Risk of cervical cancer death higher for those with HIV

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Women with HIV infection have a higher risk of developing cervical cancer, but the presence of HIV also significantly increases the risk of dying of the cancer, according to findings from a study of African patients.

Even in the context of “good access to and use of antiretroviral treatment,” patients who received curative guideline-concordant therapy still had more than a 2-fold risk for death from cervical cancer, note the authors, led by Dr Scott Dryden-Peterson, from Brigham and Women’s Hospital in Boston, Massachusetts.

The high death rate, however, did not appear to stem from HIV infection itself. Instead, cervical cancer in this population appeared to progress earlier, which may have accounted for the high mortality rate.

Another issue was challenges related to receiving cancer therapy, the authors point out. The study was conducted in sub-Saharan Africa, and access to optimal cancer care was problematic for both HIV-infected and non-HIV-infected patients with cervical cancer. Even though most patients (82.9%) were considered candidates for potentially curative therapy, only 62% completed the planned brachytherapy regimen and only 81% received at least one dose of cisplatin.

Writing in an accompanying editorial, Dr Linda R Mileshkin and Dr Alison E Freimund, both from the Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia, point out that malignancies associated with human papillomavirus (HPV) have a high rate of occurrence in HIV-infected individuals.

Cervical cancer has been designated as an Aids-defining condition, but they note that even though the introduction of highly active antiretroviral treatment (HAART) has reduced the incidence of some of the associated cancer types, the incidence of cervical cancer has not declined.

This has been the case in Botswana, where the study was conducted. Despite a successful HIV treatment program resulting in “remarkable” declines in HIV-associated mortality, the incidence of cervical cancer remains among the highest in the world – with nearly two thirds of all cases occurring in women with HIV infection.

“The link among HPV, HIV, and cervical cancer is becoming better understood and attributed to enhanced HPV carcinogenesis in the setting of HIV-related immuno-suppression as well as to more frequent infections, with multiple and/or high-risk HPV sub-types in women with HIV,” write Mileshkin and Freimund.

Some evidence also suggests that cervical cancer may be more aggressive in HIV-infected women. They are more likely to present with advanced-stage disease and have a poorer response to treatment.

“Because the majority of the disease burden is seen in low- and middle-income countries, with regions of a high prevalence of cervical cancer corresponding with regions of a high prevalence of HIV infection, our understanding of the impact of concurrent HIV on cervical cancer and its response to treatment is paramount,” they note.

A concerning finding of this study is the low number of patients who completed the radiotherapy regimen, even though they were considered candidates for potentially curative therapy.

These data highlight the “challenges of delivering a complex treatment like chemo-radiation for cervical cancer in a developing nation and the need to better understand barriers to treatment completion in all women with cervical cancer,” the editorialists write.

Of importance, the rates of radiation-related toxicity did not seem to differ between HIV-infected and non-HIV-infected patients, and “this finding is different from the small number of other studies in the literature reviewed in a recent Cochrane analysis, which suggested that toxicity from radiotherapy for cervical cancer generally is higher in patients with HIV,” they comment.

Although no guidelines for the treatment of locally advanced cervical cancer in women with HIV have been published in the past 10 years, the Cochrane review found that early initiation of HAART was associated with higher rates of treatment completion, the editorialists add.

But clearly, a major barrier to the optimal treatment of cervical cancer as well other malignancies is lack of access to radiation therapy, which is limited to varying degrees in low- and middle-income countries. One analysis, they point out, showed that brachytherapy is available in only 20 of 52 African countries.

“If we are to reduce the number of deaths from cervical cancer in women with and without HIV, it is paramount that access to screening, vaccination, and treatment facilities in those areas of the world with the greatest burden of disease is addressed,” Mileshkin and Freimund conclude.

In the current study, Dryden-Peterson and colleagues sought to estimate the effect of HIV on survival in a cohort of 348 patients with cervical cancer in Botswana, who had free access to antiretroviral treatment and chemo-radiation therapy. Of this group, 231 (66.4%) patients had HIV infection and 96 (27.6%) did not. Most women with HIV (189 [81.8%]) had received antiretroviral therapy before they were diagnosed with cancer. At a median follow-up of 19.7 months, 117 (50.7%) women with HIV and 40 (41.7%) without HIV had died, but only 1 death could be attributed to HIV; the others were cancer related.

The 3-year survival rates were 35% for women with HIV and 48% for those without HIV. Adjusted analysis showed that HIV infection significantly increased mortality risk among all women (hazard ratio, 1.95). In the subset of patients who received concordant curative treatment, HIV was also associated with higher mortality (hazard ratio, 2.63; 95% confidence interval, 1.05 – 6.55).

The authors note that the effect of HIV on survival remained even when CD4 cell counts were near the normal range. Although most women (n = 271 [82.9%]) were candidates for potentially curative therapy, only 85 (48.0%) with HIV infection and 40 (48.0%) without completed the recommended radiation treatment. Roughly one third also received an inadequate radiation dose. Information on chemotherapy was available for 198 (76.7%) women; 114 (84.4%) participants with HIV infection and 46 (73.0%) without received at least one cycle of concurrent cisplatin (P = .080).

A complete or nearly complete tumour response was seen in 115 (83.9%) women with HIV and 54 (88.5%) without HIV (P = .52).

Abstract
Purpose: Cervical cancer is the leading cause of cancer death among the 20 million women with HIV worldwide. We sought to determine whether HIV infection affected survival in women with invasive cervical cancer.
Patients and Methods: We enrolled sequential patients with cervical cancer in Botswana from 2010 to 2015. Standard treatment included external beam radiation and brachytherapy with concurrent cisplatin chemotherapy. The effect of HIV on survival was estimated by using an inverse probability weighted marginal Cox model.
Results: A total of 348 women with cervical cancer were enrolled, including 231 (66.4%) with HIV and 96 (27.6%) without HIV. The majority (189 [81.8%]) of women with HIV received antiretroviral therapy before cancer diagnosis. The median CD4 cell count for women with HIV was 397 (interquartile range, 264 to 555). After a median follow-up of 19.7 months, 117 (50.7%) women with HIV and 40 (41.7%) without HIV died. One death was attributed to HIV and the remaining to cancer. Three-year survival for the women with HIV was 35% (95% CI, 27% to 44%) and 48% (95% CI, 35% to 60%) for those without HIV. In an adjusted analysis, HIV infection significantly increased the risk for death among all women (hazard ratio, 1.95; 95% CI, 1.20 to 3.17) and in the subset that received guideline-concordant curative treatment (hazard ratio, 2.63; 95% CI, 1.05 to 6.55). The adverse effect of HIV on survival was greater for women with a more-limited stage cancer (P = .035), those treated with curative intent (P = .003), and those with a lower CD4 cell count (P = .036). Advanced stage and poor treatment completion contributed to high mortality overall.
Conclusion: In the context of good access to and use of antiretroviral treatment in Botswana, HIV infection significantly decreases cervical cancer survival.

Authors
Scott Dryden-Peterson, Memory Bvochora-Nsingo, Gita Suneja, Jason A Efstathiou, Surbhi Grover, Sebathu Chiyapo, Doreen Ramogola-Masire, Malebogo Kebabonye-Pusoentsi, Rebecca Clayman, Abigail C Mapes, Neo Tapela, Aida Asmelash, Heluf Medhin, Akila N Viswanathan, Anthony H Russell, Lilie L Lin, Mukendi KA Kayembe, Mompati Mmalane, Thomas C Randall, Bruce Chabner, Shahin Lockman

Medscape report
Journal of Clinical Oncology abstract
Journal of Clinical Oncology editorial


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