David M. Aboulafia

Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group.

PURPOSE Cytotoxic chemotherapy is frequently required for the more severe manifestations of human immunodeficiency virus (HIV)-related Kaposis sarcoma. Combinations of bleomycin and vincristine (BV) or BV with the addition of doxorubicin (ABV) are the most commonly used regimens against which new treatments may be compared. We report a multicenter phase III study that compared pegylated liposomal doxorubicin (PLD) to the BV combination. PATIENTS AND METHODS We conducted a randomized study that compared PLD 20 mg/m2 with a combination of bleomycin 15 IU/m2 and vincristine 2 mg in 241 patients with HIV-related Kaposis sarcoma. Both regimens were administered by intravenous infusion every 3 weeks for six cycles. RESULTS A total of 121 patients received PLD and 120 patients the BV combination. The response to PLD was superior to BV: 58.7% versus 23.3% (P < .001). Patients who were randomized to receive BV, however, were more likely to terminate treatment early because of an adverse event (26.7% v 10.7%), and fewer completed the full six cycles of treatment (30.8% v 55.4%). Treatment with BV was associated with a significantly higher incidence of peripheral neuropathy (P < .001), whereas PLD treatment was more commonly associated with neutropenia and delays in receiving treatment (P < or = .001). CONCLUSION Pegylated liposomal doxorubicin is an effective treatment for HIV-related Kaposis sarcoma with a higher response rate than the BV combination. It is well tolerated but more myelosuppressive.

INCIDENCE, LOCATION, AND DIAGNOSTIC EVALUATION OF METASTATIC BONE DISEASE

Metastatic carcinoma is the most common malignancy of bone. The clinical presentation of patients with skeletal metastasis is variable. When asked to evaluate a patient with a pathologic lesion or unexplained bone pain, the orthopedic surgeon should follow a logical sequence of steps in evaluating the patient with suspected metastasis to optimize care and avoid complications. In the majority of cases, a systematic approach to the patient with skeletal metastasis leads to the correct diagnosis.

Safety and Immunogenicity of the Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Men

BACKGROUND Human immunodeficiency virus type 1 (HIV-1)-infected men are at increased risk for anal cancer. Human papillomavirus (HPV) vaccination may prevent anal cancer caused by vaccine types. METHODS AIDS Malignancy Consortium Protocol 052 is a single-arm, open-label, multicenter clinical trial to assess the safety and immunogenicity of the quadrivalent HPV (types 6, 11, 16, and 18) vaccine in HIV-1-infected men. Men with high-grade anal intraepithelial neoplasia or anal cancer by history or by screening cytology or histology were excluded. Men received 0.5 mL intramuscularly at entry, week 8, and week 24. The primary end points were seroconversion to vaccine types at week 28, in men who were seronegative and without anal infection with the relevant HPV type at entry, and grade 3 or higher adverse events related to vaccination. RESULTS There were no grade 3 or greater adverse events attributable to vaccination among the 109 men who received at least 1 vaccine dose. Seroconversion was observed for all 4 types: type 6 (59 [98%] of 60), type 11 (67 [99%] of 68), type 16 (62 [100%] of 62), and type 18 (74 [95%] of 78). No adverse effects on CD4 counts and plasma HIV-1 RNA levels were observed. CONCLUSIONS The quadrivalent HPV vaccine appears safe and highly immunogenic in HIV-1-infected men. Efficacy studies in HIV-1-infected men are warranted. Clinical trials registration. NCT 00513526.

Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma

Rituximab plus intravenous bolus chemotherapy is a standard treatment for immunocompetent patients with B-cell non-Hodgkin lymphoma (NHL). Some studies have suggested that rituximab is associated with excessive toxicity in HIV-associated NHL, and that infusional chemotherapy may be more effective. We performed a randomized phase 2 trial of rituximab (375 mg/m(2)) given either concurrently before each infusional etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) chemotherapy cycle or sequentially (weekly for 6 weeks) after completion of all chemotherapy in HIV-associated NHL. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by intravenous bolus cyclophosphamide given every 21 days for 4 to 6 cycles. In the concurrent arm, 35 of 48 evaluable patients (73%; 95% confidence interval, 58%-85%) had a complete response. In the sequential arm, 29 of 53 evaluable patients (55%; 95% confidence interval, 41%-68%) had a complete response. The primary efficacy endpoint was met for the concurrent arm only. Toxicity was comparable in the 2 arms, although patients with a baseline CD4 count less than 50/microL had a high infectious death rate in the concurrent arm. We conclude that concurrent rituximab plus infusional EPOCH is an effective regimen for HIV-associated lymphoma.

Etanercept for the treatment of human immunodeficiency virus-associated psoriatic arthritis.

Etanercept may play an important role in modulating the inflammatory activity and progression of human immunodeficiency virus (HIV)-associated psoriasis and psoriatic arthritis. We report the case of a 45-year-old homosexual man with a CD4 cell count of less than 0.05 x 10(9)/L and an HIV viral load of 4200 copies/mL (while receiving highly active antiretroviral therapy) who developed extensive psoriatic plaques, 4.5-kg weight loss, onychodystrophy, and psoriatic arthropathy with severe periarticular bone demineralization. The arthritis progressed despite the use of several disease-modifying medications, including corticosteroids, hydroxychloroquine, and minocycline. Because of uncontrolled, progressive, and disabling arthritis and resulting profound disability, he was treated with etanercept. Within 3 weeks, his psoriasis had improved dramatically and his joint inflammation had stabilized. For the next 4 months, immunologic and viral parameters remained stable, but his clinical course was complicated by frequent polymicrobial infections. Etanercept was thus discontinued despite continued improvements in his psoriasis, psoriatic arthritis, and functional status. While both cutaneous and joint manifestations of psoriasis improved dramatically, the experience with this patient dictates that caution and careful follow-up must be exercised when prescribing etanercept in the setting of HIV infection.

Randomized Phase II Trial of Matrix Metalloproteinase Inhibitor COL-3 in AIDS-Related Kaposi's Sarcoma: An AIDS Malignancy Consortium Study

PURPOSE Matrix metalloproteinases (MMPs) are involved in tumor metastasis and are overexpressed in Kaposis sarcoma (KS) cells. In a phase I trial of the MMP inhibitor COL-3 in patients with AIDS-related KS, the drug was well tolerated, KS regression was observed, and MMP-2 levels decreased significantly in responders compared with nonresponders. The aim of this trial was to extend these initial observations. PATIENTS AND METHODS This was a randomized, parallel-group, phase II study. COL-3 was administered orally once daily at one of two doses (group A received 50 mg and group B received 100 mg) to patients with AIDS-related KS. Antiretroviral therapy was permitted but not required. Serial tumor assessments and plasma levels of MMPs were obtained. Study end points were progressive KS and recurrent dose-limiting toxicity. RESULTS Seventy-five patients received COL-3: 37 in group A and 38 in group B. Fifty-seven patients (76%) had received prior KS therapy. Thirty-three patients (44%) had more than 50 KS lesions. The response rate in group A was 41%, which was significantly greater than the prespecified target rate of 20% (95% CI, 25% to 58%; P = .003); the response rate of group B was 29% (P = not significant). There were significant declines in MMP-2 and MMP-9 plasma levels from baseline to minimum value with treatment (MMP-2, P < .001; MMP-9, P = .001). The most common adverse events were photosensitivity and rash. CONCLUSION COL-3, when administered as 50 mg/d, is both active and well tolerated in the treatment of AIDS-related KS. COL-3 is a promising agent for the treatment of this opportunistic neoplasm of AIDS.

Regression of Acquired Immunodeficiency Syndrome-Related Pulmonary Kaposi's Sarcoma After Highly Active Antiretroviral Therapy

Kaposis sarcoma (KS) is the most common neoplasm affecting people with the human immunodeficiency virus (HIV) infection. The skin is the most common site of disease; however, KS can also involve visceral organs such as the lungs, leading to severe morbidity and contributing to death in almost 30% of patients with the acquired immunodeficiency syndrome (AIDS). New antiretroviral strategies incorporating combination nucleoside analogues with a protease inhibitor lead to increased circulating CD4+ lymphocyte counts, decreased plasma levels of HIV, and decreased mortality from AIDS-defining opportunistic infections. The effects of highly active antiretroviral therapy (HAART) on AIDS-associated KS remain largely unknown. Herein the case of an antiretroviral-naive man with advanced AIDS (CD4+ helper T-lymphocyte count, 35/mm3; HIV viral RNA quantification, more than 800,000 copies/mL), and symptomatic pulmonary KS is described. After HAART was initiated, his CD4+ cell count increased fourfold, his HIV-viral load decreased to nondetectable levels, and the pulmonary KS regressed dramatically. To my knowledge, this report represents the first documented case of pulmonary KS regression after the initiation of HAART. Although this finding is preliminary, if confirmed by other clinicians, the effect of potent antiretrovirals on KS growth and development will have important implications on the manner in which KS is staged and treated.

Malignancies in HIV/AIDS: From Epidemiology to Therapeutic Challenges

The incidence of AIDS-defining cancers (ADCs) – Kaposi sarcoma, primary central nervous system lymphoma, non-Hodgkin lymphoma, and cervical cancer – although on the decline since shortly after the introduction of HAART, has continued to be greater even in treated HIV-infected persons than in the general population. Although the survival of newly infected people living with HIV/AIDS now rivals that of the general population, morbidity and mortality associated with non-AIDS-defining cancers (NADCs) such as lung, liver, anal, and melanoma are significant and also continue to rise. Increasing age (i.e. longevity) is the greatest risk factor for NADCs, but longevity alone is not sufficient to fully explain these trends in cancer epidemiology. In this review, we briefly review the epidemiology and etiology of cancers seen in HIV/AIDS, and in this context, discuss preclinical research and broad treatment considerations. Investigation of these considerations provides insight into why malignancies continue to be a major problem in the current era of HIV/AIDS care.

Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma: evidence of symptom palliation from chemotherapy.

Paclitaxel and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency virus (HIV)‐associated Kaposi sarcoma (KS). A randomized trial comparing the efficacy and toxicity of paclitaxel and PLD was performed, and the effects of therapy on symptom palliation and quality of life were determined.

Thrombotic Complications in Patients Infected with HIV in the Era of Highly Active Antiretroviral Therapy: A Case Series

BACKGROUND Recent reports suggest that patients infected with human immunodeficiency virus (HIV) may have an increased risk of developing thrombosis, but the etiology, risk factors, and clinical course remain largely undefined, with few descriptive case series. METHODS We identified 30 patients from an HIV outpatient clinic (treatment population, 650 persons) who had had a total of 43 venous or arterial thromboses during 1996-2002. Data pertaining to demographic characteristics, medical history, thrombosis presentation, and clinical outcomes were abstracted from patient medical records. RESULTS The median patient age at the time of thrombosis was 43 years. Although the presence of persistent antibody to phospholipids was the most common abnormal finding in the laboratory, evaluation of thrombophilia, cases of low levels of proteins C and S and antithrombin III, and elevated levels of factor VIII and homocysteine were also identified. Seventy-seven percent of the patients smoked cigarettes, 57% had dyslipidemia, and 43% had a malignancy (most commonly Kaposi sarcoma). Although the Centers for Disease Control and Prevention (CDC) classification for 16 patients (53%) was C3, most showed evidence of immune reconstitution (median CD4 cell count, 290 cells/ mu L) and control of the virus (median HIV load, 2290 copies/mL). Lower extremity, deep vein thrombosis and pulmonary emboli accounted for 66% of all thrombotic events. The median time to diagnosis of thrombosis was 1 day (range, 3 h to 3 weeks). CONCLUSIONS Patients in this series were characterized by a relatively young age at the time of thrombosis, a predominance of elevated levels of lipids, a history of malignancy, and an advanced CDC HIV classification but not by a low CD4 cell count or an elevated HIV load.