A prospective cohort study identifies two types of HIV+ Kaposi Sarcoma lesions: proliferative and inflammatory.

Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH) in many countries where KS-associated herpesvirus is endemic. Treatment has changed little in 20 years, but the disease presentation has. This prospective cohort study enrolled 122 human immunodeficiency virus (HIV) positive KS patients between 2017 and 2019 in Malawi. Participants were treated with bleomycin, vincristine and combination antiretroviral therapy, the local standard of care. One-year overall survival was 61%, and progression-free survival was 58%. The 48-week complete response rate was 35%. RNAseq (n = 78) differentiated two types of KS lesions, those with marked endothelial characteristics and those enriched in inflammatory transcripts. This suggests that different KS lesions are in different disease states consistent with the known heterogeneous clinical response to treatment. In contrast to earlier cohorts, the plasma HIV viral load of KS patients in our study was highly variable. A total of 25% of participants had no detectable HIV; all had detectable KSHV viral load. Our study affirms that many KS cases today develop in PLWH with well-controlled HIV infection and that different KS lesions have differing molecular compositions. Further studies are needed to develop predictive biomarkers for this disease.

Comparison of best supportive care, CHOP, or R-CHOP for treatment of diffuse large B-cell lymphoma in Malawi: a cost-effectiveness analysis.

BACKGROUND: Cost-effectiveness data for cancer treatment are needed from sub-Saharan Africa, where diffuse large B-cell lymphoma (DLBCL) is a common, curable cancer. In high-income countries, the standard of care for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemoimmunotherapy. Rituximab is often not available in sub-Saharan Africa due to perceived unaffordability, and treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is common. We aimed to evaluate the cost-effectiveness of treatment in Malawi, comparing best supportive care, CHOP, or R-CHOP in patients with DLBCL. METHODS: For this cost-effectiveness analysis, we used published Malawi microcosting data, clinical data from a prospective cohort treated with CHOP, and clinical trial data evaluating R-CHOP. We used a decision-tree model to calculate costs per disability-adjusted life-year (DALY) averted from the health system perspective for the treatment of patients with DLBCL with best supportive care, CHOP, or R-CHOP, running the model on a per-patient basis and a Malawi population-level basis. We used the WHO definitions of cost-effective (three times the GDP per capita of the country) and extremely cost-effective (equal to the GDP per capita of the country) as willingness-to-pay thresholds for Malawi. FINDINGS: On a per-patient level, compared with best supportive care, CHOP was estimated to avert a mean 7·4 DALYs at an incremental cost of US$1384, for an incremental cost-effectiveness ratio (ICER) of $189 per DALY averted, which is substantially lower than the willingness-to-pay threshold (extremely cost-effective). Compared with CHOP, R-CHOP was estimated to avert 2·8 DALYs at an incremental cost of $3324, resulting in an ICER of $1204 per DALY averted, which is slightly higher than the cost-effective willingness-to-pay threshold. In probabilistic sensitivity analyses, CHOP remained cost-effective for DLBCL treatment in more than 99% of simulations, whereas R-CHOP was lower than the threshold in 46% of simulations. INTERPRETATION: We estimated CHOP to be cost-effective for DLBCL treatment in Malawi, and that the addition of rituximab might be cost-effective. Despite upfront costs, DLBCL treatment is probably a prudent investment relative to other accepted health interventions in sub-Saharan Africa. FUNDING: National Institutes of Health.

Safety and efficacy of rituximab in patients with diffuse large B-cell lymphoma in Malawi: a prospective, single-arm, non-randomised phase 1/2 clinical trial.

BACKGROUND: There are no clinical trials involving patients with diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa since antiretroviral therapy (ART) for HIV became widely available in this region. We aimed to establish the safety and efficacy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL in Malawi. METHODS: This prospective, single-arm, non-randomised phase 1/2 clinical trial was done at Kamuzu Central Hospital Cancer Clinic (Lilongwe, Malawi). Eligible patients were adults (aged 18-60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0-2, a CD4 count of 100 cells per µL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000 × 109 cells per L or higher, a platelet count of 100 × 109 platelets per L or higher, a serum creatinine concentration of 132·60 µmol/L or less, a total bilirubin concentration of 34·21 µmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities that would compromise the protocol objectives were excluded. Eligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. HIV-positive patients received concurrent ART. The primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Secondary efficacy outcomes included the proportion of patients with a complete response after six cycles of treatment, and progression-free survival and overall survival at 12 months and 24 months. This trial is registered with ClinicalTrials.gov, NCT02660710. FINDINGS: Between Aug 1, 2016, and July 31, 2019, 76 patients were screened, of whom 37 were eligible for the study and received R-CHOP. The median age of patients was 44 years (IQR 39-49) and 16 (43%) were women. Of all 37 patients, 20 (54%) had stage III or IV DLBCL, and the age-adjusted international prognostic index was 2 or higher in 25 (68%) patients. 27 (73%) patients were HIV-positive, with a median CD4 count of 208 cells per µL (IQR 144-422), and 21 (78%) patients were receiving ART at enrolment. Patients completed a median of six cycles (IQR 4-6). Grade 3 or 4 non-haematological toxic effects were reported in 12 (32% [95% CI 19-49]) patients, the most common of which was infection (nine [24%] patients). Of 16 (43%) deaths, ten were due to progression of DLBCL, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4-26%). Grade 3 or 4 neutropenia was observed in 26 (70%) patients, and grade 3 or 4 anaemia was observed in 11 (29%) patients. A total of 22 (59%) patients had a complete response. Overall survival was 68% (95% CI 50-80) at 12 months and 55% (37-70) at 24 months, and progression-free survival was 59% (42-73) at 12 months and 53% (35-68) at 24 months. INTERPRETATION: R-CHOP could be feasible, safe, and efficacious in patients with DLBCL in Malawi. This is the first completed clinical trial on DLBCL focused on sub-Saharan African populations. Given the paucity of data on treatment of DLBCL from this region, these results could inform emerging cancer treatment programmes in sub-Saharan Africa. FUNDING: The University of North Carolina Lineberger Comprehensive Cancer Center.

Outcomes and prognostic factors for women with breast cancer in Malawi.

BACKGROUND: Breast cancer incidence in sub-Saharan Africa (SSA) is increasing, and SSA has the highest age-standardized breast cancer mortality rate worldwide. However, high-quality breast cancer data are limited in SSA. MATERIALS AND METHODS: We examined breast cancer patient and tumor characteristics among women in Lilongwe, Malawi and evaluated risk factor associations with patient outcomes. We consecutively enrolled 100 women ≥ 18 years with newly diagnosed, pathologically confirmed breast cancer into a prospective longitudinal cohort with systematically assessed demographic data, HIV status, and clinical characteristics. Tumor subtypes were further determined by immunohistochemistry, overall survival (OS) was estimated using Kaplan-Meier methods, and hazards ratios (HR) were calculated by Cox proportional hazard analyses. RESULTS: Of the 100 participants, median age was 49 years, 19 were HIV-positive, and 75 presented with late stage (III/IV) disease. HER2-enriched and triple-negative/basal-like subtypes represented 17% and 25% tumors, respectively. One-year OS for the cohort was 74% (95% CI 62-83%). Multivariable analyses revealed mortality was associated with HIV (HR, 5.15; 95% CI 1.58-16.76; p = 0.006), stage IV disease (HR, 8.86; 95% CI 1.07-73.25; p = 0.043), and HER2-enriched (HR, 7.46; 95% CI 1.21-46.07; p = 0.031), and triple-negative subtypes (HR, 7.80; 95% CI 1.39-43.69; p = 0.020). CONCLUSION: Late stage presentation, HER2-enriched and triple-negative subtypes, and HIV coinfection were overrepresented in our cohort relative to resource-rich settings and were associated with mortality. These findings highlight robust opportunities for population- and patient-level interventions across the entire cascade of care to improve breast cancer outcomes in low-income countries in SSA.

Modified EPOCH for high-risk non-Hodgkin lymphoma in sub-Saharan Africa.

Aggressive non-Hodgkin lymphoma (NHL) is among the most common cancers in sub-Saharan Africa (SSA), where CHOP is standard treatment and outcomes are poor. To address this, we treated 17 newly diagnosed adult patients in Malawi with Burkitt (n = 8), plasmablastic (n = 8), and primary effusion lymphoma (n = 1) with a modified EPOCH regimen between 2016 and 2019. Twelve patients (71%) were male and the median age was 40 years (range 16-63). Eleven (65%) were HIV infected, median CD4 count was 218 cells/µL (range 9-460), and nine (82%) had suppressed HIV RNA < 400 copies/mL. Patients received a median of six cycles (range 2-8) and median follow-up was 14 months (range 2-34) among patients still alive. Grade 3/4 neutropenia was observed in 26% of cycles and in 65% of patients. Sixteen (94%) responded to EPOCH and 10 (59%) achieved a complete response. One-year overall survival (OS) was 62% (95% confidence interval [CI], 42%-91%). Five patients (29%) died from progressive NHL and three (18%) from treatment-related complications. These data suggest EPOCH with setting-appropriate modifications may be a practical, safe, and effective option for improving high-risk NHL outcomes in Malawi and comparable settings, which deserves further prospective evaluation.

Microcosting Analysis of Diffuse Large B-Cell Lymphoma Treatment in Malawi.

PURPOSE: To describe the cost of treating diffuse large B-cell lymphoma (DLBCL) in Malawi under the following circumstances: (1) palliation only, (2) first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), (3) salvage etoposide, ifosfamide, and cisplatin (EPIC), and (4) salvage gemcitabine and oxaliplatin (GEMOX). METHODS: We conducted a microcosting analysis from the health system perspective in the context of a prospective cohort study at a national teaching hospital in Lilongwe, Malawi. Clinical outcomes data were derived from previously published literature from the cohort. Cost data were collected for treatment and 2-year follow-up, reflecting costs incurred by the research institution or referral hospital for goods and services. Costs were collected in Malawian kwacha, inflated and converted to 2017 US dollars. RESULTS: On a per-patient basis, palliative care alone cost $728 per person. Total costs for first-line treatment with CHOP chemotherapy was $1,844, of which chemotherapy drugs made up 15%. Separate salvage EPIC and GEMOX cost $2,597 and $3,176, respectively. Chemotherapy drugs accounted for 30% of EPIC and 47% of GEMOX. CONCLUSION: To our knowledge, this is among the first published efforts to characterize detailed costs of cancer treatment in sub-Saharan Africa. The per-patient cost of first-line treatment of DLBCL in Malawi is low relative to high-income countries, suggesting that investments in fixed-duration, curative-intent DLBCL treatment may be attractive in sub-Saharan Africa. Salvage treatment of relapsed/refractory DLBCL costs much more than first-line therapy. Formal cost-effectiveness modeling for CHOP and salvage treatment in the Malawian and other low-resource settings is needed to inform decision makers about optimal use of resources for cancer treatment.

Mature outcomes and prognostic indices in diffuse large B-cell lymphoma in Malawi: a prospective cohort.

Outcomes for diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa (SSA) are poorly described. We report mature data from one of the first prospective SSA cohorts. Patients aged ≥18 years with DLBCL were enrolled in Malawi 2013-2017. Participants were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy and concurrent antiretroviral therapy (ART) if positive for human immunodeficiency virus (HIV+). Eighty-six participants (mean age 47 years, standard deviation 13) were enrolled: 54 (63%) were male and 51 (59%) were HIV+, of whom 34 (67%) were on ART at DLBCL diagnosis. Median CD4 count was 0·113 cells × 109 /l (interquartile range [IQR] 0·062-0·227) and 25 (49%) had HIV viral load <400 copies/µl. Participants received median six cycles CHOP (IQR 4-6). No patients were lost to follow-up and the 2-year overall survival was 38% (95% confidence interval 28-49). In multivariable analyses, Eastern Cooperative Oncology Group performance status (PS) ≥2 and lactate dehydrogenase (LDH) >2× upper limit of normal (ULN) were associated with mortality. HIV status was not associated with mortality. A simplified prognostic model of LDH >2× ULN and PS ≥2 performed at least as well as the age-adjusted International Prognostic Index. DLBCL can be successfully treated in SSA and outcomes did not differ by HIV status. A simplified prognostic model prognosticates well and may be easier to use in resource-limited settings but requires validation.

Frequent HIV and Young Age Among Individuals With Diverse Cancers at a National Teaching Hospital in Malawi.

Purpose Cancer surveillance provides a critical evidence base to guide cancer control efforts, yet population-based coverage in Africa is sparse. Hospital-based registries may help fill this need by providing local epidemiologic data to guide policy and forecast local health care needs. We report the epidemiology of patients with cancer recorded by a de novo hospital-based cancer registry at Kamuzu Central Hospital, Malawi, the sole provider of comprehensive oncology services for half the country and location of a high-volume pathology laboratory. Methods We conducted active case finding across all hospital departments and the pathology laboratory from June 2014 to March 2016. Patient demographics, tumor characteristics, treatment, and HIV status were collected. We describe epidemiology of the cancer caseload, registry design, and costs associated with registry operations. Results Among 1,446 registered patients, Kaposi sarcoma and cervical cancer were the most common cancers among men and women, respectively. Burkitt lymphoma was most common cancer among children. The current rate of pathology confirmation is 65%, a vast improvement in the diagnostic capacity for cancer through the hospital's pathology laboratory. Among leading cancer types, an alarming proportion occurred at young ages; 50% of Kaposi sarcoma and 25% of esophageal, breast, and cervical cancers were diagnosed among those younger than 40 years of age. A systematic, cross-sectional assessment of HIV status reveals a prevalence of 58% among adults and 18% among children. Conclusion We report a high caseload among typically young patients and a significant burden of HIV infection among patients with cancer. In low- and middle-income countries with intermittent, sparse, or nonexistent cancer surveillance, hospital-based cancer registries can provide important local epidemiologic data while efforts to expand population-based registration continue.

CHOP Chemotherapy for Aggressive Non-Hodgkin Lymphoma with and without HIV in the Antiretroviral Therapy Era in Malawi.

There are no prospective studies of aggressive non-Hodgkin lymphoma (NHL) treated with CHOP in sub-Saharan Africa. We enrolled adults with aggressive NHL in Malawi between June 2013 and May 2015. Chemotherapy and supportive care were standardized, and HIV+ patients received antiretroviral therapy (ART). Thirty-seven of 58 patients (64%) were HIV+. Median age was 47 years (IQR 39-56), and 35 (60%) were male. Thirty-five patients (60%) had stage III/IV, 43 (74%) B symptoms, and 28 (48%) performance status ≥ 2. B-cell NHL predominated among HIV+ patients, and all T-cell NHL occurred among HIV- individuals. Thirty-one HIV+ patients (84%) were on ART for a median 9.9 months (IQR 1.1-31.7) before NHL diagnosis, median CD4 was 121 cells/µL (IQR 61-244), and 43% had suppressed HIV RNA. HIV+ patients received a similar number of CHOP cycles compared to HIV- patients, but more frequently developed grade 3/4 neutropenia (84% vs 31%, p = 0.001), resulting in modestly lower cyclophosphamide and doxorubicin doses with longer intervals between cycles. Twelve-month overall survival (OS) was 45% (95% CI 31-57%). T-cell NHL (HR 3.90, p = 0.017), hemoglobin (HR 0.82 per g/dL, p = 0.017), albumin (HR 0.57 per g/dL, p = 0.019), and IPI (HR 2.02 per unit, p<0.001) were associated with mortality. HIV was not associated with mortality, and findings were similar among patients with diffuse large B-cell lymphoma. Twenty-three deaths were from NHL (12 HIV+, 11 HIV-), and 12 from CHOP (9 HIV+, 3 HIV-). CHOP can be safe, effective, and feasible for aggressive NHL in Malawi with and without HIV.

Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi.

INTRODUCTION: Clinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region. METHODS: We describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi's 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015. RESULTS AND DISCUSSION: MCD patients had a median age of 42.4 years (range 37.2-51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6-9.3) than KS (11.0 g/dL, range 9.1-12.0, p=0.011) or NHL (11.2 g/dL, range 4.5-15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7-3.2) than KS (3.7 g/dL, range 3.2-3.9, p=0.013) or NHL (3.4 g/dL, range 1.8-4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108-1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2-105.3) than KS (14.2 months, range 6.8-21.9, p=0.039) or NHL (13.8 months, range 0.2-98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL. CONCLUSIONS: HIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and supportive care are needed to address this likely under-recognized public health problem in SSA.