Barriers and Facilitators to Long-Acting Injectable HIV Pre-Exposure Prophylaxis Implementation in Primary Care Since Its Approval in the United States.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is a highly effective method to mitigate the HIV epidemic, but uptake of PrEP has been slow and is associated with racial and gender disparities. Oral PrEP requires high levels of adherence to be effective, which may disadvantage certain high-risk groups. The first injectable HIV PrEP, a drug given every 2 months rather than as a daily pill, was approved by the US Food & Drug Administration in December 2021. SETTING: A Family Medicine practice in a single health organization in the United States (November 2022 to February 2023). METHODS: We conducted interviews with patients and key stakeholders to characterize factors affecting long-acting injectable (LAI) PrEP implementation. Data collection and analysis were guided by the Consolidated Framework for Implementation Research. Interviews were transcribed and analyzed using guided content analysis. RESULTS: Twenty-five patients (n = 13) and practice stakeholders (n = 12) were interviewed. Overall, stakeholders described a very low uptake of LAI PrEP. Barriers to LAI PrEP included a lack of awareness, insurance and access issues, a lack of streamlined workflow, and a trust in pills over injectables. Facilitators to LAI PrEP implementation included the absence of a pill burden, a culture of shared decision making, and pharmacy support. CONCLUSIONS: Although uptake has been slow, we have identified several promising strategies for improving rollout and implementation of LAI PrEP. Approaches that can bolster rollout of LAI PrEP include having an interdisciplinary care team that is supported by PrEP navigators and pharmacists and are informed by a patient-centered model of care to increase patient engagement and trust.

Care of Patients With HIV Infection: Diagnosis and Monitoring.

Appropriate screening for HIV infection is the cornerstone of HIV-related care. There have been several recent changes in testing technology and screening recommendations. The US Preventive Services Task Force recommends universal HIV screening at least once for adolescents and adults ages 15 to 65 years, and additional screening for patients at higher risk, although evidence is insufficient to determine optimum rescreening intervals. All pregnant women should be screened for HIV infection in the first trimester, and pregnant women at high risk should be screened again in the third trimester. The Centers for Disease Control and Prevention recommends use of an algorithm using fourth-generation tests for screening; this decreases the window period between infection and detection to as few as 14 days, thereby reducing the number of false-negative results. Home HIV testing kits, which require follow-up confirmatory testing, also are available. Clinicians should be aware of HIV-specific laws in their states, including those criminalizing HIV exposure and transmission. Thorough medical and laboratory evaluations are essential at initiation of care for patients with HIV infection, along with appropriate follow-up monitoring, as recommended in various guidelines.

Care of Patients With HIV Infection: Medical Complications and Comorbidities.

Care of patients with HIV infection starts with diagnosis as soon as possible, preferably at or near the time of acute infection. Opportunistic infections, malignancies, and other conditions develop progressively over time, particularly in untreated patients. The AIDS-defining opportunistic infections most common in the United States include Pneumocystis jirovecii pneumonia, Candida esophagitis, toxoplasmic encephalitis, tuberculosis, disseminated Mycobacterium avium complex, cryptococcal meningitis, and cytomegalovirus retinitis. Specific prophylaxis regimens exist for several opportunistic infections, and effective antiretroviral therapy reduces the risk of most others. Other AIDS-defining conditions include wasting syndrome and HIV encephalopathy. AIDS-defining malignancies include Kaposi sarcoma, systemic non-Hodgkin lymphoma, primary central nervous system lymphoma, and invasive cervical cancer. Although not an AIDS-defining condition, anal cancer is common in patients with HIV infection. Other HIV-related conditions include thrombocytopenia, recurrent bacterial respiratory infections, HIV-associated nephropathy, and HIV-associated neurocognitive disorder.

Care of Patients With HIV Infection: Antiretroviral Drug Regimens.

The advent of combination antiretroviral drug regimens has transformed HIV infection from a fatal illness into a manageable chronic condition. All patients with HIV infection should be considered for antiretroviral therapy, regardless of CD4 count or HIV viral load, for individual benefit and to prevent HIV transmission. Antiretroviral drugs affect HIV in several ways: entry inhibitors block HIV entry into CD4 T cells; nucleotide and nucleoside reverse transcriptase inhibitors prevent reverse transcription from RNA to DNA via chain-terminating proteins; nonnucleoside reverse transcriptase inhibitors prevent reverse transcription through enzymatic inhibition; integrase strand transfer inhibitors block integration of viral DNA into cellular DNA; protease inhibitors block maturation and production of the virus. Current guidelines recommend six combination regimens for initial therapy. Five are based on tenofovir and emtricitabine; the other uses abacavir and lamivudine. Five include integrase strand transfer inhibitors. HIV specialists should assist with treating patients with complicated HIV infection, including patients with treatment-resistant HIV infection, coinfection with hepatitis B or C virus, pregnancy, childhood infections, severe opportunistic infections, complex drug interactions, significant drug toxicity, or comorbidities. Family physicians can treat most patients with HIV infection effectively by choosing appropriate treatment regimens, monitoring patients closely, and retaining patients in care.

Care of Patients With HIV Infection: Primary Care.

With the advent of antiretroviral therapy and improved access to care, the average life expectancy of patients with HIV infection receiving optimal treatment approaches that of patients in the general population. AIDS-related opportunistic infections and malignancies are no longer the primary issues; instead, traditional age- and lifestyle-related conditions are a growing concern. Patients with HIV infection are at higher risk of cardiovascular disease, diabetes, hypertension, and some non-AIDS-related cancers than patients in the general population. Family physicians need to be knowledgeable about screening for and managing chronic comorbid conditions as this population ages. Health maintenance, including appropriate vaccinations, prophylaxis against opportunistic infections, and routine screening for sexually transmitted infections, remains an important part of care. As HIV infection becomes a chronic condition, emerging strategies in prevention, including preexposure prophylaxis, fall within the scope of practice of the family physician.

MMP-13 In-Vivo Molecular Imaging Reveals Early Expression in Lung Adenocarcinoma.

INTRODUCTION: Several matrix metalloproteinases (MMPs) are overexpressed in lung cancer and may serve as potential targets for the development of bioactivable probes for molecular imaging. OBJECTIVE: To characterize and monitor the activity of MMPs during the progression of lung adenocarcinoma. METHODS: K-rasLSL-G12D mice were imaged serially during the development of adenocarcinomas using fluorescence molecular tomography (FMT) and a probe specific for MMP-2, -3, -9 and -13. Lung tumors were identified using FMT and MRI co-registration, and the probe concentration in each tumor was assessed at each time-point. The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells. Immunohistochemical staining of overexpressed MMPs in animals was assessed on human lung tumors. RESULTS: In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors. In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001). CONCLUSION: MMP-13 is detected in early pulmonary invasive adenocarcinomas and may be a potential target for molecular imaging of lung cancer.

Combined in vivo molecular and anatomic imaging for detection of ovarian carcinoma-associated protease activity and integrin expression in mice.

Most patients with epithelial ovarian cancer (EOC) experience drug-resistant disease recurrence. Identification of new treatments is a high priority, and preclinical studies in mouse models of EOC may expedite this goal. We previously developed methods for magnetic resonance imaging (MRI) for tumor detection and quantification in a transgenic mouse model of EOC. The goal of this study was to determine whether three-dimensional (3D) fluorescence molecular tomography (FMT) and fluorescent molecular imaging probes could be effectively used for in vivo detection of ovarian tumors and response to therapy. Ovarian tumor-bearing TgMISIIR-TAg mice injected with fluorescent probes were subjected to MRI and FMT. Tumor-specific probe retention was identified in vivo by alignment of the 3D data sets, confirmed by ex vivo fluorescent imaging and correlated with histopathologic findings. Mice were treated with standard chemotherapy, and changes in fluorescent probe binding were detected by MRI and FMT. Ovarian tumors were detected using probes specific for cathepsin proteases, matrix metalloproteinases (MMPs), and integrin α(v)ß(3). Cathepsin and integrin α(v)ß(3) probe activation and retention correlated strongly with tumor volume. MMP probe activation was readily detected in tumors but correlated less strongly with tumor volume. Tumor regression associated with response to therapy was detected and quantified by serial MRI and FMT. These results demonstrate the feasibility and sensitivity of FMT for detection and quantification of tumor-associated biologic targets in ovarian tumors and support the translational utility of molecular imaging to assess functional response to therapy in mouse models of EOC.

Structural characterization of an equilibrium unfolding intermediate in cytochrome c.

Although the denaturant-induced unfolding transition of cytochrome c was initially thought to be a cooperative process, recent spectroscopic studies have shown deviations from two-state behavior consistent with accumulation of an equilibrium intermediate. However, little is known about the structural and thermodynamic properties of this state, and whether it is stabilized by the presence of non-native heme ligands. We monitored the reversible denaturant-induced unfolding equilibrium of oxidized horse cytochrome c using various spectroscopic probes, including fluorescence, near and far-UV CD, heme absorbance bands in the Soret, visible and near-IR regions of the spectrum, as well as 2D NMR. Global fitting techniques were used for a quantitative interpretation of the results in terms of a three-state model, which enabled us to determine the intrinsic spectroscopic properties of the intermediate. A well-populated intermediate was observed in equilibrium experiments at pH 5 using either guanidine-HCl or urea as a denaturant, both for wild-type cytochrome c as well as an H33N mutant chosen to prevent formation of non-native His-heme ligation. For a more detailed structural characterization of the intermediate, we used 2D 1H-15N correlation spectroscopy to follow the changes in peak intensity for individual backbone amide groups. The equilibrium state observed in our optical and NMR studies contains many native-like structural features, including a well-structured alpha-helical sub-domain, a short Trp59-heme distance and solvent-shielded heme environment, but lacks the native Met80 sulfur-iron linkage and shows major perturbations in side-chain packing and other tertiary interactions. These structural properties are reminiscent of the A-state of cytochrome c, a compact denatured form found under acidic high-salt conditions, as well as a kinetic intermediate populated at a late stage of folding. The denaturant-induced intermediate also resembles alkaline forms of cytochrome c with altered heme ligation, suggesting that disruption of the native methionine ligand favors accumulation of structurally analogous states both in the presence and absence of non-native ligands.