Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1αP), a potent human immunodeficiency virus–1 (HIV-1)–suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.

Comparisons of death-related variables during the 3 eras were performed. The number of deaths declined over the study period, with 987 deaths in the pre-HAART era, 159 deaths in the early HAART era (1997-1999), and 78 deaths in the late HAART era (2000-2003) (P < 0.01). The annual death rate peaked in 1995 (10.3 per 100 patients) and then declined to <2 deaths per 100 persons in the late HAART era (P < 0.01). The proportion of deaths attributable to infection decreased, but infection remained the leading cause of death in our cohort, followed by cancer. Of those who died, there was an increasing proportion of non-HIV-related deaths (32% vs. 9%; P < 0.01), including cardiac disease (22% vs. 8%; P < 0.01) and trauma (8% vs. 2%; P = 0.01) in the post-HAART versus pre-HAART era. Despite the absence of intravenous drug use and the low prevalence of hepatitis C coinfection in our cohort, an increasing proportion of deaths in the HAART era were attributable to liver disease, although the numbers are small. Despite increasing concerns regarding antiretroviral resistance, the death rate among HIV-infected persons in our cohort continues to decline. Our data show a lower death rate than that reported among many other US HIV-infected populations; this may be the result of open access to health care. A shift in the causes of death toward non-HIV-related causes suggests that a more comprehensive health care approach may be needed for optimal life expectancy; this may include enhanced screening for malignancy and heart disease as well as preventive measures for liver disease and accidents.

Durable control of human immunodeficiency virus (HIV) replication and lack of disease progression in the absence of antiretroviral therapy were studi

Objective: To describe trends in incidence rates of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) during the HIV epidemic and to evaluate predictors, including the impact of antiretroviral therapy, of cancer development. Design: Retrospective analysis of a multicenter, prospective natural history study including 4498 HIV-infected US military beneficiaries with 33 486 person-years of follow-up. Methods: Predictors evaluated included demographics, clinical data, time-updated CD4 cell counts, HIV viral loads, and antiretroviral history. Time periods were classified as early pre (1984–1990), late pre (1991–1995), early post (1996–2000), and late post (2001–2006) HAART eras. Cox proportional hazard models were used to evaluate the association of specific factors with cancer. Results: Ten percent of HIV-infected persons developed cancer. ADC rates increased between the early and late pre-HAART eras (7.6 and 14.2 cases per 1000 person-years) and have since declined from 5.4 to 2.7 in the early and late HAART eras, respectively (P < 0.001). Rates of NADCs have risen over the four periods (2.9, 2.8, 4.2, 6.7, P = 0.0004). During the late HAART era, 71% of cancers were NADCs. Predictors for ADCs included low CD4 cell count, noncancer AIDS diagnosis, and lack of HAART. NADCs were predicted by increasing age and white race (due to skin cancers). Conclusion: Although the rate of ADCs continues to fall, the rate of NADCs is rising and now accounts for the majority of cancers in HIV-infected persons. The development of NADCs is associated with increasing age among HIV patients. HAART use is protective for ADCs, but did not significantly impact NADCs.

The prevalence and factors associated with overweight/obesity among human immunodeficiency virus (HIV)-infected persons are unknown. We evaluated prospective data from a U.S. Military HIV Natural History Study (1985–2004) consisting of early diagnosed patients. Statistics included multivariate linear regression and longitudinal linear mixed effects models. Of 1682 patients, 2% were underweight, 37% were overweight, and 9% were obese at HIV diagnosis. Multivariate predictors of a higher body mass index (BMI) at diagnosis included more recent year of HIV diagnosis, older age, African American race, and earlier HIV stage (all p<0.05). The majority of patients (62%) gained weight during HIV infection. Multivariate factors associated with a greater increase in BMI during HIV infection included more recent year of diagnosis, lower BMI at diagnosis, higher CD4 count, lower HIV RNA level, lack of AIDS diagnosis, and longer HIV duration (all p<0.05). Nucleoside agents were associated with less weight gain; other drug classes had no significant impact on weight change in the HAART era. HIV-infected patients are increasingly overweight/obese at diagnosis and during HIV infection. Weight gain appears to reflect improved health status and mirror trends in the general population. Weight management programs may be important components of HIV care.

BACKGROUND: The objective of this study was to determine the rates and predictors of non‐AIDS‐defining cancers (NADCs) among a cohort of human immunodeficiency virus (HIV)‐infected individuals.METHODS: The authors conducted a retrospective study of 4144 HIV‐infected individuals who had 26,916 person‐years of follow‐up and who had open access to medical care at 1 of the United States military HIV clinics during the years 1988–2003. Cancer incidence rates were race specific and were adjusted for age; these were compared with national rates using logistic regression to assess predictors of NADC development.RESULTS: One hundred thirty‐three NADCs were diagnosed with a rate of 980 diagnoses per 100,000 person‐years. The most frequent NADCs were skin carcinomas (basal cell and squamous cell), Hodgkin disease, and anal carcinoma. The results showed that there were higher rates of melanoma, basal and squamous cell skin carcinomas, anal carcinoma, prostate carcinoma, and Hodgkin disease among the HIV‐infected cohort compared with age‐adjusted rates for the general United States population. Predictors of NADCs included age older than 40 years (odds ratio [OR], 12.2; P < 0.001), Caucasian/non‐Hispanic race (OR, 2.1; P < 0.001), longer duration of HIV infection (OR, 1.2; P < 0.001), and a history of opportunistic infection (OR, 2.5; P < 0.001). The use of highly active antiretroviral therapy (HAART) was associated with lower rates of NADCs (OR, 0.21; P < 0.001). A low CD4 nadir or CD4 count at diagnosis (< 200 cells/mL) was not predictive of NADCs.CONCLUSIONS: The most frequent NADCs were primary skin malignancies. Melanoma, basal and squamous cell skin carcinomas, anal carcinoma, prostate carcinoma, and Hodgkin disease occurred at higher rates among HIV‐infected individuals. The implementation of screening programs for these malignancies should be considered. Most risk factors for the development of NADCs are nonmodifiable; however, the use of HAART appeared to be beneficial in protecting against the development of malignant disease. Cancer 2005. Published 2005 by the American Cancer Society.