Incidence of self-reported tuberculosis treatment with community-wide universal testing and treatment for HIV and tuberculosis screening in Zambia and South Africa: A planned analysis of the HPTN 071 (PopART) cluster-randomised trial.

BACKGROUND: HIV is a potent risk factor for tuberculosis (TB). Therefore, community-wide universal testing and treatment for HIV (UTT) could contribute to TB control, but evidence for this is limited. Community-wide TB screening can decrease population-level TB prevalence. Combining UTT with TB screening could therefore significantly impact TB control in sub-Saharan Africa, but to our knowledge there is no evidence for this combined approach. METHODS AND FINDINGS: HPTN 071 (PopART) was a community-randomised trial conducted between November 2013 to July 2018; 21 Zambian and South African communities (with a total population of approximately 1 million individuals) were randomised to arms A (community-wide UTT and TB screening), B (community-wide universal HIV testing with treatment following national guidelines and TB screening), or C (standard-of-care). In a cohort of randomly selected adults (18 to 44 years) enrolled between 2013 and 2015 from all 21 communities (total size 38,474; 27,139 [71%] female; 8,004 [21%] HIV positive) and followed-up annually for 36 months to measure the population-level impact of the interventions, data on self-reported TB treatment in the previous 12 months (self-reported TB) were collected by trained research assistants and recorded using a structured questionnaire at each study visit. In this prespecified analysis of the trial, self-reported TB incidence rates were measured by calendar year between 2014 and 2017/2018. A p-value ≤0.05 on hypothesis testing was defined as reaching statistical significance. Between January 2014 and July 2018, 38,287 individuals were followed-up: 494 self-reported TB during 104,877 person-years. Overall incidence rates were similar across all arms in 2014 and 2015 (0.33 to 0.46/100 person-years). In 2016 incidence rates were lower in arm A compared to C overall (adjusted rate ratio [aRR] 0.48 [95% confidence interval (95% CI) 0.28 to 0.81; p = 0.01]), with statistical significance reached. In 2017/2018, while incidence rates were lower in arm A compared to C, statistical significance was not reached (aRR 0.58 [95% CI 0.27 to 1.22; p = 0.13]). Among people living with HIV (PLHIV) incidence rates were lower in arm A compared to C in 2016 (RR 0.56 [95% CI 0.29 to 1.08; p = 0.08]) and 2017/2018 (RR 0.50 [95% CI 0.26 to 0.95; p = 0.04]); statistical significance was only reached in 2017/2018. Incidence rates in arms B and C were similar, overall and among PLHIV. Among HIV-negative individuals, there were too few events for cross-arm comparisons. Study limitations include the use of self-report which may have been subject to under-reporting, limited covariate adjustment due to the small number of events, and high losses to follow-up over time. CONCLUSIONS: In this study, community-wide UTT and TB screening resulted in substantially lower TB incidence among PLHIV at population-level, compared to standard-of-care, with statistical significance reached in the final study year. There was also some evidence this translated to a decrease in self-reported TB incidence overall in the population. Reduction in arm A but not B suggests UTT drove the observed effect. Our data support the role of UTT in TB control, in addition to HIV control, in high TB/HIV burden settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01900977.

Uptake of HIV Testing Services Through Novel Community-Based Sexual and Reproductive Health Services: An Analysis of the Pilot Implementation Phase of the Yathu Yathu Intervention for Adolescents and Young People Aged 15-24 in Lusaka, Zambia.

Adolescents and young people aged 15-24 are underserved by available HIV-testing services (HTS). Delivering HTS through community-based, peer-led, hubs may prove acceptable and accessible to adolescents and young people, thus increasing HIV-testing coverage. We used data from the pilot phase of a cluster-randomised trial of community-based sexual and reproductive health services for adolescents and young people in Lusaka, Zambia, between September 2019 and January 2020, to explore factors associated with uptake of HTS through community-based hubs. 5,757 adolescents and young people attended the hubs (63% female), among whom 75% tested for HIV (76% of females, 75% of males). Community-based hubs provided HTS to 80% of adolescents and young people with no history of HIV-testing. Among females, uptake of HTS was lower among married/cohabiting females; among males, uptake was lower among unmarried males and among individuals at risk of hazardous alcohol use. The high number of adolescents and young people accessing hubs for HIV testing suggests they are acceptable. Enhanced targeting of HTS to groups who may not perceive their HIV risk needs to be implemented.

The effect of systematic screening of the general population on TB case notification rates.

BACKGROUND: Understanding how TB case notification rates (TB-CNR) change with TB screening and their association with underlying TB incidence/prevalence could inform how they are best used to monitor screening impact.METHODS: We undertook a systematic review to identify articles published between 1 January 1980 and 13 April 2020 on TB-CNR trends associated with TB screening in the general-population. Using a simple compartmental TB transmission model, we modelled TB-CNRs, incidence and prevalence dynamics during 5 years of screening.RESULTS: Of 27,282 articles, seven before/after studies were eligible. Two involved population-wide screening, while five used targeted screening. The data suggest screening was associated with initial increases in TB-CNRs. Increases were greatest with population-wide screening, where screening identified a large proportion of notified people with TB. Only one study reported on sustained screening; TB-CNR trends were compatible with model simulations. Model simulations always showed a peak in TB-CNRs with screening. Following the peak, TB-CNRs declined but were typically sustained above baseline during the intervention. Incidence and prevalence decreased during the intervention; the relative decline in incidence was smaller than the decline in prevalence.CONCLUSIONS: Published data on TB-CNR trends with TB screening are limited. These data are needed to identify generalisable patterns and enable method development for inferring underlying TB incidence/prevalence from TB-CNR trends.

Does tuberculosis screening improve individual outcomes? A systematic review.

BACKGROUND: To determine if tuberculosis (TB) screening improves patient outcomes, we conducted two systematic reviews to investigate the effect of TB screening on diagnosis, treatment outcomes, deaths (clinical review assessing 23 outcome indicators); and patient costs (economic review). METHODS: Pubmed, EMBASE, Scopus and the Cochrane Library were searched between 1/1/1980-13/4/2020 (clinical review) and 1/1/2010-14/8/2020 (economic review). As studies were heterogeneous, data synthesis was narrative. FINDINGS: Clinical review: of 27,270 articles, 18 (n=3 trials) were eligible. Nine involved general populations. Compared to passive case finding (PCF), studies showed lower smear grade (n=2/3) and time to diagnosis (n=2/3); higher pre-treatment losses to follow-up (screened 23% and 29% vs PCF 15% and 14%; n=2/2); and similar treatment success (range 68-81%; n=4) and case fatality (range 3-11%; n=5) in the screened group. Nine reported on risk groups. Compared to PCF, studies showed lower smear positivity among those culture-confirmed (n=3/4) and time to diagnosis (n=2/2); and similar (range 80-90%; n=2/2) treatment success in the screened group. Case fatality was lower in n=2/3 observational studies; both reported on established screening programmes. A neonatal trial and post-hoc analysis of a household contacts trial found screening was associated with lower all-cause mortality. Economic review: From 2841 articles, six observational studies were eligible. Total costs (n=6) and catastrophic cost prevalence (n=4; range screened 9-45% vs PCF 12-61%) was lower among those screened. INTERPRETATION: We found very limited patient outcome data. Collecting and reporting this data must be prioritised to inform policy and practice. FUNDING: WHO and EDCTP.

Costs and cost-effectiveness of tuberculosis cultures using solid and liquid media in a developing country.

SETTING: The expansion of culture has been proposed to aid tuberculosis (TB) control in developing countries. OBJECTIVES: To examine the cost and cost-effectiveness at the Zambian National TB Reference Laboratory of homemade and commercially produced Löwenstein-Jensen culture (HLJ and CLJ) as well as automated and manually read liquid culture (AMGIT and MMGIT). DESIGN: Costs were estimated from the provider's perspective and based on the average monthly throughput. Cost-effectiveness estimates were based on yield during the study period. RESULTS: All techniques show comparable costs per culture (between US$28 and $32). Costs per Mycobacterium tuberculosis specimen detected were respectively US$197, $202, $312 and $340 for MMGIT, AMGIT, CLJ and HLJ. When modelled for the maximum throughput, costs were above US$95 per M. tuberculosis specimen detected for all techniques. When only performed among smear-negative specimens, costs per additionally identified M. tuberculosis would be US$487 for MMGIT and higher for other methods. CONCLUSION: Based on cost-effectiveness grounds, liquid media compare well with conventional solid media, especially where yield of MGIT is substantially higher than that of LJ media. The results indicate high overall costs per culture; the expansion of culture to decentralised levels with lower throughputs may result in even higher costs.

A combined medical and surgical approach to hydatid disease: 12 years' experience at the Hospital for Tropical Diseases, London.

BACKGROUND: There is no consensus as to the most appropriate treatment for the varied and often complicated presentations of hydatid disease in Britain. We looked at our own results over a 12-year period to see if a consistent and logical plan had emerged. PATIENTS AND METHODS: 70 patients presenting between 1986 and 1998 were analysed retrospectively, with regard to their presentation, diagnosis, treatment and outcome, with particular reference to the use of chemotherapy, and to the difficulties of post-treatment assessment by serology and imaging. RESULTS: 37 patients had been treated previously. 35 had hepatic cysts and 26 multiple cysts. 4 patients were treated by surgery alone, 44 by chemotherapy and surgery, and 14 by chemotherapy alone. The combined use of albendazole and praziquantel pre-operatively reduced significantly the number of cysts that contained viable protoscolices: 1/25 versus 5/8 that received albendazole alone (P = 0.00013). During the 12-year period, it became our policy to aim for 3 months drug treatment (albendazole throughout with praziquantel for 2 weeks), re-assess and proceed either to surgery or to continue with chemotherapy. CONCLUSIONS: It is possible to construct an algorithm for the management of patients with hydatid disease by chemotherapy and surgery, but the assessment of results by indirect techniques remains difficult.

Malaria at Christmas: risks of prophylaxis versus risks of malaria.

PIP: A large increase in the number of falciparum malaria cases imported into the UK was reported to the malaria reference laboratory in the first quarter of 1998. Contributory factors were unusually heavy rains in east Africa and a reduction in the use of the most effective antimalarial drug, mefloquine. There was also an increase in the number of cases of severe malaria in the UK. During December 1997 and January 1998, the Hospital for Tropical Diseases, London, treated 5 patients for severe malaria and gave advice on 20 more patients with malaria who had been admitted to intensive care units throughout England. 4 of the severe cases treated at the hospital are reported. In 3 of those 4 cases, incorrect, misleading, or inadequate advice was given by health care professionals. Media coverage of the adverse effects of antimalarial drugs has contributed to confusion about prophylactic regimens among both health care professionals and the public. The incidence of falciparum malaria among travellers who do not take prophylactic drugs is about 0.6% in east Africa and 3.5% in west Africa over a 2-week travel period. Travellers need to take measures to avoid being bitten by mosquitoes and should be taught to promptly seek medical help if they develop a fever while abroad or after they return. Moreover, using any one of the recommended prophylactic regimens is better than not using a potent regimen or no prophylaxis at all. Mefloquine is 90% protective against malaria in sub-Saharan Africa. While the efficacy of proguanil and chloroquine in 1987 was about 70% in west Africa and 50% in east Africa, those levels are now probably lower. The side effects of antimalarial drugs are discussed.^ieng

Enhancement of class I HLA antigen expression by cytomegalovirus: role in amplification of virus infection.

We have investigated the effect of cytomegalovirus (CMV) infection on the expression of class I HLA antigens on fibroblasts in vitro. Scanning and integrating microdensitometry was used to quantitate the level of cytoplasmic class I antigen expression, and an antibody binding assay was used to quantitate cell surface expression of class I HLA molecules. CMV infection resulted in a significant increase in the level of cytoplasmic and cell surface class I HLA antigen expression of fibroblast monolayers. The maximal effect was seen at 72 hours postinfection and was observed with both the laboratory strain of CMV, strain AD169, and with CMV purified directly from clinical specimens. Part of the increased HLA expression was mediated by interferon released from infected cells; however, an additional direct effect of the virus itself has not been ruled out. Interferon-induced increased expression of class I HLA antigens was accompanied by increased binding of CMV to the cells, consistent with our recent demonstration that class I HLA molecules can function as a cellular receptor for CMV.