Greta Dreyer

Human papillomavirus prevalence and type distribution in invasive cervical cancer in sub‐Saharan Africa

In sub‐Saharan Africa, invasive cervical cancer (ICC) incidence and mortality are among the highest in the world. This cross‐sectional epidemiological study assessed human papillomavirus (HPV) prevalence and type distribution in women with ICC in Ghana, Nigeria, and South Africa. Cervical biopsy specimens were obtained from women aged ≥21 years with lesions clinically suggestive of ICC. Histopathological diagnosis of ICC was determined by light microscopy examination of hematoxylin and eosin stained sections of paraffin‐embedded cervical specimens; samples with a confirmed histopathological diagnosis underwent HPV DNA testing by polymerase chain reaction. HPV‐positive specimens were typed by reverse hybridization line probe assay. Between October 2007 and March 2010, cervical specimens from 659 women were collected (167 in Ghana, 192 in Nigeria and 300 in South Africa); 570 cases were histologically confirmed as ICC. The tumor type was identified in 551/570 women with ICC; squamous cell carcinoma was observed in 476/570 (83.5%) cases. The HPV‐positivity rate in ICC cases was 90.4% (515/570). In ICC cases with single HPV infection (447/515 [86.8%]), the most commonly detected HPV types were HPV16 (51.2%), HPV18 (17.2%), HPV35 (8.7%), HPV45 (7.4%), HPV33 (4.0%) and HPV52 (2.2%). The prevalence of single and multiple HPV infections seemed higher among HIV‐positive women and HPV type distribution appeared to differ according to tumor type and HIV status. In conclusion, HPV16, 18, 45 and 35 were the most common HPV types in sub‐Saharan African women with ICC and HPV infections were more common in HIV‐positive women.

BRCA1 mutations in South African breast and/or ovarian cancer families: Evidence of a novel founder mutation in Afrikaner families

Germ‐line mutations within BRCA1 are responsible for different proportions of inherited susceptibility to breast/ovarian cancer, and the spectrum of mutations within this gene is often unique to certain populations. At this time, there have been no reports regarding the role of BRCA1 in South African breast and/or ovarian cancer families. We therefore screened 90 South African breast/ovarian cancer families for BRCA1 mutations by means of PCR‐based mutation detection assays. Eighteen families (20%) were identified with BRCA1 disease‐causing mutations. Four Ashkenazi Jewish families were identified with the 185delAG mutation, whereas 2 Afrikaner and 1 Ashkenazi Jewish family were found to harbor the 5382insC mutation. Five of the families (5.56%), all of whom are Afrikaners, were found to carry the novel E881X mutation. Genotype analyses show that these patients share a common ancestor. Genealogic studies have identified 3 possible founding couples for this mutation, all of whom arrived in the Cape from France in the late 1600s. Of the remaining mutations detected, 3 have not been reported previously and include the S451X, 1493delC (detected twice) and 4957insC mutations.

Cost effectiveness of high-risk HPV DNA testing for cervical cancer screening in South Africa

OBJECTIVE To determine the cost effectiveness of several cervical cancer screening strategies utilizing HPV testing in South Africa. METHODS We developed a lifetime Markov model of the costs, quality of life, and survival associated with screening and treating cervical cancer and its precursors. Screening strategies evaluated included: 1) conventional cytology, 2) cytology followed by HPV testing for triage of equivocal cytology, 3) HPV testing, 4) HPV testing followed by cytology for triage of HPV-positive women, and 5) co-screening with cytology and HPV testing. Primary outcome measures included quality-adjusted life-years saved (QALYs), incremental cost-effectiveness ratios, and lifetime risk of cervical cancer. Costs are in 2006 South African Rand (R). RESULTS In a cohort of 100,000 women, starting at age 30 and screening once every 10 years reduced the lifetime risk of cervical cancer by 13-52% depending on the screening strategy used, at an incremental cost of R13,000-R42,000 per QALY. When strategies were compared incrementally, cytology with HPV triage was less expensive and more effective than screening using cytology alone. HPV testing with the use of cytology triage was a more effective strategy and costs an additional R42,121 per QALY. HPV testing with colposcopy for HPV-positive women was the next most effective option at an incremental cost of R1541 per QALY. Simultaneous HPV testing and cytology co-screening was the most effective strategy and had an incremental cost of R25,414 per QALY. CONCLUSIONS In our model, HPV testing to screen for cervical cancer and its precursors is a cost-effective strategy in South Africa.

Age-specific prevalence of cervical human papillomavirus infection and cytological abnormalities in women in Gauteng Province, South Africa

BACKGROUND Women accessing the public health system in Gauteng province, South Africa are largely unscreened for cervical cancer and have a high background prevalence of human immunodeficiency virus (HIV) infection. OBJECTIVES This cross-sectional study describes the age-specific prevalence of human papillomavirus (HPV) infection and cytological abnormalities among this urban and peri-urban population. METHOD Over the period March 2009 - September 2011, 1 524 women attending public sector primary healthcare clinics were invited to participate in a cervical cancer screening study. All participants were screened with conventional cytology and HPV testing undertaken using the HPV linear array genotyping kit (Roche Molecular Systems). RESULTS Of 1 472 women with valid cytology results, abnormalities were detected in 17.3% (n = 255), of which 9.1% (n = 134) were high-grade squamous intraepithelial lesions, and 0.5% (n = 8) suggestive of squamous carcinoma. Of the 1,445 women with complete data, the overall and high-risk HPV DNA prevalences were 74.6% (n = 1 078) and 54.3% (n = 784), respectively. HPV type 16 and/or 18 were detected in 19.5% (n = 282) of women. Age-specific prevalence of HPV showed a plateau-shaped curve. CONCLUSIONS The prevalences of HPV infection and abnormal cytology were much higher than previously reported in general populations in South Africa and elsewhere. Higher age-specific prevalence and similar plateau-like age-specific epidemiological curves have previously only been described in studies among HIV-positive women. These findings have implications for planning and development of cervical screening programmes in developing countries with largely unscreened populations with a high background prevalence of HIV.

Cervical cancer and human papillomavirus : South African guidelines for screening and testing

Cervical carcinoma is still the most common cancer of women on the African continent. Mortality remains high - worldwide at 50% - mainly because of late presentation, advanced stage of disease and absence of a functioning screening process. The aetiological link between human papillomavirus (HPV) infection and cervical cancer has been well established and a number of high-risk HPV genotypes have been identified. HPV infection is the most common sexually transmitted infection (STI) in the world today - up to 80% of sexually active females will harbour HPV at some point in their lives. The majority of women will experience natural elimination of HPV infection because of an intact immune system. Persistent infection with a high risk type HPV puts women at high risk to develop precursors of cervical cancer or carcinoma itself. As part of a public health response to this serious problem, several HPV vaccines are under development. Use of vaccines still poses unanswered questions in many respects.

Cancer prevalence in 129 breast-ovarian cancer families tested for BRCA1 and BRCA2 mutations

BACKGROUND Women who carry germline mutations in the breast-ovarian cancer susceptibility genes, BRCA1 and BRCA2, are at very high risk of developing breast and/or ovarian cancer. Both genes are tumour suppressor genes that protect all cells from deregulation, and there are reports of their involvement in other cancers that vary and seem to depend on the population investigated. It is therefore important to investigate the other associated cancers in different populations to assist with risk assessments. OBJECTIVES To assess the cancer risk profile in BRCA-mutation-positive and negative South African breast-ovarian cancer families, mainly of Caucasian origin. DESIGN Descriptive study in which the prevalence of all cancers in the pedigrees of BRCA1- and BRCA2-mutation-positive groups and a group of families without mutations in either gene were compared with the general population. RESULTS As expected, female breast and ovarian cancer was significantly increased in all three groups. Furthermore, male breast cancer was significantly elevated in the BRCA2-positive and BRCA-negative groups. Stomach cancer prevalence was significantly elevated in the BRCA2-positive families compared with the general population. CONCLUSIONS These results can be applied in estimation of cancer risks and may contribute to more comprehensive counselling of mutation-positive Caucasian breast and/or ovarian cancer families.

The Vaccine and Cervical Cancer Screen (VACCS) project : acceptance of human papillomavirus vaccination in a school-based programme in two provinces of South Africa

BACKGROUND The incidence of cervical cancer in South Africa (SA) remains high, and the current screening programme has had limited success. New approaches to prevention and screening tactics are needed. OBJECTIVES To investigate acceptance of school-based human papillomavirus (HPV) vaccination, as well as the information provided, methods of obtaining consent and assent, and completion rates achieved. METHODS Information on cervical cancer and HPV vaccination was provided to 19 primary schools in Western Cape and Gauteng provinces participating in the study. Girls with parental consent and child assent were vaccinated during school hours at their schools. RESULTS A total of 3 465 girls were invited to receive HPV vaccine, of whom 2 046 provided written parental consent as well as child assent. At least one dose of vaccine was delivered to 2 030 girls (99.2% of the consented cohort), while a total of 1 782 girls received all three doses. Sufficient vaccination was achieved in 91.6% of the vaccinated cohort. Of all invited girls, 56.9% in Gauteng and 50.7% in the Western Cape were sufficiently vaccinated. CONCLUSION This implementation project demonstrated that HPV vaccination is practical and safe in SA schools. Political and community acceptance was good, and positive attitudes towards vaccination were encountered. During the study, which mimicked a governmental vaccine roll-out programme, high completion rates were achieved in spite of several challenges encountered.

Unique human papillomavirus-type distribution in South African women with invasive cervical cancer and the effect of human immunodeficiency virus infection.

Objectives Cervical cancer is the most common cause of cancer-related deaths among South African women. Viral types associated with cervical cancer may differ not only between countries and regions, but possibly also between human immunodeficiency virus (HIV)–infected and noninfected women. Methods In a population with high HIV prevalence, human papillomavirus (HPV)–type infections detected with DNA analyses were reported in a cohort of 299 women diagnosed with invasive cervical cancer. Results One hundred fifty-four women tested HIV negative, 77 tested HIV positive, and HIV status was unknown for 68 women. The mean age for HIV-positive women was 41.3 years, and that for HIV-negative women was 55.8 years (P < 0.001). Ninety-two percent of women tested HPV-DNA positive. Human papillomavirus types 16 and/or 18 were present in 62% of HIV-negative women and 65% of HIV-positive women. The 5 most common HPV types in HIV-positive women were, in decreasing frequency, HPV 16, 18, 45, 33, and 58. In HIV-negative women, the most common HPV types were HPV 16, 18, 35, and 45, followed by HPV 33 and 52. Human papillomavirus type 45 was more likely in the HIV positive compared with the HIV negative (odds ratio, 3.07; 95% confidence interval, 1.07–8.77). The HIV-positive women had more multiple high-risk HPV-type infections than did the HIV-negative women (27% vs 8%, P = 0.001). Conclusions A high number of women in South Africa with cervical cancer are HIV positive. Without viral cross-protection, HPV vaccines should prevent around 65% of cervical cancers in this population. Human papillomavirus type 45 infection is significantly linked to HIV and important for future vaccine developments.

Selection of women at risk for cervical cancer in an HIV-infected South African population

Objective: Cervical cancer is the leading cause of cancer-related death in women in South Africa. This study evaluates DNA methylation levels in cervical (pre)cancer and aims to assess the value of high-risk human papillomavirus (hrHPV) testing and methylation analysis, alone or in combination, on physician-taken cervical scrapes to detect cervical cancer, and cervical intraepithelial neoplasia grade 3 (CIN3) in an HIV-infected South African population. Design: Prospective observational multicentre cohort study. Methods: Women from a cohort of women living with HIV (n = 355) and a referral cohort (n = 109, 60% HIV seropositive) were included. Cervical scrapes were collected for hrHPV testing and methylation analysis of cell adhesion molecule 1, T-lymphocyte maturation-associated protein, and microRNA124-2 genes. Histologic endpoints were available for all participants. Performance for detection of CIN3 or worse (CIN3+) was determined in the cohort of women living with HIV and different testing strategies were compared. Results: HrHPV and methylation positivity rates increased with severity of cervical disease in the two study cohorts, each reaching 100% in samples of women with carcinoma. HrHPV testing showed a sensitivity for CIN3+ of 83.6%, at a specificity of 67.7%. Methylation analysis showed a comparable CIN3+ sensitivity of 85.2%, but a significantly lower specificity of 49.6%. HrHPV testing with reflex methylation analysis showed a CIN3+ sensitivity of 73.8%, at a specificity of 81.5%. Conclusion: In this HIV-infected South African population, stratifying hrHPV-positive women with reflex methylation analysis detects all cervical carcinomas and yields an acceptable sensitivity and specificity for CIN3+.

The impact of HIV infection on women receiving radiation for cervical cancer

Abstract Background: The objective of the study was to compare patient characteristics, treatment toxicity and interruptions, and survival in human immunodeficiency virus (HIV)-positive and HIV-negative cervical cancer patients receiving radiation as primary or adjuvant treatment. Method: Demographics, clinical and tumour characteristics, and the outcomes of 51 HIV-positive and 47-HIV negative consecutive cervical cancer patients were assessed and compared, including co-morbidities, performance status, treatment type and toxicities, and survival. Results: HIV-positive women were 13 years younger (p < 0.001), more often had anaemia (p 0.021) and needed pretreatment blood transfusion (p 0.037) more often than HIV-negative women. Performance status, kidney function, International Federation of Gynecology and Obstetrics stage, histology types and treatment intent and planning did not differ between the two groups. Treatment interruptions (p 0.004), transfusion during treatment (p 0.012), treatment toxicities (p 0.040) and average deficit (p 0.021) occurred significantly more in HIV-positive patients. Survival was significantly worse in HIV-positive women (p 0.029) and was associated with insufficient radiation (p < 0.001) and treatment interruptions (p 0.051). Conclusion: In spite of being younger, the pretreatment correction of anaemia and the prescription of sufficient radiation dosages, HIV-infected cervical cancer patients experienced poorer survival. Treatment interruption and incomplete radiation contributed to poor outcomes.