Sex Differences in HIV Testing - 20 PEPFAR-Supported Sub-Saharan African Countries, 2019.

Despite progress toward controlling the human immunodeficiency virus (HIV) epidemic, testing gaps remain, particularly among men and young persons in sub-Saharan Africa (1). This observational study used routinely collected programmatic data from 20 African countries reported to the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) from October 2018 to September 2019 to assess HIV testing coverage and case finding among adults (defined as persons aged ≥15 years). Indicators included number of HIV tests conducted, number of HIV-positive test results, and percentage positivity rate. Overall, the majority of countries reported higher HIV case finding among women than among men. However, a slightly higher percentage positivity was recorded among men (4.7%) than among women (4.1%). Provider-initiated counseling and testing (PITC) in health facilities identified approximately two thirds of all new cases, but index testing had the highest percentage positivity in all countries among both sexes. Yields from voluntary counseling and testing (VCT) and mobile testing varied by sex and by country. These findings highlight the need to identify and implement the most efficient strategies for HIV case finding in these countries to close coverage gaps. Strategies might need to be tailored for men who remain underrepresented in the majority of HIV testing programs.

Integrating mental health services into human immunodeficiency virus clinics: Lessons from task-sharing between clinical and lay healthcare providers in Ethiopia.

Background: Globally, mental health problems are more common among people living with human immunodeficiency virus (PLHIV) than among the general population. Mental health problems affect human immunodeficiency virus (HIV) treatment adherence and retention. To address this challenge, partners used a task-sharing approach among lay healthcare works and clinicians to integrate mental health services into HIV services at pilot hospitals in the Amhara and Tigray regions of Ethiopia. In this model, trained lay healthcare workers proactively screened patients using a mental health screening tool and subsequently linked potential clients with trained clinicians working at HIV clinics for further diagnosis and treatment. Methods: We retrospectively gathered secondary data, including demographic characteristics and diagnosis information, from mental health clinicians' and case managers' quarterly reports from HIV clinics during the implementation period (January 1, 2013 to March 31, 2014). Results: During the initial three-month implementation period of the project (January to March 2013), case managers screened 5,862 PLHIV for mental health disorders. Case managers referred 687 (11.7%) patients with suspected mental health disorders to clinicians for further evaluation and management. Of the total patients screened by case managers in this period, clinicians confirmed that 454 (7.7%) had a mental health disorder. Overall, the concordance between the case managers' screening results and the clinicians' diagnoses was 67.8% over the 15-month pilot implementation period. Conclusions: Routine screening of PLHIV for mental health disorders helps to proactively identify and manage patients with co-morbidities. The integration of mental health services into HIV care through a task-sharing approach is a feasible strategy that could increase access to mental health services among PLHIV.

Magnitude of opportunistic diseases and their predictors among adult people living with HIV enrolled in care: national level cross sectional study, Ethiopia.

BACKGROUND: Opportunistic diseases cause morbidity and mortality among human immunodeficiency virus (HIV) infected persons. There is dearth of evidence on the magnitude and predictors of opportunistic diseases among PLHIV in Ethiopia. This study was conducted to determine the magnitude and predictors of opportunistic diseases among adults enrolled in the national HIV/AIDS care and treatment services and generate information for program planning and medicine quantification in the country. METHODS: A health facility-based cross-sectional study was conducted. Probability proportional to size and random sampling methods were employed to select health facilities and medical records of adult HIV-infected patients respectively. A total of 7826 medical records were reviewed from 60 health facilities nationwide. Socio-demographic and clinical data including diagnosis of opportunistic diseases were collected from the medical records. Period prevalence of opportunistic diseases over one year period was determined. Bivariate and multivariate logistic regression was used to measure associations between independent variables and the dependent variable, occurrence of opportunistic diseases. RESULTS: Of the total of 7826 study participants, 3748 (47.9%) were from hospitals and 4078 were from health centers. The majority (61.8%) were female. The median age was 32 years with interquartile range (IQR) of 27-40. The median duration of stay in HIV care was 56 (IQR = 28-80) months; 7429 (94.9%) were on antiretroviral treatment. A total of 1665 cases of opportunistic diseases were recorded with an overall prevalence estimated at 21.3% (95% confidence interval (CI): 20.36, 22.18%). Skin diseases (4.1%), diarrhea (4.1%), bacterial pneumonia (3.6%), recurrent upper respiratory tract infections (3.1%) and tuberculosis (2.7%) were the leading opportunistic diseases. Isoniazid preventive therapy coverage among eligible patients was 24.8%. Persons with a CD4 count < 200 cells/mm3 [adjusted odds ratio (AOR) 1.80, 95% CI: 1.45, 2.23]; and who were bed ridden or ambulatory functional status [AOR (95% CI) = 3.19 (2.32, 4.39)] were independent predictors of diagnosis of opportunistic diseases. CONCLUSION: Opportunistic diseases were found to be pervasive among HIV infected adults in Ethiopia. Proactive identification and management, and prevention of opportunistic diseases should be strengthened especially among females, ambulatory or bed-ridden, and patients with low CD4 cell count.

Predictors of Survival among Adult Ethiopian Patients in the National ART Program at Seven University Teaching Hospitals: A Prospective Cohort Study.

BACKGROUND: In Ethiopia, the publicly funded antiretroviral treatment (ART) program was started in 2005. Two hundred seventy-five thousand patients were enrolled in the national ART program by 2012. However, there is limited data on mortality and predictors of death among adult patients in the ART program. The study aimed to estimate mortality and risk factors for death among adult, ART-naïve patients, started in the national ART program from January 2009 to July 2013. METHODS: Multi-site, prospective, observational cohort study of adult, age > 18 years, ART-naïve patients, started in the national ART program at seven university-affiliated hospitals from January 2009 - July 2013. Kaplan-Meier and Cox regression analyses were used to estimate survival and determine risk factors for death. RESULTS: A total of 976 patients, 594 females (60.9 %), were enrolled into the study. Median age of the cohort was 33years. The median CD4 count at start of ART was 144 cells/µl (interquartile range (IQR) 78-205), and 34.2% (330/965) had CD4 < 100. Sixty-three percent (536/851) had viral load greater than 5 log copies/ml (IQR 4.7-5.7) at base line. One hundred and one deaths were recorded during follow-up period, all-cause mortality rate 10.3%; 5.4 deaths/100 person years of observation, 95% confidence interval 4.4-6.5. Seventy percent of the deaths occurred within six months of starting ART. Cox regression analyses showed that the following measures independently predicted mortality: age >51 years, (Adjusted Hazard Ratio (AHR) 4.01, P=0.003), WHO stages III&IV, (AHR 1.76, p = 0.025), CD4 count, <100, (AHR 2.36, p =0.006), and viral load >5 log copies /ml (CHR 1.71, p = 0.037). CONCLUSION: There is high early on- ART mortality in patients presenting with advanced immunodeficiency. Detecting cases and initiating ART before onset of advanced immunodeficiency might improve survival.

Knowledge and Awareness of Cervical Cancer among HIV-Infected Women in Ethiopia.

Introduction. Cervical cancer is one of the leading causes of cancer death among Ethiopian women. Low awareness of cervical cancer, in combination with low health care seeking behavior, is a key challenge for cervical cancer prevention. This study assessed the knowledge of cervical cancer among HIV-infected women in Ethiopia. Methods. A facility-based cross-sectional survey was conducted from August to September 2012 among HIV-infected women between 21 and 49 years of age. Basic descriptive statistics were performed using SPSS. Results. A total of 432 HIV-infected women participated in this study. About 71% of participants had ever heard of cervical cancer. Among women who had ever heard of cervical cancer, 49% did not know the cause while 74% were able to identify at least one risk factor for cervical cancer. Only 33% of women were able to correctly address when women should seek care and 33% identified at least one treatment option for cervical cancer. Conclusion. This study revealed that knowledge about cervical cancer was generally low, in particular for health care seeking behavior and treatment of cervical cancer. Health awareness programs should be strengthened at both community and health facility levels with emphasis highlighting the causes, risk factors, care seeking behaviors, and treatment options for cervical cancer.

The Single-Visit Approach as a Cervical Cancer Prevention Strategy Among Women With HIV in Ethiopia: Successes and Lessons Learned.

INTRODUCTION: Cervical cancer is the second most common form of cancer for women in Ethiopia. Using a single-visit approach to prevent cervical cancer, the Addis Tesfa (New Hope) project in Ethiopia tested women with HIV through visual inspection of the cervix with acetic acid wash (VIA) and, if tests results were positive, offered immediate cryotherapy of the precancerous lesion or referral for loop electrosurgical excision procedure (LEEP). The objective of this article is to review screening and treatment outcomes over nearly 4 years of project implementation and to identify lessons learned to improve cervical cancer prevention programs in Ethiopia and other resource-constrained settings. METHODS: We analyzed aggregate client data from August 2010 to March 2014 to obtain the number of women with HIV who were counseled, screened, and treated, as well as the number of annual follow-up visits made, from the 14 tertiary- and secondary-level health facilities implementing the single-visit approach. A health facility assessment (HFA) was also implemented from August to December 2013 to examine the effects of the single-visit approach on client flow, staff workload, and facility infrastructure 3 years after initiating the approach. RESULTS: Almost all (99%) of the 16,632 women with HIV counseled about the single-visit approach were screened with VIA during the study period; 1,656 (10%) of them tested VIA positive (VIA+) for precancerous lesions. Among those who tested VIA+ and were thus eligible for cryotherapy, 1,481 (97%) received cryotherapy treatment, but only 80 (63%) women eligible for LEEP actually received the treatment. The HFA results showed frequent staff turnover, some shortage of essential supplies, and rooms that were judged by providers to be too small for delivery of cervical cancer prevention services. CONCLUSION: The high proportions of VIA screening and cryotherapy treatment in the Addis Tesfa project suggest high acceptance of such services by women with HIV and feasibility of implementation in secondary- and tertiary-level health facilities. However, success of cervical cancer prevention programming must address wider health system challenges to ensure sustainability and appropriate scale-up to the general population of Ethiopia and other resource-constrained settings.

Collaboratively reframing mental health for integration of HIV care in Ethiopia.

BACKGROUND: Integrating mental health with general medical care can increase access to mental health services, but requires helping generalists acquire a range of unfamiliar knowledge and master potentially complex diagnostic and treatment processes. METHOD: We describe a model for integrating complex specialty care with generalist/primary care, using as an illustration the integration of mental health into hospital-based HIV treatment services in Ethiopia. Generalists and specialists collaboratively developed mental health treatments to fit the knowledge, skills and resources of the generalists. The model recognizes commonalities between mental health and general medical care, focusing on practical interventions acceptable to patients. It was developed through a process of literature review, interviews, observing clinical practice, pilot trainings and expert consultation. Preliminary evaluation results were obtained by debriefing generalist trainees after their return to their clinical sites. RESULTS: In planning interviews, generalists reported discomfort making mental health diagnoses but recognition of symptom groups including low mood, anxiety, thought problems, poor child behaviour, seizures and substance use. Diagnostic and treatment algorithms were developed for these groups and tailored to the setting by including possible medical causes and burdens of living with HIV. First-line treatment included modalities familiar to generalists: empathetic patient-provider interactions, psychoeducation, cognitive reframing, referral to community supports and elements of symptom-specific evidence-informed counselling. Training introduced basic skills, with evolving expertise supported by job aides and ongoing support from mental health nurses cross-trained in HIV testing. Feedback from trainees suggested the programme fit well with generalists' settings and clinical goals. CONCLUSIONS: An integration model based on collaboratively developing processes that fit the generalist setting shows promise as a method for incorporating complex, multi-faceted interventions into general medical settings. Formal evaluations will be needed to compare the quality of care provided with more traditional approaches and to determine the resources required to sustain quality over time.

Safety and efficacy of single dose versus multiple doses of AmBisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial.

BACKGROUND: Anti-leishmanial drug regimens that include a single dose AmBisome could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown. METHODOLOGY: A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1-5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR. PRINCIPAL FINDINGS: The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73-93%), 40% (95%CI 19-64%), and 58% (95%CI 41-73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label. CONCLUSIONS: The tested AmBisome regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified. TRIALS REGISTRATION: www.clinicaltrials.govNCT00832208.

Arginase activity - a marker of disease status in patients with visceral leishmaniasis in ethiopia.

The underlying mechanisms resulting in the profound immune suppression characteristic of human visceral leishmaniasis (VL) are not fully understood. Here, we tested the hypothesis that arginase, an enzyme associated with immunosuppression, is higher in patients with VL and contributes to impaired T cell responses. We recruited patients with VL before and after treatment and healthy controls and measured the arginase metabolism in the blood of these individuals. Our results show that arginase activity is significantly higher in the blood of patients with active VL as compared to controls. These high levels of arginase decline considerably once the patients are successfully treated. We identified the phenotype of arginase-expressing cells among PBMCs as neutrophils and show that their frequency was increased in PBMCs of patients before treatment; this coincides with reduced levels of L-arginine in the plasma and decreased expression levels of CD3ζ in T cells.

Polymorphism in the HASPB repeat region of East African Leishmania donovani strains.

BACKGROUND/OBJECTIVES: Visceral leishmaniasis (VL) caused by Leishmania donovani is a major health problem in Ethiopia. Parasites in disparate regions are transmitted by different vectors, and cluster in distinctive genotypes. Recently isolated strains from VL and HIV-VL co-infected patients in north and south Ethiopia were characterized as part of a longitudinal study on VL transmission. METHODOLOGY/PRINCIPAL FINDINGS: Sixty-three L. donovani strains were examined by polymerase chain reaction (PCR) targeting three regions: internal transcribed spacer 1 (ITS1), cysteine protease B (cpb), and HASPB (k26). ITS1- and cpb--PCR identified these strains as L. donovani. Interestingly, the k26--PCR amplicon size varied depending on the patient's geographic origin. Most strains from northwestern Ethiopia (36/40) produced a 290 bp product with a minority (4/40) giving a 410 bp amplicon. All of the latter strains were isolated from patients with HIV-VL co-infections, while the former group contained both VL and HIV-VL co-infected patients. Almost all the strains (20/23) from southwestern Ethiopia produced a 450 bp amplicon with smaller products (290 or 360 bp) only observed for three strains. Sudanese strains produced amplicons identical (290 bp) to those found in northwestern Ethiopia; while Kenyan strains gave larger PCR products (500 and 650 bp). High-resolution melt (HRM) analysis distinguished the different PCR products. Sequence analysis showed that the k26 repeat region in L. donovani is comprised of polymorphic 13 and 14 amino acid motifs. The 13 amino acid peptide motifs, prevalent in L. donovani, are rare in L. infantum. The number and order of the repeats in L. donovani varies between geographic regions. CONCLUSIONS/SIGNIFICANCE: HASPB repeat region (k26) shows considerable polymorphism among L. donovani strains from different regions in East Africa. This should be taken into account when designing diagnostic assays and vaccines based on this antigen.

Arginase activity in the blood of patients with visceral leishmaniasis and HIV infection.

BACKGROUND: Visceral leishmaniasis is a parasitic disease associated with high mortality. The most important foci of visceral leishmaniasis in Ethiopia are in the Northwest and are predominantly associated with high rates of HIV co-infection. Co-infection of visceral leishmaniasis patients with HIV results in higher mortality, treatment failure and relapse. We have previously shown that arginase, an enzyme associated with immunosuppression, was increased in patients with visceral leishmaniasis and in HIV seropositive patients; further our results showed that high arginase activity is a marker of disease severity. Here, we tested the hypothesis that increased arginase activities associated with visceral leishmaniasis and HIV infections synergize in patients co-infected with both pathogens. METHODOLOGY/PRINCIPAL FINDINGS: We recruited a cohort of patients with visceral leishmaniasis and a cohort of patients with visceral leishmaniasis and HIV infection from Gondar, Northwest Ethiopia, and recorded and compared their clinical data. Further, we measured the levels of arginase activity in the blood of these patients and identified the phenotype of arginase-expressing cells. Our results show that CD4(+) T cell counts were significantly lower and the parasite load in the spleen was significantly higher in co-infected patients. Moreover, our results demonstrate that arginase activity was significantly higher in peripheral blood mononuclear cells and plasma of co-infected patients. Finally, we identified the cells-expressing arginase in the PBMCs as low-density granulocytes. CONCLUSION: Our results suggest that increased arginase might contribute to the poor disease outcome characteristic of patients with visceral leishmaniasis and HIV co-infection.

Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial.

BACKGROUND: Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India. METHODS: A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4-60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data. FINDINGS: The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: -1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens. CONCLUSION: The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.govNCT00255567.

Geographical variation in the response of visceral leishmaniasis to paromomycin in East Africa: a multicentre, open-label, randomized trial.

BACKGROUND: Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India. METHODS: This was a 3-arm multicentre, open-label, randomized, controlled clinical trial to compare three treatment regimens for VL in East Africa: paromomycin sulphate (PM) at 15 mg/kg/day for 21 days versus sodium stibogluconate (SSG) at 20 mg/kg/day for 30 days; and the combination of both dose regimens for 17 days. The primary efficacy endpoint was cure based on parasite-free tissue aspirates taken 6 months after treatment. FINDINGS: Overall, 135 patients per arm were enrolled at five centres in Sudan (2 sites), Kenya (1) and Ethiopia (2), when the PM arm had to be discontinued due to poor efficacy. The trial has continued with the higher dose of PM as well as the combination of PM and SSG arms. These results will be reported later. Baseline patient characteristics were similar among treatment arms. The overall cure with PM was significantly inferior to that with SSG (63.8% versus 92.2%; difference 28.5%, 95%CI 18.8% to 38.8%, p<0.001). The efficacy of PM varied among centres and was significantly lower in Sudan (14.3% and 46.7%) than in Kenya (80.0%) and Ethiopia (75.0% and 96.6%). No major safety issues with PM were identified. CONCLUSION: The efficacy of PM at 15 mg/kg/day for 21 days was inadequate, particularly in Sudan. The efficacy of higher doses and the combination treatment warrant further studies.

Inference of population structure of Leishmania donovani strains isolated from different Ethiopian visceral leishmaniasis endemic areas.

BACKGROUND: Parasites' evolution in response to parasite-targeted control strategies, such as vaccines and drugs, is known to be influenced by their population genetic structure. The aim of this study was to describe the population structure of Ethiopian strains of Leishmania donovani derived from different areas endemic for visceral leishmaniasis (VL) as a prerequisite for the design of effective control strategies against the disease. METHODOLOGY/PRINCIPAL FINDINGS: Sixty-three strains of L. donovani newly isolated from VL cases in the two main Ethiopian foci, in the north Ethiopia (NE) and south Ethiopia (SE) of the country were investigated by using 14 highly polymorphic microsatellite markers. The microsatellite profiles of 60 previously analysed L. donovani strains from Sudan, Kenya and India were included for comparison. Multilocus microsatellite typing placed strains from SE and Kenya (n = 30) in one population and strains from NE and Sudan (n = 65) in another. These two East African populations corresponded to the areas of distribution of two different sand fly vectors. In NE and Sudan Phlebotomus orientalis has been implicated to transmit the parasites and in SE and Kenya P. martini. The genetic differences between parasites from NE and SE are also congruent with some phenotypic differences. Each of these populations was further divided into two subpopulations. Interestingly, in one of the subpopulations of the population NE we observed predominance of strains isolated from HIV-VL co-infected patients and of strains with putative hybrid genotypes. Furthermore, high inbreeding irreconcilable from strict clonal reproduction was found for strains from SE and Kenya indicating a mixed-mating system. CONCLUSIONS/SIGNIFICANCE: This study identified a hierarchical population structure of L. donovani in East Africa. The existence of two main, genetically and geographically separated, populations could reflect different parasite-vector associations, different ecologies and varying host backgrounds and should be further investigated.

Safety and effectiveness of meglumine antimoniate in the treatment of Ethiopian visceral leishmaniasis patients with and without HIV co-infection.

In sub-Saharan Africa, visceral leishmaniasis (VL) is treated with either Pentostam(TM) (sodium antimony gluconate) or generic sodium stibogluconate (SSG), except in Uganda where Glucantime(®) (meglumine antimoniate) has been in use for at least a decade. Between January 2008 and February 2009, 54 Ethiopian VL patients were treated with Glucantime. The medical charts of these patients were reviewed to assess the effectiveness and safety profile of Glucantime in a routine healthcare setting. None of the patients from south Ethiopia (n=24) and 46.4% of the patients from north Ethiopia (n=30) were HIV co-infected. At completion of treatment (Day 31), cure rates were 78.6% (95% CI 59.0-91.7%) in north Ethiopia and 100% (95% CI 85.8-100%) in south Ethiopia. Thirty-three non-serious and six serious adverse events (two pancreatitis, one renal failure and three deaths) were observed in 26 patients. One-third of the non-serious adverse events were due to biochemical pancreatitis. During treatment, a case-fatality rate of 10.0% in north Ethiopia and 0.0% in south Ethiopia was noted. These data show that Glucantime can be as effective as Pentostam or SSG in HIV-negative patients. The data also point to clinical pancreatitis as a safety concern, especially in patients with HIV co-infection.