Journal Article Annotations
2024, 3rd Quarter
Annotations by John A R Grimaldi MD, Mary Ann Cohen MD, FAPM, Kelly Cozza MD, DFAPA, FACLP and Luis Pereira MD
October, 2024
Findings:
This double-blind, randomized, controlled trial compared the safety and efficacy of twice-yearly subcutaneous lenacapavir (HIV capsid inhibitor), daily oral tenofovir alafenamide/emtricitabine (F/TAF), and daily oral tenofovir disoproxil/emtricitabine (F/TDF) for prevention of HIV acquisition in adolescent girls and young women in South Africa and Uganda. HIV incidence in the lenacapavir arm was ZERO and significantly less than the background HIV incidence in which the trial was conducted. None of the participants in the lenacapavir arm acquired HIV. HIV incidence with lenacapavir was also superior to HIV incidence in the F/TDF arm, the secondary endpoint. F/TAF and F/TDF adherence was low and no safety concerns were found.
Strengths and limitations:
The study design was randomized, blinded and enrolled a subpopulation that has been disproportionately affected by HIV and historically excluded from HIV clinical trials, including pregnant and lactating women and adolescents. Pregnancy outcomes were assessed and lenacapavir pharmacokinetics were evaluated in pregnancy and infant exposure. Since a placebo arm would not have been ethical, a novel approach was used to calculate background HIV prevalence. Estimates were based on those participants who tested positive for HIV at study entry and a testing strategy that determined timing of infection. Adherence to oral F/TDF and F/TAF were assessed and confirmed findings from other studies demonstrating the efficacy of oral PrEP, when taken as prescribed. Study findings may not be generalizable to other geographic regions, such as the US, and subpopulations, such as men who have sex with men, cisgender men, and transgender women. Lenacapavir’s moderate inhibition of CYP3A4 activity may affect its use with certain psychiatric medications. Another limitation may be lenacapavir’s high cost. The study was a conducted in a controlled research setting, which differs from a real-world situation. Since there were no HIV infections in the lenacapavir arm, the study does not inform us about drug resistance in those persons who acquire HIV due to low adherence.
Relevance:
When the results of this study were shown at the recent International AIDS Conference, there was spontaneous applause, and the presenter received a standing ovation at the end of their presentation. The optimism has generated media coverage predicting the end of the HIV epidemic. This degree of excitement may also be a counter-reaction to the persistent high, unacceptable rates of new HIV infections globally, despite 40 years of significant advances in the development of biomedical interventions to prevent and control HIV infection. Additionally, none of the previous PrEP trials in women in Africa has resulted in zero new HIV infections. To the contrary, results from PrEP studies using oral drugs have produced disappointing outcomes, especially among women. Meta-analyses have concluded that PrEP efficacy is dose-responsive and depends on adherence. This trial demonstrated far superior adherence and acceptability of twice-yearly subcutaneous injections compared to daily oral medication administration. It also showed that levels of an HIV capsid inhibitor can remain high enough over a 6-month period to prevent acquisition of HIV.
Findings:
This vignette-based study assessed barriers and likelihood of psychiatry and family medicine residents prescribing oral, long-acting injectable (LAI), or on-demand pre-exposure prophylaxis (PrEP) to patients diagnosed with schizophrenia on oral antipsychotic medication (SCZ-oral), schizophrenia on LAI antipsychotic medication (SCZ-LAI), bipolar disorder (BP), major depressive disorder (MDD), or no psychiatric disorder (control condition). Although a large majority of psychiatry and family medicine (FM) residents were aware of PrEP, less than half of each group were aware of on-demand PrEP, and an even smaller percentage were aware of LAI-PrEP. A large majority of residents in each group responded that PrEP was indicated for patients with each psychiatric disorder, although significantly fewer psychiatry residents, versus FM residents, responded that PrEP was indicated for the control condition. LAI-PrEP was the most frequently recommended modality for the SCZ-oral, SCZ-LAI, and BP conditions, while daily PrEP was most often recommended for MDD. LAI-PrEP and daily PrEP were recommended with equal frequency for the control condition. The patient’s condition did not influence the likelihood that either psychiatry or FM residents would prescribe PrEP. However, FM residents were significantly more likely to prescribe PrEP for each psychiatric condition, compared to psychiatry residents. The resident groups were equally likely to prescribe PrEP for the control condition. Non-adherence to PrEP was more likely to be a factor influencing FM residents’ decision to prescribe PrEP, compared to psychiatry residents. However, psychiatry residents, versus FM residents,were more likely to respond that PrEP was outside the scope of their practice as a factor in their decision regarding prescribing PrEP.
Strengths and limitations:
Study strengths include randomization of resident participants to receive one of five clinical vignettes, the use of a control condition comprising a patient with no psychiatric diagnosis, and the inclusion of a family medicine resident comparison group. The study also included a relatively large number of residents in training at both academic medical centers, as well as community hospitals, representing all races/ethnicities from all regions of the US. Since the study participants were residents, study findings may not be applicable to physicians with full autonomy. Similarly, the study utilized clinical vignettes, which further limits generalizability to real-world settings. The use of FM residents as a control group may also be a study limitation since they may be less likely to have routine clinical encounters with patients with serious mental illness such as schizophrenia and bipolar disorder.
Relevance:
The efficacy of PrEP in preventing acquisition of HIV and its central role in the US Ending the HIV Epidemic initiative sends a powerful message to our mental health colleagues. The US Preventive Services Task Force has given the use of PrEP its strongest recommendation, and CDC guidelines specify that “patient request for PrEP is sufficient justification for prescription.” Ample research has demonstrated that people with mental illness are more likely to have HIV, and that people with HIV are more likely to have a mental illness. Yet, studies have also revealed limited availability of HIV testing and prevention interventions in mental health and substance use treatment settings. Additionally, there is a scarcity of research regarding PrEP uptake in this vulnerable population. Studies demonstrating the benefits of “reverse integration” of primary care interventions for hypertension, diabetes, and dyslipidemia, co-located within psychiatric care delivery, further justify investment in training both residents and practicing psychiatrists in HIV prevention interventions, including PrEP. These settings are already equipped to provide LAI antipsychotic and substance use-related medications, thus obviating the need to create new workflows and infrastructures for LAI-PrEP. Psychiatrists are uniquely positioned to provide PrEP to patients, given their medical background and treatment of chronic conditions that require frequent monitoring. Psychiatrists also have expertise in helping patients with behavioral change, and discussing psychologically sensitive topics such as sexuality and physical intimacy.