Fred Okuku

Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda

Introduction Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS. Methods Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR). Results 78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7–6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7–9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0–2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8–5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs). Conclusions HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda.

Contribution of HIV infection to mortality among cancer patients in Uganda

Objective:HIV infection is associated with cancer risk. This relationship has resulted in a growing cancer burden, especially in resource-limited countries where HIV is highly prevalent. Little is known, however, about how HIV affects cancer survival in these settings. We therefore investigated the role of HIV in cancer survival in Uganda. Design:Retrospective cohort (N = 802). Methods:Eligible cancer patients were residents of Kyadondo County, at least 18 years of age at cancer diagnosis, and diagnosed between 2003 and 2010 with one of the following: breast cancer, cervical cancer, non-Hodgkins lymphoma, Hodgkins lymphoma, or esophageal cancer. Patients were classified as HIV-infected at cancer diagnosis based on a documented positive HIV antibody test, medical history indicating HIV infection, or an HIV clinic referral letter. The primary outcome, vital status at 1 year following cancer diagnosis, was abstracted from the medical record or determined through linkage to the national hospice database. The risk of death during the year after cancer diagnosis was compared between cancer patients with and without evidence of HIV infection using Cox proportional hazards regression. Results:HIV-infected cancer patients in Uganda experienced a more than two-fold increased risk of death during the year following cancer diagnosis compared to HIV-uninfected cancer patients [hazard ratio 2.28; 95% confidence interval (CI) 1.61–3.23]. This association between HIV and 1-year cancer survival was observed for both cancers with (hazard ratio 1.56; 95% CI 1.04–2.34) and without (hazard ratio 2.68; 95% CI 1.20–5.99) an infectious cause. Conclusion:This study demonstrates the role of HIV in cancer survival for both cancers with and without an infectious cause in a resource-limited, HIV-endemic setting.

Burkitt lymphoma in UGANDA, the legacy of Denis Burkitt and an update on the disease status

Burkitt lymphoma (BL) was first described in Uganda in 1958 as a sarcoma of the jaw but later confirmed to be a distinct form of Non Hodgkin lymphoma (NHL). This discovery was the defining moment of cancer research in Uganda, which eventually led to the establishment of a dedicated cancer research institute, the Uganda Cancer Institute (UCI) in 1967. The centre was dedicated to Denis Burkitt in recognition of his contribution to cancer research in East Africa. BL is still the commonest NHL in childhood in Uganda. Its incidence has significantly increased recently due to yet unknown factors. Although the human immunodeficiency virus (HIV) was considered a possible reason for the increase, there is no evidence that it has substantially impacted on the epidemiology of the disease. However, for those patients with BL who are co infected with HIV there is a clear impact of the disease on clinical presentation and outcome. HIV‐infected patients commonly present with extra facial sites and tend to have poor overall survival (median survival of 11·79 months). In summary, BL, as a disease entity in Uganda, has maintained the same clinical characteristics since its discovery, despite the emergence of HIV during the intervening period.

Infection-Related Cancers in Sub-Saharan Africa: A Paradigm for Cancer Prevention and Control

There is much commonality between chronic noncommunicable and communicable diseases which is best exemplified by cancers of infectious origin. It provides the perfect opportunity for harnessing the advances that have been made in the control of communicable diseases to attempt the control of noncommunicable diseases. There are possibilities at various levels of intervention, at primary, secondary and tertiary levels, which fit well within a well-planned national cancer control strategy. Prevention should proceed through steps of disruption of transmission, improvement in disease recognition and diagnosis, as well as through prompt effective treatment. This principle should work for both infection and the resultant cancer. Research is very important in understanding how best to use the available knowledge and how best to sequentially implement strategies. Finally, policies that acknowledge infection-related cancers as a major problem in the region should be in place.

Evaluation of a predictive staging model for HIV-associated Kaposi sarcoma in Uganda.

Background: HIV-associated Kaposi sarcoma (KS) is commonly staged using the AIDS Clinical Trials Group criteria, which classify 3 variables— tumor extent (T), immune status (I), and systemic symptoms (S)—into good risk (0) and poor risk (1). Although validated in the United States and Europe, these criteria have not been systematically evaluated in sub-Saharan Africa, where the burden of KS is greatest. Methods: We reviewed medical charts of adult patients with HIV-associated KS seen at the Uganda Cancer Institute from 1992 to 2007. Vital status at 2 years after KS diagnosis was determined from the medical chart, or by contacting the patient or next of kin. Survival estimates used Kaplan–Meier methods. Predictors were evaluated for 2 periods: 0–4 months and 4–24 months after diagnosis. Results: At 2 years after diagnosis, 167 (41%) patients were alive, 156 (39%) had died, and 81 (20%) were lost to follow-up. The Kaplan–Meier estimate of 2-year survival was 57%. S1 was associated with death in months 0–4 [hazard ratio: 6.4, 95% confidence interval: 1.9–21.1], whereas T1 was associated with death in months 4–24 [hazard ratio: 4.0, 95% confidence interval: 1.4 to 11.5]. Immune status was not associated with survival. Conclusions: Systemic symptoms were strongly associated with death in the early period after KS diagnosis, whereas tumor status was most predictive of death in the 4- to 24-month period. These findings suggest that different processes may influence outcomes in early and late periods following KS diagnosis. Further studies are needed to confirm these observations and to identify better predictors of KS survival in sub-Saharan Africa.

Evaluation of the AIDS clinical trials group staging criteria for Kaposi Sarcoma in a resource limited setting

Background Kaposi sarcoma (KS) is commonly staged using by the AIDS Clinical Trials Group (ACTG) criteria. The three variables of the ACTG are dichotomized as good risk (0) and poor risk (1). Good risk immune status (I0) is defined as CD4 T-cell count ≥200cells/µl, and poor risk (I1) as CD4 < 200cells/µl. Although validated in the US and Europe, no evaluation has been done in resourcelimited settings during the HAART era. We sought to determine whether the ACTG staging criteria is predictive of overall survival among Ugandan patients with HIV-associated KS. Methods Data were abstracted from medical records of adult patients with HIV-associated KS seen at the Uganda Cancer Institute (UCI) from 2000-2006. The primary outcome was 2-year overall survival. Vital status at 2 years was determined from the medical chart, or by contacting the patient or next of kin using the phone contact provided in the chart or ART clinic. Survival was modeled using Kaplan-Meier methods. Factors associated with survival were evaluated using Cox proportional hazards.

AIDS-associated Kaposi sarcoma in Uganda: response to treatment with highly active antiretroviral therapy and chemotherapy

Address: 1Department of Epidemiology, University of Washington; Seattle, Washington, USA, 2Department of Laboratory Medicine, University of Washington; Seattle, Washington, USA, 3Deparment of Medicine, University of Washington; Seattle, Washington, USA, 4Program in Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA, 5Program in Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington; USA, 6Uganda Cancer Institute, Kampala, Uganda and 7Infectious Disease Institute, Kampala, Uganda * Corresponding author

Whom to treat? Factors associated with chemotherapy recommendations and outcomes among patients with NHL at the Uganda Cancer Institute

Introduction Cancer treatment options in sub-Saharan Africa are scarce despite an increasing burden of disease. Identification of those cancer patients who would benefit most from the limited resources available would allow broader and more effective therapy. Methods We conducted a retrospective analysis of patients over the age of 18 at the time of a pathologic diagnosis of NHL between 2003 and 2010 who were residents of Kyandondo County (Uganda) and presented to the Uganda Cancer Institute for care. Results A total of 128 patients were included in this analysis. Chemotherapy was recommended to 117 (91.4%) of the patients; the odds of recommending chemotherapy decreased for each additional month of reported symptoms prior to diagnosis. Of the 117 patients to whom chemotherapy was recommended, 111 (86.7%) patients received at least 1 cycle of chemotherapy; HIV infected patients, as well as those with a lower hemoglobin and advanced disease at the time of diagnosis were significantly less likely to complete therapy. Among the patients who initiated chemotherapy, twenty patients died prior to treatment completion (including nine who died within 30 days). Hemoglobin level at the time of presentation was the only variable associated with early mortality in the adjusted model. Conclusion In resource-poor areas, it is essential to align health care expenditures with interventions likely to provide benefit to affected populations. Targeting cancer therapy to those with a favorable chance of responding will not only save limited resources, but will also prevent harm in those patients unlikely to realize an effect of cancer-directed therapy.

Association Between HIV Infection and Cancer Stage at Presentation at the Uganda Cancer Institute

Purpose The HIV epidemic has contributed to the increasing incidence of cancer in sub-Saharan Africa, where most patients with cancer present at an advanced stage. However, improved access to HIV care and treatment centers in sub-Saharan Africa may facilitate earlier diagnosis of cancer among patients who are HIV positive. To test this hypothesis, we characterized the stage of cancer and evaluated the factors associated with advanced stage at presentation among patients in Uganda. Methods We conducted a retrospective analysis of adult patients with any of four specific cancers who presented for care in Kampala, Uganda, between 2003 and 2010. Demographic, clinical, and laboratory data were abstracted from the medical record, together with the outcome measure of advanced stage of disease (clinical stage III or IV). We identified measures for inclusion in a multivariate logistic regression model. Results We analyzed 731 patients with both AIDS-defining cancers (cervical [43.1%], and non-Hodgkin lymphoma [18.3%]), and non–AIDS-defining cancers (breast [30.0%] and Hodgkin lymphoma [8.6%]). Nearly 80% of all patients presented at an advanced stage and 37% had HIV infection. More than 90% of patients were symptomatic and the median duration of symptoms before presentation was 5 months. In the multivariate model, HIV-positive patients were less likely to present at an advanced stage as were patients with higher hemoglobin and fewer symptoms. Conclusion Patients with limited access to primary care may present with advanced cancer because of a delay in diagnosis. However, patients with HIV now have better access to clinical care. Use of this growing infrastructure to increase cancer screening and referral is promising and deserves continued support, because the prognosis of HIV-positive patients with advanced cancer is characterized by poor survival globally.

Prostate Cancer Burden at the Uganda Cancer Institute

Purpose In Uganda, the incidence of prostate cancer is increasing at a rate of 5.2% annually. Data describing presentation and outcomes for patients with prostate cancer are lacking. Methods A retrospective review of medical records for men with histologically confirmed prostate cancer at the Uganda Cancer Institute (UCI) from January 1 to December 17, 2012, was performed. Results Our sample included 182 men whose mean age was 69.5 years (standard deviation, 9.0 years). Patients who presented to the UCI had lower urinary tract symptoms (73%; n = 131), bone pain (18%; n = 32), increased prostate-specific antigen (PSA; 3%; n = 5), and other symptoms (6%; n = 11). Median baseline PSA was 91.3 ng/mL (interquartile range, 19.5-311.3 ng/mL), and 51.1% of the patients (n = 92) had a PSA value above 100 ng/mL. Gleason score was 9 or 10 in 66.7% of the patients (n = 120). Ninety percent (n = 136) had stage IV disease, and metastatic sites included bone (73%; n = 102), viscera (21%; n = 29), and lymph nodes (4%; n = 5). Spinal cord compression occurred in 30.9% (n = 55), and 5.6% (n = 10) experienced a fracture. A total of 14.9% (n = 27) underwent prostatectomy, and 17.7% (n = 32) received radiotherapy. Gonadotropin-releasing hormone agonist was given to 45.3% (n = 82), 29.2% (n = 53) received diethylstilbestrol, and 26% (n = 47) underwent orchiectomy. Chemotherapy was administered to 21.6% (n = 39), and 52.5% (n = 95) received bisphosphonates. During the 12 months of study, 23.8% of the men (n = 43) died, and 54.4% (n = 98) were lost to follow-up. Conclusion UCI patients commonly present with high PSA, aggressive Gleason scores, and stage IV disease. The primary treatments are hormonal manipulation and chemotherapy. Almost 25% of patients succumb within a year of presentation, and a large number of patients are lost to follow-up.