Between 1984 and 2006, 4,498 participants were followed for a total of 33,486 person years. The study cohort had a median age at HIV diagnosis of 28 (IQR 24-33) years; 91% were male. Race was reported as: African-American for 45%, Caucasian/non-Hispanic for 44% and other for 11% (). HIV seropositive date was prior to 1996 for 2,443 (77%) of participants. The median length of follow-up was 6.6 (IQR 3.7-10.1) years. Median baseline CD4 cell count at HIV diagnosis was 510 (IQR 353-680) cells/mm3. During the study period, 24% experienced an AIDS-defining event other than cancer ().
Cohort characteristics at time of HIV diagnosis and during follow-up.
At least one cancer event was recorded for 446 individuals (10%). The first cancer was AIDS-defining for 311 (70%) and non-AIDS-defining for 135 (30%). The median time from HIV diagnosis to an ADC was 5.6 (IQR 3.6-7.9) years and for a NADC was 6.0 (IQR 2.8-11.7) years. reports the specific types of cancers diagnosed. Of those whose first cancer was AIDS-defining, KS was the most frequent (73%; n=227); the most common NADC was skin cancer (47%; n=63). Skin cancers were mostly basal carcinomas (n=48), followed by melanoma (n=10) and squamous (n=5). Thirty-three persons (7.4% of those with cancer) developed two different cancers during the study period as shown in . Eleven people had two different ADCs: 10 had KS followed by NHL, and one person had NHL followed by KS. Four people with an initial ADC subsequently developed a NADC (lung, anal, Hodgkin’s, and skin cancer). Eight people with an initial NADC later developed an ADC (5 KS and 3 NHL cases), which was most commonly an initial skin cancer followed by KS. Finally, 10 people had a two NADCs develop; most commonly this was the development of two different types of skin cancer.
Of those who developed cancer, the diagnosis occurred in the pre-HAART era for 302 (68%) and in the post-HAART era for 144 (32%), resulting in pre- and post-HAART cancer rates (per 1,000 person years) of 16.1 and 9.8, respectively. The rate of ADCs increased significantly between the early and late pre-HAART eras (7.6 and 14.2, respectively), then declined significantly during the early and late post-HAART intervals (5.4 and 2.7, respectively) (). The rates for NADCs were stable in the pre-HAART era at approximately 3 cases per 1,000 person years. However, since the availability of HAART, NADC rates increased to 4.2 and 6.7 in the early and late post-HAART era, respectively (p=0.004). The rates of non-skin NADC were less than 2 per 1,000 person years in the pre-HAART and early post-HAART eras, but increased to 4.1 per 1,000 person years during the late post-HAART era (p=0.0003). Furthermore, the proportion of cancers that were NADCs significantly increased from 20% in the pre-HAART era to 36% in the early post-HAART era and 71% in the late post-HAART era (p<0.0001).
Cancer event rates per 1,000 person-years (with 95% confidence intervals) for intervals formed by HAART availability dates.
The rates over time for the most common cancer types are shown in and . Rates for both KS and NHL increased significantly before HAART, but have steadily declined since 1996. The rate of anal cancer was stable in the pre-HAART era (0.1-0.2 cases per 1,000 person-years), but significantly increased to a rate of 1.3 in the late post-HAART era (p=0.001). Skin, renal, and prostate cancer also had the highest rates during the late post-HAART era.
Cancer incidence rates per 1000 person-years by HAART availability time periods.
The age-adjusted incidence among males in our HIV cohort was 13.0 per 1,000 person years for any cancer event (excluding basal cell and squamous), compared to 5.5 for males in the general population. Limiting the events to NADCs (excluding basal cell and squamous), the age-adjusted incidence among males in our cohort was 6.5 per 1,000 person years. The age-adjusted incidence among HIV positive males (compared to the general population) was 4.0 (vs. 0.004) for KS, 2.7 (vs. 0.2) for NHL, 1.6 (vs. 0.03) for Hodgkin’s disease, and 0.2 (vs. 0.01) for anal carcinoma. For each type of event, the age-adjusted incidence for our overall cohort was similar to the age-adjusted incidence for the males (data not shown).
The univariate proportional hazards regression models for any cancer, ADCs, NADC, and non-skin NADCs are shown in . For all models, increased age was significantly associated with an increased risk of a cancer event, while HAART use was associated with a significantly decreased risk. African American race (compared to Caucasians) and increased CD4 cell count throughout follow-up were significantly associated with a decreased risk of an ADC or NADC event, but were not associated with a non-skin NADCs. ADCs were also associated with male gender, occurrence of a non-cancer AIDS diagnosis, and higher HIV viral loads. The association of ADCs and male gender was due to KS (data not shown).
Univariate analyses for time to first cancer event.
In the multivariate model, the predictors of any cancer and an ADC included male gender and a non-cancer AIDS event, while factors associated with a reduced risk of a cancer event included African American race, increased CD4 cell counts, and HAART (). HIV viral load was not included in the multivariate models because measurements were unavailable for 30% of the cohort.
Multivariate analyses for time to first cancer event.
NADCs were associated with increasing age, Caucasian race, and lack of HAART in the multivariate model; there was no association with gender, CD4 cell counts or prior non-cancer AIDS events (). The relationship between Caucasian race and an elevated risk of NADCs was due to the high number of skin cancers; of the 63 cases of skin cancers, 93% occurred in the Caucasian race group. Models were repeated for non-skin NADCs ( and ). From the multivariate model for non-skin NADCs, age was still associated with cancer development and HAART remained protective. There were no associations with race, AIDS events, or CD4 cell counts.
Comparing those with NADCs to those with ADCs at the time of cancer diagnosis, those with a NADC were more likely to be older (median 42 vs. 35 years, p<0.0001) and Caucasian (68% vs. 52%, p=0.006); have an HIV diagnosis date after 1996 (13% vs. 3%, p<0.0001); have higher median CD4 counts (430 vs. 72 cells/mm3, p<0.0001) and lower median HIV viral loads (3.4 vs. 4.8 log, p<0.0001); have received HAART for a greater percentage of their follow-up time (15% vs. 3%, p<0.0001); and were less likely to have a prior AIDS defining event (16% vs. 45%, p<0.0001). The median CD4 cell counts at cancer occurrence for those with an ADC during the early pre-HAART, late pre-HAART, early post-HAART, and late post-HAART eras were 40, 80, 44, and 242 cells/mm3, respectively (p=0.14). For the same intervals, those with NADCs had median CD4 cell counts at cancer diagnosis of 410, 370, 361, and 474 cells/mm3, respectively (p=0.05).
During the study period, 1,523 (34%) participants of the overall cohort died. Death occurred among 85% of patients with an ADC, 40% of those with an NADC, 46% with a non-skin NADC, and 30% without cancer (p<0.0001). For patients with an ADC compared to a NADC, the hazard ratio for time from cancer diagnosis to death was 3.7 (95% CI 2.7 – 4.9, p<0.0001). The estimated mortality at one, three, and five years after cancer diagnosis was 51%, 76%, and 84%, respectively for those with an ADC; 15%, 29%, and 41% for those with a NADC; and 26%, 38%, and 49% for those with a non-skin NADC.