Marcus A. Conant

ORAL "HAIRY" LEUCOPLAKIA IN MALE HOMOSEXUALS: EVIDENCE OF ASSOCIATION WITH BOTH PAPILLOMAVIRUS AND A HERPES-GROUP VIRUS

An outbreak of a new form of oral leucoplakia, found principally on the lateral borders of the tongue, is reported in male homosexuals in the San Francisco area. Many of the patients showed evidence of immunosuppression, and candida was often found in the lesions. The characteristic histology is similar to that of the flat wart of skin. There was immunocytochemical evidence of papillomavirus core antigen in 77% of 30 biopsy specimens, but no papillomaviruses were detected by electron microscopy in samples from 6 randomly selected patients. In 5 of these 6 patients there was evidence of a herpes-type virus. Pneumocystis carinii pneumonia has developed in 8 of 37 patients in a 33-month period. This leucoplakia may presage AIDS, may be associated with both papillomavirus and a herpes-type virus, and may offer clues to the pathogenesis of other forms of oral epithelial hyperplasia and dysplasia.

Recombinant Alpha-2 Interferon Therapy for Kaposi's Sarcoma Associated with the Acquired Immunodeficiency Syndrome

In a randomized prospective study we tested the toxicity and efficacy of recombinant alpha-2 interferon in the treatment of Kaposis sarcoma associated with the acquired immunodeficiency syndrome. High doses (50 X 10(6) U/m2 body surface area, intravenously) or low doses (1 X 10(6) U/m2, subcutaneously) of recombinant alpha-2 interferon were administered to 20 patients for 5 days/wk, every other week, for four treatment cycles. Therapy was well tolerated subjectively and caused only mild hematologic and hepatic toxicity at both dose levels. No consistent or sustained changes were seen in immunologic variables during or after treatment. Six patients with Kaposis sarcoma, four at high dose and two at low dose, had objective responses (complete or partial) to treatment. However, therapy did not appear to eradicate cytomegalovirus carriage or prevent opportunistic infections related to cytomegalovirus.

Kaposi's sarcoma: Epidemiology, pathogenesis, histology, clinical spectrum, staging criteria and therapy

The acquired immunodeficiency syndrome (AIDS) epidemic has had a profound impact on our understanding of Kaposis sarcoma (KS). Epidemiologic features suggest a sexually transmitted cofactor in the pathogenesis of AIDS-associated KS (AIDS-KS), and several putative agents have received intense scrutiny. Cell culture studies suggest that the angiogenesis of AIDS-KS is stimulated by both human immunodeficiency virus proteins and growth factors that may be involved in the development and progression of AIDS-KS, thereby providing a rationale for new therapeutic interventions. The dermatologist is uniquely qualified to provide care for the majority of patients with KS, as many patients have cutaneous lesions amendable to local therapy (cryotherapy, intralesional therapy, simple excision). Patients requiring more aggressive local therapy (radiation therapy) or systemic therapies (interferon, chemotherapy) can be easily recognized. Standardized staging criteria provide assistance for determining appropriate local or systemic therapy and for evaluating and comparing responses to new therapies. This article reviews the epidemiology, pathogenesis, histologic features, clinical spectrum, staging criteria, and treatment of KS.

A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy

Objective To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response. Design A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States. Participants A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor. Interventions Randomization was to antiretroviral therapy guided by PRT or SOC. Main outcome measures The percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of ‘active’ (less than fourfold resistance) antiretroviral agents used (secondary). Results At week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P = 0.036, ITT observed;P = 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P = 0.005 for 400 copies/ml;P = 0.049 for 50 copies/ml assay detection limit). Significantly more subjects in the PRT arm were treated with two or more ‘active’ antiretroviral agents than in the SOC arm (P = 0.003). Conclusion Antiretroviral treatment guided prospectively by PRT led to the increased use of ‘active’ antiretroviral agents and was associated with a significantly better virological response.

Acquired immune dysfunction in homosexual men: immunologic profiles.

Homosexual men with Kaposi sarcoma, lymphadenopathy syndrome, opportunistic infection, and nonhomosexual traditional Kaposi sarcoma were evaluated for B cell, T cell, and complement immunity and compared to normal controls and homosexual controls. No significant immunologic abnormalities were found in the traditional Kaposi group. All homosexual groups, including the homosexual controls, had a significant decrease in the helper/suppressor cell ratio. Functional abnormalities of T-cell immunity were observed in the homosexual Kaposi sarcoma, lymphadenopathy syndrome, and opportunistic infection groups. Significant elevations of IgG, IgM, IgA, and IgE were found in the lymphadenopathy group, while only IgG and IgA were elevated in the Kaposi sarcoma group. C3, C4, and immune complexes were normal, while total hemolytic complement activity was increased in the Kaposi sarcoma and lymphadenopathy syndrome groups.

A Preliminary Evaluation of Nelfinavir Mesylate, an Inhibitor of Human Immunodeficiency Virus (HIV)-1 Protease, to Treat HIV Infection

A phase I/II dose-ranging open-label 28-day monotherapy study of the safety, pharmacokinetics, and antiviral activity of nelfinavir mesylate (Viracept), an inhibitor of human immunodeficiency virus (HIV)-1 protease, was done in 65 HIV-1-infected subjects. After 28 days, 54 responding subjects entered an open-label extension that allowed for the addition of nucleoside inhibitors of reverse transcriptase and dose escalation to maintain durability. The drug was well-tolerated and demonstrated robust antiviral activity, with demonstrable superiority of the 750 mg and 1000 mg three times daily regimens. Thirty subjects who continued to receive therapy at 12 months attained a persistent 1.6 log10 reduction in HIV RNA, accompanied by a mean increase in CD4 cells of 180-200/mm3. Studies of viral genotype and phenotype after virus rebound revealed that the initial active site mutation allowing for nelfinavir resistance is mediated by a unique amino acid substitution in the HIV-1 protease D30N, which does not confer in vitro phenotypic cross-resistance to the currently available protease inhibitors.

Vinblastine Therapy for Kaposi's Sarcoma in the Acquired Immunodeficiency Syndrome

Single-agent intravenous vinblastine, 4 to 8 mg/week, was used to treat 38 patients with Kaposis sarcoma related to the acquired immunodeficiency syndrome. The dose was titrated in relation to the total leukocyte count. Ten patients had an objective response, and 19 had stable disease during therapy. Apart from expected modest neutropenia, toxicity was minimal. A lower response rate was seen in patients with anemia, an elevated erythrocyte sedimentation rate, or any lymphoma-like B symptom. Opportunistic infections were common regardless of type of response but were commoner in patients who did not respond. Vinblastine used in low doses weekly is effective in treating Kaposis sarcoma related to the acquired immunodeficiency syndrome and has minimal associated toxicities.

Oral manifestations of tumor and opportunistic infections in the acquired immunodeficiency syndrome (AIDS): Findings in 53 homosexual men with Kaposi's sarcoma

Fifty-three homosexual men with Kaposis sarcoma (KS) were studied. Twenty-seven had biopsy-proved oral KS, the palate being the most common site. Past or present infections with cytomegalovirus, hepatitis, venereal diseases, and gastrointestinal microorganisms occurred in more than 70%. Oral candidiasis was confirmed in 57%. Heavy marijuana smoking was the most common habit. Transmission of AIDS is thought to be by a viral agent. Precautions involving the use of gloves, eyeglasses, and masks, similar to those recommended for the management of patients with hepatitis B, are urged.

treatment of Aids-related Cutaneous Kaposi's Sarcoma With Topical Alitretinoin (9 - cis -retinoic Acid) Gel

BACKGROUND Kaposis sarcoma (KS) is the most frequent malignancy in patients with HIV. Given the promise that retinoids show in the treatment of various hyperproliferative skin disorders and in vitro evidence of inhibition of proliferation of KS cells, a randomized, controlled clinical trial was conducted. METHODS AND RESULTS A 12-week, multicenter, randomized, double-blind, vehicle-controlled safety and efficacy evaluation of topical alitretinoin 0.1% gel applied to cutaneous KS lesions was conducted in HIV-infected patients. The primary efficacy endpoint was the patients response rate, as determined by evaluating six index lesions representative of the patients overall KS cutaneous disease using AIDS Clinical Trials Group (ACTG) response criteria applied to topical therapy. Of 268 patients entered in the blinded treatment phase of the study (alitretinoin group, n = 134; vehicle group, n = 134), 47 patients (35%) treated with alitretinoin 0.1% gel had a positive response, compared with 24 patients (18%) treated with vehicle gel. Of 184 patients receiving open-label alitretinoin treatment following the blinded phase of the trial, 90 patients (49%) met criteria for a positive response. This superior efficacy of alitretinoin gel over vehicle gel was maintained when the data were adjusted or analyzed for age, race, Kamofsky scores, baseline CD4+ lymphocyte counts, number of raised lesions at baseline, and aggregate area of index lesions. Alitretinoin 0.1% gel was superior to vehicle gel regardless of the number of concurrent antiretroviral therapies. Most adverse events were mild to moderate in severity, limited to the application site, and reversible on reduction in frequency or suspension of application. Relatively few patients (7%) discontinued alitretinoin therapy because of to related adverse events. CONCLUSIONS The results show that alitretinoin gel application is safe and generally well tolerated, and they indicate the superiority of alitretinoin 0.1% gel over vehicle gel in the treatment of cutaneous AIDS-related KS lesions.

A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients

OBJECTIVE To assess the safety of imiquimod, an immune response modifier, in the topical treatment of external anogenital warts in HIV-infected patients. SETTING Clinical sites in the United Kingdom (eight) and the United States (five). DESIGN A prospective, randomized, double-blind, vehicle-controlled study of imiquimod 5% cream or vehicle applied for 8+/-2 h three times per week for a maximum of 16 weeks in HIV-seropositive males (n = 97) and females (n = 3) aged 18 years or more with clinically diagnosed external anogenital warts, CD4 T lymphocyte count of > or = 100 x 10(6) cells/l and Karnofsky score > or = 70. MAIN OUTCOME MEASURES Safety was assessed through the incidence and severity of local skin reactions and other adverse events, and through clinical laboratory tests. Wart clearance was documented by two-dimensional measurements of warts and by photography. RESULTS Among the patients treated with imiquimod (n = 65) and vehicle (n = 35), the most common local skin reaction was erythema, (41.9 and 26.7%, respectively) and the incidence of patients reporting at least one adverse event was 69.2 and 65.7%, respectively. No clinically meaningful differences or changes in laboratory values were observed between treatment groups, nor were drug-related adverse effects observed in regard to HIV disease. While there was no significant difference between treatment groups in the number of patients who totally cleared their baseline warts (imiquimod 11% versus vehicle 6%, P = 0.488), more imiquimod-treated patients experienced a > or = 50% reduction in baseline wart area (38% versus 14%, P = 0.013). CONCLUSION Most local skin reactions were mild and no adverse effects on HIV disease were observed. Topically applied imiquimod 5% cream reduced wart area and may have clinical utility in treating external anogenital warts in some HIV-infected patients.