Clifford Gunthel

Risk factors for Kaposi's sarcoma in men seropositive for both human herpesvirus 8 and human immunodeficiency virus

Objective: To identify risk factors for Kaposis sarcoma (KS) among men seropositive for both human herpesvirus 8 (HHV-8) and HIV. Design: Cross-sectional study of 91 HHV-8 seropositive, HIV seropositive men who have sex with men (57 with KS), and 70 controls at lower risk for KS. Methods: Patients received clinical evaluations. Blood, oral fluids, semen, rectal brush, rectal swab, and urine were collected, and tests for HHV-8 were performed. Results: Men with KS were more likely to have HHV-8 DNA in peripheral blood mononuclear cells (PBMC) than men without KS [35.1 versus 5.9%, odds ratio (OR), 8.6, 95% confidence interval (CI), 1.9–39.9]. The prevalence of HHV-8 DNA in oral fluids was similar for the two groups (37.0 versus 32.4%; OR, 1.2; 95% CI, 0.5–3.0). HHV-8 DNA was rarely detected in specimens of other types from these men, or in any specimens from the 70 controls. Among men with KS, HHV-8 DNA in PBMC was associated with new KS lesions (OR, 4.5; 95% CI, 1.4–14.5), and HHV-8 DNA in oral fluids was associated with oropharyngeal KS lesions (OR, 3.1; 95% CI, 1.0–10.1). Men with high HHV-8 antibody titers were more likely to have KS (OR, 9.6; 95% CI, 1.2–78.2), but were less likely to have new KS lesions (OR, 0.2; 95% CI, 0.0–1.1) or HHV-8 DNA in PBMC (OR, 0.2; 95% CI, 0.0–1.6) or oral fluids (OR, undefined; P = 0.001). Conclusions: In HHV-8- and HIV-seropositive men, HHV-8 DNA is associated with KS. Among men without KS, HHV-8 DNA is most commonly found in oral fluids. High HHV-8 antibody titers may protect against circulating HHV-8 and new KS lesions.

Repeated measures study of human herpesvirus 8 (HHV-8) DNA and antibodies in men seropositive for both HHV-8 and HIV

Objective: To study the natural history and pathogenesis of human herpesvirus 8 (HHV-8) infection in HHV-8-seropositive, immunosuppressed men. Design: Longitudinal study of 87 HHV-8- and HIV-seropositive men [42 with Kaposis sarcoma (KS)] during four visits over a 2 month period. Methods: Patients provided oral fluid and blood. HHV-8 antibody titers were measured with peptide-based enzyme-linked immunosorbent assays (ELISA) for ORF65 and K8.1; HHV-8 DNA was detected with polymerase chain reaction ELISA. Results: HHV-8 DNA was present in oral fluid or peripheral blood mononuclear cells (PBMC) at one or more of the four visits in 71% of men with KS and 56% of men without KS. The strongest correlate of HHV-8 DNA in PBMC was the presence of KS [odds ratio (OR), 8.7; 95% confidence interval (CI), 3.4–22]. Detection of HHV-8 DNA in oral fluid or PBMC was often intermittent, but individuals who shed virus at one time point were more likely to shed at other times. Some men had incomplete epitope recognition in their anti-HHV-8 antibody response. High antibody titers were associated with the absence of circulating HHV-8, particularly for the ORF65 seroassay (OR, 0.16; 95% CI, 0.05–0.51). Conclusions: Among HHV-8 seropositive men, circulating virus is common even in the absence of disease. The link between KS and HHV-8 DNA in PBMC suggests that anti-herpes drugs may impede KS development or progression. Seroassays should target multiple epitopes to achieve maximal sensitivity. HHV-8 replication may be limited by high antibody titers or other immune function for which antibodies are a marker.

Human herpesvirus 8 presence and viral load are associated with the progression of AIDS-associated Kaposi's sarcoma.

Objective:We present the largest longitudinal study to date that examines the association between Kaposis Sarcoma (KS) disease progression and the presence and viral load of human herpesvirus 8 (HHV-8). Methods:Ninety-six men were enrolled at HIV clinics in Atlanta, Georgia, who had KS (n = 47) or were without KS but seropositive for HHV-8. Visits occurred at 6-month intervals for 2 years at which the patients KS status was evaluated and oral fluid and blood were collected for quantification of HHV-8 DNA and antibodies. Results:The presence of HHV-8 DNA in blood was more common (P < 0.001) and the viral load higher (P < 0.001) in men with KS in comparison with men without KS. Mean HHV-8 viral loads in blood and oral fluids were associated with disease status, being highest among patients with progressing KS, intermediate among patients with stable KS, and lowest among patients with regressing KS. Consistent with our previous report high antibody titers to HHV-8 orf 65 were inversely associated with HHV-8 shedding in oral fluid. Conclusions:We observed a significant association between changes in KS disease severity and the presence and viral load of HHV-8. HHV-8 viral load in blood may provide useful information to clinicians for assessment of the risk of further disease progression in patients with KS.

Non–AIDS-Defining Malignancies in Patients with HIV in the HAART Era

The introduction of highly active antiretroviral therapy (HAART) has drastically changed the scope and spectrum of diseases associated with HIV, shifting from AIDS-related to non–AIDS-related diseases. Studies linking HIV/AIDS databases to cancer registries have shown a dramatic decrease in AIDS-related malignancies and a steady increase in non–AIDS-defining malignancies (NADM). We review the causes underlying the rise in incidence of NADM and the clinical presentation, pathology, and treatment outcomes of the four most commonly encountered NADM in the HAART era. Meta-analysis of published studies show an increase in NADM over the general population, mostly among infection-related cancers such as anal cancer, Hodgkin lymphoma, and liver cancer. Among the non-infection-related cancers, lung and skin cancers predominate. The overall effect of HAART on NADM is unsettled. As HIV-infected individuals survive longer, better screening strategies are needed to detect cancer earlier, and prospective data are needed to assess the impact of HAART on cancer outcomes.

Purified Tat induces inflammatory response genes in Kaposi's sarcoma cells

Objective:Kaposis sarcoma (KS) is a neoplasm strongly associated with HIV-1 infection and marked by leukocytic infiltration. The infiltrating leukocytes are a possible source of inflammatory cytokines, human herpesvirus 8 (HHV8) and the HIV-1 transactivator protein Tat. This study examines whether Tat directly induces expression of cellular adhesion molecules and cytokines in KS cells and whether this induction differs in kinetics and magnitude from induction by tumour necrosis factor (TNF) α. Design and method:Changes in gene expression in response to recombinant Tat compared with those to TNFα were evaluated at the messenger (m) RNA and protein level using cells that were cultured from KS lesions. Results:Tat induced the expression of the adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and the cytokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6). The inductions were observed at both the protein and mRNA levels. The pattern of mRNA induction over time in response to Tat differed from that to TNFα, with higher peak levels that occurred earlier in response to Tat. The expression of these genes is, in part, regulated by the transcription factor NF-κB. Tat and TNFα activated comparable levels of NF-κB. Conclusions:The ability of the HIV-1 Tat to induce the expression of genes with kinetics that are distinct from those seen in TNFα induction suggests that mechanisms in addition to activation of NF-κB contribute to the observed induction. Tat may contribute to the pathogenesis of AIDS-related KS through induction of cellular genes that are pro-proliferative and proinflammatory and may enhance the recruitment of leukocytes, which are a possible source of further cytokines, Tat and HHV8.

Human immunodeficiency virus-associated lung cancer in the era of highly active antiretroviral therapy.

Lung cancer is the leading cause of death among non‐acquired immunodeficiency syndrome (AIDS)‐defining malignancies. Because highly active antiretroviral therapy (HAART) has improved the survival of patients with human immunodeficiency virus (HIV), the authors evaluated lung cancer outcomes in the HAART era.

Oral sampling and human papillomavirus genotyping in HIV-infected patients

BACKGROUND Oral human papillomavirus (HPV) is associated with several health complications especially in combination with HIV infections. Screening may be useful, but methodologies and results have varied widely in previous studies. We conducted a pilot study in an HIV-positive population to evaluate HPV detection in four different oral sample types. METHODS Upon enrollment, an oral-rinse (OR) sample was collected in 10 ml saline. Additional samples of the buccal mucosa, tonsils, and oral lesion if present were collected with cytology brushes. DNA was extracted using LC-MagNAPure, and the Linear Array HPV genotyping Assay (Roche) was used for HPV genotyping. RESULTS In samples from 100 HIV-positive participants, HPV was detected in 39 (%) of the oral rinses, 13 (%) mucosal and 11 (12.9%) tonsil brushings. Of seven lesion brushings collected, four were HPV positive. All participants with HPV detected in mucosal, tonsil, or lesion brushings were also positive in the OR sample. Among the rinse samples, 27 different genotypes were detected with HPV84 (n = 6), HPV55 (n = 5), and HPV83 (n = 5) being the most common. Multiple infections were detected in 17 samples (range 2-9, mean 1.9 types). As potential cofactors, only receptive oral sex was significantly associated with HPV (P = 0.018, odds ratio 2.9, 95% CI 1.2-6.9). CONCLUSION Sampling is a significant factor for oral prevalence studies. Oral rinse provides the best representation for HPV in the oral cavity. To evaluate associated cofactors other than receptive oral sex, larger studies with case-control design are necessary.

Improvement in lipid profiles over 6 years of follow-up in adults with AIDS and immune reconstitution

The aim of the study was to evaluate long‐term changes in lipids and to assess other coronary heart disease (CHD) risk factors in highly experienced AIDS patients with immune reconstitution, and to examine their association with antiretroviral therapy (ART).

State of the art: Gastrointestinal malignancies in the human immunodeficiency virus (HIV) population

The gastrointestinal tract is one of the most common sites for the development of primary neoplasms arising in patients with pre-existing infection with the human immunodeficiency virus (HIV). Over the past decade, new information on the clinical manifestation, natural history, treatment options, and related toxicity have been reported, mostly notably the integration of highly active antiretroviral therapy (HAART). The following is a concise review summarizing the current state-of-the-art for GI tract malignancies in the HIV-positive patient and is designed to assist the clinical oncology team in developing a rationale plan when caring for these patients.

Human immunodeficiency virus lymphomas in the era of antiretrovirals: Is it finally time to change the discussion?

It seems so long ago when we debated the wisdom of standard versus less intensive chemotherapy regimens for patients with human immunodeficiency virus (HIV)-associated lymphomas. In a former time, when the prognosis for this disease was universally dismal, less aggressive, more tolerable chemotherapy regimens were proposed for these high-grade lymphomas. The advent of the effective combined antiretroviral therapy (cART) era finally put the discussions of modified therapy in HIV-associated lymphomas to rest. Recent data suggest that HIV-infected individuals are not only living longer, but their survival is approaching that of HIV-seronegative patients. Projections from the North American Acquired Immunodeficiency Syndrome Cohort Collaboration on Research and Design estimate that individuals who start cART in their 20s can expect to survive into their early 70s. Individuals with AIDS and lymphoma have also benefited from advances in lymphoma therapies, including rituximab treatment, infusional chemotherapy regimens, and stem cell transplantation technologies. If we now have the therapeutic tools to virtually eliminate HIV viremia and restore immune function in the cART era, then is it now time to shift our focus away from the uniqueness of HIV-associated lymphomas and focus on the larger issues of health care disparities, disease prevention, and survivorship in this population? In their article in this issue of Cancer, Olszewski and colleagues report on trends in HIV-associated lymphomas by analysis of the National Cancer Data Base. Not surprisingly, their findings reflect the national demographic shift in the HIV-seropositive population, namely, the rising proportion of African Americans and Latinos who are HIV-infected. Shockingly, a recent Centers for Disease Control and Prevention report estimates that one-half of all African American men who have sex with men and one-quarter of all Hispanic men who have sex with men will be diagnosed with HIV in their lifetimes. Moreover, Olszewski et al have documented health care disparities among patients with HIV-associated lymphomas and have identified older age, African American race, and lack of private insurance as risks for not receiving chemotherapy. Previous reports have also associated older age and non-Hispanic African American race with cancer treatment disparities in HIV-infected individuals. In a study of older, non-HIV–positive patients with non-Hodgkin lymphoma (NHL), African American patients were less likely to receive chemotherapy and had a survival disadvantage compared with white patients. Racial treatment disparities are not unique to HIV-associated malignancies, but the shift in demographics in the HIV population appears to emphasize these observations. As HIV-directed therapies continue to improve, HIV infection status as an independent factor may become less of a determinant in lymphoma treatment inequities. Of course, the inequities of health care associated with race and socioeconomic status are complex. Investment in local public health departments, with more concerted HIV prevention stategies, may help to hinder these described trends in the future. An additional reason why HIV-associated lymphomas are viewed as a separate entity may be the need for antiretroviral therapy. Although cART prescribing data are not analyzed in the Olszewski report, concomitant chemotherapy and antiretroviral therapy have become standard practice. Do these antiretroviral agents complicate chemotherapy regimens, and are they perhaps perceived as barriers to cancer treatment? Newer agents are more tolerable, have fewer side effects, require a lower pill burden, and have greater potency than earlier therapies. In fact, this greater potency has raised the question of whether 2 antiretroviral agents are sufficient compared with the conventional 3-drug combinations usually used to control HIV viremia. The most recent Department of Health and Human Services HIV treatment guidelines have recommended a shift away from nonnucleoside reverse transcriptase inhibitors and many of the protease inhibitor-