Low CD4 cell count increases the risk of several cancers after starting HIV therapy

A large US study has provided important new insights into the incidence and timing of cancers among people taking antiretroviral therapy. Published in the online edition of Clinical Infectious Diseases, the study showed that incidence of AIDS-defining cancers was highest in the six months after starting HIV therapy and then fell dramatically.

In contrast, after the first year of HIV treatment, annual rates of non-AIDS defining cancers increased by approximately 7%, an increase attributed to ageing. A lower CD4 cell count at the time antiretroviral treatment was started was a risk factor for several cancers.

The investigators believe their findings show the importance of early antiretroviral therapy and the integration of "aggressive" cancer screening into routine HIV care.

Cancers are an important cause of serious illness and death in people living with HIV. However, the timing and incidence of malignancies after starting antiretroviral therapy has received little attention.

A team of investigators in the United States therefore examined the records of approximately 11,500 people who started triple-drug HIV therapy between 1996 and 2011. Trends in cancer incidence were monitored for up to ten years after treatment initiation. The investigators also sought to identify factors associated with a cancer diagnosis.

The investigators divided cancers into several categories: AIDS-defining cancers (Kaposi’s sarcoma, non-Hodgkin’s lymphoma and cervical cancer); non-AIDS-defining cancers; lymphomas; cancers related to human papillomavirus (HPV); other virus-related cancers; and virus-unrelated cancers.

The patients were racially diverse and overwhelmingly male (80%). The median age for starting antiretroviral therapy was 38 years. Most people were immunosuppressed when they started treatment, median CD4 cell count being just 202 cells/mm³. The majority of people (47%) started treatment with a regimen based on a protease inhibitor and 42% started treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination.

Patients were followed for a median of three years and 10% of patients contributed ten years of follow-up.

There were 457 cancer diagnoses during 46,318 person-years of follow-up.

This provided an incidence rate of 987 cases per 100,000 person-years.

Overall incidence of AIDS-defining cancers was similar to the incidence rate for non-AIDS-defining cancers (515 vs 466 per 100,000 person-years).

Kaposi’s sarcoma was the most common AIDS-defining cancer, with an incidence rate of 304 cases per 100,000 person-years. The most common non-AIDS-defining malignancy was anal cancer (69 cases per 100,000 person-years). Among women, the most common non-AIDS cancer was breast cancer (128 cases per 100,000 person-years).

The timing of cancer diagnosis varied according to whether the malignancy was AIDS-defining or non-HIV-related.

Incidence of Kaposi’s sarcoma was especially high in the first six months after HIV therapy was started (1342 cases per 100,000 person-years). Incidence then fell dramatically during the second six months of therapy (348 cases per 100,000 person-years). Incidence of the cancer then remained at low rates throughout the rest of follow-up (164 cases per 100,000 person-years).

A similar trend was observed for lymphomas (both non-Hodgkin and Hodgkin). Incidence was highest in the first six months after treatment initiation (660 cases per 100,000 person-years) and then fell sharply in the next six months (269 cases per 100,000 person-years).

In contrast, incidence of all non-AIDS-defining cancers increased with longer duration of follow-up. The increase was 7% for each additional year of treatment. Incidence climbed from 416 cases per 100,000 person-years after the first year of therapy to 615 cases per 100,000 person-years after ten years of treatment.

"This increase is likely a consequence of increasing cancer incidence with advancing age, as noted in the general population", write the authors.

Each ten-year increase in age was associated with a doubling in the risk of non-lymphoma cancers and HPV-related cancers (adjusted HR = 2.33; 95% CI, 1.97-2.74).

CD4 cell count at the time HIV therapy was started was also associated with subsequent cancer risk.

Immune suppression at the time of treatment initiation was an especially strong predictor of Kaposi’s sarcoma. The pattern of a high incidence of this malignancy in the first six months of treatment followed by a steep decline was seen only in people with a baseline CD4 cell count below 200 cells/mm³ (p = 0.002). People with a CD4 cell count above this level when they started therapy had a low incidence of Kaposi’s sarcoma throughout follow-up.

A low CD4 cell count was also associated with the development of lymphomas and diagnosis with HPV-related cancers.

The investigators found no evidence that overall cancer incidence declined over time, therefore suggesting "incremental improvements in antiretroviral therapy during the modern antiretroviral therapy era have not had dramatic effects on cancer incidence". They believe this finding "emphasizes the continued need for cancer screening and prevention measures in the HIV population…for instance increased HPV vaccination and anal pap smear screening may help prevent anal cancer, one of the most common malignancies in this population."

The authors also believe their study further supports efforts to reduce rates of late HIV diagnosis.