What’s the deal with the Food and Drug Administration (FDA) approving Descovy as a new HIV prevention pill, except for “receptive vaginal sex”?
First of all, that’s a nice way of acknowledging that some transmen still have a vagina. Or, as many prefer, “front hole” (sounds less feminine that way).
But it also says other things. For one, there is evidence that the way the drug affects the vagina might matter.
And for another, in the words of the FDA, that “Descovy is not indicated in individuals at risk of HIV infection from receptive vaginal sex because the effectiveness in this population has not been evaluated.”
For now, there’s a highly effective and safe HIV prevention drug already available that does cover vaginas—Truvada. Descovy for PrEP (pre-exposure prophylaxis, or prevention) was only studied in cisgender men who have sex with men (MSM) and transgender women.
To a great extent, the vaginal exclusion points to a problem across different medical conditions: research is being conducted mostly in cisgender men.
It also points to issues surrounding the extrapolation of research laboratory measures.
In the final analysis, everyone from the activist community to the FDA agrees that both medications now on the market for preventing HIV are effective (except for that one exclusion) and generally safe.
Oh, and research for cisgender women and adolescent girls is underway to help determine vaginal protection with Descovy.
“It is not new that cisgender women are greatly overlooked when it comes to HIV prevention research, and frankly, for most sexual and reproductive justice matters,” said Dázon Dixon Diallo, founder and CEO of SisterLove, in Atlanta, in a press release about the agency’s 30th anniversary gala in October. “We look forward to working with Gilead [maker of Truvada and Descovy] to conduct these trials in important locales, and in accordance with the needs and desires of populations of cisgender women in all our diversities.”
At press time, SisterLove was set to convene a meeting in early December at the International Conference on AIDS and STIs in Africa (ICASA 2019) in Kigali, Rwanda, to provide the company with a set of recommendations and expectations going forward.
Two PrEP studies of cisgender women found much lower levels of tenofovir in their vaginal tissue compared to the levels (concentrations) in their rectal tissue.
The test tube vs. the body
Monica Gandhi, MD, MPH, told parts of the story behind Truvada and Descovy for prevention in a webinar held by community advocates in October just a couple of weeks after Descovy received FDA approval for PrEP. Dr. Gandhi is director of the Center for AIDS Research as well as the Ward 86 HIV Clinic, both part of the University of California, San Francisco.
She pointed out how measurements of drug levels in the body taken during a study may indicate something that turns out not to be the case in real life.
Although Descovy is a newer version of Truvada, they operate differently. Both drugs started out as HIV treatment before being studied and approved for HIV PrEP.
One of the differences between Descovy and Truvada is drug levels in the body. This is because the tenofovir in each drug works and is absorbed differently. Descovy contains tenofovir alafenamide (TAF), and Truvada contains tenofovir disoproxil fumarate (TDF); both contain a second drug, emtricitabine (FTC).
So, how about genital levels? For prevention of a sexually transmitted infection like HIV, researchers wanted to see how a medication works in what they clinically call “genital compartments.”
Two PrEP studies of cisgender women found much lower levels of tenofovir in their vaginal tissue compared to the levels (concentrations) in their rectal tissue. This suggested that PrEP might not be as effective for vaginal sex. That, plus actual disappointing results indicating ineffectiveness, led to a concern about PrEP for this “compartment.”
One idea arising from the different studies of Truvada and Descovy was that maybe men only need to take PrEP four times a week, while women need perfect adherence, taking a PrEP pill every day.
But then, at the International AIDS Conference in Mexico City last July, two demonstration studies of cisgender women reported effectiveness in the real world without perfect adherence, said Dr. Gandhi.
How did that good news happen?
Pharmacokinetics vs. pharmacodynamics (or, the test tube vs. the body)
The contradiction started with two studies that looked at Truvada PrEP for cisgender women, FEM-PrEP and VOICE, Dr. Gandhi said.
Unlike other PrEP studies that also had thousands of participants but which found Truvada was effective in preventing HIV in cisgender women (Partners PrEP, TDF2, and the Bangkok FTV Study), FEM-PrEP and VOICE were stopped because they weren’t going to be able to show a high level of protection against HIV.
“It was surprising when FEM-PrEP and VOICE closed early,” said Dr. Gandhi.
To help figure out what went wrong, the studies compared self-reports of drug adherence to actual blood levels of the drug, which would suggest just how adherent participants actually were.
The women reported high levels of adherence, saying they took more than 90% of their Truvada doses. The drug levels in their blood samples, however, were low, indicating that adherence was actually less than 30%.
Then it was found that the tenofovir (TFV) levels from Truvada were 30 times higher in rectal tissue of the cisgender women compared to the levels found in their vaginal tissue.
There was an even greater difference in the level of tenofovir diphosphate (TFV-DP), the active metabolite of tenofovir. Let’s just say that an interesting thing about TFV-DP is that it indicates the level of drug adherence over several weeks. You can’t just pop a pill before going in to get blood drawn to show that you’ve been taking your meds.
So, for TFV-DP (drumroll, please): the level in the rectal tissue was 120 times higher than in the vaginal tissue.
Researchers then arrived at a logical question. They already knew that cisgender men were being protected against HIV by taking Truvada only four days a week. (The FDA-approved PrEP dose is one pill a day.) Given the discrepancy in genital tissue and the disappointing lack of protection in FEM-PrEP and VOICE, might cisgender women need better drug adherence to PrEP to achieve prevention against HIV?
Maybe not. The two PrEP demonstration studies in cisgender women reported in Mexico City (HPTN 082 and the 3P study) found high levels of HIV prevention with—surprise—drug levels indicating four Truvada doses a week.
This continued a question raised by PrEP research over the years—how much do genital drug levels matter? The answer remains uncertain.
The doctor explains
It’s a case of findings in the lab (pharmacokinetics) vs. findings in real bodies (pharmacodynamics), Dr. Gandhi said.
“It was a combination of those surprising findings of FEM-PrEP and VOICE and the pharmacokinetic data that led to a relatively long period of time where we have the dogma that women had to take higher frequency of TDF/FTC [Truvada] doses than men,” said Dr. Gandhi. “And so, that idea that there were lower levels of tenofovir in the cervical/vaginal tract compared to the rectal tract led to a modeling study that said probably women need higher doses, and higher number of doses, of TDF/FTC than men do for the same amount of efficacy. And modeling in the iPrEX OLE study showed, for men at least, that probably four doses a week was okay for PrEP efficacy. And the relative dogma was that women needed seven doses per week for efficacy—full daily adherence—for this to work.”
Instead, “It’s when you study a drug in trials or in real life or in demonstration projects—that’s when you get closer to the truth than some of our [mathematical] models.
“There was very high PrEP uptake in HPTN 082 and, very importantly, very low incidence of HIV despite the fact that women were taking around four doses a week. At three, six, and 12 months, there are low levels of tenofovir diphosphate [as measured] in dried blood spots, but importantly, there were very few seroconverters,” she said.
Blood levels and vaginal tissue concentrations are just two of the many differences that surround Truvada vs. Descovy for PrEP.
“The same finding occurred in the 3P study … high-risk young population with STIs and partners suspected of having other partners. And again, the PrEP adherence as assessed by tenofovir diphosphate concentrations in dried blood spots was not seven doses a week. It was more like four doses a week. And importantly, there were no HIV seroconversions here as well,” she said. “And I’m building this argument because, again, the studies were not done with TAF/FTC [Descovy], but maybe we need the host [human] studies before we extrapolate from pharmacokinetic data.” There was one seroconversion in 3P.
“Any extrapolation that we want to make for women or men from the pharmacokinetics for TAF and FTC vs. TDF/FTC may not tell us what eventually happens in the real world with men and women, just like those two demonstration projects told us different things from the pharmacokinetics and what happened in demonstration projects,” said Dr. Gandhi. “And it is important to say that women are still underrepresented in clinical trials.”
There are many ways to compare PrEP using either Truvada or Descovy. Like cost issues, side effects, and pharmacological workings (fentamoles, anyone?).
Blood levels and vaginal tissue concentrations are just two of the many differences that surround Truvada vs. Descovy for PrEP. Descovy is now being put to the test for vaginal protection against HIV—in real bodies. In the meantime, there’s protection with Truvada.
And hey, Truvada may avoid the weight gain suspected of HIV treatment containing Descovy.
But that’s another story out of the many involved.
“What we have shown is that women can be enrolled in clinical trials,” said Dawn Averitt, founder of The Well Project, an organization focusing on women and HIV.
Dr. Gandhi walks you through her slides in the recorded webinar from AVAC, the Treatment Action Group (TAG), The Well Project, and the Women’s Research Initiative (WRI) at avac.org/event/webinar-advocates-debrief-science-daily-ftaf-vs-tdfftc-prep. Read the FDA briefing document of August 7, 2019 that includes a discussion of tenofovir levels throughout the body at fda.gov/media/129607. Read a comprehensive and powerful essay on PrEP research, “Where were the Women? Gender Parity in Clinical Trials” by Robert H. Goldstein, MD, PhD, and Rochelle P. Walensky, MD, MPH, published online October 30 in the New England Journal of Medicine: nejm.org/doi/full/10.1056/NEJMp1913547.
Kidney and bone safety
The side effects of most concern with tenofovir have been the potential for bone and kidney toxicities. (That’s in addition to the potential for a hepatitis B reactivation upon stopping medication—it’s important to know your hep B status before starting.)
The DISCOVER study that brought Descovy to market for PrEP showed an increased eGFR (a marker for, or sign of, kidney dysfunction) for Descovy compared to a decreased eGFR for Truvada. The lower the eGFR, the worse the kidney functioning is.
At one year, the median change in eGFR was an increase of 1.8 mL/min for people on Descovy and a decrease of 2.3 for those on Truvada (a 4.1 mL/min difference).
The long-term clinical significance of changes in eGFR, however, is not known.
There was a greater difference for people who started the study with Truvada but switched to Descovy when they were allowed to in the trial (after one year in the study). The increase was 3.9 for those who switched to Descovy vs. a decrease of 0.6 for those staying on Truvada (a 4.1 mL/min difference).
There was also a difference between the two PrEP drugs in terms of bone mineral density (BMD). From baseline to one year, there was an increase of 0.5% in lumbar spine measurement for Descovy vs. a 1.1% decrease for Truvada. There was an increase of 0.2% in hip BMD with Descovy vs. a 1.0 decrease for Truvada.
Again, the long-term clinical significance is unknown.
“It’s not a claim that something was safer, but there was significantly less impact on BMD. This is what we saw,” said Calita Mathole, the senior community liaison in the Chicago area for Gilead Sciences, the maker of both drugs, in a presentation for the staff of TPAN, publisher of Positively Aware. “I wouldn’t say safer on kidneys,” she added.
The Gilead slides do note, however, that individuals under 25 years of age are still experiencing bone growth. Meaning, you wouldn’t want to risk harming that growth.
The medical take
For HIV treatment, Descovy is approved for people with greater kidney dysfunction (CrCl less than 30) compared to Truvada (CrCl less than 50). In fact, Descovy recently received an indication from the U.S. Food and Drug Administration (FDA) for use in dialysis patients with a CrCL under 15.
Gilead has to exercise caution in not overplaying a safety card for Descovy. That’s been a bone of contention for activists, some of whom have heard evidence to the contrary.
For medical providers, however, the differences are important to weigh for their patients.
“TAF [in Descovy] is considered safer than TDF [in Truvada] for renal and bone safety,” said Eric Farmer, PharmD, HIV clinical pharmacist at the Indiana University Health LifeCare Clinic at Methodist Hospital in Indianapolis. “The net safety difference depends on the patient. If you have a 16-year-old male whose bones are still developing, then perhaps it is better to go with TAF vs. TDF so you don’t have any inhibitory effect on bone growth. If you have a 60-year-old male who has fallen and broken a hip before, TAF is likely safer again because of the lack of effect on bone.
“If a 50-year-old man with diabetes has an eGFR of 50 mL/min and you put him on Truvada and decrease his eGFR to 40 mL/min, this is clinically significant because you decreased the eGFR by 20%,” he said. “Versus if you put a 25-year-old patient with an eGFR of more than 120 mL/min on Truvada and it decreases the eGFR by 10 mL/min to 110 mL/min, the percent change is much smaller—8%—and much less clinically significant.
“My professional opinion is there is indeed a safety difference that is demonstrated in clinical studies between TAF and TDF, but that difference may not be large enough or clinically significant enough to justify using TAF in every single patient,” said Dr. Farmer. “Some patients can use TDF safely.”