CE / CME
Pharmacists: 0.75 contact hour (0.075 CEUs)
Nurses: 0.75 Nursing contact hour, including 0.75 hour of pharmacotherapy credit
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: November 07, 2022
Expiration: November 06, 2023
In this module, Ariela Noy, MD, discusses important data and clinical strategies for screening for and treating HIV-associated cancers in transgender individuals.
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails alongside the expert commentary.
Clinical Care Options plans to measure the educational impact of this activity. One question will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Before continuing with this educational activity, please take a moment to answer the following questions.
It is important for healthcare professionals (HCPs) caring for transgender individuals to be aware of the relationship between HIV infection and cancer.
First, many transgender people are at risk for HIV-associated cancers. Of the estimated 329.5 million people living in the United States, approximately 1 million identify as transgender (0.3%), yet 2% of new HIV diagnoses were in transgender people in 2019.1 A recent meta-analysis of 98 studies from 2000-2019 estimated that, worldwide, 20% of transfeminine people and 2.6% of transmasculine people live with HIV.2 These are markedly higher rates than the estimated 0.7% of adults worldwide living with HIV.3 These high rates reflect the social marginalization and stigmatization of transgender people that lead to poor mental health, substance use, and transactional sex—all of which place an individual at greater risk for HIV infection.4,5 For more information on the increased risk of HIV infection among transgender individuals, please see this module from Antonio E. Urbina, MD.
Second, HIV infection increases the risk of multiple cancers, including non-AIDS–defining cancers (NADCs), due to immunodeficiency.6
Third, antiretroviral therapy (ART) reduces the incidence of AIDS-defining cancers but increases the risk for NADCs.7 Prior to the introduction of ART, 10% of HIV-related deaths were due to cancer. After the broad adoption of ART, other factors emerged that increased the risk of cancer in people living with HIV (PLWH). These include longer overall survival (OS), increased age, the intrinsic risk of both AIDS-defining cancers and NADCs, and an increased prevalence of coinfections and risk factors for cancer. It is important to also note that ART interruptions of substantial duration increase the risk for AIDS-defining cancers, as was reported in the SMART trial comparing cancer rates in PLWH who were randomized to receive continuous ART vs CD4+ cell count–determined ART.8
As I mentioned earlier, an important risk factor is stigma, which prevents diagnosis and treatment.9 To help address HIV-related stigma, HCPs can adopt a strategy called “opt-out testing,” in which the patient is notified that the HIV test will be performed and has the option to decline or defer being tested.10
Furthermore, data show transgender patients face stigma in accessing cancer treatment, leading to this population being diagnosed at later stages of disease, being less likely to receive therapy, and having poorer survival outcomes.11 In general, care does not differ for transgender individuals, although HIV and cancer services should be tailored to meet the social, psychological, and physiological needs of this population. For an expert perspective on creating a compassionate and inclusive healthcare environment that optimizes care of transgender patients, please see this module from Lauren Radziejewski, DNP.
Multiple HIV-associated cancers occur at a markedly higher frequency in PLWH.12 Of these, 3 are considered AIDS-defining cancers—meaning the diagnosis of one of these malignancies in an individual with HIV infection confirms an AIDS diagnosis. The 3 AIDS-defining cancers are non-Hodgkin lymphoma (NHL), Kaposi sarcoma, and human papillomavirus (HPV)-associated cervical cancer.
NHL once occurred predominantly in the setting of advanced HIV infection with low CD4+ cell counts but is now increasingly common among PLWH who have normal CD4+ counts in the current era of ART.13 The incidence of NHL has decreased among PLWH since the advent of ART, but NHL still occurs at an 11.5-fold higher rate among those with vs without HIV infection.14 Despite being a rare subtype in the general population, Burkitt lymphoma occurs at a 20-fold higher incidence among PLWH.
Kaposi sarcoma is rare in the general population but poses a substantial lifetime risk of 4.4% for PLWH receiving ART vs 0.01% for people who are HIV negative.15
Of the HPV-associated cancers with an increased incidence among PLWH, cervical cancer is the only one considered AIDS defining. HPV-associated anal and oral cancers are both NADCs, but as I will discuss below, HIV-associated anal cancer has many parallels with HIV-associated cervical cancer, and I consider its label as an NADC to be a historical artifact. A new term “HIV-associated cancer” is coming into use.
Finally, as I mentioned earlier, NADCs are becoming increasingly important. Their classification as NADCs is somewhat artificial and a result of these malignancies not being well understood and/or not linked with HIV infection at the time the CDC defined AIDS. This does not mean that NADCs are infrequent or unimportant in the setting of HIV infection. In addition to HPV-associated anal and oral cancers, other common NADCs include Hodgkin lymphoma, lung cancer, and hepatocellular cancer associated with hepatitis B and/or C virus.
When managing DLBCL in PLWH, full-dose chemotherapy is associated with good outcomes and should be used when possible.20 Concurrent rituximab is also now the standard of care. There were some early concerns about toxicity observed with concurrent rituximab in the AIDS Malignancy Consortium study (AMC-034), but more data and clinical experience have largely ameliorated this concern while supporting the superior outcomes achieved with concurrent rituximab.21
Among PLWH with DLBCL, adverse risk factors include a CD4+ cell count <100 cells/mm3; prior opportunistic infections, especially if recent; poor performance status; stage III or IV disease; and lack of ART.17,22 It is important that patients agree to and are adherent to ART, because ART use is associated with an OS benefit.23
Another adverse risk factor is expression of Myc protein.24 Results from a recent study from the AIDS Malignancy Consortium are shown in this graph. Event-free survival (EFS) was comparable for patients with HIV-associated DLBCL who received R-EPOCH with vs without vorinostat, but the 3-year EFS rate was almost halved among those with vs without Myc expression (44% vs 83%, respectively).
Based on earlier studies, the National Cancer Institute initiated CTSU/9177, a multicenter study in which patients with previously untreated Burkitt lymphoma, with or without HIV infection, received risk-adapted, dose-adjusted R-EPOCH.20 Patients with high-risk disease received 6 cycles of dose adjusted R-EPOCH with 1 dose of rituximab on Day 1 along with intrathecal methotrexate for central nervous system prophylaxis. Those with low-risk disease received dose-adjusted RR-EPOCH for 2 cycles with 2 doses of rituximab per cycle on Days 1 and 5. The low-risk patients were then assessed by PET scan after 2 cycles and if they had residual disease, treatment was escalated to include 4 more cycles of dose-adjusted R-EPOCH plus intrathecal methotrexate, whereas those who were negative for residual disease received only 1 more cycle of dose adjusted RR-EPOCH.
This graph shows that HIV status had no effect on EFS in this trial. Of note, this analysis was not limited by low patient numbers: The trial enrolled 28 PLWH and 85 persons without HIV infection. PLWH received full-dose chemotherapy and dose escalation, unlike in DLBCL studies. These results support my comment earlier that full-dose chemotherapy should be used in PLWH.
Multiple studies have evaluated other regimens for the treatment of Hodgkin lymphoma in the setting of HIV infection. For example, a nonrandomized trial reported that the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) was associated with a 2-year progression-free survival (PFS) rate of 90% in PLWH with advanced-stage Hodgkin lymphoma, but treatment-related mortality was quite high at 6%.27 Given this toxicity, BEACOPP is not considered a preferred regimen in this setting.28
More recently, the AMC-085 trial reported the addition of brentuximab vedotin to an AVD (doxorubicin, vinblastine, and dacarbazine) chemotherapy backbone was effective in HIV-associated lymphoma.29 The graph here shows brentuximab vedotin plus AVD was associated with a 2-year OS rate of 92% and a 2-year PFS rate of 86%. These positive outcomes are consistent with the randomized ECHELON-2 trial, which demonstrated the addition of brentuximab vedotin to AVD significantly improved survival vs ABVD in people without HIV infection.30 The safety profile for brentuximab vedotin plus AVD is also consistent between these studies.
In the setting of relapsed/refractory Hodgkin lymphoma, high-dose chemotherapy with autologous peripheral blood stem cell transplant can be used in patients with well-controlled HIV infection.31 Preliminary data also suggest benefit from immune checkpoint inhibitor–based therapy in patients with HIV-associated Hodgkin lymphoma.32 The ongoing AMC-095 trial is assessing nivolumab in patients with HIV-associated relapsed/refractory classical Hodgkin lymphoma (NCT02408861).
Because Kaposi sarcoma is caused by human herpesvirus 8 (HHV-8) infecting endothelial cells, this malignancy poses a notable public health challenge in regions with endemic HHV-8 seroprevalence, such as sub-Saharan Africa.34 HHV-8 can be transmitted not only through sexual activity, but also through saliva, meaning that the practice of premasticating food for toddlers can transmit HHV-8.
HHV-8 infection presents a greater risk to PLWH.35 Healthy individuals possess functioning T-cells that, after a de novo HHV-8 infection, can inhibit the productive lytic phase of the virus, inhibit reactivation, and keep HHV-8–infected cells in a latent state. In the setting of advanced HIV infection, in which CD4+ T-cells are not present to suppress these processes, the early Kaposi sarcoma lesion liberates growth factors borrowed from the human genome (eg, VEGF, PDGF, IL-6). The lesion continues to grow, and because more and more cells are becoming infected, ultimately a transformative event occurs. Some HIV proteins, such as TAT and NEF, also contribute to this process.
The risk of Kaposi sarcoma increases with a declining CD4+ cell count and with an increasing HHV-8 viral load.36,37 Both ART and the antiviral ganciclovir can substantially reduce HHV-8 reactivation.
Treatment of Kaposi sarcoma depends on ART and varies by the extent of disease. If possible, it is important to avoid steroids for comorbid conditions. For example, repeated pulse therapy for asthma could exacerbate disease in an individual with limited Kaposi sarcoma. Steroids also can be an issue if the individual is being treated for lymphoma and is receiving steroids as part of their chemotherapy regimen.
An important part of managing Kaposi sarcoma is to optimize ART. In the setting of early Kaposi sarcoma, ART optimization may be sufficient to control the disease entirely. Multiple therapeutic options exist for patients with early, relatively asymptomatic, nonvisceral Kaposi sarcoma. These options include local treatment, α-interferon, and radiation.40 An investigational, pathogenesis-directed therapy via clinical trial enrollment also can be considered.
Patients with advanced, symptomatic, and/or visceral Kaposi sarcoma are most commonly treated with liposomal doxorubicin and paclitaxel. Additional benefit has been shown with immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide. Refractory disease can be treated on clinical trials. For example, the ongoing phase I AMC-095 trial is evaluating nivolumab and ipilimumab for individuals with HIV-associated relapsed/refractory metastatic solid tumors (NCT02408861) and nivolumab for classical Hodgkin lymphoma as mentioned above. The phase II AMC-096 trial is evaluating an inhibitor of the EphB4-EphrinB2 angiogenic pathway specifically in patients with edema (NCT02799485).
We will now discuss HPV-associated anogenital cancers. As I mentioned earlier, HPV-associated cervical cancer is an AIDS-defining cancer, but HPV-associated anal cancer is not. Again, this is a historical artifact, and we will see the parallels between these 2 diseases shortly.
Other, rarer HPV-associated anogenital cancers occur, but we will be focusing on cervical and anal cancer. Both cervical and anal cancer are associated with a high-risk HPV subtype, with the most prevalent being HPV 16 and 18.41 These HPV viruses encode 2 proteins that are involved in oncogenesis. PLWH with lower CD4+ cell counts are at greater risk of the HPV persisting and the neoplasm progressing to cancer.42
There are important social and psychological considerations when it comes to screening and treating cervical cancer in transgender men. The University of California, San Francisco Transgender Care and Treatment Guidelines recommend that if a transgender person has a specific body part or organ (eg, possessing a cervix at birth) that meets screening criteria, then HCPs should recommend screening regardless of hormone use.43
To learn more about how HCPs can best provide cancer screening and care to transgender individuals, please see this module from Lauren Radziejewski, DNP, and this module from Madeline Deutsch, MD, MPH.
Less research has been done on the incidence of anal cancer among transgender individuals specifically. Given that HIV infection is more prevalent among transgender people—particularly transgender women—than the general population, it is expected that HPV-related cancers occur more often in this population.45
Now that we know who is at greater risk for HPV-associated anogenital cancers, what can HCPs do to mitigate this risk and treat these cancers in these vulnerable populations?
Tumor progression in the anus mirrors progression in the cervix.47 Following HPV infection of normal epithelium, a period of mild dysplasia can progress from an incipient phase to a severe dysplastic phase, followed by the development of in situ carcinoma and, ultimately, invasive carcinoma. This process occurs over years but is accelerated in the presence of HIV infection, with further acceleration in the setting of low CD4+ cell count. This provides a biologic rationale for applying a screening approach to anal cancer similar to what we just discussed for cervical cancer.
When we look at the results, ANCHOR demonstrated that treatment of high-grade anal lesions significantly reduced the rate of progression to anal cancer by 57% vs active monitoring (P = .03). These findings were published in 2022 in The New England Journal of Medicine and set a new standard of care for anal cancer screening.
For an example of how anal cancer screening is being applied on the population level for PLWH, we can look at the New York State Department of Health guidelines on screening for anal dysplasia and cancer in the setting of HIV infection.49 The guidelines recommend that in all PLWH aged 35 years or older, HCPs should:
In patients younger than 35 years of age who are presenting with signs and symptoms, the guidelines recommend performing high-resolution anoscopy in those with low- or high-grade squamous intraepithelial lesions. If anal cytology indicates anal squamous cells of unclear significance, the patient should undergo HPV testing. Finally, screening for anal cancer can be discontinued in an individual whose life expectancy is <10 years or in someone who has 2 consecutive negative anal cytology specimens and is not sexually active.
The challenge with this approach is that this vaccine should be given before HPV exposure, which means vaccinating young teenagers.
Although smoking is more prevalent among PLWH and transgender individuals than the general population, not much research has been done into lung cancer in PLWH.45,51
Early evidence suggests that HIV infection may influence the age of lung cancer onset, which has implications for screening.52 The AMC-111 trial is not yet open, but this study will evaluate the impact of behavior modification and screening on smoking cessation in PLWH (NCT04949464). Screening will be performed earlier than in the general population, and participants will have an app that helps them with behavior modification.
At Memorial Sloan Kettering Cancer Center, we have an in-house program to decrease smoking prevalence based on “lung age awareness”—essentially, a spirometer test that lets HCPs provide feedback such as, “You’re 45 years old, but your lungs are 60” to help people understand how important it is to stop smoking.
As shown in this pie chart of HIV-related eligibility in new drug applications from 2011-2015, only 7 applications did not note HIV exclusion, 9 had a likely exclusion—meaning individuals will be excluded for something like “active infection”—and, finally, 65 explicitly excluded PLWH.
The ASCO-Friends of Cancer Research HIV Working Group issued multiple recommendations to modernize clinical trial eligibility criteria for PLWH.53 We recommended criteria to define a population of PLWH who are sufficiently healthy to participate in almost any oncology study, with separate criteria for phase I, II, and III trials. We also recommended that eligibility criteria select PLWH who are likely to have long-term survival in the absence of cancer.
We further noted that, because more is known about a particularly therapeutic agent in later-phase trials, it is less conscionable to exclude PLWH, given the increased level of experience with that drug.
Most importantly, we recommended eligibility criteria should be fair—meaning requirements should not be more stringent for PLWH compared with people who do not have HIV infection. For example, if we look at clinical trials for breast cancer, by the time someone is on their eighth anticancer treatment, we would not mandate a certain CD4+ cell count because this population would have expected chemotherapy-related cytopenias. In this case, it would be morally unjust to prevent someone who has HIV infection and breast cancer from entering the same study as those without HIV infection.
In conclusion, HIV infection increases the risk of certain cancers, including those linked to immune deficiency and NADCs. Because transgender individuals have a high risk for HIV infection, it is important for HCPs caring for these patients to be aware of the relationship between HIV infection and cancer. ART is highly effective in preventing AIDS-defining cancers but has increased the incidence of NADCs due to extended life expectancy among PLWH. Stigma prevents cancer diagnosis and treatment and is an important barrier to healthcare for transgender individuals. Guidelines on cancer screening for transgender individuals and PLWH are available and should be widely adopted to improve outcomes in these vulnerable populations.
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