Improving identification of symptomatic cancer at primary care clinics: A predictive modeling analysis in Botswana.

In resource-limited settings, augmenting primary care provider (PCP)-based referrals with data-derived algorithms could direct scarce resources towards those patients most likely to have a cancer diagnosis and benefit from early treatment. Using data from Botswana, we compared accuracy of predictions of probable cancer using different approaches for identifying symptomatic cancer at primary clinics. We followed cancer suspects until they entered specialized care for cancer treatment (following pathologically confirmed diagnosis), exited from the study following noncancer diagnosis, or died. Routine symptom and demographic data included baseline cancer probability assessed by the primary care provider (low, intermediate, high), age, sex, performance status, baseline cancer probability by study physician, predominant symptom (lump, bleeding, pain or other) and HIV status. Logistic regression with 10-fold cross-validation was used to evaluate classification by different sets of predictors: (1) PCPs, (2) Algorithm-only, (3) External specialist physician review and (4) Primary clinician augmented by algorithm. Classification accuracy was assessed using c-statistics, sensitivity and specificity. Six hundred and twenty-three adult cancer suspects with complete data were retained, of whom 166 (27%) were diagnosed with cancer. Models using PCP augmented by algorithm (c-statistic: 77.2%, 95% CI: 73.4%, 81.0%) and external study physician assessment (77.6%, 95% CI: 73.6%, 81.7%) performed better than algorithm-only (74.9%, 95% CI: 71.0%, 78.9%) and PCP initial assessment (62.8%, 95% CI: 57.9%, 67.7%) in correctly classifying suspected cancer patients. Sensitivity and specificity statistics from models combining PCP classifications and routine data were comparable to physicians, suggesting that incorporating data-driven algorithms into referral systems could improve efficiency.

Universal Testing, Expanded Treatment, and Incidence of HIV Infection in Botswana.

BACKGROUND: The feasibility of reducing the population-level incidence of human immunodeficiency virus (HIV) infection by increasing community coverage of antiretroviral therapy (ART) and male circumcision is unknown. METHODS: We conducted a pair-matched, community-randomized trial in 30 rural or periurban communities in Botswana from 2013 to 2018. Participants in 15 villages in the intervention group received HIV testing and counseling, linkage to care, ART (started at a higher CD4 count than in standard care), and increased access to male circumcision services. The standard-care group also consisted of 15 villages. Universal ART became available in both groups in mid-2016. We enrolled a random sample of participants from approximately 20% of households in each community and measured the incidence of HIV infection through testing performed approximately once per year. The prespecified primary analysis was a permutation test of HIV incidence ratios. Pair-stratified Cox models were used to calculate 95% confidence intervals. RESULTS: Of 12,610 enrollees (81% of eligible household members), 29% were HIV-positive. Of the 8974 HIV-negative persons (4487 per group), 95% were retested for HIV infection over a median of 29 months. A total of 57 participants in the intervention group and 90 participants in the standard-care group acquired HIV infection (annualized HIV incidence, 0.59% and 0.92%, respectively). The unadjusted HIV incidence ratio in the intervention group as compared with the standard-care group was 0.69 (P = 0.09) by permutation test (95% confidence interval [CI], 0.46 to 0.90 by pair-stratified Cox model). An end-of-trial survey in six communities (three per group) showed a significantly greater increase in the percentage of HIV-positive participants with an HIV-1 RNA level of 400 copies per milliliter or less in the intervention group (18 percentage points, from 70% to 88%) than in the standard-care group (8 percentage points, from 75% to 83%) (relative risk, 1.12; 95% CI, 1.09 to 1.16). The percentage of men who underwent circumcision increased by 10 percentage points in the intervention group and 2 percentage points in the standard-care group (relative risk, 1.26; 95% CI, 1.17 to 1.35). CONCLUSIONS: Expanded HIV testing, linkage to care, and ART coverage were associated with increased population viral suppression. (Funded by the President's Emergency Plan for AIDS Relief and others; Ya Tsie ClinicalTrials.gov number, NCT01965470.).

HIV infection is not associated with the initiation of curative treatment in women with cervical cancer in Botswana.

BACKGROUND: Cervical cancer is the leading cause of cancer death in Sub-Saharan Africa. The risk of developing cancer is increased for women living with human immunodeficiency virus (HIV) infection. It is unknown which factors predict the initiation of curative chemoradiotherapy (CRT) in resource-limited settings and whether HIV is associated with initiating curative CRT in settings with a high HIV burden. METHODS: All women living with and without HIV infection who were initiating curative and noncurative CRT for locally advanced cervical cancer in Botswana were prospectively enrolled in an observational study. The factors associated with receiving CRT were evaluated in all patients and the subgroup of women living with HIV. RESULTS: Of 519 enrolled women, 284 (55%) initiated CRT with curative intent. The curative cohort included 200 women (70.4%) who were living with HIV and had a median CD4 count of 484.0 cells/µL (interquartile range, 342.0-611.0 cells/µL). In the noncurative cohort, 157 of 235 women (66.8%) were living with HIV and had a median CD4 count of 476.5 cells/µL (interquartile range, 308.0-649.5 cells/µL). HIV status was not associated with initiating curative CRT (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.58-1.56). The factors associated with receiving curative CRT treatment on multivariable analysis in all patients included baseline hemoglobin levels ≥10 g/dL (OR, 1.80; 95% CI, 1.18-2.74) and stage I or II versus stage III or IV disease (OR, 3.16; 95% CI, 2.10-4.75). Women aged >61 years were less likely to receive curative treatment (OR, 0.43; 95% CI, 0.24-0.75). Among women who were living with HIV, higher CD4 cell counts were associated with higher rates of CRT initiation. CONCLUSIONS: The initiation of CRT with curative intent does not depend on HIV status. Significant predictors of CRT initiation include baseline hemoglobin level, disease stage, and age.

Multilevel Factors Affecting Time to Cancer Diagnosis and Care Quality in Botswana.

BACKGROUND: Cancer incidence is increasing in Africa, and the majority of patients are diagnosed with advanced disease, limiting treatment options and survival. We sought to understand care patterns and factors contributing to delayed diagnosis and treatment initiation among patients with cancer in Botswana. PATIENTS AND METHODS: We recruited 20 patients who were enrolled in a prospective cancer cohort in Botswana to a qualitative substudy that explored cancer care pathways and factors affecting cancer care access and quality. We conducted an in-depth interview with each participant between October 2014 and January 2015, using a a structured interview guide with questions about initial cancer symptoms, previous consultations, diagnosis, and care pathways. Medical records were used to confirm dates or treatment details when needed. RESULTS: Individual and interpersonal factors such as cancer awareness and social support facilitated care-seeking behaviors. However, patients experienced multiple delays in diagnosis and treatment because of provider and health system barriers. Health system factors, such as misdiagnosis, understaffed facilities, poor referral communication and scheduling, and inadequate laboratory reporting systems, affected access to and quality of cancer care. CONCLUSION: These findings highlight the need for interventions at the patient, provider, and health system levels to improve cancer care quality and outcomes in Botswana. Results also suggest that widespread cancer education has potential to promote early diagnosis through family and community networks. Identified barriers and facilitators suggest that interventions to improve community education and access to diagnostic technologies could help improve cancer outcomes in this setting. IMPLICATIONS FOR PRACTICE: The majority (54%) of patients with cancer in Botswana present with advanced-stage cancer despite universal access to free health care, limiting the options for treatment and decreasing the likelihood of positive treatment outcomes. To reduce time from symptom onset to cancer treatment initiation, causes of delay in cancer care trajectories must be identified. The narratives of the patients interviewed for this study give insight into psychosocial factors, outlooks on disease, lower-level provider delays, and health system barriers that contribute to substantial delays for patients with cancer in Botswana. Identification of problems and barriers is essential for development of effective interventions to mitigate these factors, in order to improve cancer outcomes in this population.

Impact of efavirenz on hormone-positive breast cancer survival in women living with HIV.

Women living with HIV and breast cancer have poorer survival than HIV-negative women. Efavirenz-estrogen interactions are documented; however, the survival impact is unknown. Survival between women with estrogen-receptor positive breast cancer taking efavirenz (n = 38) and nonefavirenz regimens (n = 51) were compared. The 5-year overall-survival was 48.9% [95% confidence interval (CI) 33.0-72.2 and 51.1% (95% CI 34.0-76.8)] in the efavirenz and nonefavirenz groups, respectively suggesting efavirenz is unlikely driving poorer survival in women living with HIV and estrogen-receptor positive breast cancer.

A Novel Approach to Equitable Distribution of Scarce Therapeutics: Institutional Experience Implementing a Reserve System for Allocation of COVID-19 Monoclonal Antibodies.

BACKGROUND: In fall 2020, the Food and Drug Administration issued emergency use authorization for monoclonal antibody (mAb) therapies for outpatients with COVID-19. The Commonwealth of Massachusetts issued guidance outlining the use of a reserve system with a lottery for allocation of mAbs in the event of scarcity that would prioritize socially vulnerable patients for 20% of the infusion slots. The Mass General Brigham health system subsequently implemented such a reserve system. RESEARCH QUESTION: Can a reserve system be deployed successfully in a large health system in a way that promotes equitable access to mAb therapy among socially vulnerable patients with COVID-19? STUDY DESIGN AND METHODS: We conducted a retrospective review of the operation of the reserve system for allocation of mAb therapies to identify how referrals moved through the allocation process and what proportion of patients who were offered and received mAb therapies were socially vulnerable. RESULTS: Notwithstanding multiple operational challenges, the reserve system for allocation of mAb therapy worked as intended to enhance the number of socially vulnerable patients who were offered and received mAb therapy. A significantly higher proportion of patients offered mAb therapy were socially vulnerable (27.0%) than would have been the case if the infusion appointments had been allocated using a pure lottery system without a vulnerable reserve (19.8%), and a significantly higher proportion of patient who received infusions were socially vulnerable (25.3%) than would have been the case if the infusion appointments had been allocated using a pure lottery system (17.6%) INTERPRETATION: Our health system experience demonstrates that a reserve system with a lottery for tiebreaking is a viable way to distribute scarce therapeutics when enhancing access for certain groups is desirable.

Accuracy of Pathologic Diagnosis in Patients With Lymphoma and Survival: A Prospective Analysis From Botswana.

PURPOSE: With intense HIV epidemics, southern African countries have a high burden of classic Hodgkin lymphoma (CHL) and non-Hodgkin lymphoma (NHL). However, suboptimal access to pathology resources limits subtype classification. We sought to assess the diagnostic accuracy of specimens classified as lymphoma and to determine association between discordant pathologic diagnosis and overall survival. METHODS: Seventy patients with CHL or NHL and treated at three Botswana hospitals from 2010 to 2016 were analyzed. Local pathologic assessment relied primarily on morphology. All cases underwent secondary US hematopathology review, which is considered gold standard. RESULTS: The median follow-up was 58 months. The overall reclassification rate was 20 of 70 cases (29%). All 20 CHL cases were correctly classified in Botswana, and mixed cellularity was the most common subtype, diagnosed in 11 (55%) cases. Of 47 confirmed NHL cases, diffuse large B-cell lymphoma was the final US diagnosis in 28 cases (60%), another aggressive B-cell NHL in nine (19%), an indolent B-cell NHL in six (13%), and T-cell NHL in four (9%). Common types of diagnostic discordance included NHL subtype reclassification (11 of 20, 55%) and CHL reclassified as NHL (7 of 20, 35%). Concordant versus discordant diagnosis after secondary review was associated with improved 5-year overall survival (60.1% v 26.3%, P = .0066). Discordant diagnosis was independently associated with increased risk of death (adjusted hazard ratio 2.733; 95% CI, 1.102 to 6.775; P = .0300) even after stratifying results by CHL versus NHL. CONCLUSION: In this single prospective cohort, discordant pathologic diagnosis was associated with a nearly three-fold increased risk of death. Limited access to relatively basic diagnostic techniques impairs treatment decisions and leads to poor patient outcomes in low-resource countries.

Population uptake of HIV testing, treatment, viral suppression, and male circumcision following a community-based intervention in Botswana (Ya Tsie/BCPP): a cluster-randomised trial.

BACKGROUND: In settings with high HIV prevalence and treatment coverage, such as Botswana, it is unknown whether uptake of HIV prevention and treatment interventions can be increased further. We sought to determine whether a community-based intervention to identify and rapidly treat people living with HIV, and support male circumcision could increase population levels of HIV diagnosis, treatment, viral suppression, and male circumcision in Botswana. METHODS: The Ya Tsie Botswana Combination Prevention Project study was a pair-matched cluster-randomised trial done in 30 communities across Botswana done from Oct 30, 2013, to June 30, 2018. 15 communities were randomly assigned to receive HIV prevention and treatment interventions, including enhanced HIV testing, earlier antiretroviral therapy (ART), and strengthened male circumcision services, and 15 received standard of care. The first primary endpoint of HIV incidence has already been reported. In this Article, we report findings for the second primary endpoint of population uptake of HIV prevention services, as measured by proportion of people known to be HIV-positive or tested HIV-negative in the preceding 12 months; proportion of people living with HIV diagnosed and on ART; proportion of people living with HIV on ART with viral suppression; and proportion of HIV-negative men circumcised. A longitudinal cohort of residents aged 16-64 years from a random, approximately 20% sample of households across the 15 communities was enrolled to assess baseline uptake of study outcomes; we also administered an end-of-study survey to all residents not previously enrolled in the longitudinal cohort to provide study end coverage estimates. Differences in intervention uptake over time by randomisation group were tested via paired Student's t test. The study has been completed and is registered with ClinicalTrials.gov (NCT01965470). FINDINGS: In the six communities participating in the end-of-study survey, 2625 residents (n=1304 from standard-of-care communities, n=1321 from intervention communities) were enrolled into the 20% longitudinal cohort at baseline from Oct 30, 2013, to Nov 24, 2015. In the same communities, 10 791 (86%) of 12 489 eligible enumerated residents not previously enrolled in the longitudinal cohort participated in the end-of-study survey from March 30, 2017, to Feb 25, 2018 (5896 in intervention and 4895 in standard-of-care communities). At study end, in intervention communities, 1228 people living with HIV (91% of 1353) were on ART; 1166 people living with HIV (88% of 1321 with available viral load) were virally suppressed, and 673 HIV-negative men (40% of 1673) were circumcised in intervention communities. After accounting for baseline differences, at study end the proportion of people living with HIV who were diagnosed was significantly higher in intervention communities (absolute increase of 9% to 93%) compared with standard-of-care communities (absolute increase of 2% to 88%; prevalence ratio [PR] 1·08 [95% CI 1·02-1·14], p=0·032). Population levels of ART, viral suppression, and male circumcision increased from baseline in both groups, with greater increases in intervention communities (ART PR 1·12 [95% CI 1·07-1·17], p=0·018; viral suppression 1·13 [1·09-1·17], p=0·017; male circumcision 1·26 [1·17-1·35], p=0·029). INTERPRETATION: It is possible to achieve very high population levels of HIV testing and treatment in a high-prevalence setting. Maintaining these coverage levels over the next decade could substantially reduce HIV transmission and potentially eliminate the epidemic in these areas. FUNDING: US President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention.

Explaining disparities in oncology health systems delays and stage at diagnosis between men and women in Botswana: A cohort study.

PURPOSE: Men in Botswana present with more advanced cancer than women, leading to poorer outcomes. We sought to explain sex-specific differences in time to and stage at treatment initiation. METHODS: Cancer patients who initiated oncology treatment between October 2010 and June 2017 were recruited at four oncology centers in Botswana. Primary outcomes were time from first visit with cancer symptom to treatment initiation, and advanced cancer (stage III/IV). Sociodemographic and clinical covariates were obtained retrospectively through interviews and medical record review. We used accelerated failure time and logistic models to estimate standardized sex differences in treatment initiation time and risk differences for presentation with advanced stage. Results were stratified by cancer type (breast, cervix, non-Hodgkin's lymphoma, anogenital, head and neck, esophageal, other). RESULTS: 1886 participants (70% female) were included. After covariate adjustment, men experienced longer excess time from first presentation to treatment initiation (8.4 months) than women (7.0 months) for all cancers combined (1.4 months, 95% CI: 0.30, 2.5). In analysis stratified by cancer type, we only found evidence of a sex disparity (Men: 8.2; Women: 6.8 months) among patients with other, non-common cancers (1.4 months, 95% CI: 0.01, 2.8). Men experienced an increased risk of advanced stage (Men: 67%; Women: 60%; aRD: 6.7%, 95% CI: -1.7%, 15.1%) for all cancers combined, but this disparity was only statistically significant among patients with anogenital cancers (Men: 72%; Women: 50%; aRD: 22.0%, 95% CI: 0.5%, 43.5%). CONCLUSIONS: Accounting for the types of cancers experienced by men and women strongly attenuated disparities in time to treatment initiation and stage. Higher incidence of rarer cancers among men could explain these disparities.

Impact of HIV Infection on the Clinical Presentation and Survival of Non-Hodgkin Lymphoma: A Prospective Observational Study From Botswana.

PURPOSE: Botswana has a high prevalence of HIV infection. Currently, there are few data regarding the sociodemographic factors, clinical characteristics, and outcomes of non-Hodgkin lymphoma (NHL)-an AIDS-defining cancer-in the country. PATIENTS AND METHODS: This study used a prospective cancer registry to identify patients with a new diagnosis of NHL reporting for specialty cancer care at three hospitals in Botswana between October 2010 and August 2016. Treatment patterns and clinical outcomes were analyzed. RESULTS: One hundred four patients with a new diagnosis of NHL were enrolled in this study, 72% of whom had HIV infection. Compared with patients not infected with HIV, patients infected with HIV were younger (median age, 53.9 v 39.1 years; P = .001) and more likely to present with an aggressive subtype of NHL (65.5% v 84.0%; P = .008). All patients infected with HIV received combined antiretroviral therapy throughout the course of the study, and similar chemotherapeutic regimens were recommended for all patients, regardless of subtype or HIV status (six to eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). There was no difference in 1-year mortality among patients not infected with HIV and patients infected with HIV (unadjusted analysis, 52.9% v 37.1%; hazard ratio [HR], 0.73; P = .33; adjusted analysis, HR, 0.57; P = .14). However, when compared with a cohort of patients in the United States matched by subtype, stage, age, sex, and race, patients in Botswana fared worse (1-year mortality, 22.8% v 46.3%; HR, 1.89; P = .001). CONCLUSION: Among patients with NHL reporting for specialty cancer care in Botswana, there is no association between HIV status and 1-year survival.

Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma.

A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.

High HIV-1 RNA Among Newly Diagnosed People in Botswana.

HIV-1 RNA level is strongly associated with HIV transmission risk. We sought to determine whether HIV-1 RNA level was associated with prior knowledge of HIV status among treatment-naive HIV-infected individuals in Botswana, a country with high rates of antiretroviral treatment (ART) coverage. This information may be helpful in targeting HIV diagnosis and treatment efforts in similar high HIV prevalence settings in a population-based survey. HIV-infected individuals were identified during a household survey performed in 30 communities across Botswana. ART-naive persons with detectable HIV-1 RNA (>400 copies/mL) were divided into two groups, newly diagnosed and individuals tested in the past who knew about their HIV infection at the time of household visit, but had not taken ART. Levels of HIV-1 RNA were compared between groups, overall and by age and gender. Among 815 HIV-infected ART-naive persons with detectable virus, newly diagnosed individuals had higher levels of HIV-1 RNA (n = 490, median HIV-1 RNA 4.35, interquartile range (IQR) 3.79-4.91 log10 copies/mL) than those who knew about their HIV-positive status (n = 325, median HIV-1 RNA 4.10, IQR 3.55-4.68 log10 copies/mL; p values <.001, but p value = .011 after adjusting for age and gender). A nonsignificant trend for higher HIV-1 RNA was found among newly diagnosed men 30 years of age or older (median HIV-1 RNA 4.58, IQR 4.07-5.02 log10 copies/mL vs. 4.17, 3.61-4.71 log10 copies/mL). Newly diagnosed individuals have elevated levels of HIV-1 RNA. This study highlights the need for early diagnosis and treatment of HIV infection for purposes of HIV epidemic control, even in a setting with high ART coverage.

Parallel synthesis of ureas and carbamates from amines and CO2 under mild conditions.

A mild and efficient library synthesis technique has been developed for the synthesis of ureas and carbamates from carbamic acids derived from the DBU-catalyzed reaction of amines and gaseous carbon dioxide. Carbamic acids derived from primary amines reacted with Mitsunobu reagents to generate isocyanates in situ which were condensed with primary and secondary amines to afford the desired ureas. Similarly, carbamic acids from secondary amines reacted with alcohols activated with Mitsunobu reagents to form carbamates.