Viremic – Cases in HIV

Announcer:
Welcome to Viremic–Cases in HIV, hosted by Dr. Eileen Scully and Dr. Christopher Hoffmann, both HIV specialists at Johns Hopkins, who explore quandaries in adult HIV care. Each case discussion includes
medical history and diagnoses, challenges in care and treatment, and key evidence and guidelines
that inform clinical decision making.

Cases are presented as a composite from the hosts’ clinical practice, with all identifying details removed to protect the privacy of patients. Case discussions are for informational purposes only and not offered as medical or clinical practice advice for patients or clinicians. Any mention of specific medications or commercially available products is a description of use only, not an endorsement.

Dr. Eileen Scully:
Welcome to Viremic. I’m Eileen Scully, an infectious disease physician here at Johns Hopkins, who’s coming to you today for our regular discussion of the joys and challenges of caring for people living with HIV. Today, I have the privilege of being joined by Dr. Sanjeev Shah. Dr. Shah is the chief medical officer of MetroPlus Health in New York, and in addition to his leadership roles in healthcare, he’s an infectious disease specialist and a teacher. [See endnote number 1] As is the through line with many of the guests we’ve had on the podcast, Dr. Shah has had a career marked by focusing on the delivery of care to those who are most likely to be overlooked. We’re fortunate to have this type of leadership and vision in healthcare today. So, thank you so much for joining us today, Dr. Shah. We’re excited to have you here on Viremic.

Dr. Sanjiv Shah:
My pleasure Eileen, thanks for the invitation.

Eileen:
Now before we dive into our case, I want to ask you to comment on how you would talk to current trainees and early career infectious disease providers about how to chart a career in this specialty and what makes you happy to be an infectious disease specialist.

Sanjiv:
Well, Eileen, you mentioned MetroPlus Health Plan, and a little bit of background there will perhaps give you some insights into my journey. This health plan is based exclusively in New York City, and it’s owned by New York City Health and Hospitals, which some of you may know is the largest municipal healthcare system in the United States. It serves millions of New York City residents, and it does so regardless of their health insurance status, including tens of thousands of people who don’t have any health insurance at all. In my clinical time, I see patients at an FQHC on the Lower East Side of Manhattan where the vast majority of the patients I’m privileged to serve are immigrants. And I’m also a proud immigrant. I was born in Africa, came to the UK as an immigrant, went to medical school there, and then in 1991 came as an immigrant again to the United States.

I grew up, admittedly, in a much more privileged background than the patients I see, but that perspective has shaped my thinking into ID. I did my internal medicine residency at Mount Sinai Hospital in New York City, and as a resident at Sinai, you go to Elmhurst Hospital in Queens, which is part of New York City H&H. That’s where I met a pretty remarkable individual, Dr. Joseph Masci. [See endnote number 2.] He’s the reason I went into ID, and I’ve since discovered, since he passed and we gathered for his memorial service, so many ID doctors were inspired by Joe Masci who was a brilliant clinician and academic. He taught us then as residents about the social determinants of health long before it entered the modern lexicon.

Then, when I did my ID fellowship in the Bronx and stayed in the Bronx for clinical care, I again was shaped very much by the patients I saw, many from where I grew up in Tanzania, East Africa, but others from West Africa and Sub-Saharan Africa. And I also got to know CBOs (community-based organizations). I never heard the term during my fellowship but learned it when I started practicing in the Bronx and how crucial they were to bring people to care. You could be the most astute clinician with deep knowledge, but unless you contextualize it in the care of people, it was almost lost, you know, or even secondary. There I got to know many issues… women from West Africa and Sub-Saharan Africa who were living with HIV, who brought their children for care, but not themselves. And you realize then that you are missing something if you focused on just lecturing them or telling them what should be done and for their interest but understanding their backgrounds and care.

So that’s been my journey, but I’m very fortunate in that regard to be in New York, in New York State, where it’s taken such a critical role at the forefront of ending the HIV epidemic, not just through clinical guidelines that we’re going to discuss later, but also through advocacy for many people, including the uninsured. That’s the majority of the population I see in my clinical time.

Eileen:
Thank you so much for those thoughts. One thing that resonates is that for me, caring for people with HIV is the perfect combination of the most interesting scientific and medical questions, but also ethical challenges and opportunities to serve. The kind of career arc that you just described, the inspiration, is exactly what appeals to people at the start of their career, and I hope someone who’s listening will take steps towards becoming an infectious disease physician. So, thank you again.

Now let’s turn to our case for discussion today, when we will use your full spectrum of knowledge.

Our hypothetical patient is a 32-year-old woman. She and her husband have been trying to have a child unsuccessfully for a few years and initiated the process of an infertility workup. In the course of that workup, she has a new diagnosis of HIV, with a positive screen on an antigen/antibody combination and a differentiation assay that is positive for HIV-2. She presents to you for consultation and for discussion of what this diagnosis means for her.

To give a little more background, she’s generally been healthy for many years with no excess infectious illnesses, no history of oral thrush or pneumonia. She’s originally from Cape Verde, where her husband is also from, and they moved to the U.S. about 5 years prior to this visit. He is also in good health, and they are monogamous. She is on no medications other than prenatal vitamins and has not had any significant hospitalizations or illnesses.

To start us off, I was hoping you could walk us through a little bit about HIV-2—where it is found globally and how frequently we see it in practice here in the United States.

Sanjiv:
That context is very useful. I look at data that I’m most familiar with, from the end of 2023, when UNAIDS and the WHO estimated there are about 40 million people living with HIV AIDS. Amongst that group, about 1 to 2 million are living with HIV -2, and there is a smaller proportion of those individuals who are co-infected with both HIV-1 and HIV-2.

I think Eileen, you’re familiar in terms of the historically zoonotic origin of HIV. HIV-1 is closely related to the simian immunodeficiency virus, SIV, from chimpanzees, whereas HIV-2 is closely related to SIV from sooty mangabeys. So, there’s a distinction right there. In terms of its isolation, HIV-2 was first isolated in West Africa—the first case reported from the island community of Cape Verde in the mid-1980s amongst individuals where it’s endemic in West Africa. The highest rates are in Cape Verde, the Ivory Coast, Guinea-Bissau, Gambia, Nigeria, and Sierra Leone.

That HIV presence in West Africa coincided with its emergence in epidemic form through a lot of the colonial wars for independence that did promulgate both the blood-borne transmission of HIV-2 as well as the sexual transmission. Through these wars of colonial liberation, there was dissemination of HIV-2 amongst those communities and then spread to other parts of the world, including Portugal. Guinea-Bissau, for example, is a former Portuguese colony. So, some of the veterans who were in those wars came back to Portugal and had contracted HIV-2 during this period.

But now HIV-2 is seen worldwide. It’s not just in West Africa. It’s seen in Europe, as I mentioned, Portugal, Spain, other parts of Europe, South America, Asia, and in the United States. Here in America, in terms of HIV testing surveillance analysis covering, say, the period 2010 to 2017, Peruski and colleagues reported 327,700 HIV cases diagnosed in the U.S. during that period, of which 102 were confirmed to be HIV-2 infections; a minority, 11, were dual HIV-1/HIV-2 infections.

When Peruski and colleagues reported that data in 2020, they noted that the majority of those cases were diagnosed in people from West Africa who are now living in the Northeast United States and had acquired HIV-2 through heterosexual transmission. There was a 50-50 split between males and females.

New York State did a similar analysis over pretty much a similar timeframe, 2010 through 2020, and they found 34,949 diagnosed HIV cases, and 43 had HIV-2 infection, 3 had dual infections (HIV-1 and HIV-2) and 25 had probable HIV-2 infection. Amongst the 71 cases in New York State, 54% were male and 80% were non-Hispanic black. A third of the cases were diagnosed when these individuals were 55 years old or older.

That speaks to the whole notion that HIV-2 is less virulent, less pathogenic, and therefore has slower disease progression. Therefore, these individuals may have longer periods of being AIDS-free, clinically free of any sense of acquired HIV infection, and therefore may be presenting later in the course of their lives. Of course, the other reason is people have to think of HIV-2, and clinicians have to think about that as a possibility. I remember one of the cases I saw, Eileen, was somebody who was thought to have idiopathic CD4 lymphopenia without HIV infection. As a result of some persistent inquiries by our team in the Bronx, the person was found to have HIV-2, so that’s another reason why people may be making the diagnosis later on.

That’s the epidemiologic background that I’m familiar with here in the United States and the world.

Eileen:
That’s perfect and sets the stage for many of our listeners who probably have seen this once or twice, but actually it’s not something that we see every single day in most clinics. That last point that you made about the late diagnosis hearkens back to when HIV-2 was not clearly identified by screening tests, but it was one of those things you had to suspect in the case of an unusual HIV-1 screen where it was not quite positive, but not quite negative. But that’s not really the case with our modern diagnostics today in general. Is that correct?

Sanjiv:
That’s true, and you alluded to a hypothetical patient having this so-called fourth generation HIV-1/HIV-2 antigen-antibody combination immunoassay as our patient underwent, which does detect, first of all, HIV-1 p24, so early [identification of] antigenemia trying to narrow that window period where HIV may remain undiagnosed by antibodies, but then also has the HIV-1 and HIV-2 antibody detection. If that combination assay is reactive, goes on to do a supplemental differentiation assay between HIV-1 and HIV-2, and then presumably through that, this individual was diagnosed with HIV-2. Just to note that there is no HIV-2 antigen test in this assay.

Because HIV 2 RNA levels can be low or even undetectable in a person living with HIV 2 infection, a negative HIV 2 RNA nucleic acid test does not rule out HIV 2 infection. So, if your clinical suspicion is high, and the individual you’re managing has an elevated risk of HIV-2 infection, ordering the HIV-2 DNA testing through Wadsworth or repeating the HIV testing algorithm in a couple of weeks, beginning with the differentiation assay that we mentioned should always be considered.

Eileen:
Great. Now I’d like to circle back to another one of your comments in that really nice overview of the epidemiology. Could you comment a little bit more about the natural history of HIV-2 infection and some of the limitations of clinical monitoring in that setting?

Sanjiv:
When you’re diagnosed with HIV-1 infection, there is a protocol that you follow. Obviously, you get the viral load test, and then you do a baseline genotypic testing because you will certainly recommend the initiation of treatment. It’s certainly shared decision-making, but the recommendation from the clinician would be to start treatment as soon as possible.

The same is true for HIV-2, but there are barriers. There is no commercially available genotypic testing, or phenotypic testing for that matter. It’s only reserved for research laboratories. We’re very fortunate to have the New York State Department of Health, Wadsworth Center for Bloodborne Viruses, which does offer HIV-2 testing free of charge for healthcare providers in New York and their patients in New York, where you can submit specimens for HIV-2 viral load testing.

I know it’s not commercially available through other labs. There is a lab at the University of Washington that does viral load testing. But again, that’s limited, so you have to make sure that your clinic is able to send specimens to Wadsworth, if you’re in New York for both quantitative or perhaps qualitative HIV-2 viral load testing if you’re trying to sort out the diagnosis. They are very amenable. I’ve spoken to them. It’s a great crackerjack team there that leads that work. They’re available through a phone number and they have a very good website where you can learn how to send specimens. And that’s really the goal. The goal here certainly in New York is to say HIV-1 and HIV-2 should be evaluated similarly, if at all possible.

So viral load testing should be done. We don’t have to go through the historical way of looking to see if the CD4 count is increasing or decreasing to suggest treatment failure. You can do viral load monitoring. You can’t do resistance testing, but everything else is very similar. There are treatment nuances that we’ll get into. But then I think everything else is the same.

The case we had was clearly somebody who’s reactive for the HIV-2 antibodies, but when you get indeterminate results, it’s worth knowing you have a laboratory like Wadsworth available to help you with both qualitative and quantitative testing for HIV-2 if you suspect it.

Sometimes the way to sort out indeterminate results, Eileen, is to repeat the test in 4 to 12 weeks, not go much beyond that. But if you really do suspect it, involve labs like Wadsworth to help you discern what’s going on. There’s also now an FDA-approved, I believe from Roche, a COVAS HIV1/HIV2 qualitative assay that may be used to detect both HIV-1 and HIV-2 RNA. So, there are various things in the armamentarium of monitoring that are available if you know the right lab to send the specimen to.

Eileen:
That’s tremendously helpful, and I think it highlights one of the main differences between these two viruses, which as you mentioned, there’s in general, slower disease progression associated with HIV-2 and slower CD4 decline. The difficulties in getting viral load monitoring historically have not just been the lack of commercial availability with the numbers that you gave us earlier in the discussion. It’s not surprising that there aren’t a lot of commercial labs beating down the doors to develop an assay for 100 patients. That said, there’s also some technical challenges in the amplification of HIV-2 that has made it a little bit more difficult to make a good quantitative viral load assay. So, I think both of those limitations have come into the lack of consistent laboratory monitoring. While we recommend treatment, clearly there’s just a little bit less of the data that we’re so used to getting with frequency in individuals with HIV-1.

To circle back to a point you made earlier about the occurrence of HIV-1 and -2 infection together, that is also something that people need to be cognizant of and to think about as they make therapeutic choices, which we’ll get into next, that HIV-2 does not prevent co-infection with HIV-1.

There’s some older data suggesting there may be some interactions between the viruses and maybe even slowing a progression. But the bottom line is that, in general, they can occur together. In that setting, you would want to treat both of them with effective therapy, and we need to think about other infections, including hepatitis B, as we make our regimen choice.

So now let’s focus back on the question at hand. We have this patient presenting pursuing fertility, obviously with a new diagnosis that’s got to impact a lot of her decision making. What are the things that you think about as you choose a regimen for HIV-2? We can start thinking not in terms of pregnancy, but circle back to that as it is applicable.

Sanjiv:
I think clinicians have to keep in mind when it comes to HIV-2 which antiretrovirals work, which classes work, and then, importantly, to recognize which classes of medications don’t work.

One rule to always remember is that non-nucleoside reverse transcriptase inhibitors or NNRTIs do not work against HIV-2 reverse transcriptase. So that’s a class to avoid. Amongst other classes, like the protease inhibitors, there are varying activities. So atazanavir, fosamprenavir, tipranavir, and nelfinavir are PIs that don’t work against HIV -2. But the NRTIs do work; the integrase inhibitors do work, and boosted darunavir in the PI class works against HIV-2. (not certainly considering this in terms of initial regimens). There are other agents that don’t work. For example, the attachment inhibitor fostemsavir does not work against HIV-2. There’s limited data that Ibalizumab, the monoclonal IgG4 antibody that prevents HIV cell entry by binding to the host CD4 receptor, has in vitro evidence of activity, but not a lot of in vivo data that’s available, as you can imagine, with the limited number of cases there are. Most recently, lenacapavir, the capsid inhibitor, does have activity against HIV-2, but it looks to be less potent compared to its activity against HIV-1.

So, in terms of the approach with this individual, the preferred regimen, the preferred approach to consider and discuss with her is a 2-NRTI-plus integrase-inhibitor regimen—tenofovir based, not abacavir based. I mentioned that not because abacavir doesn’t have activity against HIV-2, but we don’t now use abacavir readily in new infections because of the cardiovascular and cerebrovascular risk associated with its use.

So, my recommendation is to use a tenofovir-based NRTI regimen along with an integrase inhibitor. A good combination single tablet regimen might be Biktarvy, or if you’re using a multi-tablet regimen, a combination of tenofovir, 3TC, or FTC plus dolutegravir.

Eileen:
And I’ll just point out here for listeners that there’s a link in the show notes to the guidelines, which provide a really beautiful tabular summary of this information.

I think the beautiful part about this is that while there are things that we can’t use, first line, first option medications are actually all still on the table for us. And importantly, our first line agents for conception and pregnancy are also on the table and effective against HIV-2. So that’s a nice part of this particular challenge.

Thanks also for mentioning those novel agents, again, would likely be considered only after someone has already exhausted the initial attempts at therapy. We should see full viral suppression that should be quantitatively assessable based on viral load testing. And if there’s not, there are cases that have been reported of documented HIV-2 resistance, again, without easy availability of commercial assays. But likely we could infer resistance if someone is adherent to a regimen and unable to achieve suppression.

So now I’ll bring us back to one more question around the initiation of treatment. For this patient, let’s suppose that her husband undergoes testing and ends up being seronegative, and they remain committed to proceeding with family planning. Can you comment on the relative transmissibility of HIV-2 and how you think about prevention of transmission, both through sexual contact and through vertical transmission to an infant.

Sanjiv:
Sure, as I alluded to earlier, HIV-2 has in general lower levels of viremia compared to HIV-1; and therefore, it’s transmitted less efficiently than HIV-1 through sexual behavior as well as mother-to-child transmission. But the risk is not zero, and for that reason we do recommend that for herself and her own immunologic recovery or lack of deterioration of her immune system that she would go on antiretroviral treatment.

As you said, the current choices available, an integrase inhibitor-based regimen will work both outside of pregnancy and within the pregnancy, should they be able to conceive. But the fact that the husband is HIV negative and HIV-2 negative and wants to remain that way, if they’re trying to become pregnant, I would recommend that he go on PrEP at least for the first 6 months while she’s achieving viral suppression on her regimen. That’s the conventional agents that are currently available for prevention—Truvada, Descovy, lenacapavir or cabotegravir all can be used as PrEP agents. He would stay on that for 6 months, assuming she achieves viral suppression. Then the principles of U=U apply, so he could come off PrEP. In terms of the treatment for prevention of vertical transmission, the key is achieving viral suppression in the mum, and as long as that’s achieved, the risk of transmission is zero, again, based on the U=U principle.

Eileen:
Okay, great. So, to summarize what we’ve talked about today, HIV-2 remains rare, but continues to occur at a measurable frequency in particular in regions with high diversity and patients coming from certain populations where there is endemic HIV-2 circulation.

Fourth-generation assays that do the antibody differentiation step will likely identify HIV-2 for clinicians, but it’s something to suspect and then pursue that type of testing if you have indeterminate or confusing testing for HIV-1 and you don’t have the HIV-2 differentiation antibody available. And as you highlighted, if there still is confusion, considering direct viral testing using HIV-2 quantitative or qualitative virologic assays is a next step for differentiating the presence of HIV-2 infection thinking about how to treat it.

There is an attenuated course, but as we in general recommend treatment for all people living with HIV, both for immune preservation, for prevention of transmission, and for prevention of potential complications from immune activation, we do generally recommend treatment for HIV-2, and you beautifully summarized the must-need-to-know concerns about various antiretrovirals, but we have lots of our first-line agents available.

So, thank you so much for this really beautiful overview. Do you have any closing comments on this particular clinical scenario or other things that we’ve not brought up that you think would be useful for a treating clinician?

Sanjiv:
Well, Eileen, your summary was brilliant. So, thank you very much for that summation. I would encourage folks to go to the HIV-2 guideline available at hivguidelines.org. Remember the availability of Wadsworth, a great lab in New York State, to do some of the testing that is necessary for the appropriate management of HIV2 infections. And then always remember that if you’re having problems or trying to help figure things out, New York State does have the HIV Clinical Education Initiative, where you can access the expertise of an HIV expert, might have expertise in HIV-2 and the availability to have that discussion will ensure that you’re taking the best possible care of the patient you’re fortunate to serve with HIV-2 infection.

Eileen:
Well, thank you so much, Dr. Shah, for joining us today on the podcast. And thanks to all of our listeners here on Viremic. Please check the show notes for links to those guidelines and resources. And we’ll look forward to our next case.

Sanjiv:
Thank you.

Announcer:
Viremic is sponsored by the Clinical Guidelines Program, a collaborative effort of the New York State Department of Health AIDS Institute and the Johns Hopkins University Division of Infectious Diseases.

Visit the program’s website at: HIVguidelines.org.

Viremic’s case discussions are for informational purposes only and not offered as medical or clinical practice advice for patients or clinicians. Any mention of specific medications or commercially available products is a description of use only, not an endorsement

The podcast is produced and edited by Mary Beth Hansen and Brian Hatcher with assistance from Jesse Ciekot and Laura LeBrun Hatcher.

Endnotes:
1.) Dr. Shah is also Vice-Chair of the NYSDOH AI Clinical Guidelines Program Medical Care Criteria Committee for development of guidelines on HIV treatment and prevention in adults, and he is lead author of the program’s guideline on Diagnosis and Management of HIV-2 in Adults. (https://www.hivguidelines.org/guideline/hiv-2/?mycollection=hiv-testing-acute-infection)

2.) See AIHA: Dr. Joseph R. Masci Legacy Project (https://www.aiha.com/dr-joseph-r-masci-legacy-project)