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Welcome to the deep dive. Today we are taking on uh one of the most clinically critical and historically complex infectious diseases: HIV infection and AIDS.

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It's a huge topic.

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It is. Our mission here is to give you a really high-yield, structured look at the essential clinical knowledge. We're talking everything from the basic science to the absolute latest in therapeutics and prevention.

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And we're going to frame it around those core tasks you face in practice. Yeah. You know, history taking, diagnosis, and management.

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Exactly. So let's start with that foundational science.

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Aaron Powell Right. And you know, that structure is so essential because the entire clinical approach to HIV, it really pivots on one single concept. Which is the virus specifically targets and destroys CD4 lymphocytes. So for you as a clinician, this means the absolute CD4 count is, well, it's the master key.

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Master key. I like that.

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It's the single best measure of immune dysfunction. It dictates the stage of infection and uh most critically the risk of life-threatening opportunistic complications.

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Okay, let's unpack this. Starting with how the virus actually moves from person to person. We all know the classic transmission routes.

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Trevor Burrus, Jr. Sure. Sexual contact, parental exposure. Trevor Burrus, Jr.

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Right. Primarily injection drug use, sharing needles, and then perinatal transmission from mother to child.

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Exactly. But if we only focus on those vectors, we're really missing the revolution that effective treatment has brought to prevention.

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This is a huge point.

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It is. This is where we leverage that basic science of viral suppression for a massive public health win. We now operate under the concept of undetectable equals untransmittable.

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U equals you.

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U U. When a patient is on effective antiretroviral therapy, RT, and their viral load is suppressed below 200 copies per milliliter, the risk of sexual transmission is eliminated.

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It's not just reduced, it's gone.

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It's gone. And that completely reframes the conversation with patients, with the community. It's empowering.

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Absolutely transformative. But you did mention there's a persistent challenge we're still facing. Even with these amazing drugs, primary drug resistance.

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We do. We're seeing it in some uh highly concentrated urban areas, we're seeing resistant strains being transmitted in about eight to ten percent of new infections.

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Wow. So right from the start.

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Right from the start. And that is why immediate comprehensive baseline testing is just it's non-negotiable. It really highlights why the clinical urgency to screen and to start treatment has never been higher.

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Aaron Powell And that urgency leads us directly into our first clinical task area. History taking and the physical exam. I mean, you can't diagnose what you don't even suspect. Exactly. So how aggressively should clinicians be assessing risk factors in just routine practice today?

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Aaron Ross Powell It has to be universal. It really does. Clinicians must routinely assess sexual history. You know, asking about men who have sex with men, MSM, any history of sharing needles.

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And partners with unknown status.

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Aaron Powell And whether a patient has partners with unknown or known positive HIV status. Risk assessment isn't a one-time thing. It's not a checkbox on a form. It's an ongoing conversation.

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Aaron Powell And when we talk symptoms, the classic presentations they get missed so often, right? Especially early on.

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They really do. I mean, the acute HIV infection, that seroconversion illness, it's often totally asymptomatic.

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Nothing.

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Exactly. And even when symptoms do show up, they are so nonspecific. You know, they're what we call protein.

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Yeah.

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Just all over the place.

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So it looks like a million other things.

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Aaron Powell, it looks like mono, it looks like the flu. Patient comes in with fever, this profound fatigue, maybe a rash. And because these symptoms just resolve on their own, the diagnosis gets missed unless the clinician has a really high index of suspicion and specifically orders that HIV test.

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Aaron Powell Right. But then once the infection progresses to a chronic or more advanced stage, those constitutional symptoms they become impossible to ignore.

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Aaron Powell That's where you see the persistent unexplained weight loss, the chronic low-grade fevers, those drenching night sweats.

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And what about more localized symptoms?

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Aaron Powell We also look for things that just persist. So chronic pulmonary issues like a nagging dry cough or unexplained chronic diarrhea. Those are really common complaints that can signal significant immune compromise even before a major opportunistic infection takes hold.

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Okay, so let's move to the physical exam. It can be totally unremarkable in the early chronic phase, but what are the visual tip-offs that just scream advanced HIV?

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There are a few dermatologic and mucosal findings that are highly specific markers. I mean, generalized lymphodenopathy is pretty common early on, but you have to look closely at the mouth.

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What are we looking for?

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We look for oral hairy leukoplachia. It presents as these white, non-scrapable kind of corrugated lesions, usually on the side of the tongue. It's caused by the Epstein bar virus.

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And then there are the cutaneous malignancies and infections.

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Precisely. Disseminated Kaposi sarcoma, which is an AIDS-defining malignancy, presents as those hallmark violaceous or brownish lesions. They're often palpable on the skin or even on mucosal surfaces.

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And there's a look-alike for that one, isn't there?

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There is. You have to remember cutaneous bacillary angiomatosis. It can look deceptively similar to Kaposi's, but it's actually a treatable bacterial infection caused by Bartonella.

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Okay, good distinction.

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Yeah, and any of these findings, plus any new mental status changes or neuropathy, those immediately raise flags for things like HIV-associated neurocognitive disorders or OIs in the central nervous system.

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Those clinical tip-offs are so crucial, but ultimately we have to confirm the diagnosis in the lab. So let's head our second task area. Using diagnostic and laboratory studies, what's the definitive pathway?

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Okay, so we rely on a standardized three-step algorithm. Step one is the initial test. That's the fourth generation HIV antigen antibody aminoassay.

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So fourth gen is key here.

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It is. It's much faster than the old antibody-only test because it detects both HIV one and two antibodies and the HIV one P24 antigen. That antigen appears much earlier.

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So it shortens that detection window.

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By a lot. Down to a median of about two weeks post-exposure.

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Okay. So we have a reactive screening test. What's the next absolute required step?

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Step two. You have to perform an HIV one, HIV two antibody differentiation immunoassay. This tells us which subtype is present, which is essential for management and you know for public health tracking.

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Aaron Powell Right. And here's where the algorithm can get a little tricky. What if that screening test is positive, but the differentiation assay comes back negative?

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Aaron Powell That's the crucial step three. In that case, you have to perform an HIV one viral load, which is a nucleic acid test, or NAT.

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Mm-hmm. And what does that tell us?

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If the NAT is positive in this scenario, it confirms acute HIV infection. It means the patient was exposed so recently that they have the P24 antigen, maybe some early antibodies, but not enough for the differentiation test to pick them up yet.

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And catching it that early is critical.

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It's so critical. Those patients have an extremely high viral load and a very high transmission risk.

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Okay, that's a clear pathway for diagnosis. Let's pivot back to staging because that's where the CD4 count reclaims its importance. It defines the stage and helps us formulate the most likely diagnosis of complications.

SPEAKER_00: 7:13

Absolutely. The CD4 count is our immune clock. We define AIDS. The most advanced stage is either having a CD4 count less than 200 or having an AIDS-defining illness. And that's regardless of the CD4 count.

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And alongside that, we're constantly monitoring the HIV viral load.

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Yes. The viral load measures active viral replication and more importantly, tells us how well the RT is working. We measure it at baseline, again, two to four weeks after starting or changing RT. And then every three to six months to make sure that suppression is durable.

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And we can't forget resistance testing.

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Never. We do genotypic resistance testing at baseline for every single new diagnosis, and anytime we suspect that the treatment might be failing.

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Let's really synthesize this part now. Tying the CD4 count directly to specific opportunistic infections, this is where the patient's prognosis lives. So what's the roadmap here based on those numbers?

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Aaron Powell Think of the CD4 count as a stepwise defense barrier. So at any CD4 count, a patient is still susceptible to common infections. Bacterial pneumonia, TB, Kaposi sarcoma.

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But the lower thresholds unlock the really deadly OIs.

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That's right.

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So give us the thresholds. What happens when we breach 200?

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That 200 threshold is the alarm bell for PCP. Pneumocystis, Girovichi pneumonia. It's the most common AIDS-defining OI. So if a patient presents with fever, a dry cough, hypoxia, and their count is below 200, PCP has to be at the top of your list.

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And dropping further, below 100.

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Below 100, we add toxoplasmosis, especially if the patient is IgG positive and cryptococcosis. These often present as uh central nervous system problems.

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Aaron Powell And the most precarious level, the real danger zone.

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That's a CD4 count below 50.

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Below 50.

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Yeah. This is the cutoff for disseminated MAC mycobacterium avium complex, which presents with that systemic wasting and GI involvement. It also puts CMV retinitis, a major cause of blindness, and CNS lymphoma high on the differential. Knowing these cutoffs guides everything.

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And before we jump to treatment, we have to complete the lab work by screening for coinfections.

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Standard of care. You have to screen for Kibi with a PPD or an IGRA. And remember, a positive PPD in an HIV patient is defined as an induration greater than five millimeters.

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A much stricter cutoff.

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Much stricter. And we also must screen for syphilis and for baseline hepatitis A, B, and C status. Co-infection management is absolutely essential.

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Okay, let's move to clinical management and pharmaceutical therapeutics. The core principle used to be so complex, but now it seems remarkably simple.

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It really is. The principle today is simple and powerful. Treatment is recommended for all HIV-positive patients, regardless of their CD4 count.

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Regardless.

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And ideally, it's initiated immediately. We call it rapid start RT. The goal is just get that viral load suppressed as quickly as possible. A standard regimen is robust, two nucleotide reverse transcriptase inhibitors, NRTIs, plus an integrated strand transfer inhibitor and NSTI.

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And the convenience of single tablet options has just fundamentally changed adherence, hasn't it?

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Complete.

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Can you walk us through the preferred initial regimens and their trade-offs?

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Yeah, so our sources highlight three key single tablet options. First is Bictogravir combined with TAF and intrisidobain or Bictarvi. It's highly favored because it has an extremely high barrier to resistance. It's very robust and generally well tolerated.

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Okay, what about the ones that come with specific patient requirements?

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So there's diluted gravir, ebicavir, and lamividine, known as TREMEC. This is effective, but you absolutely cannot start this drug without a negative HLAB5701 genetic test.

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Because of the hypersensitivity risk?

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A severe, potentially life-threatening hypersensitivity reaction associated with ebacavir. Then there's a newer two drug redimen, diludogravir and lamividine, or devato.

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Which is appealing, less drug burden.

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Right. But it has important contraindications. You have to avoid it if the patient has a very high viral load over 500,000 copies, or if they have an active hepatitis B coinfection.

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We have to talk about adverse effects. This defines long-term adherence. Let's start with the NRTIs, which were notorious for kidney and bone issues.

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Yes. The older backbone, tenophovar DF or TDF, carried significant risks of renal toxicity and loss of bone mineral density. The newer formulation, tenophovir AF or TAF, has substantially improved bone and renal safety.

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But there's a trade-off.

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There's an important trade-off. TF is increasingly associated with significant weight gain and dyslipidemia. So it kind of shifts the long-term risk profile from renal and bone health over to metabolic health.

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That's a challenging balance for clinicians. And what about the other classes?

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Well, the proteus inhibitors, or PIs, are generally reserved for resistance cases now because they are so strongly associated with metabolic syndrome.

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Hyperlipidemia, hyperglycemia.

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Exactly. And lipidystrophy. And they often require boosting with retonavir or cobesystat, which makes them strong. CYP450 inhibitors and leads to a high potential for really dangerous drug interactions.

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And the NSTIs, the newer class.

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The NSTIs are also implicated in weight gain. And from a prescribing standpoint, you have to tell patients to separate them from polyvalent cations like antacids, iron, or calcium because they chillate and reduce absorption.

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Okay, let's talk clinical intervention timing. You said art should start quickly, even with most acute OIs. Why is that?

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Because starting art as soon as possible, even alongside OI treatment, it reduces mortality. It reduces morbidity in the majority of cases.

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There's an exception.

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There is one crucial non-negotiable exception. You must delay RT in cryptococcal or tuberculous meningitis.

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And why the delay there?

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It's to prevent severe iris, immune reconstitution, inflammatory syndrome.

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Right.

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When the immune system suddenly wakes up from RT, it mounts this overwhelming inflammatory response against the pathogens, often in the constrained space of the central nervous system. This can dramatically worsen cerebral edema and lead to severe neurologic damage or death. We have to wait.

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And for monitoring success, what are the key viral load targets we're aiming for?

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We expect a big drop, about a hundredfold or two logs, within just two weeks of starting art. And the viral load should become fully undetectable by three months. And if it doesn't, you immediately reevaluate adherence. That is the single most common cause of treatment failure.

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We've covered acute management. Let's transition now to our next task area: prevention and long-term care, starting with universal screening.

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The USPSTF recommends HIV screening for all adolescents and adults, ages 15 to 65, at least once. And more frequently for anyone with ongoing risk, screening is the gateway.

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And the prevention strategies are just revolutionary. Let's look at post-exposure prophylaxis, PEP.

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PEP is an emergency measure. It has to start within a rigid 72-hour window of exposure.

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That window is critical.

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It's critical. The preferred regimen is typically tenophobarum trisidivine plus diluted gravir or roll to gravar, taken for 28 days. The earlier the better.

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And then there is PPP, preexposure prophylaxis. Who should be on this?

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The indications are broad. It includes MSM, transgender women, heterosexuals with high risk partners, injection drug users. We have two oral options. Okay. There's TD femtrisidivine, which is effective but contraindicated if the patient's kidney function is less than 60. Then there's Tfemtrisidivine, which is gentler on the kidneys, but and this is important, it's not approved for use in cisgender women seeking PPP.

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That is a crucial clinical caveat. And we also have the newest option, the injectable. Right.

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Cabotogravule, which is injected every two months. It's transformative because it removes that daily adherence barrier. But has a unique monitoring challenge. Wait, if a patient is acutely infected when they start it, the drug can cause resistance and delay seroconversion. So precise RNA testing is required before you even start.

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Okay. Finally, let's wrap up our section on health maintenance with OI prophylaxis, which again is entirely CD4 driven.

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Absolutely. We initiate PCP prophylaxis if the CD4 is below 200, usually with TMP SMX.

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And for toxo.

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Toxoplasmosis prophylaxis starts if the CD4 drops below 100 and the patient is IgG positive. Again, usually with TMP SMX.

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What about MSC? We used to give prophylactic antibiotics for menase C for months on end.

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That is a key change in contemporary practice. Primary prophylaxis for disseminated MANC is generally no longer recommended for patients who are starting RT immediately.

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Because the immune system recovers so quickly.

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Exactly. Art restores immunity so fast that the need for prophylaxis just diminishes. It's really reserved for patients with a CD4 less than 50 who for some reason are not yet on RT.

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Shifting to vaccinations, must-haves, and major contraindications.

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All HIV patients need the pneumococcal vaccine and an annual inactivated flu vaccine. We also vaccinate non-immune patients for HEP B, often using a higher dose. And good news, Shingrix is safe.

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What's the big caveat?

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Live vaccines. MMR Varicella. They're generally contraindicated if the CD4 count is below 200 due to the risk of uncontrolled replication.

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Which brings us to patient education. What is the final message every patient needs to walk away with?

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Beyond safe sex practices and clean needle use, the core message is U equals U. Emphasize that effective treatment protects their health and the health of their partners. And we counsel them on specific avoidance strategies, like avoiding raw meat and cat litter because of the risk of toxoplasmosis.

SPEAKER_01: 16:40

Wow. We've really executed the full clinical deep dive here, moving from that pathophysiology, that key CD4 count, all the way through to the nuance of modern management, like NSTI regimens and pre-P.

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It really highlights how far we've come. This is a treatable chronic condition now.

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It truly is.

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And if there's one final thought on managing patients, it has to be adherence. We have these transformative, simple, single tablet regimens, but adherence counseling is still absolutely critical.

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Aaron Powell If they miss doses.

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If they miss doses, we fail to achieve viral suppression and we rapidly foster resistance. We have to emphasize so strongly that drug holidays are never ever recommended.

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Aaron Powell That is a perfect final point on the clinical side. So let's leave you, the listener, with a provocative thought to chew on. Considering we have the clinical tools, highly effective treatment leading to you, and extremely effective prevention with P war una ongoing systematic barrier, be it economic, social, or structural, presents the greatest challenge to eradicating new HIV infections in the US today, even when we have the science to do it. We encourage you to explore the continuing barriers to universal screening and immediate artery initiation.