Effectiveness of the female condom in preventing HIV and sexually transmitted infections: a systematic review and meta-analysis.

BACKGROUND: The effectiveness of female condoms for preventing HIV and sexually transmitted infections (STIs) remains inconclusive. We examined the effects of female condoms on the acquisition of HIV and STIs. METHODS: We searched four databases, two trial registries, and reference lists of relevant publications in October 2018 and updated our search in February 2020. We screened search output, evaluated study eligibility, and extracted data in duplicate; resolving differences through discussion. We calculated the effective sample size of cluster randomised trials using an intra-cluster correlation coefficient of 0·03. Data from similar studies were combined in a meta-analysis. We performed a non-inferiority analysis of new condoms relative to marketed ones using a non-inferiority margin of 3%. We assessed the certainty of evidence using GRADE. RESULTS: We included fifteen studies of 6921 women. We found that polyurethane female condoms (FC1) plus male condoms may be as effective as male condoms only in reducing HIV acquisition (1 trial, n = 149 women, RR 0.07, 95%CI 0.00-1.38; low-certainty evidence). However, the use of FC1 plus male condoms is superior to male condoms alone in reducing the acquisition of gonorrhoea (2 trials, n = 790, RR 0.59, 95%CI 0.41-0.86; high-certainty evidence) and chlamydia (2 trials, n = 790, RR 0.67, 95%CI 0.47-0.94; high-certainty evidence). Adverse events and failure rates of FC1 were very low and decreased during follow up. Although the functionality of newer female condoms (Woman's, Cupid, Pheonurse, Velvet, and Reddy) may be non-inferior to FC2, there were no available studies assessing their efficacy in preventing HIV and STIs. CONCLUSION: The use of female plus male condoms is more effective than use of male condoms only in preventing STIs and may be as effective as the male condom only in preventing HIV. There is a need for well conducted studies assessing the effects of newer female condoms on HIV and STIs. PROSPERO REGISTRATION NUMBER: CRD42018090710.

Access to HIV care and treatment for migrants between Lesotho and South Africa: a mixed methods study.

BACKGROUND: HIV treatment and care for migrants is affected by their mobility and interaction with HIV treatment programs and health care systems in different countries. To assess healthcare needs, preferences and accessibility barriers of HIV-infected migrant populations in high HIV burden, borderland districts of Lesotho. METHODS: We selected 15 health facilities accessed by high patient volumes in three districts of Maseru, Leribe and Mafeteng. We used a mixed methods approach by administering a survey questionnaire to consenting HIV infected individuals on anti-retroviral therapy (ART) and utilizing a purposive sampling procedure to recruit health care providers for qualitative in-depth interviews across facilities. RESULTS: Out of 524 HIV-infected migrants enrolled in the study, 315 (60.1%) were from urban and 209 (39.9%) from rural sites. Of these, 344 (65.6%) were women, 375 (71.6%) were aged between 26 and 45 years and 240 (45.8%) were domestic workers. A total of 486 (92.7%) preferred to collect their medications primarily in Lesotho compared to South Africa. From 506 who responded to the question on preferred dispensing intervals, 63.1% (n = 319) preferred 5-6 month ARV refills, 30.2% (n = 153) chose 3-4 month refills and only 6.7% (n = 34) opted for the standard-of-care 1-2 month refills. A total of 126 (24.4%) defaulted on their treatment and the primary reason for defaulting was failure to get to Lesotho to collect medication (59.5%, 75/126). Treatment default rates were higher in urban than rural areas (28.3% versus 18.4%, p = 0.011). Service providers indicated a lack of transfer letters as the major drawback in facilitating care and treatment for migrants, followed by discrimination based on nationality or language. Service providers indicated that most patients preferred all treatment services to be rendered in Lesotho, as they perceive the treatment provided in South Africa to be different often less strong or with more serious side effects. CONCLUSION: Existing healthcare systems in both South Africa and Lesotho experience challenges in providing proper care and treatment for HIV infected migrants. A need for a differentiated model of ART delivery to HIV infected migrants that allows for multi-month scripting and dispensing is warranted.

CD14(+) macrophages that accumulate in the colon of African AIDS patients express pro-inflammatory cytokines and are responsive to lipopolysaccharide.

BACKGROUND: Intestinal macrophages are key regulators of inflammatory responses to the gut microbiome and play a central role in maintaining tissue homeostasis and epithelial integrity. However, little is known about the role of these cells in HIV infection, a disease fuelled by intestinal inflammation, a loss of epithelial barrier function and increased microbial translocation (MT). METHODS: Phenotypic and functional characterization of intestinal macrophages was performed for 23 African AIDS patients with chronic diarrhea and/or weight loss and 11 HIV-negative Africans with and without inflammatory bowel disease (IBD). AIDS patients were treated with cotrimoxazole for the prevention of opportunistic infections (OIs). Macrophage phenotype was assessed by flow cytometry and immuno-histochemistry (IHC); production of proinflammatory mediators by IHC and Qiagen PCR Arrays; in vitro secretion of cytokines by the Bio-Plex Suspension Array System. Statistical analyses were performed using Spearman's correlation and Wilcoxon matched-pair tests. Results between groups were analyzed using the Kruskal-Wallis with Dunn's post-test and the Mann-Whitney U tests. RESULTS: None of the study participants had evidence of enteric co-infections as assessed by stool analysis and histology. Compared to healthy HIV-negative controls, the colon of AIDS patients was highly inflamed with increased infiltration of inflammatory cells and increased mRNA expression of proinflammatory cytokine (tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IFN-γ, and IL-18), chemokines (chemokine (C-C motif) ligand (CCL)2 and chemokine (C-X-C) motif ligand (CXCL)10) and transcription factors (TNF receptor-associated factor (TRAF)6 and T-box (TXB)21). IHC revealed significant co-localization of TNF-α and IL-1ß with CD68(+) cells. As in IBD, HIV was associated with a marked increase in macrophages expressing innate response receptors including CD14, the co-receptor for lipopolysaccharide (LPS). The frequency of CD14(+) macrophages correlated positively with plasma LPS, a marker of MT. Total unfractionated mucosal mononuclear cells (MMC) isolated from the colon of AIDS patients, but not MMC depleted of CD14(+) cells, secreted increased levels of proinflammatory cytokines ex vivo in response to LPS. CONCLUSIONS: Intestinal macrophages, in the absence of overt OIs, play an important role in driving persistent inflammation in HIV patients with late-stage disease and diarrhea. These results suggest intensified treatment strategies that target inflammatory processes in intestinal macrophages may be highly beneficial in restoring the epithelial barrier and limiting MT in HIV-infected patients.

Impaired CD4+ T-cell restoration in the small versus large intestine of HIV-1-positive South Africans receiving combination antiretroviral therapy.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection is associated with a massive depletion of intestinal CD4(+) T cells that is only partially reversed by combination antiretroviral therapy (cART). Here, we assessed the ability of nucleoside reverse-transcriptase inhibitor/nonnucleoside reverse-transcriptase inhibitor treatment to restore the CD4(+) T-cell populations in the intestine of South African patients with AIDS. METHODS: Thirty-eight patients with advanced HIV-1 infection who had chronic diarrhea (duration, >4 weeks) and/or unintentional weight loss (>10% decrease from baseline) of uncertain etiology were enrolled. Blood specimens were collected monthly, and gastrointestinal tract biopsy specimens were collected before cART initiation (from the duodenum, jejunum, ileum, and colon), 3 months after cART initiation (from the duodenum), and 6 months after cART initiation (from the duodenum and colon). CD4(+), CD8(+), and CD38(+)CD8(+) T cells were quantified by flow cytometry and immunohistochemistry analyses, and the HIV-1 RNA load was determined by the Nuclisens assay. RESULTS: CD4(+) T-cell and HIV-1 RNA levels were significantly lower, whereas CD8(+) T-cell levels, including activated CD38(+)CD8(+) T cell levels, were higher in the duodenum and jejunum, compared with the colon. After 6 months of cART, a significant but incomplete recovery of CD4(+) T cells was detected in the colon and peripheral blood but not in the duodenum. Failed restoration of the CD4(+) T-cell count in the duodenum was associated with nonspecific enteritis and CD8(+) T-cell activation. CONCLUSIONS: Strategies that target inflammation and immune activation in the small intestine may be required to expedite CD4(+) T-cell recovery and improve therapeutic outcomes.

Health trends, inequalities and opportunities in South Africa's provinces, 1990-2019: findings from the Global Burden of Disease 2019 Study.

BACKGROUND: Over the last 30 years, South Africa has experienced four 'colliding epidemics' of HIV and tuberculosis, chronic illness and mental health, injury and violence, and maternal, neonatal, and child mortality, which have had substantial effects on health and well-being. Using data from the 2019 Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2019), we evaluated national and provincial health trends and progress towards important Sustainable Development Goal targets from 1990 to 2019. METHODS: We analysed GBD 2019 estimates of mortality, non-fatal health loss, summary health measures and risk factor burden, comparing trends over 1990-2007 and 2007-2019. Additionally, we decomposed changes in life expectancy by cause of death and assessed healthcare system performance. RESULTS: Across the nine provinces, inequalities in mortality and life expectancy increased over 1990-2007, largely due to differences in HIV/AIDS, then decreased over 2007-2019. Demographic change and increases in non-communicable diseases nearly doubled the number of years lived with disability between 1990 and 2019. From 1990 to 2019, risk factor burdens generally shifted from communicable and nutritional disease risks to non-communicable disease and injury risks; unsafe sex remained the top risk factor. Despite widespread improvements in healthcare system performance, the greatest gains were generally in economically advantaged provinces. CONCLUSIONS: Reductions in HIV/AIDS and related conditions have led to improved health since 2007, though most provinces still lag in key areas. To achieve health targets, provincial governments should enhance health investments and exchange of knowledge, resources and best practices alongside populations that have been left behind, especially following the COVID-19 pandemic.

Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy.

BACKGROUND: Microbial translocation contributes to immune activation and disease progression during chronic human immunodeficiency virus type 1 (HIV-1) infection. However, its role in the African AIDS epidemic remains controversial. Here, we investigated the relationship between markers of monocyte activation, plasma lipopolysaccharide (LPS), and HIV-1 RNA in South Africans prioritized to receive combination antiretroviral therapy (cART). METHODS: Ten HIV-1-negative African controls and 80 HIV-1-infected patients with CD4 T cell counts <200 cells/microL were sampled prior to (n=60) or during (n=20) receipt of effective cART. Viral load was measured by Nuclisens; LPS by the Limulus amoebocyte lysate assay; monocyte and T cell subsets by flow cytometry; and soluble CD14, cytokines, and chemokines by enzyme-linked immunosorbent assay and customized Bio-Plex plates. RESULTS: Three distinct sets of markers were identified. CCL2, CXCL10, and CD14(+)CD16(+) monocyte levels were positively correlated with HIV-1 viremia. This finding, together with cART-induced normalization of these markers, suggests that their upregulation was driven by HIV-1. Plasma interleukin-6 was associated with the presence of opportunistic coinfections. Soluble CD14 and tumor necrosis factor were linked to plasma LPS levels and, as observed for LPS, remained elevated in patients receiving effective cART. CONCLUSIONS: Microbial translocation is a major force driving chronic inflammation in HIV-infected Africans receiving cART. Prevention of monocyte activation may be especially effective at enhancing therapeutic outcomes.

COVID-19 Is a Multi-Organ Aggressor: Epigenetic and Clinical Marks.

The progression of coronavirus disease 2019 (COVID-19), resulting from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be influenced by both genetic and environmental factors. Several viruses hijack the host genome machinery for their own advantage and survival, and similar phenomena might occur upon SARS-CoV-2 infection. Severe cases of COVID-19 may be driven by metabolic and epigenetic driven mechanisms, including DNA methylation and histone/chromatin alterations. These epigenetic phenomena may respond to enhanced viral replication and mediate persistent long-term infection and clinical phenotypes associated with severe COVID-19 cases and fatalities. Understanding the epigenetic events involved, and their clinical significance, may provide novel insights valuable for the therapeutic control and management of the COVID-19 pandemic. This review highlights different epigenetic marks potentially associated with COVID-19 development, clinical manifestation, and progression.

PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX-5.

ESX-5 is one of the five type VII secretion systems found in mycobacteria. These secretion systems are also known as ESAT-6-like secretion systems. Here, we have determined the secretome of ESX-5 by a proteomic approach in two different strains of Mycobacterium marinum. Comparison of the secretion profile of wild-type strains and their ESX-5 mutants showed that a number of PE_PGRS and PPE-MPTR proteins are dependent on ESX-5 for transport. The PE and PPE protein families are unique to mycobacteria, are highly expanded in several pathogenic species, such as Mycobacterium tuberculosis and M. marinum, and certain family members are cell surface antigens associated with virulence. Using a monoclonal antibody directed against the PGRS domain we showed that nearly all PE_PGRS proteins that are recognized by this antibody are missing in the supernatant of ESX-5 mutants. In addition to PE_PGRS and PPE proteins, the ESX-5 secretion system is responsible for the secretion of a ESAT-6-like proteins. Together, these data show that ESX-5 is probably a major secretion pathway for mycobacteria and that this system is responsible for the secretion of recently evolved PE_PGRS and PPE proteins.

A systematic review of immunogenicity, clinical efficacy and safety of human papillomavirus vaccines in people living with the human immunodeficiency virus.

The human papillomavirus (HPV) is the most prevalent sexually transmitted infection worldwide. People living with the human immunodeficiency virus (HIV) are at high risk of HPV infection. This systematic review evaluates the immunogenicity, clinical efficacy, and safety of prophylactic HPV vaccines in people living with HIV. We registered the protocol for this review in the International Prospective Register of Systematic Reviews (CRD42018109898) and prepared the review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Five randomized trials with 1042 participants are included in this review. One trial with 120 participants compared the bivalent HPV vaccine to placebo, three trials with 830 participants compared the quadrivalent vaccine to placebo, and another trial with 92 participants compared the quadrivalent to the bivalent vaccine. There was low to moderate certainty evidence suggesting that seroconversion was higher among participants in the vaccine arms compared to the placebo arms for both vaccines. In one study with very low certainty evidence, participants who received the bivalent vaccine had higher anti-HPV-18 geometric mean titers (GMTs) compared to those who received the quadrivalent vaccine, despite little difference in anti-HPV-16 GMTs between the two vaccines. There were no differences in the incident and persistent HPV infections in both groups. None of the studies reported data on the incidence of precancerous lesions, or cancer. There were no reports of serious adverse events following vaccination in any of the trials. None of the included studies assessed the effects of HPV vaccines in adolescents living with HIV. Very limited evidence suggests lower immunogenicity of HPV vaccines in HIV positive compared to HIV-negative people. Finally, the long-term effect of the HPV vaccine in the incidence of cervical precancerous lesions and cervical cancer needs to be monitored. There is an urgent need for more high-quality randomized controlled trials that can address these gaps.

Contextualised strategies to increase childhood and adolescent vaccination coverage in South Africa: a mixed-methods study.

INTRODUCTION: Despite the unparalleled success of immunisation in the control of vaccine preventable diseases, immunisation coverage in South Africa remains suboptimal. While many evidence-based interventions have successfully improved vaccination coverage in other countries, they are not necessarily appropriate to the immunisation needs, barriers and facilitators of South Africa. The aim of this research is to investigate barriers and facilitators to optimal vaccination uptake, and develop contextualised strategies and implementation plans to increase childhood and adolescent vaccination coverage in South Africa. METHODS: The study will employ a mixed-methods research design. It will be conducted over three iterative phases and use the Adopt, Contextualise or Adapt (ACA) model as an overarching conceptual framework. Phase 1 will identify, and develop a sampling frame of, immunisation stakeholders involved in the design, planning and implementation of childhood and human papillomavirus immunisation programmes in South Africa. Phase 2 will identify the main barriers and facilitators to, and solutions for, increasing vaccination coverage. This phase will comprise exploratory qualitative research with stakeholders and a review of existing systematic reviews on interventions for improving vaccination coverage. Using the findings from Phase 2 and the ACA model, Phase 3 will develop a set of proposed interventions and implementation action plans for improving immunisation coverage in South Africa. These plans will be discussed, revised and finalised through a series of participatory stakeholder workshops and an online questionnaire, conducted as part of Phase 3. ETHICS: Ethical approval was obtained from the South African Medical Research Council (EC018-11/2018). No risks to participants are expected. Various steps will be taken to ensure the anonymity and confidentiality of participants. DISSEMINATION: The study findings will be shared at stakeholder workshops, the website of Cochrane South Africa and academic publications and conferences.

Systematic review protocol on Bacillus Calmette-Guerin (BCG) revaccination and protection against tuberculosis.

INTRODUCTION: Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (M.TB) and other species of the Mycobacterium tuberculosis complex. Globally, TB is ranked as the ninth leading cause of death and the leading cause of death from a single infectious agent. The bacille Calmette-Guerin (BCG) vaccine has been used globally since 1921 for the prevention of TB in humans, and was derived from an attenuated strain of Mycobacterium bovis. Evidence from previous randomised trials show that the efficacy of primary BCG vaccination against pulmonary TB ranged from no protection to very high protection. In addition, some studies suggest a benefit of BCG revaccination. For example, a recent trial conducted in South Africa showed that BCG revaccination of adolescents could reduce the risk of TB infection by half. However, we are not aware of any recent systematic reviews of the effects of BCG revaccination. Thus, the need for this systematic review of the effects of BCG revaccination on protection against TB infection and disease. METHOD AND ANALYSIS: We will search PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, WHO International Clinical Trials Registry Platform and reference lists of relevant publications for potentially eligible studies. We will screen search outputs, select eligible studies, extract data and assess risk of bias in duplicate. Discrepancies will be resolved by discussion and consensus or arbitration. We will use the Grading of Recommendations Assessment, Development and Evaluation method to assess the certainty of the evidence. The planned systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in August 2018. ETHICS AND DISSEMINATION: Publicly available data will be used, hence no formal ethical approval will be required for this review. The findings of the review will be disseminated through conference presentations and publication in an open-access peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42018105916.

A global review of seasonal influenza vaccine introduction: analysis of the WHO/UNICEF Joint Reporting Form.

Background: Influenza is a highly contagious disease that affects the upper and lower respiratory tract caused by several subtypes of influenza viruses. While vaccination remains the mainstay strategy to protect populations against influenza, there is a global shortage and inequitable access to influenza vaccines. Although influenza vaccine production capacity increased from 500 million doses in 2006 to 1.5 billion doses in 2013, little is known about the global distribution of these vaccines albeit its introduction. We assessed the global status of influenza vaccine introduction. Research design and methods: We analyzed data from the World Health Organization (WHO) Joint Reporting Form, a publicly available source of immunization data from 194 countries of all six WHO regions. We used 2017 data, available as of July 2018. Results: By December 2017, 117 of 194 (60%) WHO Member States had introduced the seasonal influenza vaccine. European and American regions accounted for 70% (82/117) of the total number of countries that had introduced influenza vaccine. The other four regions account for only 30%. Ninety-four percent (50/53) of countries in the European region and 91% (32/35) in the American region had introduced influenza vaccine. In the Eastern Mediterranean and Western Pacific regions, 67% (14/21) and 52% (14/27), respectively, had introduced the vaccine. Yet only 27% (3/11) and 9% (4/47) in the Southeast Asian and African regions, respectively, had introduced the vaccine. Among countries (n = 117) that had introduced the vaccine, children (56%), older adults (87%), and risk groups (99%) were prioritized and given the vaccines. Conclusions: Introduction of influenza vaccine in the African and Southeast Asian regions remains suboptimal. This critically underscores the need for financing mechanisms and having countries in the regions that are lagging behind to prioritize seasonal influenza vaccine.