Cervical cancer prevention and control in women living with human immunodeficiency virus

Cervical Cancer and HIV/AIDS as Intersecting Epidemics

Invasive cervical cancer is one of the leading causes of cancer-related morbidity and mortality in women globally. It is estimated that approximately 600,000 women are diagnosed with, and more than 300,000 women die from, cervical cancer worldwide annually.1 A disproportionate amount of its global burden is experienced by women living in low- and middle-income countries (LMICs), where it is often the first or second leading cause of cancer cases and deaths in women.

With the discovery of an obligate causative infectious agent, high-risk human papillomavirus (HPV), elucidation of key steps in its natural history, and availability of highly effective primary and secondary prevention technologies, cervical cancer is an eminently preventable malignancy. Indeed, in countries with routine, effective cervical cancer screening and early detection programs, cervical cancer incidence and mortality rates have declined precipitously over the past one-half century.1, 2 HPV vaccines will likely lead to even further reductions in decades to come. Buoyed by rising global optimism about the possibility of reducing cervical cancer globally, the World Health Organization (WHO), with endorsement from over 194 countries, including the United States, has recently launched a global initiative to accelerate the elimination of cervical cancer as a public health problem by significant expansion of efforts to increase HPV vaccination to 90% coverage, screening to 70% coverage in mid-adult women, and treatment to 90% of those in need of it (“90-70-90”).3-5

Over the past 4 decades, the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic has emerged and persisted as one of the world's most serious public health, development, and economic challenges. With an estimated 37.7 million (uncertainty bound, 30.2-45.1 million) people living with HIV (PLWH) worldwide in 2020,6 53% of all PLWH were women and girls. HIV/AIDS disproportionally affects people in LMICs, where cervical cancer is also exceedingly common. More than two-thirds of PLWH live in sub-Saharan Africa (SSA).7, 8 Untreated HIV leads to severe impairment of the immune system, increasing the risk of developing opportunistic infections as well as infection-related cancers and other chronic comorbidities that are otherwise rare in people with normal immune function.

Since the mid-1990s, the availability of combination antiretroviral therapy (ART) for HIV has led to significant improvements in the management of HIV disease, including a partial or near-complete restoration of immunocompetence, with long-term adherence to ART regimens and retention within the HIV care continuum. Over the past 2 decades, catalyzed by generous bilateral and multilateral public sector and philanthropic initiatives (eg, The President's Emergency Plan For AIDS Relief [PEPFAR]),9 ART has become affordable and accessible to millions of PLWH, including in some of the most resource-limited settings in SSA. This has led to dramatic increases in the lifespans of PLWH10, 11 as well as several considerably improved trajectories in the incidence of HIV-associated opportunistic infections,12 cancers,13-15 and comorbidities.16 In fact, in resource-rich areas of the world, the presence of HIV infection is thought of more like a chronic disease compared with pre-ART times in which HIV infection often led to terminal sequalae.

Women living with HIV (WLWH) have long been recognized as having a higher risk for the acquisition, persistence, and progression of high-risk HPV and its downstream consequences, including cervical cancer. In fact, invasive cervical cancer was first included as an AIDS-defining condition (ie, a marker of clinically relevant immunosuppression) by the US Centers for Disease Control and Prevention (CDC) in 1993.17, 18 Yet, just like the wide heterogeneity seen in the incidence rates of cervical cancer among women in the general population globally, incidence rates in WLWH have also varied substantially between countries. Although incidence rates of cervical cancer in WLWH have been uniformly higher than those in women without HIV (HIV-negative women) within any given setting/geographic region, recent meta-analyses have demonstrated that the attributable fraction of cervical cancers because of HIV is much greater in LMICs than in high-income countries (HICs).19 These differences are likely because of a combination of factors, such as a higher percentage women who are WLWH,6 differences in the duration20 and adherence21 that affect the degree of immune restitution, various social determinants of health (eg, nutrition, housing, and transportation), and better access to cervical cancer screening services in HICs.22 Yet, unlike other AIDS-defining cancers (Kaposi sarcoma and specific types non-Hodgkin lymphoma, ie, Burkitt lymphoma, immunoblastic lymphoma, and primary lymphoma of the brain),23 which have clearly demonstrated evidence linking dramatic declines with the availability of ART over the past 3 decades,14 cervical cancer rates have not declined by the same magnitude, and cervical cancer remains a significant comorbidity among WLWH regardless of the setting globally.

Although the relative importance of the 2 factors related to health care delivery, HIV care and cervical cancer screening services, is unclear and difficult to disentangle, their confluence likely contributes to the excessive cervical cancer burden in LMICs.

In this article, we attempt to provide a critical appraisal of the evidence to date on this topic while describing key methodologic issues inherent in studies contributing to this evidence. We also discuss the implications for clinical cancer prevention, especially as they apply to the ongoing global efforts for prevention and control of cervical cancer globally, because both the management of HIV disease and interventions for the prevention and control of cervical cancer (ie, vaccines, screening and treatment of precancerous lesions, and management of invasive cancers) can be conceived as the necessary dual arms of a multifocal public health strategy to reduce cervical cancer burden in WLWH.

Quantifying the Burden of Cervical Cancer in WLWH

Over the past 3 decades, there has been significant evolution in quantifying the burden of cervical cancer in WLWH by efforts using a variety of descriptive epidemiology approaches. These have included population registries/records-linkage studies that connect evidence from disparate sources, such as cancer registries, HIV registries/surveillance databases, and national death registers, as well as cohort and case-control studies from pooled databases of clinics and hospitals providing care for WLWH.

Results of 2 large meta-analyses conducted 14 years apart (2007 and 2021)19, 24 are consistent in their reporting that cervical cancer incidence remains approximately 6 times higher in WLWH compared with the general population or HIV-negative women (pooled risk estimate from the most recent meta-analysis, 6.07; 95% confidence interval [95% CI], 4.40-8.37).19 In 2018, 5.8% (95% CI, 4.6%-7.3%) of new cervical cancer cases were diagnosed in WLWH, most of which were attributable to HIV infection (4.9%; 95% CI, 3.6%-6.4%).19 Yet the attributable risk varies greatly across regions and countries because of the very wide variations in HIV prevalence worldwide: 40% in 9 southern African countries (Eswatini, Lesotho, Botswana, South Africa, Zimbabwe, Namibia, Mozambique, Zambia, and Malawi).19 These high-burden countries also have some of the highest HIV prevalence (between 11% and 32%) in females aged 15 years or older, and ART has been available only over the past 15 years.25-27 Other key findings from the literature on quantification of the burden include: Cervical cancer incidence rates in WLWH in HICs (in contrast to those in LMICs) have declined steadily with access to ART as well as wider availability of cervical cancer screening over the past 3 decades.13-15 The age-standardized incidence rate of cervical cancer in US WLWH is predicted to decrease from 60 per 100,000 in 2006 to 10 per 100,000 in 2030.15 Among WLWH, those with higher CD4-positive T-cell levels have a lower risk of cervical precancer and cancer.28-30 Although cervical precancer among WLWH is common, WLWH who receive regular cervical screenings have low incidence rates of invasive cervical cancer.29, 31 The magnitude of the effect of precancer risk varies with differences in the use of ART regimens and precancer detection methods.28, 29 For US WLWH who receive adequate cervical screening and follow-up care for positive screening results, incidence rates of cervical cancer are projected to converge with those of the general population within the next decade.15 WLWH non-White racial and ethnic subgroups in both HICs32, 33 and LMICs34, 35 experience significant health disparities because of systemic racism, differential access to health care, and/or other social determinants of health, resulting in higher risks of cervical cancer incidence and mortality compared with their White counterparts. Although these underserved groups are minorities in HICs, they are often the majority population in LMICs.

Therefore, HIV infection and the subsequent disparate care are important contributors to the unequal burden of cervical cancer in some of the lowest resource settings globally.25-27 Prevention and control of HIV infection and improved focus on patient-centered care resources to complement efforts for prevention and control of cervical cancer will have a profound impact on reducing the burden of cervical cancer globally.

Impact of HIV and HIV Control on HPV Natural History

There are 4 key stages in the development of cervical cancer: HPV acquisition, HPV persistence, progression to cervical precancer, and development of invasive cancer.36 In addition to factors such as age, parity, smoking status, and hormonal contraceptive use, HIV coinfection, although not causal, has a profound impact on several steps in the natural history of HPV (HPV cofactor) that increases HPV-related cancer risk in WLWH compared with HIV-negative women.

ART modifies these associations by mitigating HIV effects on the immune system. However, the evolution of ART regimens over the past 3 decades has often complicated uniform interpretations of the effect of ART across studies. Furthermore, a one-time measurement of ART status is an imperfect surrogate of adherence to ART and retention in the HIV care cascade over the long-term, which are key factors for HIV viral control and immune restitution. In addition, the development of HIV resistance to ART regimens can reduce their effectiveness for immune reconstitution despite adequate adherence.37, 38 Variations in methods to detect cervical disease status due to variability in screening and diagnostic tests (especially seen with visual screening approaches and cytologic/histopathologic interpretations) also affect the interpretation of these associations. Finally, in the context of a dynamic immune milieu with swings between relative immunosuppression and immune restoration states in WLWH, cervical HPV detection may represent reactivation of latent/quiescent infections39 as opposed to new infections, as also observed in studies among women undergoing long-term immunosuppressive therapy after solid organ transplants.40, 41

Notwithstanding these significant methodologic limitations, meta-analyses of the available literature suggest that WLWH have a higher risk of HPV acquisition, presumably due to shared behavioral risk of sexual transmission but also likely due to immune dysregulation (presumably because more incident HPV infections, even those destined to clear, persist long enough to be detected42, 43), as evidenced by the inverse association between HPV acquisition risk and markers of HIV control/immune status (eg, CD4 counts).43-45 WLWH have an approximately ≥2-fold prevalence of HPV compared with HIV-negative women.46-52 Among WLWH, HPV prevalence was lower among those receiving ART (vs not),51, 53-59 on longer (vs shorter) duration of ART,20, 54 with higher (vs lower) CD4 counts,51, 54-57, 60-75 and with a lower HIV viral load.58, 70, 71

In multiple HPV type infections, individual HPV type infections likely act independently rather than synergistically and thus contribute additively to the cervical cancer risk. A few studies in the general population have found that multiple HPV infections with non-HPV16 types increase the risk of cervical precancer and cancer.76, 77 WLWH are from 2-fold to 3-fold more likely to have multiple HPV infections (among HPV-positive women) compared with HIV-negative women.47-49, 52 Receiving ART56 and having a lower HIV viral load78 and/or higher CD4 counts73, 78 are associated with fewer multiple HPV infections.

HIV infection increases the likelihood of cervical HPV infection persisting and, given its persistence, progressing to precancer, and it reduces the likelihood of clearance/regression of low-grade and high-grade cervical abnormalities.44 A recent meta-analysis53 reported that ART was associated with reduced incidence of incident high-grade cervical abnormalities (adjusted odds ratio, 0.59), progression from low-grade to high-grade cervical abnormalities (adjusted odds ratio, 0.64), and an increased regression of cervical abnormalities (adjusted hazard ratio [HR], 1.54). Most importantly, data from 2 studies included in that meta-analysis demonstrated that ART was associated with a reduced risk (adjusted HR, 0.50) of invasive cervical cancer.53 Likewise, low CD4 counts were strongly associated with cervical cancer risk,79 and low CD4 counts at the time of ART initiation were also associated with an increased risk of cervical cancer.35 Overall, the age at cervical cancer diagnosis in WLWH is approximately 5 to 10 years younger than that in HIV-negative women,33, 80-84 highlighting the possible role of HIV coinfection as an accelerant in cervical carcinogenesis.

It is less clear whether HIV infection and immune status influence the last step of HPV-related carcinogenesis: cervical precancer developing into invasive cancer. It is unethical to observe the progression of cervical precancer into cancer, as was observed tragically in the “The Unfortunate Experiment”: from 1955 to 1976, New Zealand's National Women's Hospital withheld treatment from women diagnosed with cervical precancer.85 Over the next 30 years, approximately 30% of these women with untreated cervical precancer developed cervical cancer.85 Fortunately, no such experiment has been done among WLWH diagnosed with cervical precancer.

There are no high-quality, well powered, population-based, cross-sectional studies comparing the prevalence ratio of cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS) and invasive cervical cancer as a proxy for invasive potential in WLWH versus HIV-negative women. Such an approach (vs comparing between separate studies of WLWH or HIV-negative women with different methods, etc), by using statistical methods to control for the effects of differences in screening, variability of pathology diagnosis,86 sociodemographic determinants, and behavioral and cultural factors, might provide some indication of whether there are gross differences in the invasive potential of cervical precancer according to HIV status and the degree of immune reconstitution. HPV genotyping data might provide insights into how these factors influence HPV genotype-specific invasive potential, as has been shown in a meta-analysis of data from the general population.87 A few studies report lower CD4 counts in women diagnosed with cervical cancer versus those with precancerous abnormalities,71, 88 suggesting that immunity may play a role in this final step in cervical carcinogenesis.

Interestingly, of the few studies that have reported on stage distribution of cervical cancer, most did not find a significant difference in cancer stage at diagnosis in WLWH compared with HIV-negative women83, 89-91; one study reported more stage IIIb cervical cancer in WLWH than in HIV-negative women.92 The general lack of a difference in cancer stage distribution between WLWH and HIV-negative women may be a result of the early stage presentation of symptoms, such as postcoital bleeding in both, and/or because WLWH are generally under closer clinical surveillance than HIV-negative women.

There are some data that point to differences in the HPV type-specific natural history in WLWH compared with HIV-negative women. First, the types most commonly found in HIV-negative women, notably HPV16, are the least affected by the immune status in WLWH.93 Second, HPV16 is less commonly detected in CIN3 diagnosed in WLWH than in HIV-negative women.94 Finally, there is some evidence to suggest that HPV16 is somewhat less dominant in cervical cancers diagnosed in WLWH than in HIV-negative women.95, 96 Such type differences might play a role in the time to develop HPV-associated disease, because women with HPV16-related (and HPV18-related) cervical cancers diagnosed in the general population are approximately 5 years younger than women with cervical cancers related to other types.97 These differences also could reduce the effectiveness (eg, positive predictive value) of HPV16 and HPV18 genotyping for clinical decision making, as recommended in the general population, in the management of HPV-positive WLWH.98

These data highlight the importance of using ART in cervical cancer risk reduction. Counterintuitively, PLWH live longer on ART,10, 11 giving them more time to develop HPV-related cancers, which may partially offset its cancer risk-reducing benefits.99, 100 This may explain the time trend of increasing cervical cancer risk in WLWH compared with HIV-negative women observed in South Africa.101 Thus the integration of prevention strategies with the delivery of ART to WLWH will maximize the cervical cancer prevention benefits of ART, as discussed below.

Primary Prevention: Prophylactic HPV Vaccination

The discovery of high-risk HPV infections as the necessary cause of cervical cancer has led to revolutionary advances in cervical cancer prevention, including the development of prophylactic HPV vaccines for primary prevention. Current prophylactic HPV vaccines are based on the self-assembly of recombinantly expressed L1 protein in cell lines into virus-like particles that resemble native viral capsids but without the viral genome necessary for viral replication.

First-generation HPV vaccines, Gardasil (Merck & Company, Kenilworth, New Jersey)102 and Cervarix (GlaxoSmithKline, Rixensart, Belgium),103 target HPV16 and HPV18 (HPV16/HPV18), which cause approximately 70% of cervical cancers. Gardasil also targets HPV6 and HPV11 (HPV6/HPV11), which are non-high-risk HPV types responsible for 90% of anogenital warts (Condyloma acuminata). The next-generation HPV vaccine, Gardasil 9 (Merck & Company),104 targets HPV31, HPV33, HPV45, HPV52, and HPV58 in addition to HPV6, HPV11, HPV16, and HPV18 and is predicted to prevent approximately 90% of cervical cancers. Notably, the same types of HPV cause cervical cancer in approximately the same proportions in every region of the world, with the exception of Africa, as discussed below.105

Because HPV vaccination is only prophylactic and not therapeutic, the ideal timing of HPV vaccination is before sexual initiation and exposure to HPV (ie, HPV-naive women). On a population level, this can be achieved by vaccinating a few years before the population median age of sexual initiation. Because the median age of sexual initiation in many countries is typically from 15 to 17 years, the WHO recommends vaccination programs to target girls aged 9 to 13 years,106 and the CDC recommends routine HPV vaccination for girls (and boys) aged 11 to 12 years.107 With older cohorts of women, prophylactic vaccine is equally efficacious but less effective; ie, older age does not reduce vaccine efficacy in HPV-naive individuals but, because there are fewer HPV-naive women at older ages, overall vaccine effectiveness and cost-effectiveness of prophylactic vaccination decreases.108-110 On the basis of immunogenicity data, the WHO111 and the CDC95, 112 recommend 2-dose schedules for those younger than 15 years and 3-dose schedules for those aged 15 years and older for all HPV vaccines. There is increasingly strong evidence that a single dose of HPV vaccine is sufficient to confer protection equivalent to multiple doses.113, 114

Several countries, eg, Australia,115-121 Scotland,122 Denmark,123 and the United States,124-126 were early adopters of HPV vaccination and have documented population reductions in HPV infections and HPV-related diseases and abnormalities. Australia, for example, implemented vaccination with Gardasil in 2007, shortly after its US Food and Drug Administration approval and after a public awareness campaign. Their HPV vaccination program for females achieved >70% coverage in its first year and in subsequent years.115 Within several years after their national HPV vaccination was implemented, there was a significant decrease in anogenital warts among women and heterosexual men (because of herd protection), but not among men who have sex with men.116 Subsequently, there have been documented decreases in the prevalence of HPV16 and HPV18 in vaccinated women,117, 118 and now in unvaccinated women (because of herd protection),118 and in the prevalence of high-grade cervical abnormalities, first in younger women119, 120 and now in slightly older women,121 as HPV-vaccinated cohorts have aged.127 A meta-analysis on the impact of HPV vaccination found reductions in anogenital warts, HPV infections, and CIN grade 2 (CIN2) or more severe (CIN2+) diagnoses among girls and women and in diagnoses of anogenital warts among girls, women, boys, and men.128 Recent reports from Finland,127 Sweden,129 and Denmark130 now provide real-world evidence that HPV vaccination prevents cervical cancer.

HPV vaccination in PLWH has been well tolerated and safe and has resulted in good immune responses. One study of Gardasil131 in children living with HIV aged 7 to 12 years reported high-seroconversion, 4-year persistent, HPV type-specific immunity132 and immune memory cells133 and a significant increase in, and persistence of, antibody titers (anamnestic response) after an additional booster (fourth dose).132 A study of Gardasil in adult men living with HIV also found high seroconversion in addition to a good safety profile.134 Another study reported a seroconversion rate similar to that of Gardasil in WLWH and HIV-negative women aged 13 to 27 years.135

Some studies have noted an impact of HIV disease status (CD4 counts and viral suppression) on immune responses to HPV vaccination. One study reported lower HPV seroconversion and antibody titers in young adult WLWH not taking ART compared with those taking ART.136 Another study reported lower seroconversion and antibody titers in adult WLWH who had lower (vs higher) CD4 counts.137 A third study reported that peak antibody titers after Gardasil vaccination were 2-fold to 3-fold higher in mid-adult WLWH with full HIV viral suppression versus those without viral suppression.138

Two studies have compared the immune response to Cervarix versus the response to Gardasil in adult PLWH. Both studies found that the antibody titers after Cervarix immunization were superior to those after Gardasil.139, 140 However, it remains unclear whether this difference in antibody titers translates into meaningful differences in efficacy or duration of protection.141

Immunogenicity studies in WLWH have been of insufficient sample size to address efficacy/effectiveness in preventing clinical disease. Studies of HPV vaccination in select PLWH at high risk of anal cancer have been limited in their effective sample size because of the high degree of anal HPV exposure (and likely misclassification of exposure) to targeted HPV genotypes before enrollment142 and the possible reactivation of previously acquired, latent HPV infection, such that few truly incident events can be observed.

Another challenge in conducting placebo-controlled randomized clinical trials to demonstrate efficacy of HPV vaccines is that projected effect sizes are attenuated by lower-than-expected number of endpoints in placebo-arm participants, who may be practicing lesser risky behaviors with fewer exposures during the course of thestudy (presumably with adequate counseling and awareness of risk in relatively controlled clinical trial settings). This may result in studies being stopped as per pre-defined rules for futility, as evidenced in a recent trial of Gardasil in older men (aged 27 years and older) to prevent anal HPV infectionor anal high-grade squamous intraepithelial lesions.143 Yet, this same study suggested a signal of potential benefit for protection against oral HPV that is now under further investigation (ClinicalTrials.gov identifier NCT04255849).

Another study of Gardasil vaccination in perinatally HIV-infected versus HIV-exposed, uninfected youth reported a 5-fold higher incidence of abnormal cervical cytology among the former, suggesting that HPV vaccination is likely less effective in the context of perinatally acquired HIV infection.144 Not surprisingly, HPV vaccination with Gardasil either before145 or after146 excision of high-grade cervical/anal abnormalities in persons with HIV, did not prevent recurrence of lesions,145, 146 and it seems unlikely that Gardasil 9 will either (ClinicalTrials.gov identifier NCT03284866). However, HPV vaccination should prevent newly acquired (not latent) infection by HPV vaccine-targeted types acquired posttreatment from developing into new (vs recurrence of the same, type-specific) high-grade cervical abnormalities.

A recent study compared the effectiveness of catch-up HPV vaccination (ages 13-26 years) in women with history of immunosuppression (mostly HIV) versus those without a history of immunosuppresion.147 HPV vaccination significantly reduced the risk of CIN2+ by 19% in those without a history of immunosuppression, whereas the risk was not significantly reduced in those with such a history.

There is still a need to assess the efficacy, effectiveness, and duration and determinants of protective immunity of prophylactic HPV vaccines in PLWH. Given the immunodeficiencies related to HIV infection and the lack of defined immune correlates of protection, it is unclear whether immunogenicity, as measured by antibody or neutralizing antibody titers, is a good proxy for the efficacy and long-term effectiveness of HPV vaccines in PLWH. Some key outstanding questions for HPV vaccination in PLWH include: 1) how many doses are needed for protective immunity, and does an adjuvanted vaccine (eg, AS04 adjuvant in Cervarix) improve the protective immunity such that fewer doses are needed to achieve long-lasting, protective immunity compared with unadjuvanted HPV vaccines (eg, Gardasil); 2) does protective immunity wane; and 3) do these vaccines provide sufficiently broad coverage against the HPV types that cause cancer in PLWH?

As noted, there is some evidence to suggest that the distribution of HPV types that cause cervical cancer in WLWH is somewhat different from that in the general population/HIV-negative women such that HPV16 is somewhat less predominant in cervical precancer and cancer diagnosed in WLWH.95, 96 HPV35, a type in the same phylogenetic group (α-9) as HPV16, is particularly common in cervical cancers diagnosed among WLWH living in Africa,95 precancers diagnosed among WLWH living in SSA and Sweden,148 and precancers diagnosed among WLWH and HIV-negative women living in South Africa.149 This may be due in part to viral variants of HPV35 that cause more cancer in women of African descent than in women of other ethnicities.150 Whether there are any independent effects of HIV coinfection and African descent on the HPV type distribution in cervical cancer is uncertain given the high proportion of WLWH who are of African descent. Regardless, current HPV vaccines might be less effective in preventing cervical cancer in WLWH and/or in women of African descent than in other populations. Of note, there is already some evidence that Cervarix, which targets only HPV16 (vs HPV16, HPV31, HPV33, HPV52, and HPV58 in Gardasil 9) among α-9 types, induces some immunity, cross-protection, and herd immunity against HPV35,151-153 including immunity in WLWH.154

The optimal HPV vaccination strategy for long-term protection against cervical cancer in WLWH, especially those living in LMICs, has yet and needs to be established. The US Advisory Committee on Immunization Practices recommends 3-dose HPV vaccination (at 0, 1 or 2, and 6 months) for females and males aged 9 to 26 years who have primary or secondary immunocompromising conditions.155 However, as noted by the 2017 American Society of Clinical Oncology (ASCO) resource-stratified recommendations, HPV vaccination of WLWH is a D-level recommendation (ie, insufficient evidence quality, weak strength of recommendation).156

The use of more viable end points, such as short-term HPV persistence, which is strongly predictive of high-grade cervical abnormalities157, 158 and is accepted as a trial end point,159 will increase the feasibility of studies to answer these questions. However, the use of HPV persistence as an end point must be interpreted with caution because of the possibility of reactivation of latent HPV infections, which may have obfuscated the benefits of HPV vaccination in clinical trials in adult WLWH who were previously exposed to HPV. This will be less of an issue for trials in which HPV vaccines are given before sexual initiation, at a time when the vaccines will provide the greatest benefit regardless HIV status. Nevertheless, a long-term follow-up of WLWH participants in a trial that used 6-month HPV persistence as its end point will be important to confirm the vaccine effectiveness.

If the next generation of HPV prophylactic vaccines can produce broad-spectrum immunity, either by adding a more active adjuvant than the aluminum-based adjuvant to 9 HPV types included in Gardasil 9 or by expanding the types included with the AS04 adjuvant used with Cervarix, it will be important to establish their long-term effectiveness and the number of doses needed to achieve that protection in WLWH living in LMICs, perhaps the most vulnerable population. At least one such vaccine is under development.160

Secondary Prevention: Cervical Screening, Management, and Precancer Treatment

New guidelines161 from the WHO on cervical cancer screening and treatment recommend the use of HPV DNA testing as the primary cervical cancer screening test, although visual inspection after acetic acid (VIA) and Papanicolaou (Pap) tests may continue to be used according to local guidelines in various settings when HPV DNA testing is not operational. These guidelines recommend HPV testing-based screening for women aged 30 to 49 years every 5 to 10 years. For WLWH, these guidelines recommend HPV testing-based screening for women aged 25 to 49 years every 3 to 5 years. These are similar to recent resource-stratified guidelines for cervical cancer screening from the ASCO that recommend screening WLWH twice as frequently using HPV testing as what is recommended for HIV-negative women and the general population within the resource strata.162

Studies have demonstrated unequivocally that testing for

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