Low CD4 count during HIV therapy increases risk of virus-related non-AIDS cancers

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A poor CD4 response to antiretroviral therapy (ART) is associated with an increased risk of virus-related non-AIDS-defining cancers (NADC), US investigators report in AIDS. Several CD4 count measures were associated with this risk, all were independent of baseline immune status, viral load and age.

The authors recommend that people living with HIV who have low CD4 counts should be intensively screened for virus-related malignancies. The most frequently-occurring virus-related malignancies are those caused by human papillomavirus (anal cancer and squamous cell cancers of the oral cavity and pharynx), hepatitis B and C (liver cancer) and Epstein-Barr virus (Hodgkin lymphoma).

“Beyond the effects of immune status at ART initiation, changes in immune status after ART initiation impact on virus-related NADC risk with the influence of early CD4+ cell response being most notable,” comment the authors. “This highlights the importance of adherence to effective durable ART to reduce the risk of virus-associated cancers in a population at increased risk for repeated episodes of infection with oncogenic viruses.”


AIDS defining condition

Any HIV-related illness included in the list of diagnostic criteria for AIDS, which in the presence of HIV infection result in an AIDS diagnosis. They include opportunistic infections and cancers that are life-threatening in a person with HIV.

immune response

The immune response is how your body recognises and defends itself against bacteria, viruses and substances that appear foreign and harmful, and even dysfunctional cells.

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.


A type of cancer that starts in the tissues of the lymphatic system, including the lymph nodes, spleen, and bone marrow. In people who have HIV, certain lymphomas, such as Burkitt lymphoma, are AIDS-defining conditions.

human papilloma virus (HPV)

Some strains of this virus cause warts, including genital and anal warts. Other strains are responsible for cervical cancer, anal cancer and some cancers of the penis, vagina, vulva, urethra, tongue and tonsils.

Improvements in treatment and care mean that many people living with HIV now have a normal life expectancy. However, non-AIDS-defining cancers such as lung cancer, anal cancer and Hodgkin’s lymphoma remain more common in people living with HIV compared to the general population. The reasons for this include high rates of smoking and sexual risk behaviour. The immune suppression associated with HIV infection may also have a role.

Investigators wanted to see if CD4 cell response to HIV therapy was associated with the risk of non-AIDS-defining cancers.

Their study population comprised 9389 people who started HIV therapy between 1996 and 2011. The authors examined the association between the risk of diagnosis with non-AIDS-defining cancers and CD4 count six months after starting treatment, latest CD4 count and cumulative CD4 count. This final variable was a measure of the magnitude and durability of immune response to treatment.

Cancers were categorised as virus related and non-virus related.

Median CD4 count and viral load at treatment initiation was 200 cells/mm3 and 63,000 copies/ml, respectively. A fifth of the patients were women, 43% were white and the median age at baseline was 38 years. Six months after treatment initiation, 64% of patients had an undetectable viral load.

After the first six months of therapy, patients were followed for a median of an additional 3.3 years and contributed a total of 41,538 person-years of follow-up.

Patients provided a mean of nine CD4 count measurements. Median CD4 count during the first six months of treatment was 260 cells/mm3, increasing to 324 cells/mm3 in the second six months and 358 cells/mm3 between months 12 and 18. The pace of CD4 gain then slowed.

Analysis of cumulative CD4 count showed that the average count during the first five years of follow-up was 385 cells/mm3, increasing to 457 cells/mm3 over ten years.

A total of 164 non-AIDS-defining cancers were diagnosed, giving an incidence rate of 395 per 100,000 person years. Sixty-five cancers (40%) were virus related, the most frequent being anal cancer (n = 26).

Each 100 cells/mm3 increase in six-month CD4 count decreased the risk of diagnosis with a virus-related non-AIDS-defining cancer by 29% (HR = 0.71; 95% CI, 5.0-47.0). Similarly, each 100 cell/mm3 increase in current CD4 count decreased the risk of diagnosis with this category of cancer by 30% (HR = 0.70; 95% CI, 7-48). Higher cumulative viral load was also associated with a decreased risk of virus-related non-AIDS malignancies.

These findings were little altered when the authors limited their analysis to the 73% of patients who were taking their first antiretroviral regimen.

There was no association between immune response to therapy and the risk of non-virus-related cancers.

“A greater CD4+ cell count ART response was associated with a lower NADC incidence, specifically for NADCs related to viral coinfections,” write the authors. “The association was independent of CD4+cell count at ART initiation, HIV-1 RNA response, age and other patient factors and consistently observed for measures of early, time-varying and cumulative time-varying immunologic ART response.”

The authors believe that the long-term magnitude and durability of CD4 response “may be particularly relevant to virus-related NADCs, as longer periods of immunosuppression may provide greater susceptibility to acquisition, reactivation or persistence of oncogenic viruses.”

They recommend people with low CD4 counts during HIV therapy should have frequent screens for virus-related malignancies.


Yanik EL et al. Relationship of immunologic response to antiretroviral therapy with non-AIDS defining cancer incidence. AIDS 28: 979-97, 2014.