Evaluation of Diagnostic Algorithms, Drug Resistance, Molecular Typing, and Geospatial Clustering of Tuberculosis in Addis Ababa, Ethiopia

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Addis Ababa University


Ethiopia is one of the 30 highest burdens of TB, TB/HIV co-infection, and multidrug resistance TB countries. The objective of the paper was to determine the impact of alternative laboratory diagnostic algorithms on the patient, health system and population level using virtual implementation approach; to determine drug resistance, molecular, and spatial pattern of tuberculosis transmission; and to identify factors associated with the transmission in Addis Ababa, Ethiopia. A mathematical modeling was used for assessing the impact of alternative diagnostic algorithms. BACTECTM MGIT 960TM TB system (first-line anti-TB drugs) and GenoType MTBDRsl (second-line anti-TB drugs) were utilized for assessing drug susceptibility pattern. IS6110 Restriction Fragment Length Polymorphism, spoligotyping, and mycobacterial interspersed repetitive unit -variable number tandem repeat 24-loci typing (MIRU-VNTR) were used to analyze DNA fingerprinting. SaTScan and ArcMap were used for a purely spatial and space-time cluster analysis and mapping. Isolates were collected from pulmonary high MDR-TB risk group patients. Three of the modeled diagnostic algorithms are cost-effective. The full roll-out of Xpert MTB/RIF as the primary test for all presumptive TB cases would avert 91170 DALYs (95% credible interval [CrI] 54888 – 127448) with an additional health system cost of US$ 11.6 million over the next 10 years. The incremental cost-effectiveness ratio (ICER) is $370 per DALY averted. Same day LED fluorescence microscopy for all presumptive TB cases combined with Xpert MTB/RIF targeted to HIV-positive and High MDR-TB risk groups xv would avert 73600 DALYs (95% CrI 48373 - 99214) with an additional cost of US$5.1 million over the next 10 years. The ICER is $169per DALY averted. Same-day LED fluorescence microscopy for all presumptive TB cases (and no Xpert MTB/RIF) would avert 43580 DALYs with a reduction cost of US$ 0.2 million over the next 10years. The ICER is $13 per DALY averted. About 70% of the isolates were resistance to one or more of the first-line drugs, 61% of the isolates were multi-drug resistant, and 19% were resistant to all first-line drugs. Any resistance to INH, RMP, STM, EMB, PZA was 69%, 61%, 58%, 26% and 55% respectively. Four isolates were resistant to fluoroquinolones (pre-XDR), and belonging to T3_ETH linage. The rest isolates were susceptible to all second-line anti-TB drugs. The linage CAS1_KILI was a risk factor for MDR, resistance to one or more anti-tuberculosis drugs, and drug-resistant to INH, RMP, STM, and PZA. The linage T3_ETH was found to be a risk factor for EMB resistant. About 119 genetic profiles and 15 clusters were observed. T3_Eth International family constitutes the most predominant followed by the CAS1_KILI and CAS1_DELHI. Other International families found were CAS, H1, H3, H4, LAM9, T1, T2, T3, and T5. Some isolates were designated as an orphan. The predominantly clustered isolates were 3 bands. Clustering among 4 spoligotypes T3_ETH (41.8%), CAS1_KILI (29.4%), CAS_DELHI (10.5%), and T1 (33.3%) were observed with the overall clustering rate of 27.3%. The linage T3_ETH was significantly associated with clustering. Using spatial analysis, significant high and low rate most likely spatial and space-time clusters were identified. A significant secondary cluster was also obtained. The most likely cluster of xvi the high rate from both the purely special and space-time analyses was almost from the same area. Population density and per capita income was significantly associated with spatial clustering. The full roll-out of Xpert MTB/RIF is predicted to be the best option to substantially reduce the TB burden in Addis Ababa and is considered cost effective. Targeted use of Xpert MTB/RIF for HIV positive and high MDR risk groups with same-day LED fluorescence microscopy for all other presumptive TB cases is an alternative choice in case of budget shortage. A substantial number of drug-resistance TB, high rate of molecular clustering and existence of drug resistance hot spot indicated that the presence of recent drug- resistant TB transmission and inefficiency of TB control program in Addis Ababa city. T3_ETH and CAS1_KILI was the predominant linage and related to drug resistance tuberculosis in the city. Thus strengthen TB control program is crucial to interrupt the transmission of TB.



Tuberculosis, Modeling, Drug Resistance, Molecular Typing, Spatial Analysis, Ethiopia