Benefits of HPV Vaccination; Contraindications to Newer Obesity Drugs

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include reducing the dose of pneumococcal vaccine, benefits of human papillomavirus (HPV) vaccination, treatment of metastatic colorectal cancer, and suitability for treatment with obesity drugs.

Program notes:

0:36 Obesity drugs and contraindications

1:36 Who would be excluded in trials to evaluate?

2:36 Hard to keep all in mind when prescribing

3:20 Cervical cancer mortality in those 25 or younger

4:20 Reduction in death after HPV vaccination

5:27 Pneumococcal vaccination

6:27 Can we fractionate the dose and remain effective

7:27 Don’t know if lower dose is durable

8:28 Done in healthy infants

8:48 Combination therapy for one form of colorectal cancer

9:48 Dual immunotherapy

10:50 Outcome bad with chemotherapy

11:30 There are side effects

12:23 End

Transcript:

Elizabeth: Success with treating metastatic colorectal cancer.

Rick: If we reduce the vaccine dose to save money, is it still effective?

Elizabeth: Cervical cancer rates among young women in the United States.

Rick: And weight loss medications, are they for everybody?

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, I would like to turn first to JAMA Internal Medicine interestingly because, gosh, if I hear one more thing about all of these medicines for weight loss, I’m not sure I’m going to be able to integrate that. Let’s talk about this.

Rick: Are these weight-loss medications for everybody? Even though the FDA has made these available — GLP-1 receptor agonists, things like liraglutide [Saxenda] and semaglutide [Wegovy], and then a combination weight-loss medicine that includes that plus another receptor agonist called tirzepatide [Zepbound], so these three agents — however, they don’t restrict these populations specifically to the ones that were in the trials that tested these. There are people that aren’t in the trial and the thought is that when the FDA finally approves the medication they’ll approve it for those individuals in whom it was studied and they’ll exclude it in those individuals who weren’t a part of the study. Because those that weren’t, we don’t know whether it’s safe and effective.

When we look across the United States, what percentage of individuals who are eligible for these would be excluded in the previous trials that examined them? Overall, about a third of the patients that are currently eligible because they are overweight weren’t even included in these studies. The major exclusion criteria were people who had a major depressive disorder, malignant neoplasms, liver disease, uncontrolled hypertension. Those are the most common exclusion criteria. About a third of the patients that we’re currently giving these medications to weren’t involved in any of these trials.

Even more alarming, about a fourth of the patients who receive this combined agonist actually are on a medication that inhibits gastrointestinal motility. It slows it down. That increases the risk of a side effect with this particular medication. The overall thing is when a clinician is considering prescribing these medications in these unstudied populations, they should screen for these things I talked about.

Elizabeth: I guess I’m a little pessimistic about the ability of someone who is prescribing these things to really assess all of those things and include them in their assessment before the prescription, particularly in view of if your patient comes and says, “Look, it’s clear that I have got this obesity issue and I’d like to try these things.” I think it’s hard to push back against that. Then I would also say that I’m hoping that maybe pharmacists can step into this a little bit, because they would certainly note that these other things were in play, at least some of them.

Rick: Yes, and especially if someone is on a medication that slows gastrointestinal motility. But when the clinician is seeing a patient that has one or more of these disorders, especially like liver disease, or these medications I mentioned, they should at least discuss it with the patient and let the patient be a part of that decision-making process. These are individuals that probably should be followed a little bit more closely.

Elizabeth: Okay. That was a research letter. Let’s stick with the research letters and turn to JAMA. This is one that’s looking at cervical cancer mortality among U.S. women who are younger than 25 years of age and the relationship between that mortality and HPV vaccination.

This HPV vaccination has been recommended for routine use in U.S. women since June 2006. Studies from 2022 and 2023 indicate that there is a 12% per year decline, a 65% overall reduction in cervical cancer incidents during 2012 to 2019. Among those women younger than 25 years, there were 398 cervical cancer deaths reported in that time period from 1992 to 2021. Of course, we wouldn’t expect women to really develop cervical cancer and then to have such a fulminant case that they would die of it because they are so young. It’s a rather small number. When you overlay the HPV vaccination into this, you still see that there is that decrease, an overall 62% reduction.

We have also seen, unfortunately, that there are reductions in people getting these routine vaccinations and this is one of them. I think it would be really great to put this together with data that we have discussed from Scotland that show that they have seen exactly the same dramatic decrease, to try to increase the uptake of these vaccines.

Rick: As you mentioned, the absolute numbers are small, but you don’t expect somebody under the age of 25 to have cervical cancer and to die from it. That’s pretty sobering. But what this does is it connects the dots and here are the dots. HPV vaccination results in a decline in HPV infection, it decreases cervical cancer incidence, and that results in less cervical cancer mortality. This is in individuals under the age of 25. The other data you’ve referred to is people that are older, in which, again, HPV vaccination decreases the incidence of infection, cervical cancer, and cervical cancer mortality.

Elizabeth: Definitive. From there, let’s turn to the New England Journal of Medicine.

Rick: Elizabeth, we just finished talking about HPV vaccination. Let’s talk about vaccination to prevent pneumococcal pneumonia and pneumococcal sepsis.

This is a vaccine that’s routinely recommended, especially in individuals over the age of 50, those who are immunosuppressed, and are more likely to either get infected or have a complication. There are primarily two vaccines that are used around the world. One is called a 10-valent and the other is a 13-valent. It covers different types of pneumococcal bacteria and they have been shown to be effective. The difficulty is, of all the vaccines we have, they are among the most expensive. The cost is $2 to $3.30 per dose and they are usually three-dose vaccines, so they are expensive.

Now, currently Gavi, the Vaccine Alliance, has funded the pneumococcal vaccines in 47 low- and middle-income countries. However, that’s going to stop. The concern is, well, they are not going to be able to afford them. What this study did was, they said let’s take both of those vaccines and let’s give a lower amount. Let’s give either 20% of the vaccine or 40%, and we can do it in different booster and primary vaccines. We give two doses or three doses. Again, the whole intent is to give less so it’s less expensive, but still effective.

There were seven different study groups. I won’t go through all of the different doses. But what they did discover is if you give the 13-valent vaccine at only 40% of the current dose, it’s effective. All of the other combinations were really not effective. This will lower the cost substantially. For example, in a country that gives it, typically there would be about $9 million. It reduces the cost to about $5 million, assuming at the current cost, and that can vaccinate about 1.5 million children. This is good news.

Now, here is what we don’t know, Elizabeth. When we say it’s effective at that lower dose, we are measuring the antibody response immediately after the vaccine is given. But as you know, this vaccine is intended to last for 5 or 10 years. We don’t know whether that lower dose will be as long-lived. At least the immediate response looks good, but whether it’s as long-lived as the full dose is really unknown at this particular time.

Elizabeth: Well, this study clearly begs the question for me about dosages of vaccines and whether we might take an approach of investigating all vaccines to see what is the minimum effective dose.

Rick: I’d say the ones that we want to really target are those of the highest cost. If a vaccine costs pennies, it’s not going to pay very much to do the studies to say we can lower the dose and save more vaccine. In higher-cost vaccines like this, getting the lowest effective dose, for the least cost and still the most benefit, is what we ought to be doing.

Elizabeth: I guess I would also reflect on the fact that we know that in flu vaccines, for example, as people age, not only aren’t they going to respond to less, they actually, in point of fact, need more in order to elicit an effective and protective immune response. That’s another thing I would examine using this vaccine.

Rick: Yep. Absolutely. I should have mentioned, by the way, this study was done in healthy infants in Kenya. This, again, is a younger population and I don’t want to imply that this applies to an older population. As you mentioned, they may need a higher dose, but at least in infants a smaller dose appears to be just as effective immunologically.

Elizabeth: And it may result in fewer side effects, which would be great. Remaining in the New England Journal then, taking a look at a combination therapy for what’s called microsatellite instability-high metastatic colorectal cancer.

Colorectal cancer, as we know, is increasing particularly among young adults in the United States and worldwide. Trying to figure out ways to deal with it, I think, is really important. In this case, these are two different things that happen to the genome in this metastatic colorectal cancer and it’s associated with poor outcomes with standard chemotherapy with or without targeted therapies.

They used a combination of two different immune checkpoint inhibitors, nivolumab [Opdivo] and ipilimumab [Yervoy]. This has previously shown clinical benefit in non-randomized studies of both of these types of metastatic colorectal cancer. Their patients here were 303 patients who had not previously received systemic treatment for metastatic disease and they were randomly assigned to receive either this combination of nivolumab plus ipilimumab, chemotherapy, or nivolumab alone. They had a median follow-up of almost 32 months and they were looking at progression-free survival outcomes.

In the group that received the combination, that was 72% — and in this study they don’t include that single-agent group, they only compare it with chemotherapy — and in this case that survival was only 14%. It seems pretty clear that this combination is the way to go in folks who have this particular type of colorectal cancer.

Rick: This accounts for about 4% to 7% of metastatic colorectal cancer cases that have this particular DNA repair defect. Our DNA constantly undergoes revisions and has defects, but our body can actually repair it so we maintain normal DNA replication, normal cells, and we don’t get cancerous cells. But for individuals that can’t repair their DNA, the cells can grow autonomously and that’s what cancer cells are. The outcome is bad, even with standard chemotherapy.

Think about it, a 14% survival over the course of 24 months. This combination, immune checkpoint therapy, they’re complementary pathways that these two drugs hit and it improves survival to 72%. That is absolutely remarkable. They have fewer side effects than giving chemotherapy.

Elizabeth: Although I would also note that 16% of the patients in the nivolumab/ipilimumab group and 32% of the patients in the chemotherapy group ended up with treatment-related adverse events that led to discontinuation. It’s still not a free lunch. There are things that are associated with this that are troubling.

Rick: It’s not a free lunch, but it’s a better lunch than the chemotherapy, both in terms of how effective it is and with fewer side effects.

Elizabeth: No question about that. Then I would also note that those folks who present — these were all treatment-naive people — already had this really troubling outcome on the horizon, so being able to offer hope to that subgroup of patients I think is just really important.

Rick: Absolutely. Colorectal cancer ends up being I think the third most common cancer and I think the second most common in terms of deaths.

Elizabeth: On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.