Probiotic and Prebiotic Supplementation of Antiretroviral Therapy Improves Gastrointestinal Immunity in SIV-infected Macaques
ABSTRACT: HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, in order to enhance GI tract immunity, we treated SIV-infected pigtail macaques with ARVs supplemented with probiotics and prebiotics or with ARVs alone. In the colon, this synbiotic treatment resulted in increased expression of genes associated with antigen presenting cells (APCs), increased frequency and functionality of APCs, enhanced reconstitution and functionality of CD4+ T-cells and reduced fibrosis of lymphoid follicles. Thus, supplementing ARV treatment with synbiotic treatment in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis. Overall design: CD45+ (clone MB4-6D6) leukocytes were sorted from thawed colon samples from 4 ARV + probiotics animals and 4 ARV alone animals
Project description:HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, in order to enhance GI tract immunity, we treated SIV-infected pigtail macaques with ARVs supplemented with probiotics and prebiotics or with ARVs alone. In the colon, this synbiotic treatment resulted in increased expression of genes associated with antigen presenting cells (APCs), increased frequency and functionality of APCs, enhanced reconstitution and functionality of CD4+ T-cells and reduced fibrosis of lymphoid follicles. Thus, supplementing ARV treatment with synbiotic treatment in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis. CD45+ (clone MB4-6D6) leukocytes were sorted from thawed colon samples from 4 ARV + probiotics animals and 4 ARV alone animals
Project description:Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal Th17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4(+) T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as Th17 cells, had limited recovery. Here, we sought to promote Th17 cell recovery by administering interleukin (IL)-21 to a limited number of ARV-treated, probiotic-supplemented, Simian Immunodeficiency Virus (SIV)-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs are associated with enhanced polyfunctional Th17 expansion and reduced markers of microbial translocation and dysbiosis as compared with infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared with controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected individuals.
Project description:Mortality in patients with HIV infection is increasingly due to comorbid medical conditions. Research on how adherence to medications for comorbidities relates to antiretroviral (ARV) medication adherence and how interrelations between illness perceptions and medication beliefs about HIV and comorbidities affect medication adherence is needed to inform adherence interventions.HIV-infected adults with hypertension (HTN) (n = 151) or chronic kidney disease (CKD; n = 41) were recruited from ambulatory practices at an academic medical center. Illness perceptions and medication beliefs about HIV and HTN or CKD were assessed and adherence to one ARV medication and one medication for either HTN or CKD was electronically monitored for 10 weeks.Rates of taking, dosing, and timing adherence to ARV medication did not differ from adherence to medication for HTN or CKD, with the exception that patients were more adherent to the timing of their ARV (78%) than to the timing of their antihypertensive (68%; P = 0.01). Patients viewed HIV as better understood, more chronic, having more negative consequences, and eliciting more emotions, compared with HTN. Patients viewed ARVs as more necessary than medication for HTN or CKD. Having a realistic view of the efficacy of ARVs (r = -0.20; P < 0.05) and a high level of perceived HIV understanding (r = 0.21; P < 0.05) correlated with better ARV adherence.Patients with HIV showed similar rates of adherence to ARVs as to medications for comorbidities, despite perceiving HIV as more threatening and ARVs as more important. This can be used in adapting existing interventions for ARV adherence to encompass adherence to medications for comorbid conditions.
Project description:BACKGROUND: Religion shapes everyday beliefs and activities, but few studies have examined its associations with attitudes about HIV. This exploratory study in Tanzania probed associations between religious beliefs and HIV stigma, disclosure, and attitudes toward antiretroviral (ARV) treatment. METHODS: A self-administered survey was distributed to a convenience sample of parishioners (n = 438) attending Catholic, Lutheran, and Pentecostal churches in both urban and rural areas. The survey included questions about religious beliefs, opinions about HIV, and knowledge and attitudes about ARVs. Multivariate logistic regression analysis was performed to assess how religion was associated with perceptions about HIV, HIV treatment, and people living with HIV/AIDS. RESULTS: Results indicate that shame-related HIV stigma is strongly associated with religious beliefs such as the belief that HIV is a punishment from God (p < 0.01) or that people living with HIV/AIDS (PLWHA) have not followed the Word of God (p < 0.001). Most participants (84.2%) said that they would disclose their HIV status to their pastor or congregation if they became infected. Although the majority of respondents (80.8%) believed that prayer could cure HIV, almost all (93.7%) said that they would begin ARV treatment if they became HIV-infected. The multivariate analysis found that respondents' hypothetical willingness to begin ARV treatme was not significantly associated with the belief that prayer could cure HIV or with other religious factors. Refusal of ARV treatment was instead correlated with lack of secondary schooling and lack of knowledge about ARVs. CONCLUSION: The decision to start ARVs hinged primarily on education-level and knowledge about ARVs rather than on religious factors. Research results highlight the influence of religious beliefs on HIV-related stigma and willingness to disclose, and should help to inform HIV-education outreach for religious groups.
Project description:SIV DNA can be detected in lymphoid tissue-resident macrophages of chronically SIV-infected Asian macaques. These macrophages also contain evidence of recently phagocytosed SIV-infected CD4+ T cells. Here, we examine whether these macrophages contain replication-competent virus, whether viral DNA can be detected in tissue-resident macrophages from antiretroviral (ARV) therapy-treated animals and humans, and how the viral sequences amplified from macrophages and contemporaneous CD4+ T cells compare. In ARV-naive animals, we find that lymphoid tissue-resident macrophages contain replication-competent virus if they also contain viral DNA in ARV-naive Asian macaques. The genetic sequence of the virus within these macrophages is similar to those within CD4+ T cells from the same anatomic sites. In ARV-treated animals, we find that viral DNA can be amplified from lymphoid tissue-resident macrophages of SIV-infected Asian macaques that were treated with ARVs for at least 5 months, but we could not detect replication-competent virus from macrophages of animals treated with ARVs. Finally, we could not detect viral DNA in alveolar macrophages from HIV-infected individuals who received ARVs for 3 years and had undetectable viral loads. These data demonstrate that macrophages can contain replication-competent virus, but may not represent a significant reservoir for HIV in vivo.
Project description:HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation. These are not completely normalized with combined antiretroviral therapy (cART). Moreover, increate morbidity and mortality of cART-treated HIV-infected individuals is associated with inflammation.In order to enhance GI tract immunity, we recruited and treated 20 HIV-infected humans with cART supplemented with probiotics and followed inflammation and immunological parameters (clinical trial number NCT02164344). 11 HIV seronegative subjects were included as control group. The enumeration of CD4+, CD8+, CD38+ and HLA-DR+ lymphocytes were evaluated on peripheral blood; HIV-RNA levels, sCD14, d-dimer, C-reactive protein (CRP) high sensitivity C-reactive protein (hsCRP), IL-6 and Lipopolysaccharide Binding Protein (LBP) were assayed on plasma.We observe that cART does not normalize the levels of immune activation in HIV positive patients anyway inflammation and markers of microbial translocation were significantly reduced with probiotic supplementation. Patients show a clear and statistically significant reduction in the levels of immune activation on CD4 T-lymphocytes, for both markers CD38 and HLA-DR and their simultaneous expression, LBP and hsCRP plasma levels after probiotic diet supplementation settling to values comparable to controls.Supplementing cART with probiotics in HIV-infected individuals may improve GI tract immunity and there by mitigate inflammatory sequelae, ultimately improving prognosis.ClinicalTrials.gov NCT02164344.
Project description:The World Health Organization (WHO) recommends that the role of pharmacists in low-income settings be expanded to address the increasing complexity of HIV antiretroviral (ARV) and co-infection drug regimens. However, in many such settings including in India, many pharmacists and pharmacy workers are often neither well trained nor aware of the intricacies of HIV treatment. The aims of our study were; to determine the availability of ARVs, provision of ARVs, knowledge about ARVs, attitudes towards HIV-infected persons and self-perceived need for training among community-based pharmacies in an urban area of India.We performed a survey of randomly selected, community-based pharmacies located in Pune, India, in 2004-2005 to determine the availability of ARVs at these pharmacies, how they were providing ARVs and their self-perceived need for training. We also assessed knowledge, attitudes and perceptions on HIV and ARVs and factors associated with stocking ARVs.Of 207 pharmacies included in the survey, 200 (96.6%) were single, private establishments. Seventy-three (35.3%) pharmacies stocked ARVs and 38 (18.4%) ordered ARVs upon request. The reported median number of ARV pills that patients bought at one time was 30, a two week supply of ARVs (range: 3-240 pills). Six (2.9%) pharmacy respondents reported selling non-allopathic medicines (i.e. Ayurvedic, homeopathy) for HIV. Ninety (44.2%) pharmacy respondents knew that ARVs cannot cure HIV, with those stocking ARVs being more likely to respond correctly (60.3% vs. 34.8%, p = 0.001). Respondents of pharmacies which stocked ARVs were also more likely to believe it was a professional obligation to provide medications to HIV-infected persons (91.8% vs. 78.8%, p = 0.007) but they were also more likely to believe that HIV-infected persons are unable to adhere to their medicines (79.5% vs. 40.9%, p < 0.01). Knowledge of the most common side effects of nevirapine, abnormal liver enzyme profile and skin rash, was reported correctly by 8 (3.9%) and 23 (11.1%) respondents, respectively. Seven (3.4%) respondents reported that they had received special training on HIV, 3 (1.5%) reported receipt of special training on ART and 167 (80.7%) reported that they believed that pharmacy staff should get special training on ART.There is a high willingness to participate in HIV management among community-based pharmacies but there is a tremendous need for training on HIV therapies. Furthermore, stigmatizing attitudes towards HIV-infected persons persist and interventions to reduce stigma are needed, particularly among those that stock ARVs.
Project description:Gastrointestinal (GI) immune system competency is dependent upon interactions with commensal microbiota, which can be influenced by wide-ranging pharmacologic interventions. In simian immunodeficiency virus (SIV)-infected Asian macaque models of human immunodeficiency virus (HIV) infection, we previously noted that initiation of antiretroviral therapy (ART) is associated with a specific imbalance (dysbiosis) of the composition of the intestinal bacteriome. To determine if ART itself might contribute to dysbiosis or immune dysfunction, we treated healthy rhesus macaques with protease, integrase, or reverse transcriptase inhibitors for 1 to 2 or for 5 to 6?weeks and evaluated intestinal immune function and the composition of the fecal bacterial microbiome. We observed that individual antiretrovirals (ARVs) modestly altered intestinal T-cell proinflammatory responses without disturbing total or activated T-cell frequencies. Moreover, we observed transient disruptions in bacterial diversity coupled with perturbations in the relative frequencies of bacterial communities. Shifts in specific bacterial frequencies were not persistent posttreatment, however, with individual taxa showing only isolated associations with T-cell proinflammatory responses. Our findings suggest that intestinal bacterial instability and modest immunological alterations can result from ART itself. These data could lead to therapeutic interventions which stabilize the microbiome in individuals prescribed ART.IMPORTANCE Dysbiosis of the fecal microbiome is a common feature observed in ARV-treated people living with HIV. The degree to which HIV infection itself causes this dysbiosis remains unclear. Here, we demonstrate that medications used to treat HIV infection can influence the composition of the GI tract immune responses and its microbiome in the nonhuman primate SIV model.
Project description:Poor adherence remains a major barrier to achieving the clinical and public health benefits of antiretroviral drugs (ARVs). A systematic review and qualitative meta-synthesis was conduct to evaluate how ARV adverse drug reactions may influence ARV adherence. Thirty-nine articles were identified, and 33 reported that ARV adverse drug reactions decreased adherence and six studies found no influence. Visually noticeable adverse drug reactions and psychological adverse reactions were reported as more likely to cause non-adherence compared to other adverse drug reactions. Six studies reported a range of adverse reactions associated with EFV-containing regimens contributing to decreased adherence. Informing HIV-infected individuals about ARV adverse drug reactions prior to initiation, counselling about coping mechanisms, and experiencing the effectiveness of ARVs on wellbeing may improve ARV adherence.
Project description:OBJECTIVE:In resource-limited settings without safe alternatives to breastfeeding, the WHO recommends exclusive breastfeeding and antiretroviral (ARV) prophylaxis. Given the high prevalence of anemia among HIV-infected women, mothers and their infants (through fetal iron accretion) may be at risk of iron deficiency. We assessed the effects of maternal micronutrient-fortified lipid-based nutrient supplements (LNS) and maternal ARV treatment or infant ARV prophylaxis on maternal and infant iron status during exclusive breastfeeding from birth to 24 weeks. METHODS:The Breastfeeding, Antiretrovirals, and Nutrition study was a randomized controlled trial conducted in Lilongwe, Malawi, from 2004 to 2010. HIV-infected mothers (CD4 >200 cells/μL) and their infants were randomly assigned to 28-week interventions: maternal LNS/maternal ARV (n = 424), maternal LNS/infant ARV (n = 426), maternal LNS (n = 334), maternal ARV (n = 425), infant ARV (n = 426), or control (n = 334). Longitudinal models tested intervention effects on hemoglobin (Hb). In a subsample (n = 537) with multiple iron indicators, intervention effects on Hb, transferrin receptors (TfR), and ferritin were tested with linear and Poisson regression. RESULTS:In longitudinal models, LNS effects on maternal and infant Hb were minimal. In subsample mothers, maternal ARVs were associated with tissue iron depletion (TfR >8.3 mg/L) (risk ratio: 3.1, P < 0.01), but not in ARV-treated mothers receiving LNS (P = 0.17). LNS without ARVs was not associated with iron deficiency or anemia (P > 0.1). In subsample infants, interventions were not associated with impaired iron status (all P > 0.1). CONCLUSIONS:Maternal ARV treatment with protease inhibitors is associated with maternal tissue iron depletion; but LNS mitigates adverse effects. ARVs do not seem to influence infant iron status; however, extended use needs to be evaluated.