Antiretroviral Therapies

This week we talk about HIV, AIDS, and ART. We also discuss HAART, the Berlin Patient, and potential future cures. Recommended Book: Allergic by Theresa MacPhail Show Notes * https://www.unaids.org/en/resources/fact-sheet * https://hivinfo.nih.gov/understanding-hiv/fact-sheets/hiv-treatment-basics * https://clinicalinfo.hiv.gov/en/glossary/antiretroviral-therapy-art * https://www.paho.org/en/topics/antiretroviral-therapy * https://journals.lww.com/jaids/fulltext/2010/01010/declines_in_mortality_rates_and_changes_in_causes.13.aspx * https://link.springer.com/article/10.1007/s13181-013-0325-8 * https://academic.oup.com/jac/article/73/11/3148/5055837?login=false * https://journals.lww.com/jaids/fulltext/2016/09010/narrowing_the_gap_in_life_expectancy_between.6.aspx * https://en.wikipedia.org/wiki/Tenofovir_disoproxil * https://en.wikipedia.org/wiki/Management_of_HIV/AIDS * https://www.verywellhealth.com/cart-hiv-combination-antiretroviral-therapy-48921 * https://www.cdc.gov/hiv/risk/art/index.html * https://www.freethink.com/health/cured-of-hiv * https://www.jstor.org/stable/3397566?origin=crossref * https://www.nytimes.com/1982/05/11/science/new-homosexual-disorder-worries-health-officials.html * https://pubmed.ncbi.nlm.nih.gov/23444290/ * https://my.clevelandclinic.org/health/diseases/4251-hiv-aids * https://web.archive.org/web/20080527201701/http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf * https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(23)00028-0/fulltext Transcript In mid-May of 1981, the queer community-focused newspaper, the New York Native, published what would become the first-ever article on a strange disease that seemed to be afflicting community members in the city. What eventually became known as AIDS, but which was at the time discussed by medical professionals primarily in terms of its associated diseases, was clinically reported upon for the first time less than a month later, five official cases having been documented in an interconnected group of gay men and users of injectable drugs, who came to the attention of doctors for not being inherently immunocompromised, but still somehow contracting a rare type of pneumonia that only really impacted folks with severely impaired immune systems. In subsequent years, doctors started using a range of different terms for HIV and AIDS, calling them at different times and in different contexts the lymphotophic retrovirus, Kaposi's sarcoma and opportunistic infections, and the 4H disease, referring to heroine users, hemophiliacs, homosexuals, and Haitians, the four groups that seemed to make up almost all of the confirmed afflicted patients. The acronym GRID, for gay-related immune deficiency was also used for a time, but that one was fairly rapidly phased out when it became clear that this condition wasn't limited to the gay community—though those earlier assumptions and the terminology associated with them did manage to lock that bias into mainstream conversation and understanding of AIDS and HIV for a long time, and in some cases and in some locations, to this day. By the mid-80s, two research groups had identified different viruses that seemed to be associated with or responsible for cases of this mysterious condition, and it was eventually determined (in 1986) that they were actually the same virus, and that virus was designated HIV. HIV, short for Human Immunodeficiency Virus, is a retrovirus that, if left untreated, leads to Acquired Immunodeficiency Syndrome, or AIDS, in about 50% of patients within ten years of infection. So HIV is the virus, AIDS is a condition someone with HIV can develop after their immune system is severely damaged by the infection, and there are a bunch of diagnostic differentiations that determine when someone has transitioned from one category to the other, but in general folks with HIV will experience moderate flu- or mono-like symptoms, alongside swollen lymph nodes and rashes and throat problems and sores across their bodies in the early stages of infection, and as things progress, they develop opportunistic infections of the kind that can only really latch onto a human when their immune system is weakened or shut down. While AIDS, arriving after the immune system is well and truly damaged, brings with it a slew of opportunistic infections and associated issues, the afflicted person potentially developing all sorts of cancers, sarcomas, persistent infections, and extreme versions of the flu-like, mono-like symptoms they may have suffered earlier on. We don't know for certain how and where HIV originated—and that's true of both kinds, as there's an HIV-1 and HIV-2 virus, the former of which accounts for most infections, the latter of which is less common, and less overall infectious—but both HIV types seem to have been transmitted to humans from non-human primates somewhere in West-central Africa in the early 20th century, possibly from chimpanzees in southern Cameroon, but that's pretty speculative, and there's some evidence that these diseases may have made the leap several times; so while there's a pretty good chance, based on what we know now, that the disease made it into humans and mutated approximately somewhere in that vicinity, sometime in the early 20th century, possibly via chimps hunted and eaten by locals as bushmeat, we really don't know for certain. There are reports of what were probably HIV as far back as 1959 in the Belgian Congo, but that's a bit speculative, too, and based on imperfect notes from the time. Back then, though, and through the 1980s, folks who contracted HIV and who were not treated would typically die within 11 years of being infected, and more than half of those diagnosed with AIDS in the US from 1981 through 1992 died within 2 years of their diagnosis; such a diagnosis was a death sentence, basically; it was a really horrible and scary time. Today, the outlook for folks who contract HIV is substantially better: the life expectancy of someone who contracts the virus and who is able to get treatment is about the same as someone who is not infected; the disease isn't cured, but the level of HIV virus in the blood of a person receiving treatment is so small that it's no longer transmissible, or even detectable. What I'd like to talk about today is a new therapy that's making those sorts of outcomes possible, how some few people have now been cured of HIV entirely, and what's on the horizon in this space. — Antiretroviral therapy, or ART, typically consists of a combination of drugs based on those that were originally combined in this way in 1996 by researchers who announced their findings at the International AIDS Conference in Vancouver—they called their approach highly active antiretroviral therapy, or HAART, and this combo was based on findings from earlier drugs that addressed one of HIV's seven stages of development—but because they all hit that same, single stage, the virus was rapidly developing an immunity to them, and they were universally pretty toxic, with horrible side-effects. What's more, this drug cocktail increased patients' life expectancy by about 24 months, on average—which is a lot, about two years, but considering all those side effects, which included severe liver problems and anemia, the extra months of life generally weren't very pleasant extra months. In 1995, a class of drugs called protease inhibitors were introduced, which prevented HIV from making copies of itself using the body's structural proteins. That, combined with the effects of other, existing retrovirals, which hindered the virus's ability to hijack the body's cells to make more of itself, turned out to be a substantial improvement over just one or the other approach. The announcement in 1996 was notable because the researchers involved were able to knock the viral load in their patients down to an undetectable level, and then keep it there, by using three drugs from each of those two antiviral classes, those two different approaches. So HAART was a major improvement over what came before, but it was still imperfect; deaths tied to HIV plummeted by 50% in the US and Europe in just three years, but the life expectancy of folks using this therapy was still low compared to other people; someone who contracted HIV in their 20s and went on this therapy was still only expected to live till their early 50s; way better than a two-year increase, but still plenty of room for improvement. In addition to that lifespan duration limitation, the HAART bundle of therapies was just really difficult to maintain. Some people experienced a dramatic redistribution of body fat, some developed heart arrhythmias or insulin resistance or peripheral neuropathy or lactic acidosis—which is basically a toxic buildup of the acid that results from metabolism, which is usually cleared naturally, but when it doesn't, it's potentially deadly. Anything less than absolutely perfect adherence to the treatment schedule was also potentially deleterious to the desired outcomes; it wasn't a forgiving regimen, with some of the drugs requiring three capsules be taken every 8 hours, and there was a chance that if a portion of a dose of one drug was missed, or not administered on time, the virus could develop an immunity to it and the whole thing would fall apart. Consequently, the HAART regimen was generally reserved until things got really bad, and that meant it didn't have a very large effect on the infected population, and those who did benefit from it suffered consequences, alongside those benefits. The change in terminology from HAART to ART arrived in 2001 when a drug called Viread, the brand name for tenofovir disoproxil, was released and added into the mix, replacing some of the most toxic and cumbersome of the previous therapies with a single pill per day, and one that came with far fewer, and far less extreme, side effects. In 2005 it was finally demonstrable, with a bunch of data, that beginning this type of therapy early rather than waiting until things get really bad was worth the trade-offs—researchers showed that if folks received access to ART upon diagnosis, severe HIV associated and non HIV associated illnesses  were reduced by 61%. As of 2016 there was still an average life expectancy gap between folks with HIV who received early care and people who were not infected of about 8 years, but that gap has been steadily closing with the introduction of new, easier to use, less side effect prone drugs—drugs that tend to attack the virus at different stages, and which take different approaches to hindering and blocking it—alongside innovations in how the drugs are delivered, like introducing substances that are converted by the body into the desired drug, which massively cuts the requisite dosage, in turn lessening the strain on the body's organs and the potential side effects associated with taking a higher dose of the drug, itself. We've also seen the advent of fixed-dose combination drugs, which are exactly what they sound like: a single pill containing the entire combination of drugs one must take each day, which makes a combination therapy much easier to administration and stick with, which in turn has substantially reduced the risk of severe side effects, and prevented mutations that might otherwise make a patient's virus more immune to some component of the drug cocktail. Some newer options just use two drugs, too, compared to the previous three-or-more, and most of these have been shown to be just as effective as the earlier, more bodily stressful combinations, and a recent, 2021 drug is injectable, rather than deliverable in pill-form, and can be administered just once a month—though a version of this drug, sold under the name Cabenuva, has been approved for administration every other month. So things in this corner of the medical world are looking pretty good, due new approaches and innovations to existing therapy models. These models remain imperfect, but they're getting better every year, and contracting HIV is no longer a death sentence, nor does it mean you'll always be infectious, or even detectably infected: the amount of HIV virus in one's blood can be kept undetectably low for essentially one's entire life, so long as one is able to get on the right therapy or combination of therapies and stick with it. That said, the global HIV pandemic is far from over, and access to these drugs–many of which are pricy, if you don't have insurance that will cover them—is not equally distributed. As of late-2022, the UN's official numbers indicate that about 39 million people, globally, have HIV, about 1.3 million were infected in 2022, and about 630,000 died from AIDS-related illnesses that year. That said, of those 39 million or so who are infected, nearly 30 million are receiving some kind of antiretroviral therapy, and about 86% of people who are estimated to be infected know their status, so they can seek such therapies, and/or take other precautious to protect themselves and others; though that also means about 5.5 million people, globally, have HIV and don't realize it. Here's a really remarkable figure, though: among people who are infected and know they are infected, about 93% of them were virally suppressed as of 2022. That's astonishing; 93% of people who have HIV and are aware of it are on some kind of therapy that has allowed them to suppress the virus so that it's nearly undetectable—the difference between the two, by the way, is that suppressed means 200 copies of the HIV virus per milliliter of blood, while undetectable is generally considered to be less than 50 copies per milliliter. So huge leaps in a relatively short period of time, and a massive improvement in both duration and quality of life for folks who might otherwise suffer mightily, and then die early, because of this virus and its associated symptoms. That said, there are some interesting, new approaches to dealing with HIV on the horizon, and some of them might prove to be even more impactful than this current batch of incredibly impactful ART options. As of September 2023, five people have been confirmed cured of HIV; not suppressed and not with viral loads at undetectable levels: cured. The first of these cured people, often referred to as the Berlin Patient, received a stem cell transplant from a bone marrow donation database that contained a genetic mutation called CCR5 Delta 32, which makes those who have it essentially immune to HIV infection. Three months after he received the transplant and stopped taking ART, doctors were unable to find any trace of the virus in his blood. He died from cancer in 2020, but there didn't seem to be any HIV in his blood from when he received the stem cell transplant, onward, and that happened in the early 2000s, and was formally announced to the medical community in 2008. At least two other people—two that we know about, anyway—have been cured of HIV using the same method; though at the moment at least, this option is severely limited as it requires that patients have a bone marrow match in donor databases, and that one of those donors have that specific, relatively rare mutation; so with existing science and techniques, at least, this is unlikely to be a widespread solution to this problem—though a 2017 experiment used stem cells derived from umbilical cord blood from a baby with that mutation to treat a woman' leukemia and cure her HIV, so there's a chance other approaches that make use of the same basic concept might be developed, opening this up to more people. Cancer drugs may also help some people with HIV: a drug that's been approved to treat several cancers called Venetoclax seems to also bind to a protein that helps HIV-infected T cells dodge the body's immune system and survive, and that realization has led to a series of experiments that showed HIV was suppressed in mice receiving this drug—though it bounced back a week later, and two weeks later in mice receiving both this drug and ART. This is unlikely to be a solution unto itself, then, but there's a chance either an adjusted version of this drug, or this drug in combination with other therapies, might be effective; and there's a clinical trial testing the efficacy of Venetoclax in human HIV patients at the end of this year, and another in 2024, so we may soon know if its safe and desirable to use this drug alongside ART, and that may, in turn, lead to a better understanding of how to amplify the drug's effects, or apply this method of hindering HIV from a different angle. CRISPR, the gene-editing technology borrowed from bacteria that allows for the cutting and removing and adding of genetic information, has enabled the development of several new potential HIV cures, one of which, called EBT-101, basically enters the body, finds helper T cells, and then cuts out chunks of the HIV virus's DNA, which prevents it from being able to replicate itself or hide away, reemerging later after another treatment has suppressed it. The benefit of this approach is that it could kill the viral reservoirs that otherwise allow HIV to persist in people who have undergone treatments, and a version of it that targets SIV, which is similar to HIV, but found in non-human primates—performed exactly as they hoped it would, finding and editing the targeted DNA, raising hopes than an HIV-targeting variation may manage similar wonders in human patients. This would be great if it ends up working, as one injection would theoretically clear all HIV from a person's system in relatively short-order, but the trials done so far have been small and on monkeys, and because of the nature of the research, it's not clear the monkeys were cured of HIV—just that the treatment got where it was supposed to go and made some DNA edits. A human trial of EBT-101 will finish up in March of 2025, though the researchers plan to follow up with their subjects for up to 15 years following the trial, to assess any long-term effects from their treatment, since CRISPR and this approach to messing with genes is still such a new thing. So while this may be a solution at some point, there's a good chance it won't be a real-deal, available option for another decade, minimum. So we've come a long way in a very short period of time with HIV and AIDS treatments, and the future is looking pretty good, with even more options and approaches on the horizon, including some actual cures, alongside high-quality, actually useable treatments. But there's still room to grow in terms of infection awareness, there are still distribution issues for some of these drugs, and there's still a fair bit of prejudice, the consequence of ignorance and historical misunderstandings and biases, keeping folks and institutions from doing as much as they otherwise could in many parts of the world; so a lot to be proud of, a lot to look forward to, but still plenty of room for improvement across the board.

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