1. HIV, HPV and the Risk of Invasive Cervical Cancer in
Women in Sub-Saharan Africa
Savannah Stewart
Afrs 3424
Dr. Wamai
12/10/15
Abstract
HIV and the role it plays in the increased risk of cervical cancer in women in low income countries,
specifically those in sub-Saharan Africa is a major problem. Cervical cancer is almost always caused by
HPV, a common sexually transmitted disease and it is believed that aspects of HIV, such as replication
methods and consequential depletion of its host immunity due to attack on CD4 cells may help explain
why HPV and Invasive cervical Cancer have a higher prevalence and incidence in African countries that
also have high rates of HIV. Using articles that focus on the correlation between HIV, HPV, and Cervical
Cancer several correlations between HIV, HPV, and Invasive Cervical Cancer were determined. Social
factors such as male circumcision, lack of condom use and multiple concurrent relationships were also
taken into consideration. It was found that strong correlations exist between HIV and the progression of
HPV to Cervical Cancer through the function of the HIV protein Tat. It was also determined that there
may be an existing correlation between HIV and the presence of less common HPV infections, as well as
having multiple HPV infections present in a host with HIV due to suppressed immunity caused by HIV.
It was then determined that standard HPV vaccines would not be enough to combat Cervical Cancer in
sub-Saharan Africa. Instead, nations burdened by all three diseases would most likely benefit from
making HIV its primary focus, while implementing vaccinations against HPV, and treating current cases
of Invasive Cancer. In conclusion it was determined that correlations between HIV and HPV could give
an explanation for the large burden of Invasive Cervical Cancer in women in Sub-Saharan Africa and that
implementing the aforementioned goals it could be possible to reduce rates of HIV, HPV, and Invasive
Cervical Cancer in women in sub-Saharan Africa.
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2. 1. Introduction
Would you believe me if I told you that there is virus that has the ability to infect most
who are sexually active? A virus that often lays hidden with no visible symptoms or signs until
it’s too late? What if I told you that this virus has the ability to cause cancer and that rates of
infection of this virus only become worse when paired with HIV? I’m guessing you would think
that I’m absurd and that no such virus could exist, but you are wrong. That virus is HPV, which
is responsible for a vast majority of invasive cervical cancer today. Cervical cancer is one of the
most common cancers worldwide. However, the burden of this disease is far larger in developing
nations, much like those in sub-Saharan Africa. It is possible that this increased burden of
Cervical cancer in women in sub-Saharan Africa is linked to high rates of HIV that are also
found there through the role it plays in the acquisition and persistence of HPV.
2. Cervical Cancer and HPV
Cancer is an uncontrolled proliferation of abnormal cells within the body. Cervical cancer
specifically occurs when the squamous cells of the cervix undergo unchecked, irregular growth
resulting in squamous intraepithelial lesions (SIL), which may later lead to cancer if the cells
continue to grow in number. Today, cervical cancer is the 4th most common cancer worldwide
[1:1]. However, in developing nations, such as many found in Sub-Saharan Africa, it is the the
second most common cancer in women with a shocking 445,000 cases in 2012 alone (84% of
new cases worldwide)[1:1]. In this area, over 70,000 new cases occur annually and Invasive
Cervical Cancer (ICC) is responsible for 25% of all female cancers [2:134]. What is worse, the
continent of Africa has a population of more than 250 million women aged 15 years and older
who are at risk of developing cervical cancer [3:vii].
It has been determined that virtually all cases of cervical cancer (99%) are linked to
Human Papillomavirus [4:1]. HPV associated with cervical cancer in particular, accesses
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3. squamous cells through microabrasions in the cervical epithelium. Following infection, the early
HPV genes E1, E2, E4, E5, E6 and E7 are expressed and the viral DNA replicates from episomal
DNA [5:356]. The subsequent progression of lesions to invasive cancer is commonly associated
with the integration of the HPV genome into the host chromosomes, with associated loss or
disruption of E2, and subsequent upregulation of E6 and E7 oncogene expression[5:356]. The
increased rates of E6 and E7 inhibit the function of the p53 proto oncogene within the cell (also
known as the tumor suppressor gene) and can lead to invasive cervical cancer.
Human Papillomavirus, also known as HPV, is a very common sexually transmitted
infection and infects most sexually active adults. HPV is transmitted through sexual contact and
risk factors for contracting HPV include early first sexual intercourse, multiple sexual partners,
tobacco use, and immune system suppression [4:1]. There are many HPV types which are
categorized into high and low risk categories. Low risk forms of HPV have the ability to cause
warts on the body, genitals, or cause minor changes to the cervix, but do not lead to cancer.
However, high risk forms of HPV lead to abnormal changes in the squamous cells of the cervix
and have the ability to lead to cervical cancer. Infections with oncogenic types of HPV represent
50-75% of all HPV infection [2:vii] Out of approximately 16 types of high risk HPV it has been
discovered that HPV-16 and -18 account for for nearly 70% of invasive carcinomas, with
HPV-16 accounting for 55% of invasive cervical cancer and HPV-18 for another 15-20%
[5:573]. Two vaccines, known as Gardasil and Ceravix, have been recommended for girls and
young women aged 9-26 years. Both are effective against HPV types 16 and 18 and are
recommended for large-scale use in national immunisation programmes [6:2]. However, even
with programs to immunize African populations using these vaccines rates of Invasive Cervical
Cancer are still high. This may be linked to high rates of HIV that women in sub-Saharan Africa
suffer from as well.
3. HIV
Human Immunodeficiency Virus, also known as HIV, is a global problem. HIV can be
transmitted through a variety of bodily fluids, such as blood, semen, vaginal secretions, and
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4. breast milk [8:1]. Risk factors include unprotected sex, having multiple partners, lack of male
circumcision, and the sharing of needles. HIV is a retrovirus that performs reverse transcription
to replicate itself using the host’s cell. HIV specifically attacks the T-lymphocytes of the immune
system and results in a decrease in CD4 counts if it is left untreated. To treat the disease
antiretroviral drugs are used, but these too can leave the immune system weaker than in a host
that is not infected with HIV. This is important to note because immunocompromisation due to
HIV leaves the host susceptible to many opportunistic infections as well as other STIs. In the
year 2014 36.9 million [34.3-41.4 million] people globally were living with HIV and 2 million
people became newly infected [8:1]. Of the 36.9 million people living with HIV, 25.8 million
[24.0 million - 28.7 million] were living in sub-Saharan-Africa [8:2] and women account for
more than half of the total number of people living with HIV in sub-Saharan Africa [8:2]. With
this being said it is very possible that high rates of Invasive Cervical Cancer are occurring due to
the effect that HIV infection plays on HPV and its progression to Cervical Cancer.
4. HIV and HPV Correlations
From the data presented it is clear that the population of sub-Saharan Africa carries a
great burden of HIV and is also disproportionately affected by invasive cervical cancer. This
may be due to common modes of transmission as well as increased rates of HPV infection in
hosts due to HIV’s methods of infection and resultant destruction of host immunity. As a result,
in areas such as sub-Saharan Africa, HPV will be far more prevalent because there is also a
higher prevalence of HIV.
In a case study done in Zambia, it was found that while participants had a HPV
prevalence of 65.4% and 45% for HIV… HPV prevalence in HIV positive participants was 80%,
and 55% in HIV negative participants [9:4]. Another study done in Rwanda found that the
prevalence of any HPV was 47% in HIV-Negative women(mean age 25 years) compared to 72%
in HIV-positive women (median age 27 years)[10:169]. The increase in prevalence in HPV when
looking at both HIV positive participants and HIV negative participants is very clear. In both of
the studies conducted each group of HIV positive participants had a prevalence of HPV that was
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5. 25% higher than their HIV negative counterparts. This large increase in prevalence is enough to
ask whether or not HIV plays a role in the increase of HPV infection.
figure 1a​.
Prevalence of HPV
is given worldwide
and in Zambia.
High-risk (HR;
blue) and Low-risk
(LR; red) ​1b. ​HPV
infections by risk
type in relation to
HIV status.
High-risk (HR;
blue) and Low-risk
(LR; red) [9:7].
In addition to an increase in overall prevalence, HIV positive participants had an increase
in the types of high risk HPV present in infected participants. For example, a study done on
women in South Africa found that not only did women with HIV have a higher prevalence of
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6. HPV, they also seemed more likely to have multiple HPV infections than HIV negative women
[2:134]. Interestingly, according to research done in several studies multiple infections were not
limited to HPV-16 and -18, which was previously stated as the most common types of HPV
worldwide. In populations that suffer from HIV, HPV-16 has [been] shown to be frequent, but
not as predominating as seen in most HIV negative populations [9:2]. In the Zambian study it
was concluded that the most common HPV types types were 16 (21.6%), 18 (21.6%), 6 (7.8%),
43 (5.9%), and 58 (3.9%) [9:8]. In another study conducted on the effect of HIV on HPV it was
found that HIV-infected women appear to be more susceptible to co-infection with less prevalent
high risk HPV viral types… specifically, HPV types 51,52,53,58, and 59 [5:573].
figure 2
a ​The incidence of HPV was calculated
as a function of HIV status. The data
was normalized as percent incidence to
assesses possible effects or associations
of HIV status with HPV infection. ​3b.
The prevalence of HPV genotypes
present in patients was assessed for
both HIV positive (black) and negative
patients (gray). The graph displays
HPV genotypes on the x-axis and the
frequency of each genotype on the
y-axis. HR indicates high-risk strains
and LR, represents the low-risk strains.
[9:8]
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7. 5. Apparent Effects and Possible Causes
As more has been learned about HIV, HPV, and ICC a few correlations have been
formed to explain the roles that HIV plays in HPV infection. One correlate is between the
Tat-protein of HIV and the role that it plays in the expression of E6 and E7 in HPV. Through
research done on the biology of HPV in HIV infection it has been concluded that HIV may
intersect with HPV at the molecular level through the action of the HIV-1 tat protein, which has
been shown to transactivate the HPV long control region ​in vitro, leading to increased expression
of the HPV E6 and E7 oncogenes [11:5]. This increased expression could lead to an increase in
the inhibition of the p53 gene within host cell and lead to ICC. However, HIV-1 tat protein has
never been demonstrated by HPV-infected epithelium in vivo [11:5]. Another probable cause of
the increased rates and types of HPV in HIV positive hosts is a suppression of host immunity
caused by HIV that allows more uncommon types of HPV to rise in prevalence in populations
with high rates of HIV. In a meta-analysis conducted it was found that HPV prevalence among
HIV -positive women increases with lowering immune status[12:2338]. A study by Parhem et al
in Zambian patients at the UTH found a strong correlation between low CD4 counts and finding
cytological abnormalities [9:8]. It has also been found that immunocompromised individuals,
such as those with HIV, not only have higher rates of HPV and ICC, but are also resistant to
treatment of HPV-related diseases and prone accelerated development of HPV-associated cancer,
with low CD4+ counts to be a strong indicator [10:170]. However, it has also been discovered
HPV [is] notably more weakly associated with immune status [12:2338], thus calling into
question whether or not immunosuppression plays a significant role in the prevalence and
severity of HPV infection of women with cervical cancer.
6. Evidence Behind Claims
To determine whether or not the above claims had any scientific standing the separate
roles of the HIV protein tat and immunodeficiency were both observed in isolated studies as well
as in relation to HPV. It is known that Tat plays a large role in the reproduction of HIV. In the
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8. presence of Tat, normal cell functioning of viral hosts is altered by invading virus proteins to the
benefit of the virus [13:1]. HIV-1 is well known as a transactivator protein that contributes to
transactivation of viral and cellular genes [13:1]. Tat increases mRNA levels of proliferation
markers and decreases levels of cell cycle inhibitors [14:607]. When introduced to cells also
affected by HPV, HIV-1 Tat plays an important oncogenic role during HPV carcinogenesis by
favoring cell proliferation [14:609] and while it is generally assumed that HIV-1 plays an
oncogenic role in cancer through interference with immune functions, recent insights into
molecular pathogenesis have shown that HIV-1 proteins [Tat] can directly promote cancer
growth by interfering with cellular functions [14:607]. With this being said, it is very possible
that the Tat protein of HIV-1 pairs with the E6 and E7 genes of HPV to promote the proliferation
of cells and consequently cause ICC.
In individuals who have contracted both HIV and HPV immunosuppression has been
observed. However, it is not clear if whether this immunosuppression plays any role in the
prevalence of HPV. To determine the significance two studies were observed. One study
surveyed the CD4 counts of women with persistent HPV infection. After analyzing women with
CD4 counts of less than 200, 200-500, and more than 500 cells/mm3 and found that the rate of
HPV infection was 33,24, and 19%, respectively [15:549]. In a study on the comparison between
incidence of of cancer in HIV positive people and immunosuppressed transplant patients cancers
caused by High-risk HPV types increased rates in both populations [16:65]. Based on these
articles it appears that immunosuppression may play a significant role in the acquisition of
cervical cancer in HPV and HIV positive women and may explain why multiple types of HPV
can commonly be found in women infected with both viruses.
7. Social Implications
Developing nations, such as those in sub-Saharan Africa, have higher rates of ICC, HIV and
HPV. It has been determined that biological mechanisms by which higher rates of HPV and ICC
occur in the presence of HIV play a large role on the infection and persistence of HPV. However,
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9. social factors also play a role in the increased prevalence of these diseases. Social issues such as
high levels of multiple and concurrent sexual partnerships by men and women with insufficient
consistent , correct correct condom use, [and]... low levels of male circumcision [17:1] can be
blamed for high levels of HIV and indirectly increased levels of HPV and ICC. It has been found
that male circumcision can reduce the risk of HIV by 60% [17:1]. However, when a male
chooses not to get circumcised they leave themselves at an increased rate of infection and put all
of those they sleep with at risk as well. Another driving factor would be the use of condoms. The
use of condoms has the ability to prevent almost 100% of HIV infection. However, in many
cases condoms are not used because they reduce pleasure, the person is in a relationship and does
not see the benefit of using a condom, or the condom is used improperly. These practices are
very unsafe and leave the individuals involved susceptible to both HIV and HPV. Additionally,
multiple sexual partnerships drive the increase in prevalence of HIV in sub-Saharan Africa. In
Africa it is not unusual to find that a person is involved in more than one relationship. In fact, in
a WHO study it was concluded that 18%, 22%, and 55% of men in Tanzania, Lusaka (Zambia),
and Lesotho, respectively, reported having two or more ongoing (lasting more than a year)
sexual partnerships in the previous year [17:2]. This is dangerous for several reasons. If the men
involved in the concurrent relationships are not circumcised the risk of contracting HIV is
drastically increased. Since the people many of the relationships are ongoing it is likely that
condoms are not used during sexual intercourse. Also, by having multiple concurrent
relationships a network is created and if one person within the network becomes HIV positive
they have the ability to infect many others in the network as well. As a result of these practices
HIV rate is increased and because there are several correlations between HIV, HPV, and ICC,
the rate of those diseases increase as well.
Another social implication of understanding the correlations between HIV, HPV, and
ICC is understanding that when incidents of HIV and HPV co-infection occur, other types of
HPV besides HPV-16 and -18 arise and cause ICC. This is important because current HPV
vaccines target the most prevalent high-risk HPV types worldwide, namely HPV-16 and HPV-18
[18:355]. HPV vaccinations are type specific and as a result effectiveness of these vaccines on
the prevention of cancer may be lower in populations affected by HR-HPV types other than
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10. HPV- 16 and -18, such as many HIV HPV co-infected populations in sub-Saharan Africa
[18:355]. Any program to reduce the incidence and prevalence of HPV and ICC in African
populations will not have maximum benefits because many of those infected with both HIV and
HPV contract HPV types other than HPV-16 and -18.
8. Solutions
To reduce the incidence of HIV, HPV, and ICC HIV must be given the most attention because
most changes in HPV infection and eventual ICC occur because of HIV infection. To reduce the
incidence and prevalence of HIV in African populations, the governments of those nations must
take control of healthcare and make the reduction of HIV a national agenda. An excellent
example of a society that did just that would be Uganda. To reduce high levels of HIV the
government was a central point of the plan. The WHO worked with Uganda to create the concept
of a single national plan and budget [19:352]. In addition to an increase in funds to treat and
prevent HIV, an educational campaign was taken on by the president and a more widespread
dissemination of factual information, healthcare educators [that were] fully equipped and
functional within weeks rather than several months, and review of the use of condoms [20:353]
were used to reduce HIV rates. Another crucial factor was the continued and increased political
commitment of the Government of Uganda and especially the President [20:353]. If that level of
commitment was put into all sub-Saharan countries that suffered from HIV it could be possible
to reduce the incidence and prevalence of the disease drastically.
While pushing for a cohesive national program to lower rates of HIV, the participating
countries would most likely continue vaccinating women using current vaccines that protect
HPV-16 and -18. By doing so, it would help protect those who weren’t co-infected with HIV and
HPV from contracting HPV and later cervical cancer. In addition to vaccination, early detection
of HPV in women with HPV, especially those also infected with HIV, would be encouraged.
Treatment of those with ICC (chemotherapy or hysterectomies) would help control rates of ICC.
The use of these prevention techniques could possibly lead to an overall drop in the incidence
and prevalence of HIV, HPV, and ICC, in sub-Saharan Africa.
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11. 9. Conclusion
Today, cervical cancer is the 4th most common cancer worldwide. However, in
developing nations, such as many found in Sub-Saharan Africa, it is the the second most
common cancer in women. It has been determined that virtually all cases of cervical cancer are
linked to Human Papillomavirus and that HPV is a very common sexually transmitted infection
that infects most sexually active adults. It has also been determined that HIV has a large impact
on HPV infection and eventual invasive cervical cancer. When women are infected with both
HIV and HPV they have a higher rate of HPV infection, are more susceptible to different HPV
types other than HPV-16 and -18, and are more likely to contract multiple HPV infections. There
is a very strong possibility that this is caused by immunosuppression and the presence of the
HIV-1 Tat protein.
In addition to biological driving factors for the increased rate of HPV and ICC in HIV
positive populations, social factors also play a role. HIV and HPV have common modes of
transmission so if one participates in unsafe practices that leads to HIV infection it is likely that
they will also become infected with HPV and eventually ICC.
Although this may be the case, it is very possible to reduce the prevalence and incidence
of all three diseases. Through strong government participation and dedication to awareness and
prevention of HIV, HPV vaccinations, and treatment of ICC it is possible that a decrease of HIV,
HPV, and ICC could occur.
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