Anuradha Ganesan

Trends in the Incidence of Cancers among HIV-Infected Persons and the Impact of Antiretroviral Therapy: A 20-Year Cohort Study

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.

Clinical Outcomes of Elite Controllers, Viremic Controllers, and Long-Term Nonprogressors in the US Department of Defense HIV Natural History Study

Durable control of human immunodeficiency virus (HIV) replication and lack of disease progression in the absence of antiretroviral therapy were studied in a military cohort of 4586 subjects. We examined groups of elite controllers (ie, subjects with plasma HIV RNA levels of <50 copies/mL; prevalence, 0.55% [95% confidence interval {CI}, 0.35%-0.80%]), viremic controllers (ie, subjects with plasma HIV RNA levels of 50-2000 copies/mL; prevalence, 3.34% [95% CI, 2.83%-3.91%]), and subjects with a lack of disease progression (ie, long-term nonprogressors [LTNPs]) through 7 years of follow-up (LTNP7s; prevalence, 3.32% [95% CI, 2.70%-4.01%]) or 10 years of follow-up (LTNP10s; prevalence, 2.04% [95% CI, 1.52%-2.68%]). For elite and viremic controllers, spontaneous virologic control was established early and was typically observed when the initial viral load measurement was obtained within 1 year of estimated seroconversion. Elite controllers had favorable time to development of AIDS (P=.048), a CD4 cell count of 350 cells/microL (P= .009), and more-stable CD4 cell trends, compared with viremic controllers. LTNPs defined by 10-year versus 7-year criteria had a longer survival time (P=.001), even after adjustment for differing periods of invulnerability (P= .042). Definitions of controllers and LTNPs describe distinct populations whose differing clinical outcomes improve with the stringency of criteria, underscoring the need for comparability between study populations.

Anal Cancers among HIV-Infected Persons: HAART Is Not Slowing Rising Incidence

Objective:To evaluate the incidence rates of anal cancer over the HIV epidemic and assess the impact of HAART use on anal cancer events. Methods:We evaluated the incidence of and factors associated with anal cancer using longitudinal data from the prospective U.S. Military Natural History Study (1985–2008). Poisson regression and Cox proportional hazard models were utilized. Results:Among 4506 HIV-infected men with 37 806 person-years of follow-up, anal cancer rates (per 100 000 person-years) increased five-fold, from 11 in the pre-HAART to 55 in the HAART era (P = 0.02). Rates continued to increase, reaching 128 in 2006–2008. Persons with HIV infection for more than 15 years had a 12-fold higher rate than those with less than 5 years (348 vs. 28, P < 0.01). At cancer diagnosis (n = 19), median age was 42 years, median CD4 cell count was 432 cells/μl, 74% had a CD4 nadir cell count less than 200 cells/μl, 42% had a prior AIDS event, and 74% had received HAART. From separate models, prior AIDS event (hazard ratio 3.88, P = 0.01) and lower CD4 nadir (hazard ratio 0.85 per 50 cell, P = 0.03) were associated with anal cancer, with a trend for a history of gonorrhea (hazard ratio 2.43, P = 0.07). Duration of HAART use was not associated with a reduced risk of anal cancer (hazard ratio 0.94, P = 0.42). Conclusion:Incidence rates of anal cancer have progressively increased during the HIV epidemic. Persons with a longer duration of HIV infection have a substantially higher rate of anal cancer. As HIV-infected persons are experiencing longer life expectancies and HAART does not appear protective of anal cancer, studies on preventive strategies are needed.

High Dose Atorvastatin Decreases Cellular Markers of Immune Activation without Affecting HIV-1 RNA Levels: Results of a Double-Blind Randomized Placebo Controlled Clinical Trial

BACKGROUND 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) exhibit antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro and may modulate the immune response to HIV infection. Studies evaluating the antiviral activity of statins have yielded conflicting results. METHODS We conducted a randomized, double-blind, placebo-controlled crossover trial to investigate the effect of atorvastatin on HIV-1 RNA (primary objective) and cellular markers of immune activation (secondary objective). HIV-infected individuals not receiving antiretroviral therapy were randomized to receive either 8 weeks of atorvastatin (80 mg) or placebo daily. After a 4-6 week washout phase, participants switched treatment assignments. The study had 80% power to detect a 0.3 log(10) decrease in HIV-1 RNA level. Expression of CD38 and HLA-DR on CD4(+) and CD8(+) T cells was used to measure immune activation. RESULTS Of 24 randomized participants, 22 completed the study. Although HIV-1 RNA level was unaffected by the intervention (-0.13 log(10) copies/mL; P = .85), atorvastatin use resulted in reductions in circulating proportions of CD4(+) HLA-DR(+) (-2.5%; P = .02), CD8(+) HLA-DR(+) (-5%; P = .006), and CD8(+) HLA-DR(+) CD38(+) T cells (-3%; P = .03). Reductions in immune activation did not correlate with declines in serum levels of low-density lipoprotein cholesterol. CONCLUSIONS Short-term use of atorvastatin was associated with modest but statistically significant reductions in the proportion of activated T lymphocytes.

Increasing Rates of Obesity among HIV-Infected Persons during the HIV Epidemic

Background The prevalence and factors associated with overweight/obesity among human immunodeficiency virus (HIV)-infected persons are unknown. Methods 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. Results 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. Conclusions 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.

Invasive mold infections following combat-related injuries.

BACKGROUND Major advances in combat casualty care have led to increased survival of patients with complex extremity trauma. Invasive fungal wound infections (IFIs) are an uncommon, but increasingly recognized, complication following trauma that require greater understanding of risk factors and clinical findings to reduce morbidity. METHODS The patient population includes US military personnel injured during combat from June 2009 through December 2010. Case definition required wound necrosis on successive debridements with IFI evidence by histopathology and/or microbiology (Candida spp excluded). Case finding and data collected through the Trauma Infectious Disease Outcomes Study utilized trauma registry, hospital records or operative reports, and pathologist review of histopathology specimens. RESULTS A total of 37 cases were identified: proven (angioinvasion, n=20), probable (nonvascular tissue invasion, n=4), and possible (positive fungal culture without histopathological evidence, n=13). In the last quarter surveyed, rates reached 3.5% of trauma admissions. Common findings include blast injury (100%) during foot patrol (92%) occurring in southern Afghanistan (94%) with lower extremity amputation (80%) and large volume blood transfusion (97.2%). Mold isolates were recovered in 83% of cases (order Mucorales, n=16; Aspergillus spp, n=16; Fusarium spp, n=9), commonly with multiple mold species among infected wounds (28%). Clinical outcomes included 3 related deaths (8.1%), frequent debridements (median, 11 cases), and amputation revisions (58%). CONCLUSIONS IFIs are an emerging trauma-related infection leading to significant morbidity. Early identification, using common characteristics of patient injury profile and tissue-based diagnosis, should be accompanied by aggressive surgical and antifungal therapy (liposomal amphotericin B and a broad-spectrum triazole pending mycology results) among patients with suspicious wounds.

Obesity among Patients with HIV: The Latest Epidemic

Since the advent of highly active antiretroviral therapy (HAART), studies have been conflicting regarding weight information among patients with HIV. We performed a retrospective study among male patients with HIV between June 2004 and June 2005 at two large U.S. Navy HIV clinics to describe the prevalence and factors associated with being overweight/obese. Rates of obesity/overweight among HIV-positive patients were also compared to data from HIV-negative military personnel. Of the 661 HIV-infected patients, 419 (63%) were overweight/obese and only 5 (1%) were underweight. Patients with HIV had a mean age of 41.0 years (range, 20-73 years) and were racially diverse. The prevalence rates of being overweight/obese at the last visit were similar among both HIV-positive and -negative military members. Being overweight/obese at the last clinic visit was associated with gaining weight during the course of HIV infection (10.4 versus 4.0 pounds, p < 0.001), hypertension (36% versus 23%, p = 0.001), low high-density lipoprotein (HDL; 40% versus 31%, p < 0.001), and a higher CD4 cell count at last visit (592 versus 499 cells/mm(3), p < 0.001). These data demonstrate that patients with HIV in the HAART era are commonly overweight and/or obese with rates similar to the general population. Being overweight/obese is associated with hypertension and dyslipidemia. Weight assessment and management programs should be a part of routine HIV clinical care.

Immunogenicity of a Monovalent 2009 Influenza A (H1N1) Vaccine in an Immunocompromised Population: A Prospective Study Comparing HIV-Infected Adults with HIV-Uninfected Adults

BACKGROUND Limited data exist on the immunogenicity of the 2009 influenza A (H1N1) vaccine among immunocompromised persons, including those with human immunodeficiency virus (HIV) infection. METHODS We compared the immunogenicity and tolerability of a single dose of the monovalent 2009 influenza A (H1N1) vaccine (strain A/California/7/2009H1N1) between HIV-infected and HIV-uninfected adults 18-50 years of age. The primary end point was an antibody titer of ≥ 1:40 at day 28 after vaccination in those with a prevaccination level of ≤ 1:10, as measured by hemagglutination-inhibition assay. Geometric mean titers, influenza-like illnesses, and tolerability were also evaluated. RESULTS One hundred thirty-one participants were evaluated (65 HIV-infected and 66 HIV-uninfected patients), with a median age of 35 years (interquartile range, 27-42 years). HIV-infected persons had a median CD4 cell count of 581 cells/mm(3) (interquartile range, 476-814 cells/mm(3)) , and 82% were receiving antiretroviral medications. At baseline, 35 patients (27%) had antibody titers of >1:10. HIV-infected patients (29 [56%] of 52), compared with HIV-uninfected persons (35 [80%] of 44), were significantly less likely to develop an antibody response (odds ratio, .20; P = .003). Changes in the median geometric mean titer from baseline to day 28 were also significantly lower in HIV-infected patients than in HIV-uninfected persons (75 vs 153; P = .001). Five influenza-like illnesses occurred (2 cases in HIV-infected persons), but none was attributable to the 2009 influenza H1N1 virus. The vaccine was well tolerated in both groups. CONCLUSIONS Despite high CD4 cell counts and receipt of antiretroviral medications, HIV-infected adults generated significantly poorer antibody responses, compared with HIV-uninfected persons. Future studies evaluating a 2-dose series or more-immunogenic influenza A (H1N1) vaccines among HIV-infected adults are needed (ClinicalTrials.gov NCT00996970).

Hepatitis B Virus Coinfection Negatively Impacts HIV Outcomes in HIV Seroconverters

BACKGROUND Understanding the impact of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) coinfection has been limited by heterogeneity of HIV disease. We evaluated HBV coinfection and HIV-related disease progression in a cohort of HIV seroconverters. METHODS Participants with HIV diagnosis seroconversion window of ≤ 3 years and serologically confirmed HBV infection (HB) status were classified at baseline into 4 HB groups. The risk of clinical AIDS/death in HIV seroconverters was calculated by HB status. RESULTS Of 2352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. Unadjusted rates (95% confidence intervals [CIs]) of clinical AIDS/death for the HB-negative, resolved HB, isolated HBcAb, and chronic HB groups were 2.43 (2.15-2.71); 3.27 (2.71-3.84); 3.75 (2.25-5.25); and 5.41 (3.41-7.42), respectively. The multivariable risk of clinical AIDS/death was significantly higher in the chronic HB group compared to the HB-negative group (hazard ratio [HR], 1.80; 95% CI, 1.20-2.69); while the HRs were increased but nonsignificant for those with resolved HB (HR, 1.17; 95% CI, .94-1.46) and isolated HBcAb (HR, 1.14; 95% CI, .75-1.75). CONCLUSIONS HBV coinfection has a significant impact on HIV outcomes. The hazard for an AIDS or death event is almost double for those with chronic HB compared, with HIV-monoinfected persons.

Immunologic and Virologic Events in Early HIV Infection Predict Subsequent Rate of Progression

BACKGROUND Variability in human immunodeficiency virus (HIV) disease progression cannot be fully predicted by CD4(+) T cell counts or viral load (VL). Because central memory T (T(CM)) cells play a critical role in the pathogenesis of simian immunodeficiency virus disease, we hypothesized that quantifying these cells in early HIV infection could provide prognostic information. METHODS We measured expression of CD45RO, chemokine (C-C motif) receptor (CCR) 5, CCR7, CD27, and CD28 to enumerate naive and memory subsets in samples from recently infected individuals. We also quantified proliferation, CD127 expression, and cell-associated VL. Disease progression was compared across subgroups defined by these measurements, using Kaplan-Meier survival curves and multivariate Cox proportional hazards regression. RESULTS Four hundred sixty-six subjects contributed 101 events. The proportion or absolute count of T(CM) cells did not correlate with disease progression, defined as the time to AIDS or death. However, significant associations were observed for proliferation within CD4(+) or CD8(+) T cells, loss of naive or CD127(+) memory CD8(+) T cells, and CD4(+) T cell-associated VL. CONCLUSIONS Our results demonstrate that the extent of the immunopathogenesis established early in HIV infection predicts the course of future disease. Because antiretroviral drug treatment reverses such defects in part, our study provides mechanistic clues to why early use of antiretrovirals may prove beneficial.