As a baby boomer (barely), I have had to adjust to living in a world where the spigots of information I grew up with have been replaced by nearly an infinite number of pipelines constantly releasing torrents of data, propaganda, wisdom, falsehoods, and advice. In medicine, it is no different (feel free to head nod).
William Carlos Williams once wistfully supposed that while cleaning out his old bottles of gram stains, polishing the instruments, and growing a decent beard for a "cultivated look," he really should get around to putting his journals "on edge instead of letting them lie flat in heaps -- then begin ten years back and gradually read them to date, cataloguing important articles for ready reference." Even back then it was hard to keep up. Now, the poet-physician would be lamenting not just his unread articles but also neglected inbox messages, tweets, and post-conference podcasts.
With so much to know and only so many decades of human life, filters must be applied. Those who excite in the potential and the prospect of future breakthroughs can be fed whatever floats their cutting-edge boat. Others, of a more practical mien, will have an appetite for that which will help them in the practice of their art. It is with the latter that these top 10 stories in clinical HIV medicine are simpatico.
Will a given development in HIV make a difference in the clinic? How will this change practice? Is this something I should know if I take care of people living with HIV? The answer to each of these must be yes for the story to be a Top 10. Thus, here you will find data on the emerging side effect of weight gain, ever-simplified HIV therapies, and new drugs that you will eventually prescribe. Intriguing ounces of prevention for HIV and other sexually transmitted infections (STI) are worth not just pounds of cure, but are also worth mentioning, and so they are. Oh, and lastly, someone has a plan to eliminate HIV. I'll talk about that, too.
#1: Clarity on the Role of Integrase Inhibitors in Weight Gain
"Can this stuff make you gain weight?" Meg, a 48-year-old woman, asked as she plopped down into a seat after being checked in by the nurse.
A few months before, in late 2018, I had finally convinced Meg to switch from the lopinavir/ritonavir (Kaletra) she had been on for over a decade in favor of the integrase inhibitor dolutegravir (Tivicay) plus emtricitabine/tenofovir alafenamide (F/TAF, Descovy). It was not an easy sell to a long-term survivor who credited her regimen with saving her life, but my warnings of potential drug interactions and my "It will only be two tiny pills!" pitch wore down her reluctance. A supervisor at a nursing home and mother to two teens, Meg at first appreciated the convenience of her new meds. I smiled and did the "told you so" thing at our first post-switch follow-up.
But then the scales tipped -- literally. She wanted to know if I was responsible for the 23 lb. weight gain that ruined her waistline. And I had to admit: I was.
#2: A Renaissance for Two-Drug Antiretroviral Regimens
The GEMINI trials earned respect for the combination of dolutegravir (DTG, Tivicay) plus lamivudine (3TC, Epivir). At 96 weeks, this dual-therapy regimen remained non-inferior to dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF, Truvada) when taken as a first-line regimen, with no emergent drug resistance detected during study follow-up. That's longer-term data that would normally be worthy of Top 10 status.
But in the U.S., the real potential for 3TC/DTG -- which was approved by the U.S. Food and Drug Administration in April under the brand name Dovato -- is in maintenance, not first-line treatment. That's because, although getting a person's viral load suppressed is a taller order than keeping it that way, a switch study is arguably more relevant to us clinically as new diagnoses drop.
#3: PrEP Gets a Second Option
Where once there was just one blue PrEP pill, now there are two. In October 2019, the U.S. Food and Drug Administration (FDA) approved emtricitabine/tenofovir alafenamide (FTC/TAF, Descovy) as PrEP for those at risk of acquiring HIV-1 by any route other than vaginal sex. (We will get to that last part in a second.) The approval comes seven years after emtricitabine/tenofovir disoproxil fumarate (FTC/TDF, Truvada) became the first PrEP drug.
Expanded access to PrEP is necessary and while toxicity concerns are only one of many reasons some defer or drop PrEP, a safer way to deliver tenofovir can only help. Yet, advances in medicinal chemistry, including long-acting PrEP formulations, are only part of the solution to the problem of getting more people at risk of HIV infection on PrEP.
#4: A Clearer Picture on Dolutegravir and Pregnancy
A lot of pregnancies in Botswana were anxiously followed after results from the Tsepamo study were revealed in late 2018. At that time, the researchers leading Tsepamo, a large observational study of pregnant Botswanan women, reported a higher rate of neural tube defects in women living with HIV who were being treated with dolutegravir at the time of conception relative to women treated with other HIV meds.
In acknowledgement that the high rate of defects seen in the dolutegravir-during-conception group could have been a fluke, the investigators worked to expand the cohort by adding 10 additional hospitals to the original eight, effectively covering almost three quarters of all live births in the nation.
The updated Tsepamo results provided a medium-sized sigh of relief.
#5: The Imminent Arrival of Long-Acting Antiretroviral Therapy
Injectable cabotegravir (CAB) and rilpivirine (RPV) will certainly make the 2020 edition of our Top 10 list. Anticipated to be available early next year, a guaranteed big story will be how smoothly the rollout of this long-acting HIV therapy will be.
The launch of CAB/RPV will be interesting. Incorporating monthly injections into clinic operations will require some major adjustments in the way HIV therapy is delivered, even if it's administered to a minority of patients who both desire and are eligible for this new combination.
#6: Islatravir Is Coming. But What Will It Be?
Islatravir (formerly MK-8591 and, before that, EFdA) is an NRTTI. That is not a typo: It is a nucleoside reverse transcriptase translocation inhibitor, an adenosine analogue with a novel one-two punch mechanism that confers a very high barrier to resistance. It is also really potent in miniscule amounts for long periods of time.
This is clearly an antiretroviral not built for daily administration. But then what is it destined for? Is it only to be Starsky to doravirine's Hutch? Or will islatravir become a once-weekly oral med without an obvious dance partner? Data have been presented on its potential as an implantable for long-term treatment or prevention. Is that where this is headed? Is the answer all of the above?
#7: What DAWNING Teaches Us About Integrase, Protease, and Drug Resistance
The DAWNING study may be one of the most significant recent clinical trials that you have probably never heard of. This may be because the trial was conducted mostly in resource-limited countries, leading to it not getting as much interest in the U.S. as it deserved. Or it could be that the study's message was hard to hear above the din of the other integrase inhibitor studies I've covered in this year's Top 10.
Understanding the ramifications (or lack thereof) of prior resistance mutations can help us craft regimens that are not excessive. Certainly, when we use a newer integrase inhibitor or boosted protease inhibitor with a higher barrier to resistance, the M184V/I mutation will not be too concerning -- and DAWNING suggests that even when thymidine analog-associated mutations are present, we should not get overly concerned.
#8: Can Doxycycline Be the PrEP of STIs?
Rates of bacterial STIs in the U.S. have been climbing, especially for men who have sex with men (MSM). This trend pre-dates PrE), but as PrEP uptake has increased -- perhaps leading to more screenings for gonorrhea, chlamydia, and syphilis -- numbers have risen even more sharply. While we now have PrEP and post-exposure prophylaxis (PEP) as biomedical interventions for HIV, the same cannot be said for bacterial STIs, despite their being around much longer and being considerably more prevalent.
Doxycycline has been toyed with as a potential STI prophylaxis. As an infectious diseases specialist, I get why chronic usage of antibiotics can be problematic. However, I am also aware that we prescribe antibiotics all the time, whether it is for prophylaxis of opportunistic infections in immunocompromised people (e.g., those with advanced HIV infection, transplant recipients, people on chronic immunosuppressant therapy) or less dangerous situations such as acne. Would post-coital doxycycline make it any worse?
#9: The New Realities of Suicide and HIV
Sadly, life expectancy in the U.S. is in a decline. This is an amazing statistic given the advances in medicine we have achieved and the abundance of resources in this nation. However, driving the recent downward trend in this indicator of national well-being is not an infectious disease or cancer, but drug overdoses and suicide -- especially among white men and people in rural areas.
For people living with HIV infection, the same seems to hold.
These sobering data make clear that in the clinic, depression screening is as important as STI screening. Writ large, though, the increase in suicide and drug overdoses shows us clearly what is not going so great in America. These are statistics of despair and hopelessness, but also of threadbare resources in places of greatest need; the broken mental health system; and the consequences of a health care industry that considers medical care a commodity rather than a basic human right.
#10: Is the "Ending the HIV Epidemic" Plan For Real?
The attention of this specific U.S. president on HIV is curious. However, while it may be initially disorienting, it makes sense. Rates of new HIV diagnoses have already been declining overall, and supporting this trend is both good policy and good politics. Further, the tools to stem new infections are already at hand, including pre-exposure prophylaxis (PrEP) and treatment as prevention (a.k.a. undetectable equals untransmittable, or U=U), both of which are centerpieces of the EtE plan.
This is all encouraging. However, much remains to be seen regarding the support for interventions that are evidence-based but may be unsavory to key figures in the administration, such as syringe exchange and sexual education.
Epilogue: Remembering an Indelible Person
In 2019, HIV clinician, HIV clinical scientist, and human rights advocate Charles van der Horst, M.D., died. He was 67. He lost his life on the last leg of a grueling multi-day swim race in New York's Hudson River, which he was doing because being an HIV clinician, HIV clinical scientist, and human rights advocate was not enough, so he was also a master competitive swimmer.
Much of what has been written about Charlie since his death paints his passions in broad strokes, providing an outline of this complex and large-living man. For the fine details, each of us who knew him can easily fill in with their own stories, which are colorful and often profound.