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For a Physician’s Weekly Podcast episode, we covered two major players in the field of preventive medicine: primary prevention of HIV and secondary, post-prostatectomy prevention of prostate cancer.
We spoke with Rachel Baggaley, MBBS, MSc, the team lead for testing, prevention, and populations in the Global HIV, Hepatitis and STI Programs at the WHO about her recently published papers in Lancet HIV and BMJ. In her Lancet HIV paper, Baggaley and colleagues note that “scaling up access to PrEP cannot be achieved by medical doctors alone, and nurse-led PrEP delivery can help to lay the groundwork for supporting uptake of other HIV prevention approaches that will become available in the future.” Baggaley and team concluded in their BMJ study that “Provision of PrEP through pharmacies has been demonstrated to be feasible in the USA and acceptable to potential end users and stakeholders in multiple settings.”
We also spoke with Alan Pollack, MD, PhD, Chair and Professor of Radiation Oncology at the University of Miami’s Sylvester Comprehensive Cancer Center. He talks us through his recently published trial in The Lancet about a new intervention for secondary prevention of prostate cancer after prostatectomy. In that paper, Dr. Pollack and colleagues found that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term androgen-deprivation therapy results in meaningful reductions in progression after prostatectomy in patients with prostate cancer.
inDEPTH Perspectives from Our Contributors
Patient Demographics: At Risk for HIV - Rachel Baggaley, MBBS, MSc
During the past 4 or 5 years, WHO has assessed HIV prevention alongside viral hepatitis and STIs. Looking across populations, many who are vulnerable to HIV or who have HIV are also vulnerable to or have STIs. For viral hepatitis, it’s much more of a mixed picture, because the epidemiology of viral hepatitis (B and C) is very different in populations and across geographies. For example, the prevalence and incidence of hepatitis C is high among people who inject drugs and also in some men who have sex with men (MSM). Hepatitis B is much more geographically focused in some areas so we focus on areas that have high hepatitis B prevalence; also key is prevention of mother to child transmission.
Pre-exposure prophylaxis (PrEP) for some of these viruses is an exciting field. The first trial, iPrEx, was among MSM, and when the results came out in about 2011, WHO reacted quickly and developed guidelines on implementation science to push for PrEP utilization for communities other than MSM. As more information and results became available from other populations, we were able to make broader recommendations.
The oral PrEP recommendations from WHO for anyone who’s at substantial HIV risk were released in about 2015, and there’s been a rapid scale up of countries that have adopted oral PrEP guidance since then and a gradual increase in people accessing oral PrEP. For oral PrEP, we are now thinking of different ways to deliver it so that people have much more choice about where they might have services, which was accelerated through COVID; when people couldn’t go to clinics, we had to be much more flexible about delivering PrEP, including via online services with community pickup and self-testing, because people on PrEP should test for HIV every 3 months and self-testing can help decrease clinical contact. In July, WHO released Differentiated and Simplified Prep Delivery, which includes examples of how to make PrEP more available in communities. There are also exciting projects starting to deliver PrEP through pharmacies, again with self-testing and making it a much more normalized approach to HIV prevention. We’ve also learned that PrEP is not for life and we have to be flexible about how people want to use it. People can start and stop and restart. As long as they have all the information about how to test for HIV, this can fit very much into people’s lives. For men, we recommend also offering event-driven PrEP: take two tablets before sex, one tablet right after, and one 12 hours after that.
The long-acting cabotegravir, an intermuscular injection every 8 weeks, had two big trials—HPTN 083 among MSM men and transgender women and HPTN 084 among women in Eastern Southern Africa—with stunning results with a daily or event-driven appeal. The dapivirine vaginal ring is another option for women. The ring is impregnated with dapivirine, which is released slowly over a month. It’s difficult to establish the exact efficacy of this product because the trial results weren’t as stunning as they were for cabotegravir. In an open label extension trial, efficacy was not as high as with oral PrEP or the cabotegravir injection. That said, the European Medical Agency approved the vaginal ring as an additional option, and South Africa and several other countries also now have regulatory approval. I think it’s critical to remember that we have to listen to the voices of women about what choices they want. And I think women are the right people to make these decisions by balancing what they want with the knowledge that perhaps the vaginal ring isn’t quite as efficacious.
If we’re going to get prevention products into communities, we must make them simpler. And we must broaden the number and types of people who can deliver and support use. Many countries already have nurse-led PrEP services. We want to push for nurse-led services and for support from community healthcare workers, peer supporters, and lay providers to help with the demand, answering questions about PrEP choices, and supporting people to switch, start, and stop safely. We also want to take things out of specialist clinics and make them much more available in different community sites. That’s why pharmacy-led PrEP may be an option, particularly for those who prefer more 24/7-type service.
That people who are virally suppressed on treatment don’t transmit HIV is a huge prevention option and positive message that we need communities and healthcare professionals to understand. Access is good for oral PrEP, but it’s not great. We must try to expand that access and make it easier to obtain and afford oral PrEP. But, also, we mustn’t forget condoms. They’re effective against HIV, other STIs, hepatitis, and unplanned pregnancies.
It all comes down to choice and listening to communities to understand what they want and how they want it delivered.
Patient Demographics: High Risk for Secondary Prostate Cancer - Alan Pollack, MD, PhD
When my colleagues and I devised a study around 2005, published in The Lancet in May 2022, there were no data on the combination of hormone therapy or androgen deprivation therapy with standard prostate tumor bed treatment for patients with a rising PSA after prostatectomy, who would be candidates for salvage radiotherapy. We had lots of data at that time regarding the use of antigen deprivation therapy in combination with radiation for men who had a prostate and who were treated primarily, but we didn’t have any data on men treated in the salvage setting after a prostatectomy for a rising PSA.
That was one of three arms in our study. One was prostate bed radiotherapy alone (surgical bed standard treatment) versus prostate bed radiotherapy plus short-term androgen deprivation therapy (hormone therapy) for 4-6 months. The third arm was based on some evidence at the time that expanding the field to include the pelvic lymph nodes would provide additional benefit.
We hypothesized that there would be an incremental benefit going from the addition of androgen deprivation therapy to prostate bed radiotherapy, and that this would result in a 10% improvement in outcome, as well as that the addition of pelvic lymph node treatment would result in an additional benefit of 10%—a total of 20% compared with the control arm, which was prostate bed radiotherapy.
There was an incremental benefit for each of the additional treatments—treatment intensification—going from prostate bed only to adding androgen deprivation therapy and the further addition of pelvic lymph node treatment. We used an endpoint of Nadir plus 2 (PSA ≥2 ng/mL over the nadir PSA), which is commonly used for men who have a prostate but which was not previously used in the setting of men who’ve had their prostates removed and had a rise in PSA. It correlated very strongly in a preliminary study with clinical failure and we anticipated that this end point would be very predictive of ultimately distant metastasis and perhaps survival. That endpoint was approved by the National Cancer Institute as a reasonable endpoint to use as opposed to standard biochemical failure, which is defined as 0.2 or 0.4 and rising. This is a stronger endpoint. Our hypothesis was that the Nadir plus 2 failure rate, along with any other failure, would be around 70%; in fact, it was 71%. We hypothesized a 10% reduction in failure with the addition of androgen deprivation therapy—that went to 81%—and another 10% with the addition of pelvic lymph node treatment—and that went to 87%. The results were pretty close to what was anticipated using the 5-year freedom-from-progression endpoint.
Our results have significant clinical implications. Men who have a rising PSA have higher biochemical failure rates than the Nadir plus 2 definition. That failure results in interventions, such as a secondary androgen deprivation therapy, with the further rise in PSA. Anything we can do to limit failure in this population would be beneficial. The morbidity of the treatment is much less than the morbidity of having a recurrence and ending up on permanent androgen deprivation therapy.
We also attempted, in this study, to identify factors that predicted for a better outcome using androgen deprivation therapy. We took the median cut point of PSA, which was 0.35, and looked at patients who had lower PSAs before enrolling and being treated on this study versus those who had the higher PSAs. We found that all patients benefited from androgen deprivation therapy. There’s been a considerable amount of debate in terms of who should get androgen deprivation therapy. The results from our study indicate that all the patients would benefit, and we had patients with PSAs as low as 0.1 going up to less than 2.0.
In terms of the benefit of androgen deprivation therapy. We found that those with PSAs above the median at 0.35 benefited most. That isn’t to say that there aren’t some patients with PSAs below 0.35 who wouldn’t benefit from the addition of androgen deprivation therapy. You have to look at the other risk factors besides PSA, but PSA is one of the stronger factors. Somebody with a lot of high-risk features who was caught early with a PSA below 0.5 is likely to benefit from androgen deprivation therapy as well.
The standard of care for the treatment of men with a rising PSA post-prostatectomy is shifting to the use of androgen deprivation therapy for virtually all men, and the treatment of the pelvic lymph nodes should be strongly considered, especially if the PSA is above 0.35.