The human papillomavirus (HPV) is estimated to cause more than 90% of cervical and anal cancers, 70% of vaginal and vulvar cancers, and more than 60% of penile cancers – and the HPV vaccine, particularly in South Africa, is regarded as probably the most important approach to eliminating cervical cancer.
Although it’s just one aspect of a multi-pronged approach to this fight, it is especially critical in resource-limited countries like South Africa, where access to expensive cancer care is limited, writes Amy Green for Spotlight.
A modelling study published last November in The Lancet suggested that if South Africa vaccinated 90% of all girls aged nine to 14, it could reduce cervical cancer rates from 47.6 per 100 000 women to just 4.5 per 100 000. The vaccine works best when given to girls before they become sexually active, and is not indicated for those over 26.
In 2020, the World Health Organisation (WHO) via the World Health Assembly adopted a global strategy to accelerate cervical cancer elimination, acknowledging that too many women still die from this “preventable, treatable disease”.
This strategy seeks to eliminate cervical cancer worldwide within the next century, defining elimination as fewer than four new cases per 100 000 women.
There are more than 100 varieties of HPV, only about 14 being high-risk types actually causing diseases like cancers and genital warts. The two responsible for most cervical cancers are HPV 16 and 18. The virus is transmitted sexually or through skin-to-skin contact and is, therefore, not fully preventable through condom use.
“Virtually everyone who is sexually active gets HPV, but most of them clear the infection,” said Professor Anna-Lise Williamson, a virology professor at the University of Cape Town and an international expert on HPV and HPV vaccines.
Only about 10% of women with HPV infection on the cervix develop long-lasting HPV infections, increasing their risk for cervical cancer.
HPV was first identified in the 1950s, but only in 1983 and 1984 was a causal link between types 16 and 18 and cervical cancer established.
Two decades later, the first HPV vaccine became available in 2006 and, today, 125 countries have introduced it into their national immunisation programmes.
Williamson said it is not clearly understood how most people spontaneously clear HPV infection while others don’t.
While the progression from sustained infection to cervical cancer is usually a lengthy process, taking 15 to 20 years, it is accelerated in women with HIV, to five to 10 years.
“Women with HIV have a six-fold or higher risk of cervical cancer and, in Southern Africa, almost two-thirds of these cases are attributable to the co-factor effects of HIV,” Professor Sinead Delany-Moretlwe told Spotlight.
Delany-Moretlwe, the director of research at the Wits Reproductive Health and HIV Institute, said women with HIV were more susceptible to infection with high-risk HPV types such as 16 and 18; have a reduced ability to clear the infection; are associated with the development of lesions on the cervix, and have lower rates of these lesions regressing.
This is probably due to HIV’s impact on the immune system and its ability to respond to an HPV infection. While antiretroviral therapy (ART) is effective in improving immune function, early initiation of ART “probably only eliminates some of the risks”.
Delany-Moretlwe said in a study of 17- and 18-year-olds she did in 2019, those with HIV had twice the rate of infection with high-risk HPV types compared with their HIV-negative counterparts, despite most of those with HIV being on ART.
SA’s vaccination campaign
South Africa introduced HPV vaccination as part of the Integrated School Health Programme (ISHP) in 2014. The ISHP is jointly managed by the Departments of Health, Basic Education, and Social Development.
The programme targeted grade 4 girls older than nine attending public schools and excluded boys, as well as girls at private schools. The programme uses a bivalent vaccine given in two doses – targeting two types of HPV: the most high-risk types 16 and 18. Quadrivalent and 9-valent vaccines do exist, however, and target other high-risk types in addition to 16 and 18.
In the first round of vaccinations in April 2014, 419 520 of 503 507 eligible girls received the first dose – a coverage rate of 83%.
“To participate, parents had to provide written informed consent but acceptance was high,” said Professor Lynette Denny, director of the University of Cape Town’s Gynaecological Cancer Research Centre.
Coverage of the second dose later that year dropped to 61%.
Collapse during Covid
Denny said there was “tremendous government input, strong leadership by the National Department of Health, great collaboration with the Departments of Basic Education and Social Development, and huge resources allocated” to the HPV vaccination roll-out.
However, Covid “nearly killed” the project.
“From 2014 to 2020, coverage of the targeted girls remained high for dose one. But after Covid, coverage dropped to 3%. The cause included lockdowns, school closures, the collapse of school health programmes, lack of facilities, cold chain (problems), and poor vaccine management,” said Denny.
“The situation is improving, and coverage of the first dose appears to have increased to around 30%, but it’s still lower than the almost 85% in 2014,” she added.
Subsequently, the SA National Advisory Group on Immunisation recommended shifting the programme to target grade 5 girls who mostly missed their shots in 2020 during the pandemic.
Hesitancy
Some suggest the challenges faced by the programme now go beyond the hiccups caused by Covid. Vaccine hesitancy, spurred by the momentum of the anti-vaccine lobby around Covid jabs, is a potential barrier to achieving the high pre-pandemic coverage rates.
“The challenges vary. Demand side issues relate primarily to a lack of signed consent forms. Vaccine hesitancy has not been prevalent previously but has increased since the Covid-19 vaccination roll-out. (But the real) impact of increased vaccine hesitancy is still being quantified,” says Dr Lesley Bamford, acting chief director of Child, Youth and School Health at the Department of Health.
She said supply side issues relate to “problems reaching all 15 000 targeted schools during the campaign, especially in rural provinces, and contingencies like weather as well as Sadtu (South African Democratic Teachers Union) meetings and strikes”.
They hoped to do some research this year to discover what was driving the vaccine hesitancy.
“The hypothesis is that vaccination has become a more contentious issue in the past three years and we may need to plan for more hesitancy than previously.”
A suggestion is that the programme shift from an “opt-in” strategy to an “opt-out” one where parents need to provide a written request to not have their daughter vaccinated instead of vice versa.
Yet the proposal is contentious.
“I would not support any programme obviating the need for parental consent… Avoiding informing the public, the community, and their children is always a mistake,” said Denny.
Delany-Moreltwe said there is a “fairly simple solution”. “If we put the same amount of energy that the anti-vaccine lobby puts into their campaigns, to promote vaccines and respond to concerns in an evidence-based way, we may see some changes.”
Cost and funding
There were, and still are, concerns about the cost of the vaccine for low-and middle-income countries – a factor in South Africa’s programme design, which only targets young girls in public schools as opposed to making other age groups and boys eligible for the jab.
Bamford said a vial of the bivalent vaccines costs about R350: one vial delivers two doses.
However, other key budget items include cold chain capacity, i.e., fridges, cold boxes, and ice packs; ancillaries like syringes, needles, waste management, and disposal; cotton wool swabs; hiring of additional campaign staff; car rentals to boost the existing government fleet (since 2019, vehicles have been procured to strengthen the ISHP activities); training of seasonal workers; and data management, including hiring data capturers.
For the 2022/23 financial year, the conditional grant for the HPV programme was R226m. Initially, the grant was “managed as an indirect grant but now funds go directly to provinces as a direct grant”. Contrary to some claims, “generally, provinces do not underspend on the grant”.
In April 2022, the WHO said its Strategic Advisory Group of Experts on Immunisation’s review on the HPV vaccine decided a single dose delivers solid protection against HPV, comparable to two-dose schedules.
“There is no doubt we should move to single-dose HPV vaccination. It’s cheaper and it does not appear that the two-dose strategy is better than the one-dose,” said Denny.
Next campaign
This year’s HPV vaccination campaign in SA began on 20 February, with the first round ending on 31 March. The Health Department is still operating on the two-dose regimen: the second round is from 4-31 October.
“This matter (a one-dose strategy) has been tabled for discussion at NAGI (National Advisory Group on Immunisation,” said Bamford.
Williamson said the move to a one-dose strategy should be viewed as an opportunity to reach those most at risk – i.e. girls and women with HIV. “On diagnosis, all HIV-positive girls and women should be vaccinated immediately. We know there’s going to be disease in this group and we should lobby for them to get access to this vaccine.”
Professor Michael Herbst suggests boys be included, if resources permit. “Many women die of cervical cancer and it is important they be targeted first, but men carry the virus as well. More and more men say they have been affected by HPV-related cancers of the throat, penis, anus, neck and head,” said Herbst, health specialist consultant for the Cancer Association of South Africa.
However, Bamford said it was unlikely the programme would be extended in the near future, despite possible financial benefits of a one-dose regimen.
“For now, the focus is on achieving high coverage among the current target population. Although there are benefits to vaccinating boys, it is not considered to be cost-effective in most settings, especially where coverage in girls is greater than 50% as it is in South Africa.”
Should we accept the status quo?
Cervical cancer is the second most common cancer in South African women after breast cancer, yet the most deadly, with more than 5 000 cases diagnosed annually, most of them fatal.
“Every two minutes, a life is lost to cervical cancer. In 2020, 342 000 women died from the disease with almost a quarter of these (22.5%) in Africa,” said the authors of a report released last year by the International Agency for Research on Cancer, the Union for International Cancer Control, and the African Cancer Registry Network.
Since inception of the HPV vaccination programme in SA in 2014, more than 5m doses have been administered to girls and more than 80% of girl learners reached annually.
While this can be regarded as a resounding success some believe more can be done to reach girls and women excluded from the programme.
“It’s frustrating to be on a continent with such a high burden of disease and … see countries that have essentially controlled their cancer through cervical screening programmes, while countries without the screening programmes (like South Africa) don’t have access to the best vaccines or access to catch up,” said Williamson, referring to the 9-valent vaccine not yet registered here.
Dr Princess Nothemba Simelela, assistant director-general for Family, Women, Children, and Adolescents at the WHO, said: “We need political commitment complemented with equitable pathways for the accessibility of the HPV vaccine. Failure to do so is an injustice to the generation of girls and young women who may be at risk of cervical cancer.”
Study details
Estimating the effect of HIV on cervical cancer elimination in South Africa: Comparative modelling of the impact of vaccination and screening
Marie-Claude Boily, Ruanne Barnabas, Minttu Rönn, Cara Bayer, Cari van Schalkwyk, Nirali Soni, et al.
Published in The Lancet on 17 November 2022
Summary
Background
In 2020, the WHO launched its initiative to eliminate cervical cancer as a public health problem. To inform global efforts for countries with high HIV and cervical cancer burden, we assessed the impact of human papillomavirus (HPV) vaccination and cervical cancer screening and treatment in South Africa, on cervical cancer and the potential for achieving elimination before 2120, considering faster HPV disease progression and higher cervical cancer risk among women living with HIV(WLHIV) and HIV interventions.
Methods
Three independent transmission-dynamic models simulating HIV and HPV infections and disease progression were used to predict the impact on cervical cancer incidence of three scenarios for all women: 1) girls' vaccination (9–14 years old), 2) girls' vaccination plus 1 lifetime cervical screen (at 35 years), and 3) girls’ vaccination plus 2 lifetime cervical screens (at 35 and 45 years) and three enhanced scenarios for WLHIV: 4) vaccination of young WLHIV aged 15–24 years, 5) three-yearly cervical screening of WLHIV aged 15–49 years, or 6) both. Vaccination assumed 90% coverage and 100% lifetime protection with the nonavalent vaccine (against HPV-16/18/31/33/45/52/58). Cervical cancer screening assumed HPV testing with uptake increasing from 45% (2023), 70% (2030) to 90% (2045+). We also assumed that UNAIDS 90-90-90 HIV treatment and 70% male circumcision targets are reached by 2030. We examined three elimination thresholds: age-standardised cervical cancer incidence rates below 4 or 10 per 100 000 women-years, and >85% reduction in cervical cancer incidence rate. We conducted sensitivity analyses and presented the median age-standardised predictions of outcomes of the three models (minimum–maximum across models).
Findings
Girls' vaccination could reduce age-standardised cervical cancer incidence from a median of 47.6 (40.9–79.2) in 2020 to 4.5 (3.2–6.3) per 100 000 women-years by 2120, averting on average ∼4% and ∼46% of age-standardised cumulative cervical cancer cases over 25 and 100 years, respectively, compared to the basecase. Adding 2 lifetime screens helped achieve elimination over the century among all women (2120 cervical cancer incidence: 3.6 (1.9–3.6) per 100,000 women-years), but not among WLHIV (10.8 (5.3–11.6)), and averted more cumulative cancer cases overall (∼45% over 25 years and ∼61% over 100 years compared to basecase) than girls' vaccination alone. Adding three-yearly cervical screening among WLHIV (to girls' vaccination and 2 lifetime cervical screens) further reduced age-standardised cervical cancer incidence to 3.3 (1.8–3.6) per 100 000 women-years overall and to 5.2 (3.9–8.5) among WLHIV by 2120 and averted on average 12–13% additional cumulative cancer cases among all women and 21–24% among WLHIV than girls’ vaccination and 2 lifetime cervical screens over 25 years or longer. Long-term vaccine protection and using the nonavalent vaccine was required for elimination.
Interpretation
High HPV vaccination coverage of girls and two lifetime cervical screens could eliminate cervical cancer among women overall in South Africa by the end of the century and substantially decrease cases among all women and WLHIV over the short and medium term. Cervical cancer elimination in WLHIV would likely require enhanced prevention strategies for WLHIV. Screening of WLHIV remains an important strategy to reduce incidence and alleviate disparities in cervical cancer burden between women with and without HIV, despite HIV interventions scale-up.
See more from MedicalBrief archives:
Wits RHI launch Africa’s first HPV vaccine impact evaluation project
Eastern Cape school study shows concerning HPV prevalence
HPV vaccine significantly lowers infection rates in teen girls — CDC study
HPV vaccine critical to protect against cancer in poorer countries