Implementation of mass drug administration for neglected tropical diseases in Guinea during the COVID-19 pandemic.

BACKGROUND: Guinea reported its first case of COVID-19 on March 12, 2020. Soon thereafter, a national state of emergency was declared, all land borders were closed, schools were shut down, and public gatherings were limited. Many health activities, including field-based activities targeting neglected tropical diseases (NTDs), were paused. The World Health Organization (WHO) issued updated guidance on the resumption of NTD field-based activities on July 27, 2020. In response, the Guinea Ministry of Health (MoH) and its partners planned and resumed mass drug administration (MDA) in mid-August to September 2020 in 19 health districts. METHODOLOGY/PRINCIPAL FINDINGS: A risk-benefit assessment was conducted to identify potential risks associated with the MDA in the COVID-19 context. Following this assessment, a risk mitigation plan with barrier measures was developed to guide MDA implementation. These measures included COVID-19 testing for all national staff leaving Conakry, mask wearing, social distancing of two meters, and hand washing/sanitizing. A checklist was developed and used to monitor compliance to risk mitigation measures. Data on adherence to risk mitigation measures were collected electronically during the MDA. A total of 120 checklists, representing 120 community drug distributor (CDD) teams (two CDDs per team) and 120 households, were completed. Results indicated that washing or disinfecting hands was practiced by 68.3% of CDD teams, compared to 45.0% among households. Face masks to cover the mouth and nose were worn by 79.2% of CDD teams, while this was low among households (23.3%). In 87.5% of households, participants did not touch the dose pole and in 88.3% of CDD teams, CDDs did not touch the hands of the participants while giving the drugs. A large majority of CDD teams (94.2%) and household members (94.2%) were willing to participate in the MDA despite the pandemic. The epidemiological coverage was ≥65% for lymphatic filariasis, onchocerciasis and soil-transmitted helminths in 10 out of 19 HDs and ≥75% for schistosomiasis for school-aged children in 7 out of 11 HDs. CONCLUSIONS/SIGNIFICANCE: Guinea was one of the first countries in Africa to resume MDA activities during the COVID-19 pandemic without causing an observed increase of transmission. The development of a risk mitigation plan and a method to monitor adherence to barrier measures was critical to this unprecedented effort. The rapid incorporation of COVID-19 barrier measures and their acceptance by CDDs and household members demonstrated both the adaptability of the National NTD Program to respond to emerging issues and the commitment of the MoH to implement NTD programs.

Mapping lymphatic filariasis in Loa loa endemic health districts naïve for ivermectin mass administration and situated in the forested zone of Cameroon.

BACKGROUND: The control of lymphatic filariasis (LF) caused by Wuchereria bancrofti in the Central African Region has been hampered by the presence of Loa loa due to severe adverse events that arise in the treatment with ivermectin. The immunochromatographic test (ICT) cards used for mapping LF demonstrated cross-reactivity with L. loa and posed the problem of delineating the LF map. To verify LF endemicity in forest areas of Cameroon where mass drug administration (MDA) has not been ongoing, we used the recently developed strategy that combined serology, microscopy and molecular techniques. METHODS: This study was carried out in 124 communities in 31 health districts (HDs) where L. loa is present. At least 125 persons per site were screened. Diurnal blood samples were investigated for circulating filarial antigen (CFA) by FTS and for L. loa microfilariae (mf) using TBF. FTS positive individuals were further subjected to night blood collection for detecting W. bancrofti. qPCR was used to detect DNA of the parasites. RESULTS: Overall, 14,446 individuals took part in this study, 233 participants tested positive with FTS in 29 HDs, with positivity rates ranging from 0.0 to 8.2%. No W. bancrofti mf was found in the night blood of any individuals but L. loa mf were found in both day and night blood of participants who were FTS positive. Also, qPCR revealed that no W. bancrofti but L.loa DNA was found with dry bloodspot. Positive FTS results were strongly associated with high L. loa mf load. Similarly, a strong positive association was observed between FTS positivity and L loa prevalence. CONCLUSIONS: Using a combination of parasitological and molecular tools, we were unable to find evidence of W. bancrofti presence in the 31 HDs, but L. loa instead. Therefore, LF is not endemic and LF MDA is not required in these districts.

Baseline trachoma prevalence in Guinea: Results of national trachoma mapping in 31 health districts.

BACKGROUND: Based on previous studies, historical records and risk factors, trachoma was suspected to be endemic in 31 health districts (HDs) in Guinea. To facilitate planning for the elimination of trachoma as a public health problem, national trachoma surveys were conducted between 2011 and 2016 to determine the prevalence of trachomatous inflammation-follicular (TF) and trachomatous trichiasis (TT) in all 31 endemic HDs. METHODOLOGY/PRINCIPAL FINDINGS: A total of 27 cross-sectional surveys were conducted, each using two-stage cluster sampling (one survey in 2011 covered five HDs). Children aged 1-9 years and adults aged ≥15 years were examined for TF and TT, respectively, using the World Health Organization (WHO) simplified grading system. Indicators of household access to water, sanitation and hygiene (WASH) were also collected. A total of 100,051 people from 13,725 households of 556 clusters were examined, of whom 44,899 were male and 55,152 were female. 44,209 children aged 1-9-years and 48,745 adults aged ≥15 years were examined. The adjusted prevalence of TF varied between 1.0% (95%CI: 0.6-1.5%) to 41.8% (95%CI: 39.4-44.2%), while the adjusted prevalence of TT ranged from 0.0% (95%CI: 0.0-0.2%) to 2.8% (95%CI: 2.3-3.5%) in the 27 surveys. In all, 18 HDs had a TF prevalence ≥5% in children aged 1-9 years and 21 HDs had a TT prevalence ≥0.2% in adults aged ≥15 years. There were an estimated 32,737 (95% CI: 19,986-57,811) individuals with TT living in surveyed HDs at the time of surveys. CONCLUSIONS/SIGNIFICANCE: Trachoma is a public health problem in Guinea. 18 HDs required intervention with at least one round of mass drug administration and an estimated 32,737 persons required TT surgery in the country. The results provided clear evidence for Guinea to plan for national trachoma elimination.

Prevalence of trachoma in the Kayes region of Mali eight years after stopping mass drug administration.

BACKGROUND: In 2009, three years after stopping mass treatment with azithromycin, a trachoma impact survey in four health districts in the Kayes region of Mali found a prevalence of trachomatous inflammation-follicular (TF) among children aged 1 to 9 years of >5% and a trachomatous trichiasis (TT) prevalence within the general population (≥1-year-old) of <1%. As a result, the government's national trachoma program expanded trichiasis surgery and related activities required to achieve trachoma elimination. METHODOLOGY/PRINCIPAL FINDINGS: In 2015, to assess progress towards elimination, a follow-up impact survey was conducted in the Kayes, Kéniéba, Nioro and Yélimané health districts. The survey used district level two-stage cluster random sampling methodology with 20 clusters of 30 households in each evaluation unit. Subjects were eligible for examination if they were ≥1 year. TF and TT cases were identified and confirmed by experienced ophthalmologists. In total 14,159 people were enumerated and 11,620 (82%) were examined. TF prevalence (95% confidence interval (CI)) was 0.5% (0.3-1%) in Kayes, 0.8% (0.4-1.7%) in Kéniéba, 0.2% (0-0.9%) in Nioro and 0.3% (0.1-1%) in Yélimané. TT prevalence (95% CI) was 0.04% (0-0.25%) in Kayes, 0.29% (0.11-0.6%) in Kéniéba, 0.04% (0-0.25%) in Nioro and 0.07% (0-0.27%) in Yélimané. CONCLUSIONS/SIGNIFICANCE: Eight years after stopping MDA and intensifying trichiasis surgery outreach campaigns, all four districts reached the TF elimination threshold of <5% and three of four districts reached the TT elimination threshold of <0.1%.

Impact of point-of-care CD4 testing on linkage to HIV care: a systematic review.

INTRODUCTION: Point-of-care testing for CD4 cell count is considered a promising way of reducing the time to eligibility assessment for antiretroviral therapy (ART) and of increasing retention in care prior to treatment initiation. In this review, we assess the available evidence on the patient and programme impact of point-of-care CD4 testing. METHODS: We searched nine databases and two conference sites (up until 26 October 2013) for studies reporting patient and programme outcomes following the introduction of point-of-care CD4 testing. Where appropriate, results were pooled using random-effects methods. RESULTS: Fifteen studies, mainly from sub-Saharan Africa, were included for review, providing evidence for adults, adolescents, children and pregnant women. Compared to conventional laboratory-based testing, point-of-care CD4 testing increased the likelihood of having CD4 measured [odds ratio (OR) 4.1, 95% CI 3.5-4.9, n=2] and receiving a CD4 result (OR 2.8, 95% CI 1.5-5.6, n=6). Time to being tested was significantly reduced, by a median of nine days; time from CD4 testing to receiving the result was reduced by as much as 17 days. Evidence for increased treatment initiation was mixed. DISCUSSION: The results of this review suggest that point-of-care CD4 testing can increase retention in care prior to starting treatment and can also reduce time to eligibility assessment, which may result in more eligible patients being initiated on ART.

Tracking the progress of HIV: the impact of point-of-care tests on antiretroviral therapy.

It is now around 30 years since the discovery of HIV, the virus that causes AIDS. More than 70 million people have been infected in that time and around 35 million have died. The majority of those currently living with HIV/AIDS are in low- and middle-income countries, with sub-Saharan Africa bearing a disproportionate burden of the global disease. In high-income countries, the introduction of antiretroviral therapy (ART) has drastically reduced the morbidity and mortality associated with HIV. Patients on ART are now predicted to have near-normal life expectancy and the role of treatment is increasingly recognized in preventing new infections. In low- and middle-income countries, treatment is now more widely available and around half of those who need ART are currently receiving it. Early diagnosis of HIV is essential if ART is to be optimally implemented. Lab-based diagnostics for screening, diagnosis, treatment initiation, and the monitoring of treatment efficacy are critical in managing the disease and reducing the number of new infections each year. The introduction of point-of-care HIV rapid tests has transformed the epidemic, particularly in low- and middle-income countries. For the first time, these point-of-care tests allow for the rapid identification of infected individuals outside the laboratory who can undergo counseling and treatment and, in the case of pregnant women, allow the timely initiation of ART to reduce the risk of vertical transmission. Although survival is markedly improved with ART even in the absence of laboratory monitoring, long-term management of people living with HIV on ART, and their partners, is essential to ensure successful viral suppression. The burden of disease in many resource-poor settings with high HIV prevalence has challenged the ability of local laboratories to effectively monitor those on ART. Diagnostics used to initiate and monitor treatment are now moving out of the laboratory and into the field. These new point-of-care tests for viral load and CD4 are poised to further transform the disease and shift the treatment paradigm in low- and middle-income countries.

Diagnosis and management of antiretroviral-therapy failure in resource-limited settings in sub-Saharan Africa: challenges and perspectives.

Despite the enormous progress made in scaling up antiretroviral therapy (ART) in sub-Saharan Africa, many challenges remain, not least of which are the identification and management of patients who have failed first-line therapy. Less than 3% of patients are receiving second-line treatment at present, whereas 15-25% of patients have detectable viral loads 12 months or more into treatment, of whom a substantial proportion might have virological failure. We discuss the reasons why virological ART failure is likely to be under-diagnosed in the routine health system, and address the current difficulties with standard recommended second-line ART regimens. The development of new diagnostic tools for ART failure, in particular a point-of-care HIV viral-load test, combined with simple and inexpensive second-line therapy, such as boosted protease-inhibitor monotherapy, could revolutionise the management of ART failure in resource-limited settings.

FcgammaRIIb-mediated negative regulation of BCR signalling is associated with the recruitment of the MAPkinase-phosphatase, Pac-1, and the 3'-inositol phosphatase, PTEN.

The low-affinity receptor for IgG, FcgammaRIIb, negatively regulates B cell antigen receptor (BCR)-mediated proliferative signalling. FcgammaRIIb has been reported to mediate this inhibition by uncoupling the BCR from the RasMAPkinase pathway. We now show that FcgammaRIIb-mediated negative feedback inhibition also correlates with induction of an Erk-associated phosphatase activity that reflects the rapid association of Erk and the MAPkinase phosphatase, Pac-1, and dephosphorylation and inactivation of ErkMAPkinase. This mechanism of abrogating ongoing ErkMAPkinase signalling therefore provides a rationale for rapid immune-complex-mediated feedback inhibition of active antigen-driven B cell responses. In addition, FcgammaRIIb signalling also induces the recruitment and activation of the 3'-inositol phosphatase, PTEN, which by antagonising PI 3kinase activity and inhibiting BCR-coupling to the anti-apoptotic kinase, Akt, provides an additional mechanism for FcgammaRIIb-mediated negative regulation of BCR-coupling to ErkMAPkinase, cell survival and proliferation.

Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity.

Recent advances have made haploidentical transplantation for leukemia feasible, but the rigorous T-cell depletion used contributes to the high relapse rates observed. We have attempted to improve the graft-versus-leukemia (GVL) effect by generating allorestricted cytotoxic T lymphocytes (CTLs) directed against human CD45. Such CTLs should recognize patient hematopoietic cells including leukemia, enhancing donor cell engraftment and improving the GVL effect, but they should not recognize host nonhematopoietic tissues or donor cells from the graft. Using the T2 binding assay, 4 CD45-derived peptides were found to bind HLA-A2 molecules. These peptides were used to generate cytotoxic T-cell lines from HLA-A2(-) donors by sequential stimulation with peptide-pulsed HLA-A2(+) stimulators, and the lines obtained were screened for peptide-specific cytotoxicity. Using one of these peptides (P1218), it was possible to generate peptide-specific, allorestricted CTLs in 3 of 7 responders. P1218-specific CTL lines show potent cytotoxicity against hematopoietic cell lines coexpressing HLA-A2 and CD45 but not CD45 loss variants. Studies with stable transfectants of 293 cells demonstrated recognition by P1218-specific CTLs of endogenously expressed CD45. Likewise P1218-specific CTLs recognized peripheral blood mononuclear cells (PBMCs) from HLA-A2(+) patients with chronic myeloid leukemia (CML) and leukemic blasts in HLA-A2(+) patients with acute myeloid leukemia (AML), but they were unable to lyse HLA-A2(+) fibroblasts or HLA-A2(-) normal PBMCs. Coculture of CD34(+) PBMCs and bone marrow mononuclear cells (BMMCs) with P1218-specific CTL significantly inhibited colony-forming unit-granulocyte macrophage (CFU-GM) formation in HLA-A2(+) healthy controls and CML patients but resulted in no significant inhibition in HLA-A2(-) healthy controls. These studies demonstrate that P1218-specific cytotoxic T lymphocytes (CTLs) have potent activity against leukemic progenitors and suggest that adoptive immunotherapy with allorestricted CTLs directed against CD45 epitopes may be useful in restoring the GVL effect after HLA-A2-mismatched haploidentical transplantation. Further, because P1218-specific CTLs also recognize healthy HLA-A2(+) progenitors, such CTLs could also contribute to host myeloablation and enhance donor cell engraftment.

Differential roles for extracellularly regulated kinase-mitogen-activated protein kinase in B cell antigen receptor-induced apoptosis and CD40-mediated rescue of WEHI-231 immature B cells.

One of the major unresolved questions in B cell biology is how the B cell Ag receptor (BCR) differentially signals to transduce anergy, apoptosis, proliferation, or differentiation during B cell maturation. We now report that extracellularly regulated kinase-mitogen-activated protein kinase (Erk-MAP kinase) can play dual roles in the regulation of the cell fate of the immature B cell lymphoma, WEHI-231, depending on the kinetics and context of Erk-MAP kinase activation. First, we show that the BCR couples to an early (< or =2 h) Erk-MAP kinase signal which activates a phospholipase A(2) pathway that we have previously shown to mediate collapse of mitochondrial membrane potential, resulting in depletion of cellular ATP and cathepsin B execution of apoptosis. Rescue of BCR-driven apoptosis by CD40 signaling desensitizes such early extracellularly regulated kinase (Erk) signaling and hence uncouples the BCR from the apoptotic mitochondrial phospholipase A(2) pathway. A second role for Erk-MAP kinase in promoting the growth and proliferation of WEHI-231 immature B cells is evidenced by data showing that proliferating and CD40-stimulated WEHI-231 B cells exhibit a sustained cycling pattern (8-48 h) of Erk activation that correlates with cell growth and proliferation. This growth-promoting role for Erk signaling is supported by three key pieces of evidence: 1) signaling via the BCR, under conditions that induce growth arrest, completely abrogates sustained Erk activation; 2) CD40-mediated rescue from growth arrest correlates with restoration of cycling Erk activation; and 3) sustained inhibition of Erk prevents CD40-mediated rescue of BCR-driven growth arrest of WEHI-231 immature B cells. Erk-MAP kinase can therefore induce diverse biological responses in WEHI-231 cells depending on the context and kinetics of activation.