Enhancing HIV positivity yield in southern Mozambique: The effect of a Ministry of Health training module in targeted provider-initiated testing and counselling.

In Mozambique, targeted provider-initiated HIV testing and counselling (PITC) is recommended where universal PITC is not feasible, but its effectiveness depends on healthcare providers' training. This study aimed to evaluate the effect of a Ministry of Health training module in targeted PITC on the HIV positivity yield, and identify factors associated with a positive HIV test. We conducted a single-group pre-post study between November 2018 and November 2019 in the triage and emergency departments of four healthcare facilities in Manhiça District, a resource-constrained semi-rural area. It consisted of two two-month phases split by a one-week targeted PITC training module ("observation phases"). The HIV positivity yield of targeted PITC was estimated as the proportion of HIV-positive individuals among those recommended for HIV testing by the provider. Additionally, we extracted aggregated health information system data over the four months preceding and following the observation phases to compare yield in real-world conditions ("routine phases"). Logistic regression analysis from observation phase data was conducted to identify factors associated with a positive HIV test. Among the 7,102 participants in the pre- and post-training observation phases (58.5% and 41.5% respectively), 68% were women, and 96% were recruited at triage. In the routine phases with 33,261 individuals (45.8% pre, 54.2% post), 64% were women, and 84% were seen at triage. While HIV positivity yield between pre- and post-training observation phases was similar (10.9% (269/2470) and 11.1% (207/1865), respectively), we observed an increase in yield in the post-training routine phase for women in triage, rising from 4.8% (74/1553) to 7.3% (61/831) (Yield ratio = 1.54; 95%CI: 1.11-2.14). Age (25-49 years) (OR = 2.43; 95%CI: 1.37-4.33), working in industry/mining (OR = 4.94; 95%CI: 2.17-11.23), unawareness of partner's HIV status (OR = 2.50; 95%CI: 1.91-3.27), and visiting a healer (OR = 1.74; 95%CI: 1.03-2.93) were factors associated with a positive HIV test. Including these factors in the targeted PITC algorithm could have increased new HIV diagnoses by 2.6%. In conclusion, providing refresher training and adapting the current targeted PITC algorithm through further research can help reach undiagnosed PLHIV, treat all, and ultimately eliminate HIV, especially in resource-limited rural areas.

Vaccines and therapeutics for immunocompromised patients with COVID-19.

The COVID-19 pandemic has disproportionately impacted immunocompromised patients. This diverse group is at increased risk for impaired vaccine responses, progression to severe disease, prolonged hospitalizations and deaths. At particular risk are people with deficiencies in lymphocyte number or function such as transplant recipients and those with hematologic malignancies. Such patients' immune responses to vaccination and infection are frequently impaired leaving them more vulnerable to prolonged high viral loads and severe complications of COVID-19. Those in turn, have implications for disease progression and persistence, development of immune escape variants and transmission of infection. Data to guide vaccination and treatment approaches in immunocompromised people are generally lacking and extrapolated from other populations. The large clinical trials leading to authorisation and approval of SARS-CoV-2 vaccines and therapeutics included very few immunocompromised participants. While experience is accumulating, studies focused on the special circumstances of immunocompromised patients are needed to inform prevention and treatment approaches.

Evaluating the sustainability of differentiated service delivery interventions for stable ART clients in sub-Saharan Africa: a systematic review protocol.

INTRODUCTION: In 2015, WHO recommended immediate treatment for people living with HIV (PLHIV). As a result, the number of PLHIV needing antiretroviral therapy (ART) in sub-Saharan Africa (SSA) doubled from 12 million to over 25 million. This put a strain on already weak health systems and inspired the exploration of innovative service delivery models-differentiated service delivery (DSD). In DSD, services are tailored according to client clinical type and offer much-needed improvement in efficiency. The potential of achieving good outcomes for both clients and the health system plus the promise of sustainability motivates DSD promotion especially in low-income and middle-income countries. This review aims to evaluate the sustainability of DSD interventions. METHODS AND ANALYSIS: We will systematically review peer-reviewed English literature published between 2000 and 2019 identified by searching PubMed and EMBASE databases. Main inclusion criteria comprise studies describing DSD interventions conducted in SSA focused on stable adult ART clients, whether described alone or compared with clinic-based service delivery. Quality of included studies will be assessed employing the Down and Black's and Joanne Briggs Institute checklists for quantitative and qualitative studies, respectively. We will apply a comprehensive sustainability framework including 40 individual constructs to evaluate, score and rank each intervention for sustainability. Narrative and quantitative synthesis will be conducted as appropriate. ETHICS AND DISSEMINATION: No ethical approval is required for this study as it is a review of published or publicly available data. Review results will be published in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42019120891.

A Longitudinal Analysis Reveals Early Activation and Late Alterations in B Cells During Primary HIV Infection in Mozambican Adults.

Primary HIV infection (PHI) and subsequent chronic infection alter B-cell compartment. However, longitudinal analysis defining the dynamics of B-cell alterations are still limited. We longitudinally studied B-cell subsets in individuals followed for 1 year after PHI (n = 40). Treated and untreated chronic HIV infected (n = 56) and HIV-uninfected individuals (n = 58) were recruited as reference groups at the Manhiça District in Mozambique. B cells were analyzed by multicolor flow-cytometry. Anti-HIV humoral response and plasma cytokines were assessed by ELISA or Luminex-based technology. A generalized activation of B cells induced by HIV occurs early after infection and is characterized by increases in Activated and Tissue-like memory cells, decreases in IgM-IgD- (switched) and IgM-only B cells. These alterations remain mostly stable until chronic infection and are reverted in part by ART. In contrast, other parameters followed particular dynamics: PD-1 expression in memory cells decreases progressively during the first year of infection, Transitional B cells expand at month 3-4 after infection, and Marginal zone-like B cells show a late depletion. Plasmablasts expand 2 months after infection linked to plasma viral load and anti-p24 IgG3 responses. Most of well-defined changes induced by HIV in B-cell activation and memory subsets are readily observed after PHI, lasting until ART initiation. However, subsequent changes occur after sustained viral infection. These data indicate that HIV infection impacts B cells in several waves over time, and highlight that early treatment would result in beneficial effects on the B-cell compartment.

Evolution of the gut microbiome following acute HIV-1 infection.

BACKGROUND: In rhesus macaques, simian immunodeficiency virus infection is followed by expansion of enteric viruses but has a limited impact on the gut bacteriome. To understand the longitudinal effects of HIV-1 infection on the human gut microbiota, we prospectively followed 49 Mozambican subjects diagnosed with recent HIV-1 infection (RHI) and 54 HIV-1-negative controls for 9-18 months and compared them with 98 chronically HIV-1-infected subjects treated with antiretrovirals (n = 27) or not (n = 71). RESULTS: We show that RHI is followed by increased fecal adenovirus shedding, which persists during chronic HIV-1 infection and does not resolve with ART. Recent HIV-1 infection is also followed by transient non-HIV-specific changes in the gut bacterial richness and composition. Despite early resilience to change, an HIV-1-specific signature in the gut bacteriome-featuring depletion of Akkermansia, Anaerovibrio, Bifidobacterium, and Clostridium-previously associated with chronic inflammation, CD8+ T cell anergy, and metabolic disorders, can be eventually identified in chronically HIV-1-infected subjects. CONCLUSIONS: Recent HIV-1 infection is associated with increased fecal shedding of eukaryotic viruses, transient loss of bacterial taxonomic richness, and long-term reductions in microbial gene richness. An HIV-1-associated microbiome signature only becomes evident in chronically HIV-1-infected subjects.

IP-10 Levels as an Accurate Screening Tool to Detect Acute HIV Infection in Resource-Limited Settings.

Acute HIV infection (AHI) is the period prior to seroconversion characterized by high viral replication, hyper-transmission potential and commonly, non-specific febrile illness. AHI detection requires HIV-RNA viral load (VL) determination, which has very limited access in low-income countries due to restrictive costs and implementation constraints. We sought to identify a biomarker that could enable AHI diagnosis in scarce-resource settings, and to evaluate the feasibility of its implementation. HIV-seronegative adults presenting at the Manhiça District Hospital, Mozambique, with reported-fever were tested for VL. Plasma levels of 49 inflammatory biomarkers from AHI (n = 61) and non-HIV infected outpatients (n = 65) were determined by Luminex and ELISA. IP-10 demonstrated the best predictive power for AHI detection (AUC = 0.88 [95%CI 0.80-0.96]). A cut-off value of IP-10 ≥ 161.6 pg/mL provided a sensitivity of 95.5% (95%CI 85.5-99.5) and a specificity of 76.5% (95%CI 62.5-87.2). The implementation of an IP-10 screening test could avert from 21 to 84 new infections and save from US$176,609 to US$533,467 to the health system per 1,000 tested patients. We conclude that IP-10 is an accurate biomarker to screen febrile HIV-seronegative individuals for subsequent AHI diagnosis with VL. Such an algorithm is a cost-effective strategy to prevent disease progression and a substantial number of further HIV infections.

Dynamics of CD4 and CD8 T-Cell Subsets and Inflammatory Biomarkers during Early and Chronic HIV Infection in Mozambican Adults.

During primary HIV infection (PHI), there is a striking cascade response of inflammatory cytokines and many cells of the immune system show altered frequencies and signs of extensive activation. These changes have been shown to have a relevant role in predicting disease progression; however, the challenges of identifying PHI have resulted in a lack of critical information about the dynamics of early pathogenic events. We studied soluble inflammatory biomarkers and changes in T-cell subsets in individuals at PHI (n = 40), chronic HIV infection (CHI, n = 56), and HIV-uninfected (n = 58) recruited at the Manhiça District Hospital in Mozambique. Plasma levels of 49 biomarkers were determined by Luminex and ELISA. T-cell immunophenotyping was performed by multicolor flow cytometry. Plasma HIV viremia, CD4, and CD8 T cell counts underwent rapid stabilization after PHI. However, several immunological parameters, including Th1-Th17 CD4 T cells and activation or exhaustion of CD8 T cells continued decreasing until more than 9 months postinfection. Importantly, no sign of immunosenescence was observed over the first year of HIV infection. Levels of IP-10, MCP-1, BAFF, sCD14, tumor necrosis factor receptor-2, and TRAIL were significantly overexpressed at the first month of infection and underwent a prompt decrease in the subsequent months while, MIG and CD27 levels began to increase 1 month after infection and remained overexpressed for almost 1 year postinfection. Early levels of soluble biomarkers were significantly associated with subsequently exhausted CD4 T-cells or with CD8 T-cell activation. Despite rapid immune control of virus replication, the stabilization of the T-cell subsets occurs months after viremia and CD4 count plateau, suggesting persistent immune dysfunction and highlighting the potential benefit of early treatment initiation that could limit immunological damage.

Post-ART Symptoms Were Not the Problem: A Qualitative Study on Adherence to ART in HIV-Infected Patients in a Mozambican Rural Hospital.

OBJECTIVE: The objective of this qualitative study was to explore how clinical symptoms may affect adherence to antiretroviral therapy (ART) in HIV patients, and to explore factors, perceptions and attitudes related to adherence to therapy. DESIGN: A qualitative study was carried out in the context of the prospective cohort study "Evaluation of Immune Reconstitution Following Initiation of Highly Active Antiretroviral Treatment in Manhiça, Mozambique". In-depth Interviews were conducted twice in a sub-sample of the study cohort (51 participants), at six-month intervals. RESULTS: Most participants (73%) knew that AIDS is a chronic disease and that ART does not cure it. Nine participants (18%) were non-adherent at some point and two (4%) abandoned ART. All participants but five reported having symptoms after starting ART, mainly attributed to pills needing time to act and body's reaction to the treatment. In spite of the perceived severity of the symptoms, only two people reported they discontinued the treatment due to symptoms. Almost all participants reported feeling comfortable with the HIV clinic organization and procedures, but afraid of staff being hostile if they did not follow the rules or if the health worker visited their home. Family was one of the most important source of support according participants. Almost all participants with children said that a decisive factor to follow the treatment was the desire to be able to look after them. CONCLUSIONS: Experiencing symptoms after starting treatment was not a barrier to adherence to ART. Factors related to adherence included control measures set up by the health facility (exhaustive follow up, support, information) and family and community support. Indirect ART-related expenses did jeopardise adherence.

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK.

OBJECTIVES: To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. DESIGN: Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. METHODS: KS-IRIS case definition was standardized across sites. Cox regression and Kaplan-Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality. RESULTS: Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P=0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02-8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26-6.94); and plasma HIV-1 RNA more than 5 log10 copies/ml (hazard ratio 2.14, 95% CI 1.25-3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23-7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62-48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09-5.05), pre-ART CD4 cell count less than 200 cells/µl (hazard ratio 2.04, 95% CI 0.99-4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94-4.77). CONCLUSION: KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa.

HIV and malaria interactions: where do we stand?

Reversing the spread of HIV infection and the incidence of malaria constitute two of the Millenium Development Goals. However, despite recent achievements, both diseases still entail global heath problems. Furthermore, their overlapping geographical distribution raises concerns and challenges for potential immunological, clinical and therapeutic interactions. It has been reported that HIV infection increases malaria susceptibility and reduces the efficacy of antimalarial drugs. On the other hand, the effect of malaria on HIV-infected individuals has also been explored, with the parasitic infection increasing the risk of HIV disease progression and mother-to-child transmission of HIV. The spread of malaria and parasite resistance to antimalarials could also be accelerated by HIV-associated immunosuppresion. Current knowledge of the epidemiological, clinical, immunological and therapeutic interactions of the two diseases is reviewed in this article. We focus on the latest available data, pointing out key future research areas and challenges of the field.

Alterations in T cell subsets in human immunodeficiency virus-infected adults with co-infections in southern Mozambique.

T cell activation and depletion of naive T cells are hallmarks of human immunodeficiency virus (HIV) pathogenesis. This study explored the relationships between certain co-infections (including syphilis, hepatitis B and C, human T cell lymphotrophic viruses I and II [HTLV-I/II], Kaposi sarcoma-associated herpesvirus [KSHV], Plasmodium falciparum malaria, and tuberculosis), and levels of activated CD8 and CD4 T cell subsets as well as naive and memory CD4 T cells in HIV-infected adults in a rural area of southern Mozambique. We found that syphilis infection and to a lesser extent HTLV-I/II seropositivity were independently associated with higher CD8 T cell activation (CD8+ CD38+ HLA-DR+) whereas only syphilis was associated with higher CD4 T cell activation. Furthermore, KSHV and HTLV-I/II seropositivities were independently associated with a lower percentage of naive CD4 T cells (CD4+ CD45RA+ CD62L+). These results highlight the importance of screening and prompt treatment of syphilis, and raise questions as to whether HIV-positive persons with certain chronic viral co-infections should initiate combined antiretroviral therapy at higher CD4 cell counts.

Predictors of immune reconstitution inflammatory syndrome-associated with kaposi sarcoma in mozambique: a prospective study.

BACKGROUND: The impact and relevance of immune reconstitution inflammatory syndrome-associated with Kaposi sarcoma (IRIS-KS) has not been assessed in sub-Saharan African countries, where the bulk of HIV-1 and KS-associated herpesvirus (KSHV) coinfection occurs. Understanding the risk factors for developing IRIS-KS would aid in the identification and in the improvement of clinical management for high-risk patients. METHODS: Sixty-nine consecutive HIV-1 and KSHV coinfected Mozambican adults initiating cART were prospectively followed for development of IRIS-KS over 10 months as part of a larger prospective observational study. Plasma HIV RNA, CD4 counts, anti-KSHV lytic antibodies, and plasma KSHV DNA viral load were assessed at the pre-cART visit and at 4 and 10 months after cART initiation. A survival analysis was performed to assess potential risk factors for developing IRIS-KS. RESULTS: During the first 10 months of combined antiretroviral therapy (cART), 8 patients (8/69, 11.6%) experienced IRIS-KS at a median time of 13.8 weeks after cART initiation. Multivariate analysis identified 4 independent IRIS-KS predictors: clinical pretreatment KS [hazard ratio (HR) 91.7], detectable plasma KSHV DNA (HR 24.4), hematocrit <30% (HR 26.5), and plasma HIV-1 RNA viral load (HR 34.6 per log viral load increase). Treatment with either cART alone or with a combination of cART and systemic chemotherapy led to partial or complete clinical response in 62.5% (5/8) of IRIS-KS cases. CONCLUSIONS: This study identified 4 independent predictors of IRIS-KS, which may help to develop screening tools aiding in the identification of patients at high risk of IRIS-KS for whom close clinical supervision is warranted.