The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/ß-catenin signaling.

Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/ß-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of ß-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.

Continuing Low Awareness and Use of Pre-exposure Prophylaxis (PrEP) for HIV among People Who Inject Drugs (PWID), San Francisco, 2022.

Clinical trials provide evidence that pre-exposure prophylaxis (PrEP) prevents HIV acquisition including through sharing of injection equipment among people who inject drugs (PWID). However, uptake among many populations at risk for HIV has been slow, particularly among PWID. We examined data from the National HIV Behavioral Surveillance (NHBS) from San Francisco in 2022 to measure PrEP uptake and identify factors associated with PrEP awareness among PWID. Of 479 PWID with HIV-negative or unknown HIV status, 54.9% were aware of PrEP, 5.9% had discussed PrEP with a healthcare provider, and 1.5% had used PrEP in the past year. Lack of PrEP awareness was associated with being age 50 years and older (adjusted odds ratio [aOR] 0.40, 95% CI 0.27-0.60), being men who have sex with women (vs. men who have sex with men, aOR 0.47, 95% CI 0.24-0.92), having a disability (aOR 0.58, 95% CI 0.35-0.95), using heroin as their most frequently injected drug (aOR 0.51, 95% CI, 0.34-0.78), not having tested for HIV, HCV, or an STD in the past year (aOR 0.43, 95% CI 0.28-0.64), and not having access to new sterile needles in the past year (aOR 0.28, 95%CI 0.08-1.00). We found negligible change in the awareness and uptake of PrEP among PWID since previously measured in NHBS in 2018. Low PrEP use among PWID may be addressed by increasing provider discussion of PrEP with their PWID patients and clients during routine care, expanding testing for injection-related infections among PWID, and integrating PrEP access into harm reduction programs.

Estimating the contribution of key populations towards HIV transmission in South Africa.

INTRODUCTION: In generalized epidemic settings, there is insufficient understanding of how the unmet HIV prevention and treatment needs of key populations (KPs), such as female sex workers (FSWs) and men who have sex with men (MSM), contribute to HIV transmission. In such settings, it is typically assumed that HIV transmission is driven by the general population. We estimated the contribution of commercial sex, sex between men, and other heterosexual partnerships to HIV transmission in South Africa (SA). METHODS: We developed the "Key-Pop Model"; a dynamic transmission model of HIV among FSWs, their clients, MSM, and the broader population in SA. The model was parameterized and calibrated using demographic, behavioural and epidemiological data from national household surveys and KP surveys. We estimated the contribution of commercial sex, sex between men and sex among heterosexual partnerships of different sub-groups to HIV transmission over 2010 to 2019. We also estimated the efficiency (HIV infections averted per person-year of intervention) and prevented fraction (% IA) over 10-years from scaling-up ART (to 81% coverage) in different sub-populations from 2020. RESULTS: Sex between FSWs and their paying clients, and between clients with their non-paying partners contributed 6.9% (95% credibility interval 4.5% to 9.3%) and 41.9% (35.1% to 53.2%) of new HIV infections in SA over 2010 to 2019 respectively. Sex between low-risk groups contributed 59.7% (47.6% to 68.5%), sex between men contributed 5.3% (2.3% to 14.1%) and sex between MSM and their female partners contributed 3.7% (1.6% to 9.8%). Going forward, the largest population-level impact on HIV transmission can be achieved from scaling up ART to clients of FSWs (% IA = 18.2% (14.0% to 24.4%) or low-risk individuals (% IA = 20.6% (14.7 to 27.5) over 2020 to 2030), with ART scale-up among KPs being most efficient. CONCLUSIONS: Clients of FSWs play a fundamental role in HIV transmission in SA. Addressing the HIV prevention and treatment needs of KPs in generalized HIV epidemics is central to a comprehensive HIV response.

High Acceptability and Increased HIV-Testing Frequency After Introduction of HIV Self-Testing and Network Distribution Among South African MSM.

BACKGROUND: South African men who have sex with men (MSM) have a high burden of undiagnosed HIV infection and HIV-testing rates incommensurate with their risk. HIV self-testing (HIVST) may increase testing uptake, frequency, and earlier HIV detection and treatment. SETTING: Gert Sibande and Ehlanzeni districts, Mpumalanga Province, South Africa. METHODS: We conducted a longitudinal HIVST study among MSM between June 2015 and May 2017. Overall 127 HIV-negative MSM were provided with up to 9 test kits of their choice-oral fluid or blood fingerstick-to use themselves and distribute to their networks. Surveys conducted 3- and 6-month post-enrollment elicited information on HIVST experiences, preferences, acceptability, utilization, and distribution. We used generalized estimating equations to assess changes in testing frequency. RESULTS: Ninety-one percent of participants self-tested. All participants who self-tested reported being likely to self-test again, with over 80% preferring HIVST to clinic-based testing. Fingerstick was preferred to oral fluid tests by approximately 2:1. Returning participants distributed 728 tests to sexual partners (18.5% of kits), friends (51.6%), and family (29.8%). Six participants seroconverted during the study, and 40 new diagnoses were reported among test recipients. Frequent (semi-annual) testing increased from 37.8% before the study to 84.5% at follow-up (P < 0.001), and participants reported anticipated frequent testing of 100% if HIVST were available compared with 84% if only clinic-testing were available in the coming year (P < 0.01). CONCLUSIONS: HIVST use and network distribution is acceptable and feasible for MSM in South Africa and can increase testing uptake and frequency, potentially improving early detection among MSM and their networks.

Brief Report: High HIV Incidence in a South African Community of Men Who Have Sex With Men: Results From the Mpumalanga Men's Study, 2012-2015.

Cross-sectional studies among African men who have sex with men (MSM) populations demonstrate high HIV prevalence, but few incidence estimates exist. The Mpumalanga Men's Study in Gert Sibande, Mpumalanga province, South Africa, involved 3 serial cross-sectional surveys of MSM recruited through respondent-driven sampling between 2012 and 2015. Successive surveys recaptured a nested cohort of 179, contributing 144.3 person-years (PY) of observation. We observed 18 seroconversions, or incidence of 12.5/100 (PY) (95% confidence interval CI: 8.1 to 19.2/100 PY). Presumptions of high incidence among MSM were confirmed and demonstrate an urgent need for biomedical prevention and treatment programming for MSM in South Africa.

Power and the association with relationship quality in South African couples: Implications for HIV/AIDS interventions.

INTRODUCTION: Power imbalances within sexual relationships have significant implications for HIV prevention in sub-Saharan Africa. Little is known about how power influences the quality of a relationship, which could be an important pathway leading to healthy behavior around HIV/AIDS. METHODS: This paper uses data from 448 heterosexual couples (896 individuals) in rural KwaZulu-Natal, South Africa who completed baseline surveys from 2012 to 2014 as part of a couples-based HIV intervention trial. Using an actor-partner interdependence perspective, we assessed: (1) how both partners' perceptions of power influences their own (i.e., actor effect) and their partner's reports of relationship quality (i.e., partner effect); and (2) whether these associations differed by gender. We examined three constructs related to power (female power, male equitable gender norms, and shared power) and four domains of relationship quality (intimacy, trust, mutually constructive communication, and conflict). RESULTS: For actor effects, shared power was strongly and consistently associated with higher relationship quality across all four domains. The effect of shared power on trust, mutually constructive communication, and conflict were stronger for men than women. The findings for female power and male equitable gender norms were more mixed. Female power was positively associated with women's reports of trust and mutually constructive communication, but negatively associated with intimacy. Male equitable gender norms were positively associated with men's reports of mutually constructive communication. For partner effects, male equitable gender norms were positively associated with women's reports of intimacy and negatively associated with women's reports of conflict. CONCLUSIONS: Research and health interventions aiming to improving HIV-related behaviors should consider sources of shared power within couples and potential leverage points for empowerment at the couple level. Efforts solely focused on empowering women should also take the dyadic environment and men's perspectives into account to ensure positive relationship outcomes.

The Mpumalanga Men's Study (MPMS): results of a baseline biological and behavioral HIV surveillance survey in two MSM communities in South Africa.

The Mpumalanga Men's Study (MPMS) is the assessment of the Project Boithato HIV prevention intervention for South African MSM. Boithato aims to increase consistent condom use, regular testing for HIV-negative MSM, and linkage to care for HIV-positive MSM. The MPMS baseline examined HIV prevalence and associated risk behaviors, and testing, care, and treatment behaviors among MSM in Gert Sibande and Ehlanzeni districts in Mpumalanga province, South Africa in order to effectively target intervention activities. We recruited 307 MSM in Gert Sibande and 298 in Ehlanzeni through respondent-driven sampling (RDS) between September 2012-March 2013. RDS-adjusted HIV prevalence estimates are 28.3% (95% CI 21.1%-35.3%) in Gert Sibande, and 13.7% (95% CI 9.1%-19.6%) in Ehlanzeni. Prevalence is significantly higher among MSM over age 25 [57.8% (95% CI 43.1%-72.9%) vs. 17.9% (95% CI 10.6%-23.9%), P<0.001 in Gert Sibande; 34.5% (95%CI 20.5%-56.0%) vs. 9.1% (95% CI 4.6%-13.9%), P<0.001 in Ehlanzeni]. In Gert Sibande, prevalence is higher among self-identified gay and transgender MSM vs. other MSM [39.3% (95%CI, 28.3%-47.9%), P<0.01], inconsistent condom users [38.1% (18.1%-64.2%), P<0.05], those with a current regular male partner [35.0% (27.1%-46.4%), P<0.05], and those with lifetime experience of intimate partner violence with men [40.4%, (95%CI 28.9%-50.9%), P<0.05]. Prevalence of previous HIV testing was 65.8% (95%CI 58.8%-74.0%) in Gert Sibande, and 69.3% (95%CI 61.9%-76.8%) in Ehlanzeni. Regular HIV testing was uncommon [(34.6%, (95%CI 27.9%-41.4%) in Gert Sibande; 31.0% (95%CI 24.9%-37.8%) in Ehlanzeni]. Among HIV-positive participants, few knew their status (28.1% in Gert Sibande and 14.5% in Ehlanzeni), or were appropriately linked to care (18.2% and 11.3%, respectively), or taking antiretroviral therapy (13.6% and 9.6% respectively). MPMS results demonstrate the importance of implementing interventions for MSM to increase consistent condom use, regular HIV testing, and linkage and engagement in care for HIV-infected MSM.