Lara Stein

Part I: Cancer in Indigenous Africans—burden, distribution, and trends

Cancer is an under-emphasised issue in Africa, partly because of the overwhelming burden of communicable diseases. However cancer is a common disease in Africa with 650 000 people, of a population of 965 million, diagnosed annually. Furthermore, the lifetime risk in females (between 0 and 64 years) of cancer is about 10%, which is only about 30% lower than the risk in developed countries. In females, the lifetime risk of dying from cancer in Africa is almost double the risk in developed countries. This Review is the first of two papers and focuses on the current knowledge of the distribution and trends of the most common cancers in Africa. The cancers with the highest incidence are cervical, breast, and now HIV-associated Kaposis sarcoma. The top five cancers in males--Kaposis sarcoma (constituting 12.9% of all cancers in males) and cancer of the liver (14.8%), prostate (9.5%), bladder (6.1%), and non-Hodgkin lymphoma (5.7%)--and in females--cancer of the cervix (constituting 23.3% of all cancers in females) and breast (19.2%), Kaposis sarcoma (5.1%), cancer of the liver (5.0%), and non-Hodgkin lymphoma (3.7%)--are discussed in detail. The second paper will focus on the causes and control of cancer in Africa. The cancer burden in Africa is likely to increase as a result of increases in HIV-associated cancers, changes in lifestyles associated with economic development, and the increasing age of the population (despite AIDS). Although the knowledge of cancer in this region is improving, better surveillance of cancer incidence, mortality, and prevalence of risk factors is urgently needed to monitor the development of the cancer epidemic, formulate appropriate cancer-control strategies, and assess the outcomes of these strategies.

Cervical carcinoma and reproductive factors: Collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies.

The International Collaboration of Epidemiological Studies of Cervical Cancer has combined individual data on 11,161 women with invasive carcinoma, 5,402 women with cervical intraepithelial neoplasia (CIN)3/carcinoma in situ and 33,542 women without cervical carcinoma from 25 epidemiological studies. Relative risks (RRs) and 95% confidence intervals (CIs) of cervical carcinoma in relation to number of full‐term pregnancies, and age at first full‐term pregnancy, were calculated conditioning by study, age, lifetime number of sexual partners and age at first sexual intercourse. Number of full‐term pregnancies was associated with a risk of invasive cervical carcinoma. After controlling for age at first full‐term pregnancy, the RR for invasive cervical carcinoma among parous women was 1.76 (95% CI: 1.53–2.02) for ≥≥7 full‐term pregnancies compared with 1–2. For CIN3/carcinoma in situ, no significant trend was found with increasing number of births after controlling for age at first full‐term pregnancy among parous women. Early age at first full‐term pregnancy was also associated with risk of both invasive cervical carcinoma and CIN3/carcinoma in situ. After controlling for number of full‐term pregnancies, the RR for first full‐term pregnancy at age <17 years compared with ≥≥25 years was 1.77 (95% CI: 1.42–2.23) for invasive cervical carcinoma, and 1.78 (95% CI: 1.26–2.51) for CIN3/carcinoma in situ. Results were similar in analyses restricted to high‐risk human papilloma virus (HPV)‐positive cases and controls. No relationship was found between cervical HPV positivity and number of full‐term pregnancies, or age at first full‐term pregnancy among controls. Differences in reproductive habits may have contributed to differences in cervical cancer incidence between developed and developing countries.

The spectrum of human immunodeficiency virus-associated cancers in a South African black population: results from a case-control study, 1995-2004

The effect of the evolving HIV epidemic on cancer has been sparsely documented in Africa. We report results on the risk of cancer associated with HIV‐1 infection using data from an ongoing study. A case–control analysis was used to estimate the relative risk (odds ratio, OR) of cancer types known to be AIDS defining: Kaposis sarcoma (n = 333), non‐Hodgkin lymphoma (NHL, n = 223) and cancers of the cervix (n = 1,586), and 11 cancer types possibly associated with HIV infection: Hodgkin lymphoma (n = 154), cancers of other anogenital organs (n = 157), squamous cell cancer of the skin (SCC, n = 70), oral cavity and pharynx (n = 319), liver (n = 83), stomach (n = 142), leukemia (n = 323), melanoma (n = 53), sarcomas other than Kaposis (n = 93), myeloma (n = 189) and lung cancer (n = 363). The comparison group comprised 3,717 subjects with all other cancer types and 682 subjects with vascular disease. ORs were adjusted for age, sex (except cervical cancer), year of diagnosis, education and number of sexual partners. Significantly increased risks associated with HIV‐1 infection were found for HIV/AIDS associated Kaposis sarcoma (OR = 47.1, 95% CI = 31.9–69.8), NHL (OR = 5.9, 95% CI = 4.3–8.1) and cancer of the cervix (OR = 1.6, 95% CI = 1.3–2.0); Hodgkins disease (OR = 1.6, 95% CI = 1.0–2.7), cancers of anogenital organs other than the cervix (OR = 2.2; 95% CI = 1.4–3.3) and SCC (OR = 2.6, 95% CI = 1.4–4.9) were also significantly increased. No significant associations were found between HIV and any of the other cancers examined. Risks for HIV‐related cancers are consistent with previous studies in Africa, and are lower when compared to those observed in developed countries.

Part II: Cancer in Indigenous Africans—causes and control

Africa has contributed substantial knowledge to the understanding of certain risk factors for cancer, such as the role of several infectious agents (eg, viruses, bacteria, and parasites), aflatoxins, and certain lifestyle factors. Although the relative importance of many lifestyle factors is becoming better understood in developed countries, more work is needed to understand the importance of these factors in different African settings. In view of the substantial genetic diversity in Africa, it would be prudent not to generalize too widely from one place to the next. We argue that risks for several exposures related to certain cancers differ from the patterns seen in developed countries. In this paper, we review the current knowledge of causes of some of the leading cancers in Africa, namely cancers of the cervix, breast, liver, prostate, stomach, bladder, and oesophagus, Kaposis sarcoma, non-Hodgkin lymphoma, and tobacco-related cancers. There are no comprehensive cancer-control programmes in Africa and provision of radiotherapy, chemotherapy, and palliation is inadequate. Certain cost-effective interventions, such as tobacco control, provision of antiretroviral therapy, and malarial and bilharzial control, can cause substantial decreases in the burden of some of these cancers. Vaccinations against hepatitis B and oncogenic human papilloma viruses can make the biggest difference, but very few countries in Africa can afford these vaccines without substantial subsidization.

Transmission of Kaposi sarcoma-associated herpesvirus between mothers and children in a South African population.

Background:To assess whether Kaposi sarcoma-associated herpesvirus (KSHV) with or without HIV coinfection in South African mothers is associated with higher KSHV seropositivity in their children. Methods:We tested sera from 1287 South African children and 1179 mothers using assays for KSHV lytic K8.1 and latent ORF73 antigens. We computed odds ratios (ORs) and 95% confidence intervals (CIs) to assess associations between KSHV serostatus and risk factors. Results:KSHV seroprevalence was 15.9% (204 of 1287 subjects) in children and 29.7% (350 of 1179 subjects) in mothers. The risk of KSHV seropositivity was significantly higher in children of KSHV-seropositive mothers compared with those of KSHV-seronegative mothers. The HIV status of mothers was marginally associated with an increased risk of KSHV seropositivity in their children (OR = 1.6, 95% CI: 1.0 to 2.6; P = 0.07). KSHV seroprevalence was significantly higher in HIV-infected subjects (P = 0.0005), and HIV-infected subjects had significantly higher lytic and latent KSHV antibody levels than HIV-negative subjects. Conclusions:The risk of acquisition of KSHV was higher among children of KSHV-seropositive mothers. Although KSHV seroprevalence was significantly higher in children and mothers who were infected with HIV, the HIV status of the mother was only marginally associated with an increased risk of KSHV seropositivity in the child.

No evidence of sexual transmission of Kaposi's sarcoma herpes virus in a heterosexual South African population

Background:The transmission of Kaposis sarcoma herpes virus (KSHV) in men who have sex with men is clearly associated with sexual risk factors, but evidence of heterosexual transmission of KSHV is conflicting. Methods:Sera were obtained from 2103 South African individuals (862 miners, 95 sex workers, 731 female and 415 male township residents; mean age 33.2 years; ± 10.1). All sera were tested for antibodies to KSHV lytic K8.1 and latent Orf73, HIV, gonococcus, herpes simplex virus type 2 (HSV-2), syphilis and chlamydia. Information on social, demographic and high-risk sexual behavior was linked to laboratory data, to evaluate risk factors, expressed as odds ratios (95% confidence interval) for KSHV. Results:Overall KSHV and HIV prevalences were 47.5 and 40%, respectively (P = 0.43). The risk of HIV infection was highest in sex workers then female residents and miners, compared with male residents (P < 0.001). HSV-2 infection was highly prevalent (66%) and lower, but still substantial, prevalences (6–8%) were observed for other sexually transmitted infections (STI). No significant difference in KSHV infection was observed among the residential groups (P > 0.05). KSHV was not associated with any of the STI or any measures of sexual behavior (P > 0.05). Conclusion:The pattern of HIV and STI in sex workers suggests high rates of high-risk sexual behavior in this population. The lack of association with high-risk sexual behavior, particularly in sex workers, and with any markers of STI strongly suggest that the sexual mode does not play a significant role in KSHV transmission in this South African population.

Low socioeconomic status and risk for infection with Human Herpesvirus 8 among HIV-1 negative, South African black cancer patients

Between January 1994 and October 1997, we interviewed 2576 black in-patients with newly diagnosed cancer in Johannesburg and Soweto, South Africa. Blood was tested for HIV-1 and HHV-8 antibodies and the study was restricted to 2191 HIV-1 antibody-negative patients. We examined the relationship between infection with HHV-8 and sociodemographic and behavioural factors using unconditional logistic regression models. Of the 2191 HIV-1 negative patients who did not have Kaposis sarcoma, 854 (39.1%) were positive for antibodies against the latent nuclear antigen of HHV-8 encoded by orf73 in a immunofluorescence assay. Infection with HHV-8 was independently associated with increasing age (P trend = 0.02). For females, independent risk factors also included working in a paid domestic capacity (OR 1.63, 95% CI 1.09-2.44, P = 0.02), defining occupational status as economically non-active unemployed (OR 1.70, 95% CI 1.06-2.72, P = 0.03), having a state pension or being on a disability grant (OR 1.49, 95% CI 1.05-2.11, P = 0.02), using oral contraceptives (OR 1.43, 95% CI 1.03-1.99, P = 0.03) and having a delayed age at menarche (P trend = 0.04). The relationship between these variables and HHV-8 antibody status requires further, prospective study.

Risk factors for high anti-HHV-8 antibody titers (≥1:51,200) in black, HIV-1 negative South African cancer patients: a case control study

BackgroundInfection with human herpesvirus 8 (HHV-8), also known as Kaposis sarcoma-associated herpesvirus (KSHV), is the necessary causal agent in the development of Kaposis sarcoma (KS). Infection with HIV-1, male gender and older age all increase risk for KS. However, the geographic distribution of HHV-8 and KS both prior to the HIV/AIDS epidemic and with HIV/AIDS suggest the presence of an additional co-factor in the development of KS.MethodsBetween January 1994 and October 1997, we interviewed 2576 black in-patients with cancer in Johannesburg and Soweto, South Africa. Blood was tested for antibodies against HIV-1 and HHV-8 and the study was restricted to 2191 HIV-1 negative patients. Antibodies against the latent nuclear antigen of HHV-8 encoded by orf73 were detected with an indirect immunofluorescence assay. We examined the relationship between high anti-HHV-8 antibody titers (≥1:51,200) and sociodemographic and behavioral factors using unconditional logistic regression models. Variables that were significant at p = 0.10 were included in multivariate analysis.ResultsOf the 2191 HIV-1 negative patients who did not have Kaposis sarcoma, 854 (39.0%) were positive for antibodies against HHV-8 according to the immunofluorescent assay. Among those seropositive for HHV-8, 530 (62.1%) had low titers (1:200), 227 (26.6%) had medium titers (1:51,200) and 97 (11.4%) had highest titers (1:204,800). Among the 2191 HIV-1 negative patients, the prevalence of high anti-HHV-8 antibody titers (≥1:51,200) was independently associated with increasing age (ptrend = 0.04), having a marital status of separated or divorced (p = 0.003), using wood, coal or charcoal as fuel for cooking 20 years ago instead of electricity (p = 0.02) and consuming traditional maize beer more than one time a week (p = 0.02; p-trend for increasing consumption = 0.05) although this may be due to chance given the large number of predictors considered in this analysis.ConclusionsAmong HIV-negative subjects, patients with high anti-HHV-8 antibody titers are characterized by older age. Other associations that may be factors in the development of high anti-HHV-8 titers include exposure to poverty or a low socioeconomic status environment and consumption of traditional maize beer. The relationship between these variables and high anti-HHV-8 titers requires further, prospective study.

The spectrum of HIV-associated cancers in a South African black population: results from a case-control study, 1995–2004

Accumulating evidence confirms different patterns of HIV-associated cancers in developed and developing countries. We report results of risk for specific cancers associated with HIV-1 infection from an on-going case control study started in government hospitals in Johannesburg in 1995. Cases consisted of cancers known or suspected to be associated with HIV infection: Kaposi sarcoma (n = 333), Non-Hodgkin lymphoma (n = 223), cancer of the uterine cervix (n = 1586), Hodgkin lymphoma (n = 154), cancers of anogenital organs other than cervix (n = 157), squamous cell skin cancer (n = 70), oral cavity and pharyngeal cancers (n = 319), liver cancer (n = 83), stomach cancer (n = 142), leukaemias (n = 323), myelomas (n = 189), melanoma (n = 53), lung cancer (n = 363) and sarcomas other than Kaposi (n = 93). The comparison group comprised 3,717 patients with all other cancer types and 682 patients with cardiovascular diseases. Odds Ratios (OR) were adjusted for age, sex, year of diagnosis, education level and number of sexual partners. Significantly increased risks associated with HIV-1 infection were found for Kaposi sarcoma (OR = 47.1, 95% CI = 31.9 – 69.8), Non-Hodgkin lymphoma (OR = 5.9, 95% CI = 4.3 – 8.1), cancer of the cervix (OR = 1.6, 95% CI = 1.3 – 2.0), Hodgkin lymphoma (OR = 1.6, 95% CI = 1.0 – 2.7), cancers of anogenital organs other than cervix (OR = 2.2, 95% CI = 1.4 – 3.3) and squamous cell skin cancers (OR = 2.6, 95% CI = 1.4 – 4.9). Our study results are supported by data from the pathology-based South African National Cancer Registry. In 2001 Kaposi sarcoma was recorded as the leading cancer in black males age 20 to 44 and in black females aged 20 to 29. From age 30, cervical cancers was the most common cancer diagnosed in black women. The above figures reflect HIV-related cancers prior to the public health sector roll-out of ART (anti-retroviral therapy), which began in 2005.