Douglas Krakower, MD

home

authors

douglas-krakower-md

I think some of the most important population health opportunities for PrEP [pre-exposure prophylaxis] are thinking about ways to streamline this process for both patients and clinicians. If PrEP is as easy as 1, 2, 3, I think that would make a huge difference. We need to work on many other things, such as knowledge of PrEP, stigma in health care and community settings, cost. But if we make it easy as possible for people to access, then I think we may hit the tipping point where it becomes more widely disseminated and used.

I think the system for paying for PrEP is very complicated. If people have insurance, it’s still very complicated in terms of which formulations are on formulary. How much of a co-pay is there? There shouldn’t be a co-pay because there’s a USPSTF [US Preventive Services Task Force] grade A recommendation for PrEP, but sometimes there are prior authorizations. So we have these things called PrEP navigators to help people get onto PrEP in an affordable manner.

If you take a step back, it’s kind of crazy that we need navigators to get people from A to Z for something as straightforward as PrEP. It’s really not that complicated of a medical intervention once you think about it. It’s almost like a see one, do one, and teach one in terms of medicine. For oral PrEP, it’s usually a daily pill or maybe an intermittent regimen, which is relatively straightforward. For injectable PrEP, it will be injections every 2 months after people are on a sustained regimen. I think we just need to make this as simple as possible.

Some colleagues who are health policy experts have proposed a way to have the federal government purchase and disseminate PrEP in a centralized manner. I think this offers a really exciting potential way to make PrEP much simpler for everyone who comes into the clinic, knowing they can access it at low, or no cost ideally, in terms of the medications, the laboratory testing, the clinical fees for physicians, etc. If we lower the bar in terms of barriers to accessing PrEP, that can only help because right now, if we think about how you need to have a navigator to get you onto PrEP, we need to simplify things.

I also think in terms of the CDC [Centers for Disease Control and Prevention] recommendations for PrEP, which are very well thought out, for oral PrEP, and then in the future, long-acting injectable PrEP, which have slightly different follow-up plans, it does end up being a relatively complex care plan to implement for a clinician in a health care system. You have to think about what agent someone is on, what the follow-up schedule is, have they had labs in the recommended amount of time? Have they had additional testing for sexually transmitted infections, have they had adherence counseling?

If there are ways we can use evidence to show that people can safely use PrEP with less access to the clinic, fewer visits, less lab monitoring when it’s safe, then I think those will be ways to improve PrEP as well. That can also dovetail and synergize with telemedicine approaches to PrEP. In the future, any way we can de-medicalize PrEP and engage communities on a broader scale, I think will increase the impact and effectiveness of the intervention.

 I do believe when you look at 1.8 million new cases a year around the world, the access beyond America is very important. There are 34 million people with HIV in the world today, and roughly 1.2 million in the United States, so 30-something million people around the world, and there are new infections every single day. I think ultimately, we really need to move this from the United States to the rest of the world. We need to make PrEP cheaper, available, and get it into places where the risk is high. We need to identify the hot zones, so to speak, the high-risk areas or communities around the country, around the world, and really focus our attention into these areas and sacrifice financial gains ultimately for what’s better in the long term for community and humanity.

Videos

The benefits of addressing barriers and increasing access to HIV PrEP therapies to high-risk populations across the globe.

Opportunities for HIV PrEP in Population Health

I think that long-acting injectable PrEP [pre-exposure prophylaxis], which will hopefully be available in 2022, is something that could be used for virtually anyone. I think if someone is doing well on oral PrEP, and they want to switch to injectable PrEP, I think that’s absolutely something that people should have the option to do. In terms of the greatest benefit for improving population health and meeting national goals, we need to think about injectable PrEP as a way to not only keep people who are using oral PrEP and using it with adherence and persistence, engaged in PrEP, but how do we get new people and new populations engaged?

If people have marginalized housing, if they have issues with psychosocial challenges like depression, anxiety, PTSD [post-traumatic stress disorder], substance use disorders, all the things that make it challenging to adhere to daily pill-taking, these are populations where I think first and foremost, we want to see if there are ways to integrate the injectable PrEP option into people’s lives in a way that oral PrEP maybe couldn’t. I don’t think there’s ever going to be a one-size-fits-all, so we need to discuss all these options with all the individuals and populations who may be accessing PrEP. We shouldn’t think that we know the right answer for any specific individual and keep an open mind.

I do think that being intentional about engaging new communities in long-acting injectable PrEP could improve what people have termed as the mosaic effectiveness of PrEP, which is not just keeping people who are already on PrEP on PrEP, which they may do with things like oral tenofovir and emtricitabine, which are already in existence and are available in generic forms so it can be a very cost-effective long-term option. But can we get new people onto PrEP? I’m optimistic that there’s a lot of excitement.

There have been studies showing that hypothetical acceptability for long-term injectable PrEP is high in some of the populations that have underused oral PrEP thus far. Maybe this will be a chance to right some of those inequities. People who were in the injectable PrEP studies also gave very high marks to using injectable PrEP, and the vast majority wanted to continue using injectable PrEP. All the avenues point toward going here for engaging new populations. I think we have to be careful because of some of the lessons learned from other long-acting injectable options in terms of HIV treatment, which has also been available for the past year.

I think usage has been slow in my own practice. I talk to dozens of people about long-acting injectable antiretroviral therapy for people who are HIV positive. For the vast majority of them, they’d rather take a pill a day and see me on an annual basis and get laboratory tests done twice a year than come see the nurse in our clinic every 4 weeks. As long-acting injectable agents become less burdensome in terms of the care and the frequency of visits, I think it will expand the options even further. I know that’s still in the pipeline, but there are some agents that are being looked at that maybe could have an every 6-month injection. The future has a lot of different paths that can be taken. As long as we’re thinking about offering long-acting injectable PrEP as an important new option to as many people as possible, I think we’ll see the biggest population health benefits.

As a payor, how would we look to find patients who are eligible or probably should be on a long-acting medication if they’re on short-acting medication? That’s a good question. I think there are a lot of specifics that we’re not going to be able to get at, as far as who the patient is, preferences, etc. We don’t really see that, but we have the ability to look at claims, and so we can say, “You’re on a short-acting, but you fill a monthly prescription every 3 months. You’re not compliant.” That’s an obvious opportunity.

I think you could also look and say if we marry medical benefit data up with pharmacy data, and we say this patient, maybe they’re in an outlying town where there’s no opportunity to get into the clinic more often. We can look at those types of things, but it’s going to be difficult aside from looking at how they’re taking the short-acting. Really, it’s fill rates and how often they’ve got therapy at home to take versus when they don’t, and would a monthly therapy or a monthly administration or some long-acting agent be better for them? We would look at pharmacy claims data, which I think is the best way that we have to figure that out.

Types of patients who will likely benefit from long-acting injectable PrEP therapies in the HIV treatment pipeline.

Long-Acting Injectable PrEP Therapy for HIV

 We really need to think about ways to improve access to PrEP [pre-exposure prophylaxis] across all populations, especially in populations where HIV risk is highest and access to PrEP has been lowest. In terms of general access to PrEP, 1 thing my colleagues and I have advocated for is a routine conversation about PrEP. CDC [Centers for Disease Control and Prevention] guidelines, which were just updated for PrEP, emphasized the approach that clinicians should discuss PrEP with every sexually active adolescent and adult in America. The previous guidelines said that it should be discussed with people who may be at increased risk for HIV. But they did the right thing by broadening this, saying that clinicians should make this a routine part of primary care and that it should be integrated just as we ask people about family planning, seatbelts, and tobacco and alcohol use.

This is a piece of well-being that we need to integrate into routine health care. If we do that, then many more people will learn about PrEP just from being asked if they’ve heard of it and if they’re interested in it. Even if people say it’s not for them, they’ll learn about it. Maybe they’ll talk to their peers, family, and friends about it. That’s 1 way to do it—making PrEP conversations routine. With CDC guidelines endorsing that, health care organizations need to think about ways to do this.

In terms of other ways to improve access to PrEP, we need to meet people where they’re at. For some people who have psychosocial challenges to accessing health care and maintaining healthy behaviors, getting outside the traditional clinical setting is important. Whether it’s embedding PrEP in sterile syringe programs for people who inject drugs or working with programs that provide health care to people who have marginalized housing. That’s a great model. Some people don’t have stable housing but are willing to engage with health care programs. We have some excellent ones in Boston. For example, the Health Care for the Homeless Program has developed tremendous expertise at delivering general health care. Also, we have PrEP care for people who may not have stable housing. For populations that have mental health conditions—depression, anxiety, PTSD [post-traumatic stress disorder]—that get in the way of accessing health care and adhering to PrEP medication, we need to think very broadly about ways to engage clinical psychologists and nurses and the whole health care team to help people treat their behavioral health challenges and get them access to PrEP.

In the future, hopefully there will be more PrEP options, given that long-acting injectable agents are under FDA review and might be available as early as the first quarter of 2022. We need to think about using those options to engage new populations that have underused PrEP thus far. For people injecting drugs and coming to sterile syringe programs, if they’re coming frequently to a program like that, that’s a great time to offer people PrEP.

I was with a colleague recently who has been administering Suboxone methadone as part of a program and is eager to layer in PrEP. They’ve done it successfully with oral PrEP. When there are longer-acting options, it will be a nice synergy for certain populations.

The same will be true for other populations that have trouble accessing health care and taking a daily pill. For example, adolescents and young adults who have busy lives and are still developing in terms of social and brain development, taking a pill—if you’re otherwise healthy—might be a new phenomenon for them. [We need to] think about ways to improve access by engaging pediatricians, adolescent medicine specialists, and college health clinics and using oral and, hopefully in the future, long-acting options for people who are younger and getting introduced to a new idea of taking a pill or getting injection. All those will be ways to engage important populations in PrEP. I’m very optimistic that the future holds ways to improve PrEP on a population level if we think intelligently and intentionally about accessing these populations.

 The disparities and inequities of access have a lot to do with stigma. It has to do a lot with insurance providing treatments and coverage for PrEP. What we do as an organization or a clinic is to try to go to those communities where we think there will be high risk. We have partnerships with MSM [men who have sex with men] groups. We have partnership with a lot of local groups that have that peer support and navigation tools. We partner significantly with groups that can advise patients and bring them into care. The question is also, here’s an African American or Latinx person, they’ll feel as though, “I don’t need it for A, B, and C reasons.” How do we get that person to understand and break that inequity challenge? They’re uninsured. How can we get that person into believing that even though you’re uninsured, you can still be in PrEP because we have patient-assistance programs.

In terms of disparities and inequalities in access to PrEP, we need to access all the tools we’ve discussed. We need to invest resources in the communities and places in the United States that have been slower to have PrEP uptake. The CDC and the federal government have the Ending the HIV Epidemic initiative, which emphasizes investing our prevention resources most aggressively in 48 hot spot counties and 7 rural states. Their goal is to end the HIV epidemic by decreasing new infections by 90% by 2030.

That’s a good way to look at this from the start: where are the HIV infections happening most frequently, and where is PrEP use lowest? Those hot spot areas are a good place to look. We also need to think about racial and ethnic inequities. There’s been a long history of racism in health care and discrimination against Black and Latinx populations. We need to engage clinicians, organizations, and patients in a new conversation about making health care welcoming and inclusive, an environment where everyone can feel like they’re going to get effective and personalized health care. This is also true for people who may be transgender or nonbinary in terms of their gender identity, who have faced health care discrimination and societal discrimination for a long time. We need to get the health care system to be as welcoming and inclusive as possible.

If we do that, then hopefully communities where PrEP has been underutilized will see this as something that is a feasible, acceptable, and attractive thing that people are motivated to use. Then it benefits the patients and the health care system as well for all the reasons we’ve discussed in terms of the economic and population public health impact of HIV in the United States.

Strategies that can help address disparities in care for patients with HIV and reach high-risk groups of patients to ensure access to screening and PrEP. 

Addressing Disparities and Increasing Access to HIV PrEP

: In terms of trying to meet the quadruple aim for the [Institute for Healthcare Improvement], there are a lot of ways we could work on improving both patient experience and outcome, and clinician experiences, satisfaction and outcome. I think we need to acknowledge that PrEP [pre-exposure prophylaxis] right now is relatively complicated from the perspective of the medical aspects. There’s a fair bit of follow-up. For example, right now, for people taking oral PrEP based on the CDC guidelines, which actually were just updated last week, the idea is to have someone come in quarterly for their adherence and medication and testing. That’s really important from a safety standpoint, but it is burdensome to both patients and providers. I think we need to think about ways to safely de-medicalize PrEP to some degree so that it’s more accessible. We’re meeting patients where they are, because people have busy lives and they may be otherwise completely healthy, and so we don’t want overburden them such that they don’t opt to continue with PrEP or initiate it in the first place.

Same thing on the clinician side. I think we need to figure out ways to give clinicians tools to make HIV testing, PrEP conversations, prescribing, and follow-up much easier on them and their staff. This could be offloading busy clinicians with other health care professionals who can do a lot of the work with clients and patients to make the burden on the clinician who’s prescribing it a little less. We can think about ways to use the electronic health record and automated tools to help remind clinicians about patients who may be at increased risk for HIV acquisition based on their electronic health record history. For example, if they’ve had past sexually transmitted infections, then that would be a way to prompt them to think about talking about PrEP.

In terms of follow-up, if you have people in large numbers on PrEP in a clinician’s panel, we really need population health management tools, whether that’s personnel, where they can offload with a nurse, medical assistant or other professional who can work on managing people’s follow-up after the initial prescription and making sure that they have what they need in terms of laboratory care, adherence counseling, and getting their questions answered. That can really make a good impact on the quadruple aim of everyone’s experience and outcomes.

I think we need to think about innovative ways to get PrEP to people where they are that include giving it completely out of the health care system. That’s already underway with the idea of telemedicine for PrEP, or tele-PrEP, where you can have people at any jurisdiction in the country accessing PrEP centrally with virtual visits, having home-based lab testing, or maybe local testing, but it avoids having to take a day off of work for example, and come into the clinic 4 times a year. There are a lot of ways to innovate and improve the goals of the quadruple aim from the [Institute for Healthcare Improvement].

There are a number of population health challenges in terms of people who might be eligible for PrEP or on it. The first is raising awareness of PrEP, particularly in communities where there have been high rates of new HIV infections, such as the southeastern United States, and where PrEP use has been lower than other regions, and particularly among Black and Latinx populations. I think some of these challenges can be met by well-designed public health campaigns where people are made aware of PrEP in a broad community-wide sense. I think there have been some misconceptions that PrEP is just for certain populations. We’ve heard from research we’ve done that cisgender women have heard that PrEP is just for gay men, for example, and we know that’s not true at all. In fact, PrEP is underused among cisgender women. We need to think about ways to inform the public that this is something that’s a benefit to them so that they can access it.

I think we also need to make the access easier instead of asking people to exclusively come into health care settings where some people are otherwise healthy and don’t see a health care provider regularly. Other people may have faced stigma and discrimination or judgments by health care providers in terms of sexual health care. People may not want to see clinicians for things like PrEP. So if we can think about creative ways to use community-based organizations to implement PrEP in the future, I think those would be ways to improve access more broadly on a population level.

Once people are using PrEP and they are engaged, I think accessing paraprofessionals who are not necessarily the prescribing clinician for PrEP can also improve the number of people we can support on PrEP. For example, at the hospital where I work, there’s a pharmacist who has been really motivated to work on the PrEP-using population in the primary care clinic. It’s a very busy, big primary care clinic, and there are a number of primary care providers who prescribe PrEP to their patients. But having the pharmacist as a central person who has expertise, maybe a bit more time to manage the group, and also using the electronic health record to keep track of people, these are ways where you can really scale up on a population level without overburdening the clients or the health care professionals who are managing the PrEP.

Thinking about ways to use telemedicine for PrEP is a really creative way to do this as well for people who are in rural areas, or frankly, people who just prefer to do things virtually. The COVID-19 pandemic has given people opportunities to try new ways of accessing and using health care. While I don’t think that the whole world is going to be virtual in terms of health care, for the indefinite future, there’s no question that there are certain people and aspects of health care that can be done more efficiently and more effectively using full telemedicine or maybe a combination-hybrid model. PrEP, I think, is a really good way to do that.

There are already academic, public health, and private organizations that have robust tele-PrEP programs that have been going for several years now. These haven’t been as rigorously studied yet as I would like to know the outcomes, but my sense from talking to people who have engaged in them is that these are excellent opportunities to expand PrEP on a population level to more people. Colleagues of mine here in Boston are doing studies with colleagues in the South to see if a tele-PrEP model keeps people engaged and adherent to PrEP compared to a standard in-person model. Over the next few years, we’ll learn a lot more about some of these innovative approaches to delivering PrEP as well.

In terms of programs that can help make PrEP more effective for patients and for providers in the health care system, I think having a team-based approach is an excellent way to approach PrEP. There’s the prescribing clinician, but engaging nurses, pharmacists, medical assistants, a whole series of people on the team who may have different levels of expertise and different amounts of time.

For example, in terms of adherence counseling, research has shown that using behavioral cognitive methodologies can be really effective to help people problem-solve with their adherence, but a primary care clinician with a huge panel of patients may not have time to do that. This involves engaging nurses who can be trained in some of these methods, or behavioral health specialists, and even peer navigators who can talk at the level of a peer with someone using PrEP about their experiences and the way they’ve overcome challenges to accessing PrEP, integrating into their lives, some of the social considerations of using PrEP in terms of disclosing to partners, peers, and family. I see the future and the present, frankly, is using a team-based approach.

At one of the places where I work, we have an excellent nurse who basically manages the PrEP program except for the actual prescribing and refilling, and does an excellent job. This person has gained all the expertise as being a specialist as an infectious diseases nurse, and so the jump to PrEP is really quite straightforward. She’s able to manage many more patient cases than I could alone. Using team-based approaches and integrating those with technological tools, such as using population health management tools from the electronic health record, are ways you can scale this up most effectively. I think those have been helpful for me personally at our institution. I know that I’m not always in the clinic. I do some research as well as clinical care, and even the busiest clinicians have been pulled in so many directions with all that they’re asked to do, so we need to be offloading and working in teams to make sure this is scalable and sustainable.

: The utilization management strategies for PrEP have changed over the years. Initially, some plans had prior authorization, some plans didn’t. They are to the point where there’s not a lot of prior authorization; PrEP is a pretty standard of care recommendation. There’s really not utilization management on some of the therapies. Things like generic Truvada are available without prior authorization with a $0 co-pay, I’m assuming for most plans, including ours. There are obviously multiple therapies out there. Some of the other therapies may have prior authorization and requirements around a generic-Truvada-first type of policy. If generic Truvada doesn’t work, which I don’t know if we see failure in this population, Truvada failing may not be the issue, but contraindication or intolerance or reasons why you wouldn’t want to use generic Truvada, there are allowances to get into other therapies.

Payer perspective regarding strategies that can be deployed to help improve the patient/provider experience and utilization of PrEP therapy as prophylaxis against HIV.

Population Health and HIV PrEP

: What is the cost and utilization of someone who’s positive for HIV today? When we look at drug costs, medical care costs, laboratory costs, they all add up. And this is not being admitted to the hospital. Prior to the new advent of treatment for the last 10 years, we would see a significant amount of people admitted to the hospital for medical conditions, cryptococcal infection, acquired pneumocystis. And that number runs into hundreds of thousands of dollars per hospitalization.

Now, fewer people are being admitted to the hospital. They have costs related to medications. What does that look like? You’re looking at probably around $50,000 a year minimum in cost of care for each individual, where the physician cost is the lowest of that. Medication costs run about $50,000, laboratory costs add up to probably $5000 to $10,000 a year. And physician cost is just in the hundreds of dollars. When we look at the full cost of care of a patient with HIV who’s not admitted to the hospital, who is not with any significant comorbidity, you’re looking at $50,000 to $60,000. If you add comorbidities, cardiac disease, kidney involvement, renal involvement, and liver involvement, that number will run $80,000 easily.

When you look at the cost of PrEP [pre-exposure prophylaxis] now, which is relatively much cheaper, you can clearly see that preventing 1 case of HIV for a lifetime is such a significant improvement in your cost. For example, the cost of providing PrEP is probably less than $1000 a year, in that range. Then you look at the numbers over 10 years, and if you prevent that 1 infection, you can run the numbers and see the impact it has on the cost of HIV.

: The economic impact of HIV is still substantial in this country. There are well over 1 million people who are living with HIV, and because it’s a lifelong infection without a cure right now for the vast majority of people, people need to be on medications, usually on a daily basis indefinitely, and so that cost adds up. It’s certainly well worth it in a population level value, but it is an expensive process to keep people in treatment for HIV infection, particularly because most of the commonly used medications are still relatively expensive, upward of $20,000 per year for most of the regimens that are brand name right now. PrEP could certainly have a very important economic impact if it keeps people from becoming HIV positive.

PrEP doesn’t have to be lifelong. It can be used for people during periods when they may be engaged in behaviors that put them at risk for HIV acquisition. Unlike lifelong treatment for HIV, it could be more economically efficient over someone’s lifespan if they can intelligently choose when to use it and when not to. There have been some studies done years ago looking at the cost-effectiveness of PrEP, and the early studies showed that it’s definitely going to be cost-effective if you’re able to implement it in populations where the risk of HIV is highest. For example, men who have sex with men who have had bacterial sexually transmitted infections is a group that traditional epidemiology has shown has an increased risk for HIV acquisition, and PrEP has shown to be cost-effective in certainly that group.

Now, in 2021, we actually have generic PrEP medications, which is a relatively new phenomenon just in the past year, so that entire conversation about cost-effectiveness and economic impact has shifted. If we can engage more people in the use of very inexpensive medications, then the economic impact on HIV as a population health consideration can be really great. That should be on a societal and policy level, a strong motivator for getting the most cost-effective versions of PrEP out there to as many people as possible.

The financial burden associated with HIV and the potential effects of PrEP uptake on overall costs of care.

Economic Impact of HIV

: In terms of trying to improve the outcomes for pre-exposure prophylaxis, or PrEP, we actually need to work on all of the aspects in terms of screening, access, and adherence plans. There are gaps in all of these areas for PrEP at this point. The CDC thinks that there are probably 1.2 million or so Americans who would benefit from PrEP use, and most recent data from early this year suggest that we’re only at about a quarter of that level overall, and even lower in some other populations. We need to think about making access to HIV testing more patient-friendly, always emphasizing that it’s low or no cost to patients, getting people access to PrEP when they want it, and then having clinicians and health care organizations and community-based organizations think more about ways to ask people about what they know about PrEP and if they’re interested in it in a routine manner. Then once people are engaged in PrEP care, we have a lot of work to do in terms of keeping people adherent and persisting with the medication. The whole spectrum of the continuum of care needs more effective ways to improve it to optimize outcomes right now.

: When we look who are the appropriate candidates for PrEP, well, when we look at the demographics and who is acquiring HIV infection right now, it’s LatinX, African-American patients, younger patients under the age of 24. Let’s take these 3 groups. How do we now get those participants more involved in PrEP, understanding PrEP, what can we use? Social media is now the way to go. We have seen a lot of usage of social media, we can advertise in social media, engage in getting the question out there to those participants who can be on PrEP.

The challenge with PrEP is that a lot of people when they’re aged 16, 17, 18, 21, and 23 don’t think that they’re at high risk for acquiring HIV. They’re now moving from high school, moving to college. This is actually the greatest risk group. How do we address that? Should we get health care counselors involved, workers involved, teachers involved? And then once they’re leaving that health care setting, the pediatrician should also be aware. And a lot of these people I’m mentioning, they don’t want to talk about PrEP. They don’t even understand what PrEP means to this younger generation of potential people who can acquire HIV.

Why are people who are eligible to receive PrEP not getting it? Let’s ask the question; the population of higher-risk people in this country right now for PrEP is about a million people. How many people are on PrEP? Less than 250,000 people, probably much less than 200,000 people. So only about 25% of people who should be on PrEP are on PrEP. When the CDC says that, we are failing, and PrEP has been out for 9 years now. This strategy to prevent transmission of HIV has been available for 9 years. How are we going to engage those 750,000 people? How are we going to make them more involved with PrEP, is the question.

What does that look like? Again, social media. Again, educators. Again, looking at providers who are willing to speak to the younger generation about PrEP. And parents. I just got a call recently from the mother of a 17-year-old who wants to get her son on PrEP because she realized he has high-risk behavior. And because she’s also [HIV] positive, she obviously sees that in her son. So, getting parents more involved is also going to be a very interesting way of engaging more PrEP, getting to that number of over a million people to be on PrEP. The high risk: African-American, Latinx, the younger population, the younger generation. But I think the only way to get there is to educate, educate, educate. Get the message out there. Here’s a very effective strategy where, and we’ll discuss later different treatment strategies, if you take 1 pill once a day, you can prevent acquiring HIV by high-risk behavior.

Considerations to help identify and increase utilization of PrEP therapy among patients who are eligible for treatment.