Charles Muthoga | University of Botswana (original) (raw)
Papers by Charles Muthoga
Ponatshego, Ponego Lloyd; Lawrence, David Stephen; Youssouf, Nabila; Molloy, Sile F; Alufandika, ... more Ponatshego, Ponego Lloyd; Lawrence, David Stephen; Youssouf, Nabila; Molloy, Sile F; Alufandika, Melanie; Bango, Funeka; Boulware, David R; Chawinga, Chimwemwe; Dziwani, Eltas; Gondwe, Ebbie; +28 more... Hlupeni, Admire; Hosseinipour, Mina C; Kanyama, Cecilia; Meya, David B; Mosepele, Mosepele; Muthoga, Charles; Muzoora, Conrad K; Mwandumba, Henry; Ndhlovu, Chiratidzo E; Rajasingham, Radha; Sayed, Sumaya; Shamu, Shepherd; Tsholo, Katlego; Tugume, Lillian; Williams, Darlisha; Maheswaran, Hendramoorthy; Shiri, Tinevimbo; Boyer-Chammard, Timothée; Loyse, Angela; Chen, Tao; Wang, Duolao; Lortholary, Olivier; Lalloo, David G; Meintjes, Graeme; Jaffar, Shabbar; Harrison, Thomas S; Jarvis, Joseph N; Niessen, Louis Wilhelmus; (2019) AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study. BMJ open, 9 (4). DOI: https://doi....
Open Forum Infectious Diseases, 2017
Background. Exposure of the gut microbiome to antibiotics can harm the microbiota and lead to ant... more Background. Exposure of the gut microbiome to antibiotics can harm the microbiota and lead to antibiotic resistance. SYN-004 (ribaxamase) is a clinical-stage, oral β-lactamase enzyme intended to preserve the gut microbiome by inactivating certain IV β-lactam antibiotics in the GI tract without affecting antibiotic infection control efficacy. The use of ribaxamase for microbiome protection from both IV and orally-delivered antibiotics was explored using two large animal models of antibiotic-mediated gut dysbiosis. Methods. Ribaxamase was manufactured as enteric-coated pellets for pH-mediated release in the upper GI tract. New formulations, named SYN-007, were engineered to be released in the GI tract at a point distal to oral antibiotic absorption. Ribaxamase and SYN-007 were evaluated in a pig model of antibiotic-mediated microbiome disruption, and SYN-007 was evaluated in dogs. Pigs were treated with ceftriaxone (CRO; IV, 50 mg/kg, SID) or amoxicillin (AMX; PO, 20 mg/kg, BID) for 7 days +/-ribaxamase (PO, 75 mg, QID). Dogs received AMX (80 mg/kg, PO) +/-SYN-007 (10 mg, PO). Serum antibiotic levels were measured via HPLC or LC/MS, and fecal DNA whole genome shotgun (WGS) sequence analyses were performed. Results. In pigs, ribaxamase protected the gut microbiome from IV CRO and oral AMX and reduced propagation of antibiotic resistance genes. Ribaxamase had no effect on CRO serum levels. In contrast, AMX was not detected in the serum when delivered with ribaxamase indicating that AMX was degraded in the GI tract prior to its absorption. Delivery of delayed-release SYN-007 with oral AMX in dogs did not affect AMX absorption, as AMX serum pharmacokinetics (PK) was similar with and without SYN-007. Conclusion. Ribaxamase protected the gut microflora in pigs from damage caused by IV CRO and reduced the emergence of antibiotic resistance genes. SYN-007, a novel formulation designed to target enzyme release distal to the site of AMX absorption, did not affect AMX serum levels in dogs, indicating that the β-lactamase was not released prior to AMX absorption. SYN-007 has the potential to expand microbiome protection via antibiotic inactivation to include oral as well as IV β-lactam antibiotics.
A dissertation submitted to the Graduate School of Business, Faculty of Business, University of B... more A dissertation submitted to the Graduate School of Business, Faculty of Business, University of Botswana in partial fulfillment of the requirement of the degree of Masters of Business Administration. Citation: Muthoga, C.W. (2016) Understanding lack of full implementation of ICT systems; case study of the Integrated Patient Management System at the National Health Laboratory, University of Botswana.
Southern African Journal of HIV Medicine
Background: As the relentless coronavirus disease-2019 (COVID-19) pandemic continues to spread ac... more Background: As the relentless coronavirus disease-2019 (COVID-19) pandemic continues to spread across Africa, Botswana could face challenges maintaining the pathway towards control of its HIV epidemic.Objective: Utilising the Spectrum GOALS module (GOALS-2021), the 5-year outcomes from the implementation of the Treat All strategy were analysed and compared with the original 2016 Investment Case (2016-IC) projections. Future impact of adopting the new Joint United Nations Programme on HIV/AIDS (UNAIDS) Global AIDS Strategy (2021–2026) targets and macroeconomic analysis estimating how the financial constraints from the COVID-19 pandemic could impact the available resources for Botswana’s National HIV Response through 2030 were also considered.Method: Programmatic costs, population demographics, prevention and treatment outputs were determined. Previous 2016-IC data were uploaded for comparison, and inputs for the GOALS, AIM, DemProj, Resource Needs and Family Planning modules were der...
Wellcome Open Research
Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is r... more Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is rapidly changing. The newly-announced price for flucytosine ($0.75 per 500 mg pill) and possibly lower prices for liposomal amphotericin B (AmB-L) create opportunities to reduce CM treatment costs compared to the current standard treatment in low- and middle-income countries. Methods: We developed an Excel-based cost model to estimate health system treatment costs for CM over a two-week induction phase for multiple treatment combinations, newly feasible with improved access to flucytosine and AmB-L. CM treatment costs include medications, laboratory tests and other hospital-based costs (bed-day costs and healthcare worker time). We report results from applying the model using country-specific information for South Africa, Uganda, Nigeria, and Botswana. Results: A 14-day induction-phase of seven days of inpatient AmB-D with flucytosine, followed by seven days of high-dose fluconazole as an...
Journal of Clinical Microbiology
High cryptococcal antigen (CrAg) titers in blood are associated with subclinical meningitis and m... more High cryptococcal antigen (CrAg) titers in blood are associated with subclinical meningitis and mortality in CrAg-positive individuals with advanced HIV disease (AHD). We evaluated a novel semiquantitative lateral flow assay (LFA), CryptoPS, that may be able to identify individuals with high CrAg titers in a cohort of AHD patients undergoing CrAg screening. In a prospective cohort of patients with AHD (CD4 cell count, ≤200/μl) receiving CD4 count testing, whole blood was tested for CrAg by CryptoPS and the IMMY LFA; the two assays were conducted by two different operators, each blind to the results of the other assay.
Infection, Genetics and Evolution
Clinical Infectious Diseases
Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from ≤100 to ≤200 ce... more Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from ≤100 to ≤200 cells/µL resulted in a 3-fold increase in numbers screened. CrAg-prevalence was 3.5% at CD4 101–200 and 6.2% ≤100 cells/µL. Six-month mortality was 21.4% (9/42) in CrAg-positive CD4 ≤100 cells/µL and 3.2% (1/31) in CrAg-positive CD4 101–200 cells/µL.
Journal of Clinical Microbiology
Background: Higher cryptococcal antigen (CrAg) titers are strongly associated with mortality risk... more Background: Higher cryptococcal antigen (CrAg) titers are strongly associated with mortality risk in individuals with HIV-associated cryptococcal disease. Rapid tests to quantify CrAg level may provide important prognostic information and enable treatment stratification. Methods: We performed a laboratory-based validation of the semi-quantitative IMMY CrAgSQ assay against the current gold-standard CrAg tests. We assessed diagnostic accuracy of the CrAgSQ in HIV-positive individuals undergoing CrAg screening; determined the relationship between CrAgSQ scores and dilutional CrAg titers; assessed inter-rater reliability; and determined clinical correlates of CrAgSQ scores. Results: A total of 872 plasma samples were tested using both CrAgSQ and conventional IMMY CrAg LFA tests; 692 sequential samples from HIV-positive individuals undergoing CrAg screening and an additional 180 known CrAg-positive plasma samples archived from prior studies. Inter-rater agreement in CrAgSQ reading was ex...
Clinical Infectious Diseases
Background Evidence to inform cryptococcal antigen (CrAg)-screening guidelines among antiretrovir... more Background Evidence to inform cryptococcal antigen (CrAg)-screening guidelines among antiretroviral therapy (ART)-experienced populations are lacking. We performed a study evaluating the utility of reflex CrAg-screening in Gaborone, Botswana. Methods CD4 count data were collected from samples tested at the HIV reference laboratory from 2014-2016. CrAg screening was performed on samples with CD4 ≤100 cells/µL beginning January 2015. The proportion of CD4 counts ≤100 cells/µL was determined and the frequency and utility of repeat CrAg-testing described. Analyses were performed to ascertain the impact of ART-status on CrAg-prevalence and outcomes, and whether baseline CrAg titers could be used for risk stratification. Results Overall, 5.6% (3,335/59,300) of individuals tested had a CD4 ≤100 cells/μL; 2,108 samples with CD4 ≤100 cells/μl from 1,645 unique patients were CrAg-tested. Over half of samples were from ART-experienced individuals: 40.9% (863) on ART, and 12.1% (255) defaulters...
International Journal of STD & AIDS
In Botswana, where human immunodeficiency virus (HIV) prevalence remains high, cervical cancer is... more In Botswana, where human immunodeficiency virus (HIV) prevalence remains high, cervical cancer is the leading cause of cancer deaths in women. Multiple organizations recommend high-risk human papillomavirus (hr-HPV) testing as a screening tool; however, high coverage may not be feasible with provider-collected samples. We conducted the first assessment of self- versus provider-collected samples for hr-HPV testing in HIV-positive women in Botswana and report prevalence of hr-HPV and histological outcomes. We recruited HIV-positive women ≥25 years attending an HIV clinic in Gaborone. Self- and provider-collected samples from participants were tested for hr-HPV using Cepheid GeneXpert. Women testing positive for any hr-HPV returned for colposcopy. We used unweighted κ statistics to determine hr-HPV agreement. We report that 31 (30%) of 103 women tested positive for any hr-HPV. The most common genotypes were HPV 31/33/35/52/58. Overall agreement between self- and provider-collected samp...
Wellcome Open Research
Background: Cryptococcal antigen (CrAg) screening for antiretroviral therapy (ART)-naïve adults w... more Background: Cryptococcal antigen (CrAg) screening for antiretroviral therapy (ART)-naïve adults with advanced HIV/AIDS can reduce the incidence of cryptococcal meningitis (CM) and all-cause mortality. We modeled the cost-effectiveness of laboratory-based “reflex” CrAg screening for ART-naïve CrAg-positive patients with CD4<100 cells/µL (those currently targeted in guidelines) and ART-experienced CrAg-positive patients with CD4<100 cells/µL (who make up an increasingly large proportion of individuals with advanced HIV/AIDS). Methods: A decision analytic model was developed to evaluate CrAg screening and treatment based on local CD4 count and CrAg prevalence data, and realistic assumptions regarding programmatic implementation of the CrAg screening intervention. We modeled the number of CrAg tests performed, the number of CrAg positives stratified by prior ART experience, the proportion of patients started on pre-emptive antifungal treatment, and the number of incident CM cases ...
Journal of the Pediatric Infectious Diseases Society
Background Maternal human immunodeficiency virus (HIV) infection is associated with lower placent... more Background Maternal human immunodeficiency virus (HIV) infection is associated with lower placental transfer of antibodies specific to several childhood pathogens. Our objective for this study was to evaluate the effect of maternal HIV infection on the placental transfer of respiratory syncytial virus (RSV)-neutralizing antibodies. Methods We conducted a cross-sectional study of mothers and their newborn infants at a tertiary hospital in Gaborone, Botswana, between March 2015 and December 2015. We measured serum RSV antibody levels by using a microneutralization assay. We used multivariable linear regression to evaluate the effect of maternal HIV infection on maternal RSV antibody levels, placental transfer of RSV antibodies, and newborn RSV antibody levels. Results Of 316 mothers, 154 (49%) were infected with HIV. The placental transfer ratios for RSV antibodies to HIV-exposed, uninfected (HEU) and HIV-unexposed, uninfected infants were 1.02 and 1.15, respectively. The geometric me...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 26, 2018
Cryptococcal meningitis (CM) causes 10-20% of HIV-related deaths in Africa. We performed a phase-... more Cryptococcal meningitis (CM) causes 10-20% of HIV-related deaths in Africa. We performed a phase-II non-inferiority trial examining the Early Fungicidal Activity (EFA) of three short-course, high-dose liposomal amphotericin B (L-AmB) regimens for CM in Tanzania and Botswana. HIV-infected adults with CM were randomized to: (i) L-AmB 10mg/kg day 1 (single dose); (ii) L-AmB 10mg/kg day 1, 5mg/kg day 3 (two doses); (iii) L-AmB 10mg/kg day 1, 5 mg/kg days 3 and 7 (three doses); (iv) standard 14-day L-AmB 3mg/kg/day (control); all given with fluconazole 1200mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid (CSF) cryptococal infection (EFA). Non-inferiority was defined as an upper limit of the two-sided 95% confidence interval (CI) of difference in EFA between intervention and control less than 0.2 log10CFU/ml/day. 80 participants were enrolled. EFA for daily L-AmB was -0.41 (standard deviation 0.11, n=17) log10CFU/mL/day. Difference in mean EFA from co...
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, Jan 18, 2018
Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is commonly seen in malaria endemic areas as ... more Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is commonly seen in malaria endemic areas as it is known to confer a selective advantage against malaria. Recently, we reported a high proportion of asymptomatic reservoir of Plasmodium vivax in Botswana, that calls for intervention with primaquine to achieve radical cure of vivax malaria. Considering that individuals with this enzyme deficiency are at risk of haemolysis following primaquine treatment, assessment of the population for the relative frequency of G6PD deficiency is imperative. Samples from 3019 children from all the districts of Botswana were successfully genotyped for polymorphisms at positions 202 and 376 of the G6PD gene. Haematological parameters were also measured. The overall population allele frequency (based on the hemizygous male frequency) was 2.30% (95% CI, 1.77-2.83), while the overall frequency of G6PD-deficient genotypes A- (hemizygote and homozygote genotypes only) was 1.26% (95% CI, 0.86-1.66). G6PD de...
Scientific reports, Jan 20, 2018
Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (C... more Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (CYP2B6) enzyme is important for understanding the differences in clinical responses to malaria and HIV. This study evaluates the distribution of CYP2B6 alleles, haplotypes and inferred metabolic phenotypes among subjects with different ethnicity in Botswana. A total of 570 subjects were analyzed for CYP2B6 polymorphisms at position 516 G > T (rs3745274), 785 A > G (rs2279343) and 983 T > C (rs28399499). Samples were collected in three districts of Botswana where the population belongs to Bantu (Serowe/Palapye and Chobe) and San-related (Ghanzi) ethnicity. The three districts showed different haplotype composition according to the ethnic background but similar metabolic inferred phenotypes, with 59.12%, 34.56%, 2.10% and 4.21% of the subjects having, respectively, an extensive, intermediate, slow and rapid metabolic profile. The results hint at the possibility of a convergent adap...
Malaria journal, Mar 7, 2017
Botswana is one of the four front line malaria elimination countries in Southern Africa, with mal... more Botswana is one of the four front line malaria elimination countries in Southern Africa, with malaria control activities that include routine vector control. Past and recent studies have shown that Anopheles arabiensis is the only known vector of Plasmodium parasites in the country. This report presents a preliminary evaluation on Anopheles species composition in seven districts of Botswana with some inferences on their vectorial role. Overall, 404 Anopheles mosquito females were collected, of which 196 were larvae collected from several breeding sites, and 208 were adults obtained from indoor pyrethrum spray catches (PSC). Anopheles arabiensis (58.9%) accounted for the highest relative frequency in 5 out of 7 districts sampled. The other species collected, among those identified, were barely represented: Anopheles longipalpis type C (16.3%), Anopheles parensis (8.9%), Anopheles quadriannulatus (5.4%), and Anopheles leesoni (0.2%). PCR test for human β-globin on mosquitoes collected...
The Pediatric infectious disease journal, Jan 10, 2017
Nearly half of child pneumonia deaths occur in sub-Saharan Africa. Microbial communities in the n... more Nearly half of child pneumonia deaths occur in sub-Saharan Africa. Microbial communities in the nasopharynx are a reservoir for pneumonia pathogens and remain poorly described in African children. Nasopharyngeal swabs were collected from children with pneumonia (N=204), children with upper respiratory infection symptoms (N=55), and healthy children (N=60) in Botswana between April 2012 and April 2014. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used partitioning around medoids to cluster samples into microbiota biotypes. We then used multivariable logistic regression to examine whether microbiota biotypes were associated with pneumonia and upper respiratory infection symptoms. Mean ages of children with pneumonia, children with upper respiratory infection symptoms, and healthy children were 8.2, 11.4, and 8.0 months, respectively. Clustering of nasopharyngeal microbiota identified five distinct biotypes: Corynebacterium/Dolosigranulum-dominant (23%), Haemo...
Acta Tropica, 2016
Human cytochrome P450 2C8 is a highly polymorphic gene and shows variation according to ethnicity... more Human cytochrome P450 2C8 is a highly polymorphic gene and shows variation according to ethnicity. The CYP2C8*2 is a slow drug metabolism allele and shows 10-24% frequency in Black populations. The objective of this study was to assess the prevalence of CYP2C8*2 allele in Botswana among the San (or Bushmen) and the Bantu ethnic groups. For that purpose we recruited 544 children of the two ethnicities in three districts of Botswana from primary schools, collected blood samples, extracted DNA and genotyped them through PCR-based restriction fragment length polymorphism analysis. The results demonstrated that in the San the prevalence of the CYP2C8*2 allele is significantly higher than among the Bantu-related ethnic groups (17.5% and 8.5% for San and Bantu, respectively; P=0.00002). These findings support the evidence of a different genetic background of the San with respect to Bantu-related populations, and highlight a possible higher risk of longer drug clearance or poor level of activation of pro-drugs among the San group.
Molecular ecology, Jul 6, 2015
Cryptococcus neoformans var. grubii (Cng) is the most common cause of fungal meningitis and its p... more Cryptococcus neoformans var. grubii (Cng) is the most common cause of fungal meningitis and its prevalence is highest in sub-Saharan Africa. Patients become infected by inhaling airborne spores or desiccated yeast cells from the environment, where the fungus thrives in avian droppings, trees, and soil. To investigate the prevalence and population structure of Cng in southern Africa, we analyzed isolates from 77 environmental samples and 64 patients. We detected significant genetic diversity among isolates and strong evidence of geographic structure at the local level. High proportions of isolates with the rare MATa allele were observed in both clinical and environmental isolates; however, the mating type alleles were unevenly distributed among different subpopulations. Nearly equal proportions of the MATa and MATα mating types were observed among all clinical isolates and in one environmental subpopulation from the eastern part of Botswana. As previously reported, there was evidence...
Ponatshego, Ponego Lloyd; Lawrence, David Stephen; Youssouf, Nabila; Molloy, Sile F; Alufandika, ... more Ponatshego, Ponego Lloyd; Lawrence, David Stephen; Youssouf, Nabila; Molloy, Sile F; Alufandika, Melanie; Bango, Funeka; Boulware, David R; Chawinga, Chimwemwe; Dziwani, Eltas; Gondwe, Ebbie; +28 more... Hlupeni, Admire; Hosseinipour, Mina C; Kanyama, Cecilia; Meya, David B; Mosepele, Mosepele; Muthoga, Charles; Muzoora, Conrad K; Mwandumba, Henry; Ndhlovu, Chiratidzo E; Rajasingham, Radha; Sayed, Sumaya; Shamu, Shepherd; Tsholo, Katlego; Tugume, Lillian; Williams, Darlisha; Maheswaran, Hendramoorthy; Shiri, Tinevimbo; Boyer-Chammard, Timothée; Loyse, Angela; Chen, Tao; Wang, Duolao; Lortholary, Olivier; Lalloo, David G; Meintjes, Graeme; Jaffar, Shabbar; Harrison, Thomas S; Jarvis, Joseph N; Niessen, Louis Wilhelmus; (2019) AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study. BMJ open, 9 (4). DOI: https://doi....
Open Forum Infectious Diseases, 2017
Background. Exposure of the gut microbiome to antibiotics can harm the microbiota and lead to ant... more Background. Exposure of the gut microbiome to antibiotics can harm the microbiota and lead to antibiotic resistance. SYN-004 (ribaxamase) is a clinical-stage, oral β-lactamase enzyme intended to preserve the gut microbiome by inactivating certain IV β-lactam antibiotics in the GI tract without affecting antibiotic infection control efficacy. The use of ribaxamase for microbiome protection from both IV and orally-delivered antibiotics was explored using two large animal models of antibiotic-mediated gut dysbiosis. Methods. Ribaxamase was manufactured as enteric-coated pellets for pH-mediated release in the upper GI tract. New formulations, named SYN-007, were engineered to be released in the GI tract at a point distal to oral antibiotic absorption. Ribaxamase and SYN-007 were evaluated in a pig model of antibiotic-mediated microbiome disruption, and SYN-007 was evaluated in dogs. Pigs were treated with ceftriaxone (CRO; IV, 50 mg/kg, SID) or amoxicillin (AMX; PO, 20 mg/kg, BID) for 7 days +/-ribaxamase (PO, 75 mg, QID). Dogs received AMX (80 mg/kg, PO) +/-SYN-007 (10 mg, PO). Serum antibiotic levels were measured via HPLC or LC/MS, and fecal DNA whole genome shotgun (WGS) sequence analyses were performed. Results. In pigs, ribaxamase protected the gut microbiome from IV CRO and oral AMX and reduced propagation of antibiotic resistance genes. Ribaxamase had no effect on CRO serum levels. In contrast, AMX was not detected in the serum when delivered with ribaxamase indicating that AMX was degraded in the GI tract prior to its absorption. Delivery of delayed-release SYN-007 with oral AMX in dogs did not affect AMX absorption, as AMX serum pharmacokinetics (PK) was similar with and without SYN-007. Conclusion. Ribaxamase protected the gut microflora in pigs from damage caused by IV CRO and reduced the emergence of antibiotic resistance genes. SYN-007, a novel formulation designed to target enzyme release distal to the site of AMX absorption, did not affect AMX serum levels in dogs, indicating that the β-lactamase was not released prior to AMX absorption. SYN-007 has the potential to expand microbiome protection via antibiotic inactivation to include oral as well as IV β-lactam antibiotics.
A dissertation submitted to the Graduate School of Business, Faculty of Business, University of B... more A dissertation submitted to the Graduate School of Business, Faculty of Business, University of Botswana in partial fulfillment of the requirement of the degree of Masters of Business Administration. Citation: Muthoga, C.W. (2016) Understanding lack of full implementation of ICT systems; case study of the Integrated Patient Management System at the National Health Laboratory, University of Botswana.
Southern African Journal of HIV Medicine
Background: As the relentless coronavirus disease-2019 (COVID-19) pandemic continues to spread ac... more Background: As the relentless coronavirus disease-2019 (COVID-19) pandemic continues to spread across Africa, Botswana could face challenges maintaining the pathway towards control of its HIV epidemic.Objective: Utilising the Spectrum GOALS module (GOALS-2021), the 5-year outcomes from the implementation of the Treat All strategy were analysed and compared with the original 2016 Investment Case (2016-IC) projections. Future impact of adopting the new Joint United Nations Programme on HIV/AIDS (UNAIDS) Global AIDS Strategy (2021–2026) targets and macroeconomic analysis estimating how the financial constraints from the COVID-19 pandemic could impact the available resources for Botswana’s National HIV Response through 2030 were also considered.Method: Programmatic costs, population demographics, prevention and treatment outputs were determined. Previous 2016-IC data were uploaded for comparison, and inputs for the GOALS, AIM, DemProj, Resource Needs and Family Planning modules were der...
Wellcome Open Research
Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is r... more Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is rapidly changing. The newly-announced price for flucytosine ($0.75 per 500 mg pill) and possibly lower prices for liposomal amphotericin B (AmB-L) create opportunities to reduce CM treatment costs compared to the current standard treatment in low- and middle-income countries. Methods: We developed an Excel-based cost model to estimate health system treatment costs for CM over a two-week induction phase for multiple treatment combinations, newly feasible with improved access to flucytosine and AmB-L. CM treatment costs include medications, laboratory tests and other hospital-based costs (bed-day costs and healthcare worker time). We report results from applying the model using country-specific information for South Africa, Uganda, Nigeria, and Botswana. Results: A 14-day induction-phase of seven days of inpatient AmB-D with flucytosine, followed by seven days of high-dose fluconazole as an...
Journal of Clinical Microbiology
High cryptococcal antigen (CrAg) titers in blood are associated with subclinical meningitis and m... more High cryptococcal antigen (CrAg) titers in blood are associated with subclinical meningitis and mortality in CrAg-positive individuals with advanced HIV disease (AHD). We evaluated a novel semiquantitative lateral flow assay (LFA), CryptoPS, that may be able to identify individuals with high CrAg titers in a cohort of AHD patients undergoing CrAg screening. In a prospective cohort of patients with AHD (CD4 cell count, ≤200/μl) receiving CD4 count testing, whole blood was tested for CrAg by CryptoPS and the IMMY LFA; the two assays were conducted by two different operators, each blind to the results of the other assay.
Infection, Genetics and Evolution
Clinical Infectious Diseases
Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from ≤100 to ≤200 ce... more Increasing the CD4-count threshold for cryptococcal antigen (CrAg) screening from ≤100 to ≤200 cells/µL resulted in a 3-fold increase in numbers screened. CrAg-prevalence was 3.5% at CD4 101–200 and 6.2% ≤100 cells/µL. Six-month mortality was 21.4% (9/42) in CrAg-positive CD4 ≤100 cells/µL and 3.2% (1/31) in CrAg-positive CD4 101–200 cells/µL.
Journal of Clinical Microbiology
Background: Higher cryptococcal antigen (CrAg) titers are strongly associated with mortality risk... more Background: Higher cryptococcal antigen (CrAg) titers are strongly associated with mortality risk in individuals with HIV-associated cryptococcal disease. Rapid tests to quantify CrAg level may provide important prognostic information and enable treatment stratification. Methods: We performed a laboratory-based validation of the semi-quantitative IMMY CrAgSQ assay against the current gold-standard CrAg tests. We assessed diagnostic accuracy of the CrAgSQ in HIV-positive individuals undergoing CrAg screening; determined the relationship between CrAgSQ scores and dilutional CrAg titers; assessed inter-rater reliability; and determined clinical correlates of CrAgSQ scores. Results: A total of 872 plasma samples were tested using both CrAgSQ and conventional IMMY CrAg LFA tests; 692 sequential samples from HIV-positive individuals undergoing CrAg screening and an additional 180 known CrAg-positive plasma samples archived from prior studies. Inter-rater agreement in CrAgSQ reading was ex...
Clinical Infectious Diseases
Background Evidence to inform cryptococcal antigen (CrAg)-screening guidelines among antiretrovir... more Background Evidence to inform cryptococcal antigen (CrAg)-screening guidelines among antiretroviral therapy (ART)-experienced populations are lacking. We performed a study evaluating the utility of reflex CrAg-screening in Gaborone, Botswana. Methods CD4 count data were collected from samples tested at the HIV reference laboratory from 2014-2016. CrAg screening was performed on samples with CD4 ≤100 cells/µL beginning January 2015. The proportion of CD4 counts ≤100 cells/µL was determined and the frequency and utility of repeat CrAg-testing described. Analyses were performed to ascertain the impact of ART-status on CrAg-prevalence and outcomes, and whether baseline CrAg titers could be used for risk stratification. Results Overall, 5.6% (3,335/59,300) of individuals tested had a CD4 ≤100 cells/μL; 2,108 samples with CD4 ≤100 cells/μl from 1,645 unique patients were CrAg-tested. Over half of samples were from ART-experienced individuals: 40.9% (863) on ART, and 12.1% (255) defaulters...
International Journal of STD & AIDS
In Botswana, where human immunodeficiency virus (HIV) prevalence remains high, cervical cancer is... more In Botswana, where human immunodeficiency virus (HIV) prevalence remains high, cervical cancer is the leading cause of cancer deaths in women. Multiple organizations recommend high-risk human papillomavirus (hr-HPV) testing as a screening tool; however, high coverage may not be feasible with provider-collected samples. We conducted the first assessment of self- versus provider-collected samples for hr-HPV testing in HIV-positive women in Botswana and report prevalence of hr-HPV and histological outcomes. We recruited HIV-positive women ≥25 years attending an HIV clinic in Gaborone. Self- and provider-collected samples from participants were tested for hr-HPV using Cepheid GeneXpert. Women testing positive for any hr-HPV returned for colposcopy. We used unweighted κ statistics to determine hr-HPV agreement. We report that 31 (30%) of 103 women tested positive for any hr-HPV. The most common genotypes were HPV 31/33/35/52/58. Overall agreement between self- and provider-collected samp...
Wellcome Open Research
Background: Cryptococcal antigen (CrAg) screening for antiretroviral therapy (ART)-naïve adults w... more Background: Cryptococcal antigen (CrAg) screening for antiretroviral therapy (ART)-naïve adults with advanced HIV/AIDS can reduce the incidence of cryptococcal meningitis (CM) and all-cause mortality. We modeled the cost-effectiveness of laboratory-based “reflex” CrAg screening for ART-naïve CrAg-positive patients with CD4<100 cells/µL (those currently targeted in guidelines) and ART-experienced CrAg-positive patients with CD4<100 cells/µL (who make up an increasingly large proportion of individuals with advanced HIV/AIDS). Methods: A decision analytic model was developed to evaluate CrAg screening and treatment based on local CD4 count and CrAg prevalence data, and realistic assumptions regarding programmatic implementation of the CrAg screening intervention. We modeled the number of CrAg tests performed, the number of CrAg positives stratified by prior ART experience, the proportion of patients started on pre-emptive antifungal treatment, and the number of incident CM cases ...
Journal of the Pediatric Infectious Diseases Society
Background Maternal human immunodeficiency virus (HIV) infection is associated with lower placent... more Background Maternal human immunodeficiency virus (HIV) infection is associated with lower placental transfer of antibodies specific to several childhood pathogens. Our objective for this study was to evaluate the effect of maternal HIV infection on the placental transfer of respiratory syncytial virus (RSV)-neutralizing antibodies. Methods We conducted a cross-sectional study of mothers and their newborn infants at a tertiary hospital in Gaborone, Botswana, between March 2015 and December 2015. We measured serum RSV antibody levels by using a microneutralization assay. We used multivariable linear regression to evaluate the effect of maternal HIV infection on maternal RSV antibody levels, placental transfer of RSV antibodies, and newborn RSV antibody levels. Results Of 316 mothers, 154 (49%) were infected with HIV. The placental transfer ratios for RSV antibodies to HIV-exposed, uninfected (HEU) and HIV-unexposed, uninfected infants were 1.02 and 1.15, respectively. The geometric me...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 26, 2018
Cryptococcal meningitis (CM) causes 10-20% of HIV-related deaths in Africa. We performed a phase-... more Cryptococcal meningitis (CM) causes 10-20% of HIV-related deaths in Africa. We performed a phase-II non-inferiority trial examining the Early Fungicidal Activity (EFA) of three short-course, high-dose liposomal amphotericin B (L-AmB) regimens for CM in Tanzania and Botswana. HIV-infected adults with CM were randomized to: (i) L-AmB 10mg/kg day 1 (single dose); (ii) L-AmB 10mg/kg day 1, 5mg/kg day 3 (two doses); (iii) L-AmB 10mg/kg day 1, 5 mg/kg days 3 and 7 (three doses); (iv) standard 14-day L-AmB 3mg/kg/day (control); all given with fluconazole 1200mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid (CSF) cryptococal infection (EFA). Non-inferiority was defined as an upper limit of the two-sided 95% confidence interval (CI) of difference in EFA between intervention and control less than 0.2 log10CFU/ml/day. 80 participants were enrolled. EFA for daily L-AmB was -0.41 (standard deviation 0.11, n=17) log10CFU/mL/day. Difference in mean EFA from co...
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, Jan 18, 2018
Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is commonly seen in malaria endemic areas as ... more Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is commonly seen in malaria endemic areas as it is known to confer a selective advantage against malaria. Recently, we reported a high proportion of asymptomatic reservoir of Plasmodium vivax in Botswana, that calls for intervention with primaquine to achieve radical cure of vivax malaria. Considering that individuals with this enzyme deficiency are at risk of haemolysis following primaquine treatment, assessment of the population for the relative frequency of G6PD deficiency is imperative. Samples from 3019 children from all the districts of Botswana were successfully genotyped for polymorphisms at positions 202 and 376 of the G6PD gene. Haematological parameters were also measured. The overall population allele frequency (based on the hemizygous male frequency) was 2.30% (95% CI, 1.77-2.83), while the overall frequency of G6PD-deficient genotypes A- (hemizygote and homozygote genotypes only) was 1.26% (95% CI, 0.86-1.66). G6PD de...
Scientific reports, Jan 20, 2018
Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (C... more Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (CYP2B6) enzyme is important for understanding the differences in clinical responses to malaria and HIV. This study evaluates the distribution of CYP2B6 alleles, haplotypes and inferred metabolic phenotypes among subjects with different ethnicity in Botswana. A total of 570 subjects were analyzed for CYP2B6 polymorphisms at position 516 G > T (rs3745274), 785 A > G (rs2279343) and 983 T > C (rs28399499). Samples were collected in three districts of Botswana where the population belongs to Bantu (Serowe/Palapye and Chobe) and San-related (Ghanzi) ethnicity. The three districts showed different haplotype composition according to the ethnic background but similar metabolic inferred phenotypes, with 59.12%, 34.56%, 2.10% and 4.21% of the subjects having, respectively, an extensive, intermediate, slow and rapid metabolic profile. The results hint at the possibility of a convergent adap...
Malaria journal, Mar 7, 2017
Botswana is one of the four front line malaria elimination countries in Southern Africa, with mal... more Botswana is one of the four front line malaria elimination countries in Southern Africa, with malaria control activities that include routine vector control. Past and recent studies have shown that Anopheles arabiensis is the only known vector of Plasmodium parasites in the country. This report presents a preliminary evaluation on Anopheles species composition in seven districts of Botswana with some inferences on their vectorial role. Overall, 404 Anopheles mosquito females were collected, of which 196 were larvae collected from several breeding sites, and 208 were adults obtained from indoor pyrethrum spray catches (PSC). Anopheles arabiensis (58.9%) accounted for the highest relative frequency in 5 out of 7 districts sampled. The other species collected, among those identified, were barely represented: Anopheles longipalpis type C (16.3%), Anopheles parensis (8.9%), Anopheles quadriannulatus (5.4%), and Anopheles leesoni (0.2%). PCR test for human β-globin on mosquitoes collected...
The Pediatric infectious disease journal, Jan 10, 2017
Nearly half of child pneumonia deaths occur in sub-Saharan Africa. Microbial communities in the n... more Nearly half of child pneumonia deaths occur in sub-Saharan Africa. Microbial communities in the nasopharynx are a reservoir for pneumonia pathogens and remain poorly described in African children. Nasopharyngeal swabs were collected from children with pneumonia (N=204), children with upper respiratory infection symptoms (N=55), and healthy children (N=60) in Botswana between April 2012 and April 2014. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used partitioning around medoids to cluster samples into microbiota biotypes. We then used multivariable logistic regression to examine whether microbiota biotypes were associated with pneumonia and upper respiratory infection symptoms. Mean ages of children with pneumonia, children with upper respiratory infection symptoms, and healthy children were 8.2, 11.4, and 8.0 months, respectively. Clustering of nasopharyngeal microbiota identified five distinct biotypes: Corynebacterium/Dolosigranulum-dominant (23%), Haemo...
Acta Tropica, 2016
Human cytochrome P450 2C8 is a highly polymorphic gene and shows variation according to ethnicity... more Human cytochrome P450 2C8 is a highly polymorphic gene and shows variation according to ethnicity. The CYP2C8*2 is a slow drug metabolism allele and shows 10-24% frequency in Black populations. The objective of this study was to assess the prevalence of CYP2C8*2 allele in Botswana among the San (or Bushmen) and the Bantu ethnic groups. For that purpose we recruited 544 children of the two ethnicities in three districts of Botswana from primary schools, collected blood samples, extracted DNA and genotyped them through PCR-based restriction fragment length polymorphism analysis. The results demonstrated that in the San the prevalence of the CYP2C8*2 allele is significantly higher than among the Bantu-related ethnic groups (17.5% and 8.5% for San and Bantu, respectively; P=0.00002). These findings support the evidence of a different genetic background of the San with respect to Bantu-related populations, and highlight a possible higher risk of longer drug clearance or poor level of activation of pro-drugs among the San group.
Molecular ecology, Jul 6, 2015
Cryptococcus neoformans var. grubii (Cng) is the most common cause of fungal meningitis and its p... more Cryptococcus neoformans var. grubii (Cng) is the most common cause of fungal meningitis and its prevalence is highest in sub-Saharan Africa. Patients become infected by inhaling airborne spores or desiccated yeast cells from the environment, where the fungus thrives in avian droppings, trees, and soil. To investigate the prevalence and population structure of Cng in southern Africa, we analyzed isolates from 77 environmental samples and 64 patients. We detected significant genetic diversity among isolates and strong evidence of geographic structure at the local level. High proportions of isolates with the rare MATa allele were observed in both clinical and environmental isolates; however, the mating type alleles were unevenly distributed among different subpopulations. Nearly equal proportions of the MATa and MATα mating types were observed among all clinical isolates and in one environmental subpopulation from the eastern part of Botswana. As previously reported, there was evidence...