Can Self-Management Improve HIV Treatment Engagement, Adherence, and Retention? A Mixed Methods Evaluation in Tanzania and Uganda.

This paper presents the evaluation results of a self-management support (SMS) initiative in Tanzania and Uganda, which used quality improvement to provide self-management counseling, nutritional support, and strengthened linkages to community-based services for highest-risk patients (those with malnutrition, missed appointments, poor adherence, high viral load, or low CD4 count). The evaluation assessed improvements in patient engagement, ART adherence, and retention. Difference-in-difference models used clinical data (n = 541 in Tanzania, 571 in Uganda) to compare SMS enrollees to people who would have met SMS eligibility criteria had they been at intervention sites. Interviews with health care providers explored experiences with the SMS program and were analyzed using codes derived deductively from the data. By end-line, SMS participants in Tanzania had significantly improved visit attendance (odds ratio 3.53, 95% confidence interval 2.15, 5.77); a non- significant improvement was seen in Uganda (odds ratio 1.62, 95% confidence interval 0.37, 7.02), which may reflect a dose-response relationship due to shorter program exposure there. Self-management can improve vulnerable patients' outcomes-but maximum gains may require long implementation periods and accompanying system-level interventions. SMS interventions require long-term investment and should be contextualized in the systems and environments in which they operate.

Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis.

RIG-I-like receptors (RLRs) activate host innate immune responses against virus infection through recruiting the mitochondrial adaptor protein MAVS (also known as IPS1, VISA, or CARDIF). Here we show that MAVS also plays a pivotal role in maintaining intestinal homeostasis. We found that MAVS knockout mice developed more severe mortality and morbidity than WT animals in an experimental model of colitis. Bone marrow transplantation experiments revealed that MAVS in cells of nonhematopoietic origin plays a dominant role in the protection against colitis. Importantly, RNA species derived from intestinal commensal bacteria activate the RIG-I-MAVS pathway to induce the production of multiple cytokines and antimicrobial peptides, including IFN-ß and RegIIIγ. These results unveil a previously unexplored role of MAVS in monitoring intestinal commensal bacteria and maintaining tissue homeostasis.

Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface.

The mammalian gastrointestinal tract harbors thousands of bacterial species that include symbionts as well as potential pathogens. The immune responses that limit access of these bacteria to underlying tissue remain poorly defined. Here we show that γδ intraepithelial lymphocytes (γδ IEL) of the small intestine produce innate antimicrobial factors in response to resident bacterial "pathobionts" that penetrate the intestinal epithelium. γδ IEL activation was dependent on epithelial cell-intrinsic MyD88, suggesting that epithelial cells supply microbe-dependent cues to γδ IEL. Finally, γδ T cells protect against invasion of intestinal tissues by resident bacteria specifically during the first few hours after bacterial encounter, indicating that γδ IEL occupy a unique temporal niche among intestinal immune defenses. Thus, γδ IEL detect the presence of invading bacteria through cross-talk with neighboring epithelial cells and are an essential component of the hierarchy of immune defenses that maintain homeostasis with the intestinal microbiota.

Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury.

The intestinal mucosal surface is in direct contact with a vast beneficial microbiota. The symbiotic nature of this relationship is threatened when the surface epithelium is injured, yet little is known about how mucosal surfaces maintain homeostasis with commensal microbes following damage. Gammadelta intraepithelial lymphocytes (gammadelta IEL) reside at the gut epithelial surface, where they stimulate mucosal healing following acute injury. A genome-wide analysis of the gammadelta IEL response to dextran sulfate sodium-induced colonic damage revealed induction of a complex transcriptional program, including coordinate regulation of cytoprotective, immunomodulatory, and antibacterial factors. Studies in germfree mice demonstrated that commensal microbiota regulate key components of this transcriptional program, thus revealing a dialogue between commensal bacteria and gammadelta IEL in injured epithelia. Analysis of TCRdelta-deficient mice indicated that gammadelta T cells are essential for controlling mucosal penetration of commensal bacteria immediately following dextran sulfate sodium-induced damage, suggesting that a key function of gammadelta IEL is to maintain host-microbial homeostasis following acute mucosal injury. Taken together, these findings disclose a reciprocal relationship between gammadelta T cells and intestinal microbiota that promotes beneficial host-microbial relationships in the intestine.

Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface.

The intestinal epithelium is in direct contact with a vast microbiota, yet little is known about how epithelial cells defend the host against the heavy bacterial load. To address this question we studied Paneth cells, a key small intestinal epithelial lineage. We found that Paneth cells directly sense enteric bacteria through cell-autonomous MyD88-dependent toll-like receptor (TLR) activation, triggering expression of multiple antimicrobial factors. Paneth cells were essential for controlling intestinal barrier penetration by commensal and pathogenic bacteria. Furthermore, Paneth cell-intrinsic MyD88 signaling limited bacterial penetration of host tissues, revealing a role for epithelial MyD88 in maintaining intestinal homeostasis. Our findings establish that gut epithelia actively sense enteric bacteria and play an essential role in maintaining host-microbial homeostasis at the mucosal interface.

Using a Multicountry Learning Network to Harvest and Rapidly Spread Implementation Knowledge across Programs Aimed to Reduce Mother-to-Child Transmission of HIV and Improve Nutrition: Perspectives and Lessons Learned for Similar Large-Scale Initiatives.

As countries pursue UNAIDS's 90-90-90 target for ending the AIDS epidemic, success is dependent on learning how to deliver effective care. We describe a learning network and mechanisms used to foster communication and sharing of ideas and results across 6 countries in the Partnership for HIV-Free Survival. The network used 2 forms of peer exchange, in-person and virtual, and a variety of knowledge management mechanisms to harvest and spread key learning. Key learning included valuable insights on how to design and convene a multicountry learning network, including top enablers of success and practical insights on the network's value. The network was instrumental in accelerating learning about improving care. Our experience shows the value of creating a quality improvement-driven, multicountry learning network to accelerate the pace of improving care systems. Government ownership and adaptation of collaborative learning efforts to the country context must be considered when designing future networks.

Barriers to HIV Treatment Adherence: A Qualitative Study of Discrepancies Between Perceptions of Patients and Health Providers in Tanzania and Uganda.

Previous qualitative studies about antiretroviral therapy (ART) adherence have largely focused on patient experiences. Less is known about the perspective of health care providers-particularly in low-income countries-who serve as gatekeepers and influencers of patients' HIV care experiences. This study explored patients' and providers' perceptions of important ART adherence determinants. Interviews were conducted at HIV treatment sites in Tanzania and Uganda, with adult patients on ART (n = 148), and with health care providers (n = 49). Patients were asked about their experiences with ART adherence, and providers were asked about their perceptions of what adherence challenges are faced by their patients. All interviews were conducted in local languages; transcripts were translated into English and analyzed using a codebook informed by the social ecological model. Themes were examined across and within countries. Adherence-related challenges were frequently reported, but patients and providers did not often agree about the reasons. Many patients cited challenges related to being away from home and therefore away from their pill supply; and, in Uganda, challenges picking up refills (access to care) and related to food sufficiency/diet. Providers also identified these access to care barriers, but otherwise focused on different key determinants (e.g., they rarely mentioned food/diet); instead, providers were more likely to mention alcohol/alcoholism, stigma, and lack of understanding about the importance of adhering. These findings suggest areas of opportunity for future research and for improving clinical care by aligning perceptions of adherence challenges, to deliver better-informed and useful ART counseling and support.

Reducing Mother-to-Child Transmission of HIV Using Quality Improvement Approaches.

Over half of mother-to-child HIV transmission (MTCT) occurs postdelivery. Keeping mother-infant pairs in care remains challenging. Health workers in 3 countries used quality improvement (QI) approaches to improve data systems, mother-infant retention, and facility-based care delivery. The number and proportion of infants with known HIV status at time of discharge from early infant diagnosis programs increased in Tanzania and Uganda. We analyzed data using statistical process control charts. Mother-to-child HIV transmission did not decrease in 15 Kenyan sites, decreased from 12.7% to 3.8% in 28 Tanzanian sites, and decreased from 17.2% to 1.5% in 10 Ugandan sites with baseline data. This improvement is likely due to the combination of option B+, service delivery improvements, and retention through QI approaches. Reaching the global MTCT elimination target and maximizing infant survival will require health systems to support mother-infant pairs to remain in care and support health workers to deliver care. Quality improvement approaches can support these changes.

Applying Quality Improvement Approaches to Reduce Mother-to-Child HIV Transmission and Improve Health and Nutrition Care in Five Countries: Lessons from the Partnership for HIV-Free Survival.

The World Health Organization guidelines for treating pregnant HIV-positive women and preventing HIV transmission to infants now recommend lifelong antiretroviral treatment for pregnant and breastfeeding women. We applied quality improvement (QI) methods to support governments and facility staff to address service gaps in 5 countries under the Partnership for HIV-Free Survival (PHFS). We used 3 key strategies: break the complex problem of improving HIV-free survival into more easily implementable phases, support a national management team to oversee the project, and support facility-level staff to learn and apply QI methods to reducing mother-to-child transmission. The key results in each country were increases in data completeness and accuracy, increases in retention in care of mother-baby pairs (MBPs), increase in coverage of MBPs with appropriate services, and reduction in vertical transmission of HIV. The PHFS experience offers a model that other multicountry networks can adopt to improve service delivery and quality of care.

A Host-Produced Autoinducer-2 Mimic Activates Bacterial Quorum Sensing.

Host-microbial symbioses are vital to health; nonetheless, little is known about the role crosskingdom signaling plays in these relationships. In a process called quorum sensing, bacteria communicate with one another using extracellular signal molecules called autoinducers. One autoinducer, AI-2, is proposed to promote interspecies bacterial communication, including in the mammalian gut. We show that mammalian epithelia produce an AI-2 mimic activity in response to bacteria or tight-junction disruption. This AI-2 mimic is detected by the bacterial AI-2 receptor, LuxP/LsrB, and can activate quorum-sensing-controlled gene expression, including in the enteric pathogen Salmonella typhimurium. AI-2 mimic activity is induced when epithelia are directly or indirectly exposed to bacteria, suggesting that a secreted bacterial component(s) stimulates its production. Mutagenesis revealed genes required for bacteria to both detect and stimulate production of the AI-2 mimic. These findings uncover a potential role for the mammalian AI-2 mimic in fostering crosskingdom signaling and host-bacterial symbioses.

Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype.

These studies were conducted to determine the effects of oxidative stress on human T cell differentiation and polarization into Th1 or Th2 phenotypes. Highly purified naive CD4+ T cells were isolated from PBMC of healthy, nonatopic donors. CD4+ T cells were stimulated with anti-CD3 and anti-CD28 mAb in the presence or absence of oxidative stress as supplied by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), which generates a low level of superoxide anion. Increases in cellular superoxide were observed by exposure to DMNQ. Exposure of unpolarized CD4+ T cells to IL-12 or IL-4 resulted in a Th1 or Th2 phenotype, respectively. T cells stimulated in the absence of polarizing cytokines secreted modest amounts of IFN-gamma and TNF-alpha. Cells stimulated in the continuous presence of 5 microM DMNQ, displayed a marked up-regulation in Th2 cytokines, including IL-4, IL-5, and IL-13, but not the Th1 cytokine IFN-gamma. Th2 responses were blunted by concomitant exposure to thiol antioxidants. Long-term exposure of T cells to DMNQ resulted in growth of cells expressing CCR4, and a decrease in cells expressing CXCR3, indicating phenotypic conversion to Th2 cells. These results suggest that oxidative stress favors a Th2-polarizing condition.

Epithelial cells and their neighbors. IV. Bacterial contributions to intestinal epithelial barrier integrity.

Mammalian intestinal surfaces are in constant and intimate contact with a vast consortium of indigenous commensal bacteria. As a result, gut epithelia have evolved an array of strategies for limiting bacterial invasion into deeper tissues, helping to preserve the mutually beneficial nature of intestinal host-microbial relationships. In this review, we discuss a growing body of evidence indicating that commensal bacteria are actively involved in shaping the very barriers that confine them to the gut lumen. By modulating epithelial inflammatory responses, antimicrobial protein expression, and tissue repair functions, indigenous microbial populations are essential for the maintenance of healthy mucosal surfaces.