that the USPSTF actually identified in their systematic review. When they put out their PrEP recommendations, they said there’s really a lack of effective HIV risk-assessment tools out there. There are some that exist based on the criteria for what constitutes a good candidate for PrEP, which is similar to the USPSTF criteria for HIV screening. But those tools have some limitations. For one, they’re really developed for men who had sex with men, for the most part. A provider already has to know that a patient was in that risk group before they’re going to use 1 of these tools. They’re hard to use in a busy clinical practice, and they also underestimate HIV risk in black men who have sex with men. But HIV risk for that community is much more driven by network factors.

 Network factors and who you have been exposed to. I think the first step is to talk about sex, right? Allison, you have to deal with adolescents. You probably talk about sex a lot.

 Well, you would be surprised. I happen to talk about sex a lot in my practice. But there are studies that showed the average provider, even the adolescent provider, spends only 30 seconds talking to adolescents about sex. That just accounts for the adolescent population. Imagine what’s happening in the over-55 age group. Some physicians and patients may be uncomfortable and we may not even bring it up. Essentially, we have a whole problem talking about sex.

Screening Recommendations for HIV and Risk Stratification

Julia Marcus, PhD, MPH, discusses pre-exposure prophylaxis (PrEP) therapy and identification of high-risk patients appropriate for PrEP.

 We have to ask people what behaviors are they engaging in. I worry more, Allison, as you point out, that older folks are less likely to be asked these questions because assumptions are being made. The assumption is that they’re married; or they’re too old to have sex.

It’s not hard. You can preface the questions by saying, “I ask all my patients these questions.” So that already means: “I’m not asking you because I’m worried about 

 I ask all my patients these questions. Are you in or have been in a sexual relationship? Is it with a man? Is it with a woman? Is it with men and women?” It’s not hard to ask these questions in 30 seconds and receive a lot of information. Also, if you are taking care of somebody whom you’ve been taking care of for a while and you have a trusting relationship with the patient, it’s not hard to ask these questions.

 I think the most important thing is to routinize it, right? To make it a part of every single interaction you have with a patient. So then even if you were uncomfortable asking those questions, over time you’d become comfortable. If it’s just routine, you do it every single time.

 If you had a disease where the therapy could prolong your life for 30 years, would you want that test? I think so. That makes sense, right? Let’s talk about— Julia, let’s get into pre-exposure prophylaxis. Can you talk about this and how do we identify these patients? Then we can talk about what interventions there are.

 Pre-exposure prophylaxis, or PrEP, is the use of HIV antiretroviral medications that have been historically used for treatment, instead using them for prevention. My favorite analogy for PrEP is birth control. That it’s generally a daily pill that you can take to prevent HIV if you’re at risk of acquiring HIV.

We can also talk about other ways of taking it. For some populations, just taking it around the time of sex, specifically for men who have sex with men, has been shown to be effective. We can also identify which patients are appropriate for PrEP.

 Very similar to the indications for HIV screening in terms of HIV risk factors. HIV screening is recommended universally but in particular for people with HIV risk factors. The USPSTF [United States Preventive Services Task Force] and CDC have identified certain groups that are good candidates for PrEP, including MSM [men who have sex with men] men, who are sexually active and have a partner living with HIV, or who use condoms inconsistently for anal sex or have a recent STI [sexually transmitted infection]. It’s similar for heterosexuals, although STIs are really limited to syphilis and gonorrhea for that group, excluding chlamydia. And then for people who inject drugs, anybody who shares drug equipment or has any of the sexual risk factors.

 It’s my understanding that women, frequently women of color, sometimes underestimate their risk. That’s a problem.

 When we think about how the CDC reports how women acquire HIV, they say a risk factor is women who are having sex with a high-risk partner. If you ask the question like that, of course they’re going to underestimate their risk, right? If you’re living in a high-risk zip code and you say, “Are you having sex with a high-risk partner?” “No, I have had 1 partner. No, I’m not.” However, just living in that zip code, your partner is at higher risk of obtaining HIV. We have to think about how we ask those questions and, again, routinize how we offer treatment, offer testing, and then offer PrEP. That is when people are going to put themselves in, “Oh, yeah, I could be potentially at risk.”

 There are 2 things that are really important when you’re thinking about assessing someone who might be a good candidate for risk. The first thing is to understand your local epidemiology. Understanding what’s going on in your community, what does HIV transmission look like in your community. Are you in a place where there is high prevalence and new infections that are still turning up, like many places in the Southeast? Or are you in a place where you know there’s maybe not a lot of transmission ongoing?

And then identifying people who might be good candidates, either from having multiple partners or having condom-less sex with multiple partners who have had an STD [sexually transmitted disease] in the past that’s actually a transmitted infection. Those patients may be whom you first start the conversation with. But honestly, anyone who’s sexually active outside a relationship, in a monogamous relationship with an HIV-negative partner who wants PrEP, is a candidate for PrEP.

PrEP Therapy for High-Risk HIV Candidates

 Infectious disease experts provide insights into the currently available FDA agents approved for PrEP therapy and discuss their safety profile.

 Ian, do you want to talk about what we have for PrEP [pre-exposure prophylaxis] right now? Then maybe we can talk about what is coming or has just recently been approved.

 There are 2 FDA products for PrEP. Both include tenofovir and emtricitabine. The older form of tenofovir, tenofovir disoproxil fumarate, and emtricitabine, that’s Truvada®. And the newer form tenofovir alafenamide plus emtricitabine, that is Descovy®. The newer formulation is a little safer, less renal toxicity potential; fewer problems with decreasing bone mineral density. And the products are equally effective in a head-to-head trial.

It’s important for the audience to understand that PrEP is really effective when people adhere to it. In an early study with tenofovir disoproxil fumarate, TDF and FTC [emtricitabine], if men who have sex with men took 4 or more doses a week, nobody got infected. PrEP may not be as effective in women as it is in men, and women may need to adhere at higher rates than men who have sex with men, because of the different ways these drugs enter tissues and the concentration in mucosal tissues where people may get exposed. We can’t say that PrEP is as effective in women at lower levels who are adhering at lower levels.

 Julia, with the newer form and the TAF-FTC [tenofovir alafenamide emtricitabine—emtricitabine] versus TDF-FTC [tenofovir disoproxil fumarate–emtricitabine], how should we think about those alternatives in terms of cost or effectiveness? Do you have ideas here?

 Yes, as Ian mentioned, they are equally effective — TAF-FTC [tenofovir alafenamide emtricitabine–emtricitabine] and TDF-FTC [tenofovir disoproxil fumarate–emtricitabine]. However, that was a trial done only in men who had sex with men, and a handful of transsexual women. The FDA approval for TAF-FTC [tenofovir alafenamide emtricitabine–emtricitabine] excluded people at risk of HIV through receptive vaginal sex. In terms of safety we can think about renal and bone health. But there were also some adverse effects associated with TAF-FTC [tenofovir alafenamide emtricitabine–emtricitabine] that I think are worth considering, including increased cholesterol and weight gain compared with TDF-FTC [tenofovir disoproxil fumarate–emtricitabine]. So they really are both extremely safe drugs with very few people stopping the medication.

We’re talking about biomarkers, really.

 We’re talking about biomarkers at this point.

 They’re not really clinically significant differences. And the cost issue is really relevant here. They’re very expensive medications and TDF-FTC [tenofovir disoproxil fumarate—emtricitabine] is about to go generic later this year, so there’s an opportunity here to maintain people on TDF-FTC [tenofovir disoproxil fumarate–emtricitabine] and then switch them to generics, at a cost of approximately $24,000 a year for PrEP. I think it could make a huge difference once the cost begins to go down on generics.

 Sure. Allison, I’m curious to understand adolescents. Do you worry more about the bone effects? I know they haven’t really been studied in younger adolescents. TDF-FTC [tenofovir disoproxil fumarate—emtricitabine] has an indication I guess in younger adolescents.

 Yes, a TDF-FTC [tenofovir disoproxil fumarate—emtricitabine], such as Truvada as you noted, was studied down to age 15. There were 2 studies: the ATN 113 and then with older ages, ATN 110. The results showed some of the same bone effects that we’re seeing. But nobody knows what that’s going to mean long term.

But I’ll tell you, if you’re preventing HIV infection in these young people, you have to balance that as well. I think your point is well taken in terms of what’s clinically meaningful.

 There is certainly a difference between TAF [tenofovir alafenamide emtricitabine] and TDF [tenofovir disoproxil fumarate] in terms of bone, and it’s a sensitive time in adolescence of bone deposition. I’m not advocating 1 way or the other. I’m just saying that that’s probably something we need to think about.

 I agree. It’s certainly a part of the conversation you have, as well as the cost issues. I think these issues are going to be important. With respect to the cost issues, I believe there are some assistant programs that are available.

 One of the things we were discussing earlier is the difference between the South and the other 3 regions. As well as the differences state by state in terms of Medicaid, which affects testing and affects the expansion of care for people with HIV. We live in red states. Colleen, do you want to comment?

Safety Profiles of FDA-Approved PrEP Agents

Physician experts in infectious diseases discuss state Medicaid reimbursement policies for routine HIV screening.

: States that expanded Medicaid under the Affordable Care Act were required to adopt routine HIV testing. Those states that did not, some of them still have only medically indicated HIV testing. And that becomes problematic when we talk about how important screening and early diagnosis is. If someone is just being screened, is that a medically indicated test, or is it not? And so the issue of Medicaid reimbursement can become an issue. I know in the state of Georgia it certainly has been, where at times we’ve not even been able to test pregnant women because at some point it was considered not medically indicated if they were not symptomatic. I think everyone would disagree with that practice. I think it is something that we need to pay attention to and to understand how essential HIV testing on a routine basis is for everyone.

: In North Carolina, the availability of free STD [sexually transmitted disease] testing actually varies by county, and the county health department.

: If you have someone on PrEP [pre-exposure prophylaxis] who’s supposed to be tested for STDs and should be, it may or may not be covered. It’s really a state-by-state issue, which also factors into the cost….

: Additional testing. We’re going to transition now a little.

: I want to remind folks that if you’re worried about acute HIV infection, or you have somebody you’re considering as a candidate for PrEP and they have perhaps a recent sexual exposure, you need to do an HIV RNA [genetic material] test. You need to do a viral load test because you can occasionally miss a diagnosis with a serologic test. I just want to remind folks about that.

: I know. It’s probably worth taking a minute to remind people that, I think most everyone now probably uses a fourth-generation test for HIV testing, which tests both for antibody and antigen, or protein. And that gets almost everybody, including many of whom we missed in the bad old days who had acute infection.

But as Ian points out, it will miss some people, because you become RNA positive before you become antigen positive. The test is more sensitive, the PCR [polymerase chain reaction] test. And occasionally that can be quite important.

: Rapid testing and screening are essential for public health and expanding access to screening using rapid tests. Those actually don’t detect as well as that antigen antibody test, that blood test that most of us use in a clinical setting. So if someone has had a rapid test in the community, we’ve got to follow up with an antigen antibody test, and sometimes a viral load for people who are seeking PrEP or who may have had a recent exposure.

State Medicaid Reimbursement for Routine HIV Screening

: Allison Agwu, MD, ScM, provides an overview on the goals of antiretroviral therapy (ART) and the relevance of rapid initiation of therapy.

: Let’s switch gears a little and talk about antiretroviral therapy. And the first thing is very generally; discuss the goals of antiretroviral therapy. What are we trying to do, Allison?

: I think the goals of therapy are first, for the individual, right? And then in that individual, what you’re trying to do is to take the virus that’s in their system and get that to the lowest level that it can be. For what our test can measure, that’s undetectable, which is less than 20 copies per mL. At that level, the virus is not going to “beat up” the person’s immune system, decrease their T-cell count, and then have them progress to more immune suppression and have them have sequelae. That’s the goal. First individually, live long and prosper, for that individual.

What this also does, getting that viral load to minimal level, it decreases the risk of transmission to other individuals, for a pregnant mom to her baby, to the partners, and for someone who’s injecting drugs, to people they’re sharing needles with. There’s a public health benefit in terms of getting that viral load undetectable.

I would also emphasize that there’s an importance psychologically of getting people on therapy as well. Oftentimes we think: viral load, CD4, get that to a good place. But people most likely feel better that they’re doing something to actually take control of their health, that undetectable equals untransmittable. It’s really a powerful message for themselves and empowering for individuals. I think it should be part of the equation when we think about what the benefits are in getting people started as soon as possible.

: U=U, as Dr. Agwu said it, undetectable equals untransmittable. I think it’s really been life changing. We’ve all seen it be life changing for people who have HIV to not have concerns about whether they’re going transmit HIV to their partners. And so it’s really been one of the greatest things to watch over the last decade of that transition to understanding that stigma is such an important part of HIV prevention and care, and this is one thing that is slowly chipping away.

: Yes, it can be de-stigmatizing to really feel that way. I agree, that’s an incredibly important part of it. And sometimes I think as doctors we focus maybe a little bit too much on numbers. I have had, Allison, your experience, when patients see their viral load decreasing, they feel empowered, “I did that.” “You did that, you’re the one who did that. We prescribed the pills, but you took them and you did it.”

: It does. Particularly when we think about a lot of the communities that we work with, they’re so unempowered in so many ways. We talked about social determinants earlier. There are so many things that feel out of their control. “And here is this one thing that I was able to take control of and I did this. And therefore, I don’t have to put up with that person who treats me bad, because I’m actually good, and I am not a bad person.” And we have to really emphasize that. I think that’s why people have really hung on to that U=U message. People have gotten tattoos; it’s really been empowering.

: Colleen, one of the things that there’s a lot of discussion about is this rapid initiation of therapy. Not only should we get people on therapy, but maybe we should do it really quickly. Can you talk about that?

: Yes. There are a few reasons why we think about getting people on antiretroviral therapy as soon as possible. First, it’s for their own health benefit, like we talked about. As soon as someone is identified HIV-positive, particularly if they’re in that acute seroconversion period, we can preserve the immune system better the earlier we start.

The other reason is so that we can reduce their viral load so that they’re not transmitting on to other partners. And then the third reason that has recently come to light is, it looks like people who receive antiretroviral therapy as soon as they are diagnosed are able to stay on antiretroviral therapy and adhere to the regimen a little bit better than folks who are told, “Oh, come back in 2 weeks, and we’re going to start your medicines in 2 weeks.

It makes a lot of sense, and a lot of places have tried to implement rapid starts, and some places have done it very successfully.

I will say that in our practice in the Southeastern United States, in Atlanta, we’ve found it to be extremely resource-intensive. Because we don’t have necessarily the financial support to get the medications, we oftentimes have folks who are dealing with many other hardships in their lives, like housing and substance use, and childcare and jobs, and lack thereof. Having to deal with that whole person before they’re even ready to get on this new medication and deal with this new diagnosis is challenging. And so I think the jury is still out as to how we can implement rapid start most successfully. But I think most people think it’s a good idea.

: Biologically it makes a lot of sense with the transmission. Ian, what’s your experience with rapid start?

 Well, I think it’s been what’s been said. I think it’s great to get people on therapy as soon as possible. It’s great to convey a positive message that people can live with this disease. It’s not hard to treat people with HIV. People will survive. They can maintain whatever goals they have in their life. They’re not likely to die of HIV-related complications. And from a public health perspective, the fact that we can tell our patients that, “If your viral load is undetectable, you will not transmit your infection to your sexual partners.” That is very compelling. People don’t want to transmit their infection to anybody else.

That is a really important message. But I agree with Colleen that I don’t think it’s imperative that we start every patient as soon as they’re diagnosed, or at their first visit. There are some people who are not quite ready, and we don’t want people to start and stop. So we’ve got to convey the message that once they start, they’ve got to continue, and they’ve got to be ready for that. Sometimes because of the complexities of the lives of people living with HIV infection, sometimes their priority is not their disease, it’s their partners, it’s their housing stability, it’s their kids, it’s other factors that are higher priorities, and we’ve got to respect that.

Rapid Initiation of HIV Treatment With ART

 Experts in infectious diseases provide an overview of the current HIV treatment landscape and factors considered in choosing an initial therapeutic regimen.

 Ian, where are we with treatment options? What are the first-line options for the newly diagnosed, their efficacy, and why do we choose these regimens?

 HIV therapy is 1 of the amazing success stories of medicine since 1987. We have over 30 drugs now, but we are using a relative few number. If we discuss treatment guidelines, there are too many to consider. The Department of Health and Human Services [DHHS] and the IAS-USA Guidelines [International Antiviral Society—USA] both agree that therapy should start with an integrase inhibitor, such as the nonboosted integrase inhibitors dolutegravir, bictegravir, and raltegravir. The guidelines differ with respect to the nucleoside choices. The IAS-USA Guidelines say that if you’re using a 3-drug combination, you should use TAF-FTC [tenofovir alafenamide–emtricitabine] together with either bictegravir in the fixed-dose formulation of Biktarvy or together with dolutegravir.

Raltegravir is a preferred agent in the DHHS [Clinical] Guidelines but not in IAS-USA, because it has a lower barrier to resistance; it involves taking a few more pills. There is a new addition to the DHHS guidelines, and that is a fixed dose of dolutegravir lamivudine. It is the first 2-drug combination, 1-pill, fixed-dose combination to be a preferred agent. And we’ve got comparative studies that show that dolutegravir-lamivudine is as potent as dolutegravir-tenofovir FTC [emtricitabine]. This 2-drug combination is as potent as a 3-drug combination.

Almost everybody who takes these drugs consistently gets their viral load to an undetectable level. Resistance in people who don’t maintain virological suppression to the integrase inhibitors is uncommon if they’re on the second generation of integrase inhibitors.

 They’re safe. We have safe, potent combinations that will work effectively as long as people take them.

 In the past we used to think, “How high is their viral load?” or “How low is their CD4? Should we do something differently?” And this comes into play with our 2-drug therapy, the dolutegravir-lamivudine that you mentioned earlier, which is Dovato. Allison, are there some reasons you might not use that combination?

 I take care of a lot of adolescents. Oftentimes they’re not included in many of the studies. I tend to be a little nervous about using the 2-drug regiment. They typically don’t have a lot of other comorbidities that we need to think about when using a regimen. I think it’s great that we have them. Particularly as we think about long-term sequelae of being on just your HIV or being on antiretroviral therapy if you have the opportunity to use fewer drugs, there are fewer bone and kidney issues; it’s a good thing. Also, comorbid conditions are a part of what you think about. We don’t have to think about resistance as much. We used to be thinking about how much resistance we have when initiating therapy. We don’t really have that much. I can’t think of the last time I had somebody coming into care who had pretreatment resistance. It’s very rare. I oftentimes think about how pill size used to matter. But pills are smaller and smaller and more palatable. The adverse effects are minimal. Perhaps headache and nausea around the beginning, but that tends to go away.

I think about childbearing and what goes into it. If we’re thinking about dolutegravir, for example, there are some concerns about neural tube defects and women of childbearing age and when to use that would be important. And then adherence, again—even when people are not fully adherent, we’re not seeing a lot of resistance, but we do think about that in terms of the barriers. It would be the difference between using a raltegravir-based regimen versus using a dolutegravir- or bictegravir-based regimen.

Factors Considered in Choosing Initial HIV Therapeutic Regimen

 Colleen Kelley, MD, MPH, and Julia Marcus, PhD, MPH, discuss the metabolic issues as well as the costs associated with the initial therapeutic regimen.

 Some disease states direct us toward choosing a tenofovir-containing regimen, such as for a patient with hepatitis B or an advanced disease state with low CD4 where we might not use a 2-drug therapy. I think that’s another potential issue.

We have 2 or 3 choices for initial therapy. It’s not that complicated. This is indicative of how good things are. However, we are now worried about weight. Some therapies could contribute to weight gain. Colleen, have you seen that in your practice?

 Yes, absolutely. Historically metabolic issues have been a concern with antiretroviral agents. But this specific rapid weight gain that we’ve seen with some of the integrase inhibitors was a little surprising. I have switched people off their regimen because of weight gain and the new onset of diabetes as well as other metabolic issues.

I think the jury is still out on exactly what the cause of that is, kind of mechanistically, and in who might be at risk specifically. But I do believe it is an issue for a minority of patients, but you will see it if you treat enough people with the integrase inhibitors. So it is something to keep in mind. It doesn’t necessarily change what I’m going to do to start, but my awareness is heightened. I’m looking out for it.

 Ian, do you tell people anything different in regard to therapy?

 I do. I tell them that they may gain weight. And it’s potentially more of an issue for women than it is for men. It may not just be the integrase inhibitor, the component. There’s evidence that it might happen more in people who are on TAF [tenofovir alafenamide] than TDF [tenofovir disoproxil fumarate].

Everybody who starts antiretroviral therapy on average gains some weight. But here we’re talking about excess weight gain. In 1 study called ADVANCE, over a 96-week-period the average weight gain of women on TAF [tenofovir alafenamide], lamivudine, and dolutegravir was 10 kg. That’s a lot of weight.

I tell my patients that now that their body is not fighting HIV and burning more calories in the immunologic battle to control their infection, they’ve got to cut down the amount of food that they’re eating in order to be metabolically at equilibrium. I tell my patients to let me know if they’ve noticed that they’re starting to gain weight, because occasionally you do need to switch people off and use an alternative regimen. Maybe we should talk about what that regimen would be.

 In a moment let’s discuss SWITCH. But before we do, is there any reason to use a boosted drug as a first-line therapy? Meaning a fourth agent in the mix to prop up 1 of the other agents? Is there a reason to do that?

 I do not use a fourth agent as an initial therapy. All the boosted regimens are now an alternative or non-preferred, and there has to be some special circumstance for using them.

 A boosted protease inhibitor may not be a bad combination for an adolescent or somebody who you’re worried about adherence if you’re not getting any baseline resistance testing. It’s true that with an integrase inhibitor regimen, a second-generation integrase inhibitor regimen, there’s probably low probability of baseline resistance. But the DHHS [Department of Health and Human Services Clinical] Guidelines do endorse a boosted protease inhibitor. I’m not talking about using it as a fourth drug. I’m talking about a 3-drug combination; a boosted protease inhibitor is a preferred regimen for immediate start.

 Think back to the darunavir regimen for adolescents, the pill burden, the size, and the resistance profile. I would favor going to bictegravir for adherence than using darunavir.

 There’s now a 1-pill fixed-dose combination, so it’s not a pill burden.

In fact, it’s smaller. Somehow they got 4 drugs and combined them. It’s smaller than the 2 drugs. Julia, I know in the United States we don’t really talk that much about cost of drugs. You mentioned generics. How do we balance this? At some point this will need to be addressed.

 There’s a federal initiative to end the HIV epidemic, and the key pillars of that initiative are treatment for everyone who needs it and PrEP [pre-exposure prophylaxis]. Antiretroviral medications are really the solution all around, but they’re incredibly expensive. And the estimates of the costs that it would take to end the epidemic are potentially beyond what society can withstand. So we have to think about it. I don’t know what the solution is, but it’s a problem.

 I’m starting to see it in my practice. We talked about the 2-drug combination of dolutegravir-lamivudine. I’ve now prescribed that a few times and was told, “Well, you can give them the dolutegravir, but you have to get generic lamivudine.” You can’t give them the single tablet. I’ve had a couple of instances where for the TDF-FTC [tenofovir disoproxil fumarate—emtricitabine], I was told, “No, you can give them TDF-3TC [tenofovir disoproxil fumarate–lamivudine], because that’s generic and less expensive. From the patient point of view, they see a different expense because generics don’t have a co-pay card, for example; whereas the trade drugs might have a co-pay card, so you switch them to generic, they actually have a co-pay.

 Although maybe just to mention in the context of PrEP, the US PSTF [Preventive Services Task Force] recommendations are hopefully going to wave cost sharing for all PrEP medications starting next year.

 Even though there may be more patient-assistance programs for the brand-name medications, it may be that there’s no cost sharing for any of them.

 That would be fantastic. Especially with PrEP, small barriers can be a really huge disincentive for people that have trouble persisting. And you may think, “Oh, well, it’s $10.” But it could be the difference between a 17-year-old taking it or not taking it, right?

 Or a healthy person who is HIV negative who has no reason or motivation, to be honest—except for prevention&mdash;if it’s going to cost you something or if the complexity of figuring out how to get the cost covered is just too much.

Safety Profile and Costs of Initial HIV Therapeutic Regimen

Infectious disease experts provide insights into switching therapies for patients who have been successfully treated and the various 2-drug combinations used.

 Ian, can you discuss the patient in your practice who is currently on treatment and either has a complication or not and you’re considering switching therapies? What is your approach, and how do you optimize their regimen?

 This is the most common treatment decision that I make in my practice. I’ve been taking care of people with HIV for a long time. Most of the newly diagnosed patients see the younger physicians in our practice.

I look at the anti-retroviral regimen of every patient and decide if I am able to improve his or her combination. I want to make things simple with a few pills, convenience, and flexibility. I want my patients to be able to take their drugs during the day, not just at night with food or on an empty stomach. For patients who have no symptoms on a regimen that is not a preferred regimen, I try to switch them to a preferred regimen.

I want to get them onto an integrase inhibitor—based regimen and cut down on the number of pills. There are many options to choose from. We have resistance testing that could look at archive mutations in HIV DNA for our patients who have failed in the past or come to us from another practice with an unclear history. The goal is to detect any baseline resistance prior to switching therapy if resistance tests are not available to us.

There are agents of next generation in RTIs [reproductive tract infections]. We have next-generation integrase inhibitors. There are options for people who have failed on some of the earlier agents within therapeutic classes. There are effective 2-drug combinations. Other options include [dolutegravir lamivudine]—[dolutegravir rilpivirine] for people who have not failed on an integrase inhibitor–based regimen before, as well as the standard 3-drug combinations that have all been proven effective in the context of switching somebody with biologic suppression.

 Colleen, are the 2-drug combinations safer in people that are securely suppressed?

 Absolutely. And that’s where I’m doing most of my 2-drug combinations. Generally, I still see very advanced disease. So initiating 2 drugs still makes me a little nervous, similar to the adolescent questions. When someone is suppressed and they don’t have ongoing replication, the amount of drug pressure they need is less than their initial start. Oftentimes, I will drop them back to 2 drugs once they are stable. We can reduce the pill burden sometimes. We can eliminate drugs that may have long-term adverse effects or may be interacting with other medications that they’re taking. This is the setting where I use a 2-drug regimen.

 Previously we only had single tablets that had 3 drugs, and there are people where that third drug probably wasn’t effective.

 Because that third drug was never really working, we reassess and realize they could benefit from a [dolutegravir rilpivirine] regimen. I’ve done that. I take care of a lot of perinatal patients who acquired [HIV] in their 30s, and their nukes are not active.

 And then you can give them a regimen that has neither.

 Yes, [for] 34 years old [we use] a 1-pill regimen. That’s been effective for those patients.

 My mantra has been “the simplest, safest regimen that fits in a person’s life.” And forcing myself with every patient I treat to do that little calculation. Is this really the simplest and safest thing they could be on? Did you know virological failure is toxic? It’s an adverse effect, so we want to be careful.

Ian mentioned that you could do some testing to look for previously present resistance. It’s important to find all the old genotypes and do things that make clinical sense. I do believe we can get patients into some pretty safe places. Especially those who are on very complicated regimens.

 I recently had an 80-year-old woman who was on 3 drugs. She’d never been on 2 drugs or nucleoside therapy. She had always been on 3 drugs. She’s been suppressed since 2012 or 2011, and she had osteoporosis. And you know, whether it’s TAF [tenofovir alafenamide] or TDF [tenofovir disoproxil fumarate], does she really need that?

Switching Therapies in Patients Who Are Successfully Treated

Allison Agwu, MD, ScM, reviews the causes of virological failure or rebound to HIV therapies and the relevance of rapid initiation of therapy.

 Allison, what about virological failure and rebound? I’m sure you see it in your practice. What’s the cause of it, and how do you treat these patients?

 We are seeing it much less than we used to, and it speaks to the potency of the regimens that are available. I get nervous when I see low-volume viremia because it’s so easy to become undetectable. If a patient keeps being at 150 copies/mL, I start to worry if they are really taking their pills, even though we know nobody’s a failure if they’re less than 200 copies/mL. But that being said, in our adolescent clinic, about 20% of our kids have biologic or virological rebound.

This is the patient I treat. Nationally 12% are suppressed for adolescents, so we have bigger problems. For adults, about 25% of those live with HIV and are suppressed. But I think when we see it, oftentimes there are system issues that have gone on. I have to address if the drug is covered or if the pharmacy sent out 1 medicine and not the other medicine. Some patients are taking part of a regimen if they have the funds to get it and the means of transportation to purchase it. So there are many things that go into whether you were able to take the medicine. Then the reality is, it’s hard to take your medicine every day.

It could be 1 pill once a day, but it’s 1 pill once a day that you have to take that comes along with the stigma that goes into it when you take it. And there are real implications for that. Which is why I’m so excited about—and we’ll talk about later&mdash;some of the long-lasting or long-acting regimens that will eliminate that issue. So there are system, individual, and more systems issues that tend to impact adherence. But usually it’s adherence that’s causing it.

Another point to make is that you should make sure there are no drug interactions and somebody’s not all of a sudden taking an antacid, a calcium-containing agent that’s actually absorbing their medicine, or some herbal medication that’s impacting their treatment.

 How do you walk through those personal, home, and system issues? How do you address that? If someone comes in, and they’re on an initial regimen that you know has been effective for so many people, yet their viral load is still a 1000 or 5000 copies/mL when it should be less than 20 or 40 copies/mL. How do you walk through that?

 I’ll say that it is not just me, but it’s everybody. It’s the nurses, the specialists—it’s really the team that’s making sure. Our pharmacist says, “Hey, it’s been 2 months since you got your medicine. What’s going on here?”

 It’s a team approach to figure that out and let the patient know that it’s a safe space. Whatever you tell me, it’s a safe space and we’re going to work through it. And when you make people feel comfortable that they’re willing to share, you know what? The patient may say, “I had to pick between a $10 co-pay”—which may seem like nothing to us, but for some people it’s 30% of the money they have for that week, right? “I had to pick between that or my child’s formula.” Then we can start to have real, productive conversations about how to address those barriers.

 Colleen, how do you clinically evaluate who comes in? And if they’re viremic when you think they should be suppressed, how do you treat them?

 It is just a conversation—understanding what’s going on, what’s preventing them from being able to take the medication&mdash;and it ranges from the ever-prevalent systems issues, which is the vast majority, to things like stigma. Not wanting to acknowledge that they need to take this HIV medication. And in very rare circumstances, drug interactions and things that lead to persistent viremia.

Clinically, the question is whether you need to test for resistance. A lot of that comes from the conversation with the patient, understanding you. Were they really trying to take their medication, or have they just been off? If they’ve just been off, I’m less concerned about resistance versus someone who really does sound as though they’ve been trying to take it, they’ve been getting it in their body on a somewhat consistent basis. Then I may pursue resistance testing at that point in time.

 It’s obviously a relatively expensive test. But on the other hand, even someone who is saying that they’re taking it intermittently, it’s information that you would need. If they said, “I just stopped it.” One of the things I’m impressed with is that people really feel like they are taking it, and then your pharmacist calls their pharmacy and they’ve only gotten 3 refills in the last 6 months. Sometimes they share that it is hard to comply and they forget.

 Oftentimes, it takes multiple conversations. After multiple attempts you learn, “I’m not really taking this.”

 Sometimes it’s more effective to have a social worker or 1 of our nurse practitioners ask that question. Because the patients don’t want to tell me that they’ve done something that they know I’ll be a little unhappy about. They don’t want to disappoint me. Sometimes if somebody else asks the question in my practice, we are more likely to get the accurate information.

 We have a tablet in our clinic, and we try to collect the patient-reported outcomes, but I don’t know. Julia, if you could comment if you have any experience looking at patient-reported data in your practice, and how we should be using that more as part of our care. Do you have any thoughts about that? That’s not something we have built into structure DHR data. Patient-reported outcomes are not something that are routinely collected, but they’re so relevant. Even for the stigma barrier, particularly in places like the South that are the hardest hit, it’s really driving the epidemic to some extent. So yes, it’s really important.

 Yes, We have a depression and alcohol screens, and we get a sexual history report. It’s social desirability or something where I’ll ask, “How many partners do you have?” When they do it on the computer they’re a little more likely to say 5 instead of 1. Not that it’s good or bad, but it helps to know in terms of risk and screening and that sort of thing.

Virological Failure or Rebound to HIV Therapies

 We have some emerging treatment options. The 1 that’s probably the closest to market is called fostemsavir. It is before the FDA right now. We can’t predict what will happen, but they have to make a decision by the middle of August. Fostemsavir, like ibalizumab, blocks entry, but instead of binding to the cell, it binds to the virus, so it’s an attachment inhibitor. One advantage over ibalizumab is that it’s a pill, not an infusion. We have evidence that it has antiviral activity and does work in combination with other drugs. I think it will have a place in the world, but it’s 2 times a day. It’s likely for those people who have very limited treatment options.

It is available through compassionate use, though I’ve not used it in that setting. Have you used it in this setting?

 We have. I just saw a perinatal young woman who was out of options on a combination of fostemsavir, and ibalizumab with a nuke that is probably having a little bit of activity.

 That is the type of situation where we might be using these drugs. There is excitement because there are other drugs in the pipeline. In particular, there are long-acting agents in the pipeline. Allison, do you want to initiate this conversation and discuss the treatment and prevention?

 Yes, I think for all of us who have been treating HIV for years, we’ve all muttered the words, “We just need a shot,” or we just need something. And it’s exciting to hear that we are at the point where we’re considering shots that are injectables on the market and also long-acting oral agents. The closest to the combination of cabotegravir is an injectable integrase inhibitor and rilpivirine, which is a non—nucleoside reverse transcriptase inhibitor injectable. [They are used] together for treatment, for initial therapy, as well as transitioning, but it’s all people who then suppress and then get to the injectable agent.

Currently, the FDA application was tabled because of manufacturing issues. Apparently, it is being tested all the way down to 12-year-olds. Hopefully, if the manufacturing issues can be worked out, we’re talking about every 8 weeks per injectables for a treatment, which for some people, not everybody, will be a game changer.

There are long-acting oral agents that we’re hearing; exciting MK-591 coming from Merck & Co Inc as well as other ones. There are also injectables with the new class; capsid inhibitors, monoclonal antibodies. The treatment landscape is changing for the better. Other options will be subcutaneous and possible pumps, implants, and patches. It’s similar to the implant for birth control, for treatment as well as prevention. It is worth mentioning because cabotegravir in particular is in huge trials for prevention.

We will be talking about something very different very soon, and access will then be the question.

 And cost. Particularly when we can suppress anybody practically, right? It is 90% suppressed on oral agents. The discussions we’ll have to have on how and who and where are going to be very important. It doesn’t mean we shouldn’t have those discussions, because for the people who are living with HIV, these are maybe lifesaving, game-changing remedies for them.

Emerging Treatment Options for HIV

Expert physicians in infectious diseases review drug resistance to HIV therapy and the challenges faced by these patients because of limited treatment regimen.

 Let’s discuss drug resistance. Ian, are we seeing it?

 Drug resistance is a lot less common than it used to be. In Philadelphia, [Pennsylvania], with our needle exchange program, 90% of people who are injecting heroin every day have undetectable viral loads. I don’t think that is much different from most everybody’s practice. We’ve seen virological suppression rates of 90% in most clinic cohorts.

We don’t see resistance because the drugs work very well and have a higher genetic barrier to resistance. I still do resistance testing in people who are coming into care.

 There is a debate. And most likely you’re going to see a resistance to the NRTI class [nucleoside reverse transcriptase inhibitors]. Even though I don’t typically start a patient on an NRTI-based regimen, I still want to know if it’s there. In a small percentage, maybe even to see a baseline and M184V, it’s helpful to know this. Because if people fail again, I’d like to know where they were previously.

 Occasionally I’ll order a resistance test. I do have a handful of people who struggle taking their medications and develop resistance. But people on a boosted protease inhibitor [PI] don’t generally have PI resistance. People on a next-generation integrase inhibitor generally do not get integrase-associated mutations. We’re not seeing failure as much because these drugs do have a higher barrier to resistance.

 Do you have patients that have multidrug resistance? How do you treat them?

 I definitely do. I have people who started out single nucleoside therapy in the past. A number of years ago, when dolutegravir and raltegravir were first available, I was able to get people on a regimen that for the first time was able to suppress virus replication. But they have protease resistance, and they have NUC [nucleoside analog] resistance, they have NNRTI [non-NRTI] resistance. I have people who started on raltegravir who have integrase resistance. I have some people for whom I am wondering when I will use the next-generation drugs that are available to us, and how to time that in a way that’s most likely to be successful with a long-term strategy in mind.

 Yes. We have patients who were the first kids ever to see any of these drugs, single agent, and then tell the story of the treatment of HIV. They harbor tons of resistance. For the first time 5 years ago, they were able to be suppressed. The challenge is that they can potentially become nonadherent; I need to know what’s in my armamentarium.

 I will say that with the elvitegravir-based regimens, we saw an accumulation of integrase mutation that can impact cabotegravir. This is 1 place I definitely think it’s useful if you see failure on earlier regimens.

The other place where I see quite a bit of resistance testing is in patients who immigrate from Africa and the Caribbean, where there are different regimens, and nobody is checking for resistance. Understanding what’s coming in, there’s a lot of transient resistance as well as a lot of failure, but no viral load testing in a lot of places.

 We’re fortunate that we don’t have very many people who are viremic and have lots of resistance. A lot of really complicated people have been suppressed. I have a few patients—if they ever rebound, I don’t know what I’m going to do. Occasionally we have someone who has very limited treatment options. There’s a newer drug, ibalizumab. Colleen, can you say something about it, ibalizumab?

 Yes, ibalizumab is a monoclonal antibody that binds the CD4 receptor and prevents the virus from being able to bind the coreceptor. When the antibody is bound to the CD4, it can’t bind the TCR5 coreceptor. It is an infusion, and it is approved for heavily treatment experience, people with resistance, and no other options. Ibalizumab appears to be effective in treating those folks. I will say in our very large clinic, 6000 active patients, we really have only a handful, less than 5 that are even candidates for ibalizumab. We don’t have a lot of experience with the medication, but we are using it in very select cases.

 We have 2 people on ibalizumab. The goal is to give them other active components. It’s not going to work very well as a single drug, but occasionally we do have to do that.

: Yes, often in combination with multiple medications.

Now I think we can talk about what’s coming.

Drug Resistance or Intolerance to HIV Therapy

An overview on the challenges with the use of first-generation long-acting injectables.

: Let’s talk about cabotegravir and rilpivirine in more detail.

: Remind people about how it’s administered.

: It’s a 2-drug regimen: cabotegravir and rilpivirine. One is an integrase inhibitor and the other is a nonnucleoside; they are currently being studied. It’s injected in the upper back thigh. And eventually, it will be administered at home. It’s an intramuscular injection in the gluteus medius, in the triangle that’s formed.

: The dose is 2-mL injections. It’s not a small amount. There have been studies for every 4 weeks, but it may be administered as infrequently as every 8 weeks, after orals are taken.

: It’s only been studied after HIV-1 suppression.

: It’s for people who are either initiating therapy or transitioning who are suppressed and take the oral component for suppression. It is also to make sure that they’re not going to have a reaction before they have an intramuscular injection.

: There’s the stigma of having to take a pill every day and the chance to be free from that. Colleen, can you comment?

: Yes. Internalize stigma—it’s a constant reminder when you have that pill bottle on your bathroom stand that says, “I am HIV positive.” And if someone’s coming over to your home and maybe doesn’t know that about you and you don’t want them to know, but your pills are there and you’ve got to take them every single day, it’s a constant reminder that you’re sick and you’re HIV positive.

I know people are very excited to think that they’re not going to have to be reminded every single day when they take their pills that, “I’m HIV positive.”

: Because you’ve changed someone to an injectable, it doesn’t mean you’ve committed them to 30 years of an injectable, maybe 1 or 2 years. There are some risks with injectables.

: Yes, these drugs do last a long time. After your most recent injection with cabotegravir, it can last for a year. People will need to come in and get their injections at the recommended frequency. If they miss their injections, there is a risk of developing resistance. We don’t know exactly what those risks are—we’ll learn in the near future more about the risk for integrase resistance in people who are failing on the regimen.

It is a major risk. And although there may be some adherence problems that get solved by the injections, I think that there are other adherence risks that get created. It’ll be more incumbent upon us as providers to ensure that our patients are coming in at the appropriate frequency, and we may need to modify our practices.

Advances in the Treatment Landscape for HIV