Hypertension care cascade at a large urban HIV clinic in Uganda: a mixed methods study using the Capability, Opportunity, Motivation for Behavior change (COM-B) model

Background Persons living with HIV (PLHIV) receiving antiretroviral therapy (ART) have a high prevalence of hypertension (HTN) and increased risk of mortality from cardiovascular diseases. HTN and HIV care integration is recommended in Uganda, though its implementation has lagged. In this study, we sought to analyze the HTN and HIV care cascades and explore barriers and facilitators of HTN/HIV integration within a large HIV clinic in urban Uganda. Methods We conducted an explanatory sequential mixed methods study at Mulago ISS clinic in Kampala, Uganda. We determined proportions of patients in HTN and HIV care cascade steps of screened, diagnosed, initiated on treatment, retained, and controlled. Guided by the Capability, Opportunity, Motivation and Behavior (COM-B) model, we then conducted semi-structured interviews and focus group discussions with healthcare providers (n = 13) and hypertensive PLHIV (n = 32). We coded the qualitative data deductively and analyzed the data thematically categorizing them as themes that influenced HTN care positively or negatively. These denoted barriers and facilitators, respectively. Results Of 15,953 adult PLHIV, 99.1% were initiated on ART, 89.5% were retained in care, and 98.0% achieved control (viral suppression) at 1 year. All 15,953 (100%) participants were screened for HTN, of whom 24.3% had HTN. HTN treatment initiation, 1-year retention, and control were low at 1.0%, 15.4%, and 5.0%, respectively. Barriers and facilitators of HTN/HIV integration appeared in all three COM-B domains. Barriers included low patient knowledge of HTN complications, less priority by patients for HTN treatment compared to ART, sub-optimal provider knowledge of HTN treatment, lack of HTN treatment protocols, inadequate supply of anti-hypertensive medicines, and lack of HTN care performance targets. Facilitators included patients’ and providers’ interest in HTN/HIV integration, patients’ interest in PLHIV peer support, providers’ knowledge and skills for HTN screening, optimal ART adherence counseling, and availability of automated BP machines. Conclusion The prevalence of HTN among PLHIV is high, but the HTN care cascade is sub-optimal in this successful HIV clinic. To close these gaps, models of integrated HTN/HIV care are urgently needed. These findings provide a basis for designing contextually appropriate interventions for HTN/HIV integration in Uganda and other low- and middle-income countries.

Integration in oncogenes plays only a minor role in determining the in vivo distribution of HIV integration sites before or during suppressive antiretroviral therapy

HIV persists during antiretroviral therapy (ART) as integrated proviruses in cells descended from a small fraction of the CD4+ T cells infected prior to the initiation of ART. To better understand what controls HIV persistence and the distribution of integration sites (IS), we compared about 15,000 and 54,000 IS from individuals pre-ART and on ART, respectively, with approximately 395,000 IS from PBMC infected in vitro. The distribution of IS in vivo is quite similar to the distribution in PBMC, but modified by selection against proviruses in expressed genes, by selection for proviruses integrated into one of 7 specific genes, and by clonal expansion. Clones in which a provirus integrated in an oncogene contributed to cell survival comprised only a small fraction of the clones persisting in on ART. Mechanisms that do not involve the provirus, or its location in the host genome, are more important in determining which clones expand and persist.

GS-9822, a Preclinical LEDGIN Candidate, Displays a Block-and-Lock Phenotype in Cell Culture

ABSTRACT The ability of HIV to integrate into the host genome and establish latent reservoirs is the main hurdle preventing an HIV cure. LEDGINs are small-molecule integrase inhibitors that target the binding pocket of LEDGF/p75, a cellular cofactor that substantially contributes to HIV integration site selection. They are potent antivirals that inhibit HIV integration and maturation. In addition, they retarget residual integrants away from transcription units and toward a more repressive chromatin environment. As a result, treatment with the LEDGIN CX14442 yielded residual provirus that proved more latent and more refractory to reactivation, supporting the use of LEDGINs as research tools to study HIV latency and a functional cure strategy. In this study, we compared GS-9822, a potent, preclinical lead compound, with CX14442 with respect to antiviral potency, integration site selection, latency, and reactivation. GS-9822 was more potent than CX14442 in most assays. For the first time, the combined effects on viral replication, integrase-LEDGF/p75 interaction, integration sites, epigenetic landscape, immediate latency, and latency reversal were demonstrated at nanomolar concentrations achievable in the clinic. GS-9822 profiles as a preclinical candidate for future functional cure research.

Hypertension Care Cascade at a Large Urban HIV Clinic in Uganda: A Mixed Methods Study Using the Capability, Opportunity, Motivation for Behavior change (COM-B) model

Background: Persons Living with HIV (PLHIV) receiving antiretroviral therapy (ART) have a high prevalence of hypertension (HTN) and increased risk of mortality from cardiovascular diseases. HTN and HIV care integration is recommended in Uganda, though its implementation has lagged. In this study, we sought to analyze the HTN and HIV care cascades and explore barriers and facilitators of HTN/HIV integration within a large HIV clinic in urban Uganda.Methods: We conducted an explanatory sequential mixed methods study at Mulago ISS clinic in Kampala, Uganda. We determined proportions of patients in HTN and HIV care cascade steps of: Screened, Diagnosed, Initiated on treatment, Retained, and Controlled. Guided by the Capability, Opportunity, Motivation and Behavior (COM-B) model, we then conducted semi-structured interviews and focus group discussions with healthcare providers and hypertensive PLHIV (n=45). We coded the qualitative data deductively and analyzed the data thematically categorizing them as themes that influenced HTN care positively or negatively. These denoted barriers and facilitators, respectively.Results: Of 15,953 adult PLHIV, 99.1% were initiated on ART, 89.5% were retained in care and 98.0% achieved control (viral suppression) at one year. All 15,953 (100%) participants were screened for HTN, of whom 24.3% had HTN. HTN treatment initiation, one-year retention, and control were low at 1.0%, 15.4% and 5.0%, respectively. Barriers and facilitators of HTN/HIV integration appeared in all three COM-B domains. Barriers included low patient knowledge of HTN complications, less priority by patients for HTN treatment compared to ART, sub-optimal provider knowledge of HTN treatment, lack of HTN treatment protocols, inadequate supply of anti-hypertensive medicines and lack of HTN care performance targets. Facilitators included patients’ and providers’ interest in HTN/HIV integration, patients’ interest in PLHIV peers support, providers’ knowledge and skills for HTN screening, optimal ART adherence counseling, and availability of automated BP machines. Conclusion: The prevalence of HTN among PLHIV is high, but the HTN care cascade is sub-optimal in this successful HIV clinic. To close these gaps, models of integrated HTN/HIV care are urgently needed. These findings provide a basis for designing contextually appropriate interventions for HTN/HIV integration in Uganda and other low and middle-income countries.

Hypertension Care Cascade at a Large Urban HIV Clinic in Uganda: A Mixed Methods Study Using the Capability, Opportunity, Motivation for Behavior Change (COM-B) Model

Background: Persons Living with HIV (PLHIV) receiving antiretroviral therapy (ART) have a high prevalence of hypertension (HTN) and increased risk of mortality from cardiovascular diseases. HTN and HIV care integration is recommended in Uganda, though its implementation has lagged. In this study, we sought to analyze the HTN and HIV care cascades and explore barriers and facilitators of HTN/HIV integration within a large HIV clinic in urban Uganda.Methods: We conducted an explanatory sequential mixed methods study at Mulago ISS clinic in Kampala, Uganda. We determined proportions of patients in HTN and HIV care cascade steps of: Screened, Diagnosed, Initiated on treatment, Retained, and Controlled. Guided by the Capability, Opportunity, Motivation and Behavior (COM-B) model, we then conducted semi-structured interviews and focus group discussions with healthcare providers and hypertensive PLHIV (n=45). We coded the qualitative data deductively and analyzed the data thematically categorizing them as themes that influenced HTN care positively or negatively. These denoted barriers and facilitators, respectively.Results: Of 15,953 adult PLHIV, 99.1% were initiated on ART, 89.5% were retained in care and 98.0% achieved control (viral suppression) at one year. All 15,953 (100%) participants were screened for HTN, of whom 24.3% had HTN. HTN treatment initiation, one-year retention, and control were low at 1.0%, 15.4% and 5.0%, respectively. Barriers and facilitators of HTN/HIV integration appeared in all three COM-B domains. Barriers included low patient knowledge of HTN complications, less priority by patients for HTN treatment compared to ART, sub-optimal provider knowledge of HTN treatment, lack of HTN treatment protocols, inadequate supply of anti-hypertensive medicines and lack of HTN care performance targets. Facilitators included patients’ and providers’ interest in HTN/HIV integration, patients’ interest in PLHIV peers support, providers’ knowledge and skills for HTN screening, optimal ART adherence counseling, and availability of automated BP machines. Conclusion: The prevalence of HTN among PLHIV is high, but the HTN care cascade is sub-optimal in this successful HIV clinic. To close these gaps, models of integrated HTN/HIV care are urgently needed. These findings provide a basis for designing contextually appropriate interventions for HTN/HIV integration in Uganda and other low and middle-income countries.

Competition between PAF1 and MLL1/COMPASS confers the opposing function of LEDGF/p75 in HIV latency and proviral reactivation

Transcriptional status determines the HIV replicative state in infected patients. However, the transcriptional mechanisms for proviral replication control remain unclear. In this study, we show that, apart from its function in HIV integration, LEDGF/p75 differentially regulates HIV transcription in latency and proviral reactivation. During latency, LEDGF/p75 suppresses proviral transcription via promoter-proximal pausing of RNA polymerase II (Pol II) by recruiting PAF1 complex to the provirus. Following latency reversal, MLL1 complex competitively displaces PAF1 from the provirus through casein kinase II (CKII)–dependent association with LEDGF/p75. Depleting or pharmacologically inhibiting CKII prevents PAF1 dissociation and abrogates the recruitment of both MLL1 and Super Elongation Complex (SEC) to the provirus, thereby impairing transcriptional reactivation for latency reversal. These findings, therefore, provide a mechanistic understanding of how LEDGF/p75 coordinates its distinct regulatory functions at different stages of the post-integrated HIV life cycles. Targeting these mechanisms may have a therapeutic potential to eradicate HIV infection.

Exploring barriers and facilitators to integrated hypertension-HIV management in Ugandan HIV clinics using the Consolidated Framework for Implementation Research (CFIR)

Background: Persons Living with HIV (PLHIV) receiving antiretroviral therapy have increased risk of cardiovascular disease (CVD). Integration of services for hypertension (HTN), the primary CVD risk factor, into HIV clinics is recommended in Uganda. Our prior work demonstrated multiple gaps in implementation of integrated HTN care along the HIV treatment cascade. In this study, we sought to explore barriers to and facilitators of integrating HTN screening and treatment into HIV clinics in Eastern Uganda. Methods: We conducted a qualitative study at three HIV clinics with low, intermediate, and high HTN care cascade performance, which we classified based on our prior work. Guided by the Consolidated Framework for Implementation Research (CFIR), we conducted semi-structured interviews and focus group discussions with health services managers, health care providers and hypertensive PLHIV (n=83). Interviews were transcribed verbatim. Three qualitative researchers used the deductive (CFIR-driven) method to develop relevant codes and themes. Ratings were performed to determine valence and strengths of each CFIR construct regarding influencing HTN/HIV integration. Results: Barriers to HTN/HIV integration arose from six CFIR constructs: organizational incentives & rewards, available resources, access to knowledge & information, knowledge & beliefs about the intervention, self-efficacy and planning. The barriers include: lack of functional BP machines, inadequate supply of anti-hypertensive medicines, additional workload to providers for HTN services, PLHIV’s inadequate knowledge about HTN care, sub-optimal knowledge, skills and self-efficacy of healthcare providers to screen and treat HTN and inadequate planning for integrated HTN/HIV services. Relative advantage of offering HTN and HIV services in a one-stop centre, simplicity (non-complex nature) of HTN/HIV integrated care, adaptability and compatibility of HTN care with existing HIV services are the facilitators for HTN/HIV integration. The remaining CFIR constructs were non-significant regarding influencing HTN/HIV integration. Conclusion: Using the CFIR, we have shown that while there are modifiable barriers to HTN/HIV integration, HTN/HIV integration is of interest to patients, healthcare providers and managers. Improving access to HTN care among PLHIV will require overcoming barriers and capitalizing on facilitators using a health system strengthening approach. These findings are a springboard for designing contextually appropriate interventions for HTN/HIV integration in low- and middle-income countries.

Exploring barriers and facilitators to integrated hypertension-HIV management in Ugandan HIV clinics using the Consolidated Framework for Implementation Research (CFIR)

BackgroundPersons Living with HIV (PLHIV) receiving antiretroviral therapy have increased risk of cardiovascular disease (CVD). Integration of services for hypertension (HTN), the primary CVD risk factor, into HIV clinics is recommended in Uganda. Our prior work demonstrated multiple gaps in implementation of integrated HTN care along the HIV treatment cascade. In this study, we sought to explore barriers to, and facilitators of, integrating HTN screening and treatment into HIV clinics in Eastern Uganda.MethodsWe conducted a qualitative study at three HIV clinics with low, intermediate, and high HTN care cascade performance, which we classified based on our prior work. Guided by the Consolidated Framework for Implementation Research (CFIR), we conducted semi-structured interviews with health services managers, health care providers and hypertensive PLHIV (n=83). Interviews were transcribed verbatim. Three qualitative researchers used both deductive (CFIR model-driven) and inductive (open coding) methods to develop relevant codes and themes. Ratings were performed to determine valence and strengths of each CFIR construct regarding influencing HTN/HIV integration. ResultsOf the 39 CFIR constructs assessed, 17 were relevant to either barriers or facilitators to HTN/HIV integration. Six constructs strongly distinguished performance and were barriers, three of which were in the Inner setting (Organizational Incentives & Rewards, Available Resources, Access to Knowledge & Information); two in Characteristics of individuals (Knowledge & Beliefs about the Intervention and Self-efficacy) and one in Intervention characteristics (Design Quality & Packaging). Four additional constructs were weakly distinguishing and negatively influenced HTN/HIV integration. There were four facilitators for HTN/HIV integration related to the intervention (Relative advantage, Adaptability, Complexity and Compatibility). The remaining three constructs negatively influenced HTN/HIV integration but were non-distinguishing. ConclusionUsing the CFIR, we have shown that while there are modifiable barriers to HTN/HIV integration in the Inner setting, Outer setting, Characteristics of individuals and implementation Process, HTN/HIV integration is of interest to patients, health care providers and managers. Improving access to HTN care among PLHIV will require overcoming barriers and capitalizing on the facilitators using a health system strengthening approach. These findings are a springboard for designing contextually appropriate interventions for HTN/HIV integration in low- and middle-income countries.

Exploring barriers and facilitators to integrated hypertension-HIV management in Ugandan HIV clinics using the Consolidated Framework for Implementation Research (CFIR)

BackgroundPersons Living with HIV (PLHIV) receiving antiretroviral therapy have increased risk of cardiovascular disease (CVD). Integration of services for hypertension (HTN), the primary CVD risk factor, into HIV clinics is recommended in Uganda. Our prior work demonstrated multiple gaps in implementation of integrated HTN care along the HIV treatment cascade. In this study, we sought to explore barriers to, and facilitators of, integrating HTN screening and treatment into HIV clinics in Eastern Uganda.MethodsWe conducted a qualitative study at three HIV clinics with low, intermediate, and high HTN care cascade performance, which we classified based on our prior work. Guided by the Consolidated Framework for Implementation Research (CFIR), we conducted semi-structured interviews with health services managers, health care providers and hypertensive PLHIV (n=83). Interviews were transcribed verbatim. Three qualitative researchers used both deductive (CFIR model-driven) and inductive (open coding) methods to develop relevant codes and themes. Ratings were performed to determine valence and strengths of each CFIR construct regarding influencing HTN/HIV integration.ResultsOf the 39 CFIR constructs assessed, 17 were relevant to either barriers or facilitators to HTN/HIV integration. Six constructs strongly distinguished performance and were barriers, three of which were in the Inner setting (Organizational Incentives & Rewards, Available Resources, Access to Knowledge & Information); two in Characteristics of individuals (Knowledge & Beliefs about the Intervention and Self-efficacy) and one in Intervention characteristics (Design Quality & Packaging). Four additional constructs were weakly distinguishing and negatively influenced HTN/HIV integration. There were four facilitators for HTN/HIV integration related to the intervention (Relative advantage, Adaptability, Complexity and Compatibility). The remaining four constructs negatively influenced HTN/HIV integration but were non-distinguishing.ConclusionUsing the CFIR, we have shown that while there are modifiable barriers to HTN/HIV integration in the Inner setting, Outer setting, Characteristics of individuals and implementation Process, HTN/HIV integration is of interest to patients, health care providers and managers. Improving access to HTN care among PLHIV will require overcoming barriers and capitalizing on the facilitators using a health system strengthening approach. These findings are a springboard for designing contextually appropriate interventions for HTN/HIV integration in low- and middle-income countries.Contribution to the literatureWe used the widely used and validated CFIR to assess the HIV program for HTN/HIV integration.To our knowledge, this is the first study to explore barriers and facilitators to integrating hypertension screening and treatment into HIV clinics using the CFIR.The barriers and facilitators identified are a basis for designing contextualized implementation interventions for HTN/HIV integration in Uganda and other LMIC using a health system strengthening approach.