[Screening and therapy of anal intraepithelial neoplasia (AIN) and anal carcinoma in patients with HIV-infection]. / Screening und Therapie der analen intraepithelialen Neoplasie (AIN) und des Analkarzinoms bei HIV-Infektion.

Anal intraepithelial neoplasia (AIN) is a potential precursor of invasive anal carcinoma. Introduction of highly active antiretroviral therapy (HAART) in the treatment of HIV infection substantially reduced the incidence of some diseases associated with opportunistic viral infections. However, the incidence of AIN is reported to increase and HAART seems to have only little impact on the regression or progression of AIN. Paradoxically, improvement of survival in the HAART era results in an increased risk of anal cancer. The incidence of anal carcinoma amongst homosexual men is substantially higher compared to the normal population (35/100.000). This incidence is similar to the incidence of cervical cancer before screening for CIN with cervical cytology. Recent data suggest that the incidence of AIN and anal cancer is even higher among HIV-infected individuals. Both cancer entities share biologic similarities, including the association with human papillomavirus infection (HPV). Screening for CIN with cervical cytology and early treatment has resulted in a significant decline in the incidence of cervical carcinoma. Like cervical cancer, anal carcinoma may be preventable through identification and treatment of its precursors. Future efforts should focus on a screening protocol, training of clinicians in the diagnosis and treatment of AIN and anal carcinoma, and novel approaches to treatment of these lesions. This screening protocol could help to reduce anal cancer in HIV-infection as well as save limited resources in health care system.

Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials.

Our objective was to evaluate valaciclovir for anogenital herpes in HIV-infected individuals using 2 controlled trials conducted before highly active antiretroviral therapy (HAART) was used. In Study 1, 1062 patients (CD4+ > or = 100 cells/mm(3)) received suppressive valaciclovir or aciclovir for one year and were assessed monthly. In Study 2, 467 patients were treated episodically for > or =5 days with valaciclovir or aciclovir and evaluated daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpes. Hazard ratios [95% confidence interval (CI)] for time to recurrence for valaciclovir 500 mg twice daily and 1000 mg once daily vs aciclovir were 0.73[0.50, 1.06], P=0.10, and 1.31[0.94, 1.82], P=0.11. Valaciclovir 500 mg twice daily was superior to 1000 mg once daily, P=0.001. Valaciclovir 1000 mg twice daily was comparable to aciclovir on herpes episode duration (hazard ratio 0.92[0.75, 1.14]). Adverse events were similar among treatments. In conclusion, valaciclovir is a safe, effective, convenient alternative to aciclovir for HSV infection in HIV-infected individuals.

Immunomodulatory therapy in the management of viral infections in patients with HIV infection.

Human immunodeficiency virus (HIV) causes disease by infecting lymphocytes and progressively destroying critical regulatory and effector cells of the immune system, leaving patients vulnerable to a number of bacterial, fungal, and viral infections. Facial herpes (herpes simplex virus-1 [HSV-1]), genital herpes (HSV-2), herpes zoster (varicella zoster virus), oral hairy leukoplakia (Epstein-Barr virus), Kaposi's sarcoma (HHV-8), molluscum contagiosum, condyloma acuminata (human papillomavirus [HPV-6, HPV-11]), plantar warts (HPV-1), and facial warts and flat warts (HPV-5) are some of the cutaneous viral diseases most commonly seen in HIV-infected patients. Two immunomodulatory agents, imiquimod (Aldara), shown to be safe and effective in the management of genital warts, and alitretinoin gel, shown to be safe and effective in the treatment of Kaposi's sarcoma, may offer a new therapeutic approach to treatment of cutaneous viral diseases. There is a strong scientific rationale to suggest that imiquimod and alitretinoin gel may be useful in the treatment of a variety of cutaneous viral diseases that have been shown to respond to immunomodulatory drugs. This represents a new approach in the therapeutic treatment paradigm for treatment of cutaneous viral diseases at their site of infection.

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

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.

Persistent stress as a predictor of genital herpes recurrence.

BACKGROUND: Results of several studies suggest that psychological stress and negative mood can trigger genital herpes recurrences, but results are inconsistent. OBJECTIVE: To determine whether short-term or persistent psychological stress or specific negative moods are predictive of genital herpes recurrences in women. METHODS: A prospective cohort study followed up participants for 6 months using weekly assessments of stress and mood, monthly assessments of life change events, and diary reports of genital herpes recurrences confirmed by medical examination when feasible. The community sample consisted of 58 women, aged 20 to 44 years, with a 1- to 10-year history of visible genital herpes recurrence and at least 1 recurrence in the previous 6 months. RESULTS: Persistent stress predicted recurrence in the subsequent week (odds ratio, 1.08 per unit increase in stress; 95% confidence interval, 1.01-1.15; P=.03). After adjusting for recurrence in the previous week, the more weekly persistent stress reported, the greater the likelihood of recurrence the following week. Also, an increased recurrence rate occurred after the month during which participants experienced their highest levels of anxiety (P =.03). There were no significant associations between recurrence and short-term stress, life events, depressive mood, anger, or phase of menstrual cycle. CONCLUSIONS: Persistent stressors and highest level of anxiety predicted genital herpes recurrence, whereas transient mood states, short-term stressors, and life change events did not. Women with herpes can be reassured that short-term stressful life experiences and dysphoric mood states do not put them at risk for increased outbreaks of recurrent genital herpes.

Anonymous HIV testing using home collection and telemedicine counseling. A multicenter evaluation.

BACKGROUND: Home human immunodeficiency virus (HIV) testing has been proposed as an alternative to conventional HIV testing. Despite debate over HIV type 1 (HIV-1) home test systems, these concerns have not to our knowledge been previously studied. OBJECTIVE: To evaluate the safety and efficacy of the Home Access Health Corp (Hoffman Estates, Ill) HIV-1 test system compared with traditional HIV-1 testing with venous blood. METHODS: A total of 1255 subjects were studied prospectively in a blinded, subject-as-control evaluation at 9 outpatient clinics using intent-to-treat analysis. Subjects were provided a home collection kit (Home Access Health Corp) to collect their own finger-stick blood spot samples for laboratory analysis. Subjects received pretest counseling by telephone and their comprehension was subsequently assessed. Subject-collected blood spot samples were compared with professionally drawn blood spot samples for adequacy (sufficient for completing the Food and Drug Administration-endorsed testing) and with venous samples for accuracy. Subjects called 3 days later for anonymous results and posttest counseling. Device safety was evaluated based on adverse events incidence. Subject comprehension of HIV information was measured. RESULTS: Subject-collected blood spot sample results were in complete agreement with venous blood sample results, demonstrating 100% sensitivity and 100% specificity compared with venous controls. Ninety-eight percent of subjects obtained testable blood spot specimens compared with phlebotomists. Following pretest counseling, subjects answered 96% of HIV risk questions correctly. There were no significant adverse events. CONCLUSION: Anonymous HIV-1 home collection kits with pretest and posttest telephone counseling can provide a safe and effective alternative to conventional venous HIV-1 antibody testing.

Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection.

BACKGROUND: Most individuals infected with HIV-1 show disease progression despite both cellular and humoral immune responses. We investigated whether immunisation of patients who had symptomless HIV-1 infection with an envelope subcomponent vaccine (MNrgp120) to augment immune response can slow progression of HIV-1 disease. METHODS: In a randomised, double-blind, placebo-controlled trial, carried out in university infectious disease clinics and community infectious disease practices, we enrolled 573 HIV-infected patients with CD4 counts above 600 cells/microL (0.6 x 10(9)/L). Patients received 600 micrograms vaccine or placebo by intramuscular injection monthly for 6 months then every alternate month throughout the study. The primary endpoint was the rate of decline in CD4 count; secondary endpoints were HIV-1 RNA concentrations in plasma and minor clinical events associated with HIV. Analysis was by intention to treat. FINDINGS: At baseline, the study participants had a mean CD4 count of 775 cells/microL (SD 172) and 89% of participants had detectable HIV RNA (> 200 copies/mL). These RNA-positive individuals had a median viral load of 9250 copies/mL (IQR 2670-26960). Analysis after 15 months of follow-up of the 568 subjects who had at least one CD4 count done after randomisation showed no difference between the 287 vaccine recipients and 281 placebo recipients in rate of decline of CD4 count (yearly decrease 53.8 [SE 7.6] vs 42.3 [7.6] cells/microL; ratio of mean gradients 1.27 [95% CI 0.63-2.55]) or in plasma HIV-1 RNA concentrations (p > or = 0.63). The study was designed with power to detect a vaccine-induced reduction in rate of decline in CD4 count of 60%; these results exclude with 95% confidence a reduction of 40% or more. More vaccine-treated patients than placebo recipients showed a 50% decrease in CD4 count (11 vs 5; relative risk 2.15 [95% CI 0.76-6.12], p = 0.13). The frequencies of HIV-related minor clinical events were similar in the two groups. Pain at the injection site was the only adverse event that occurred more frequently in vaccine-treated group. INTERPRETATION: Postinfection immunisation of symptom-free HIV-infected patients with MNrgp120 vaccine did not alter HIV-1 disease progression as measured by immunological, virological, and clinical endpoints over a 15-month period.

Genital herpes: an integrated approach to management.

This review of epidemiologic, clinical, and psychosocial/psychobehavioral data related to genital herpes simplex virus infection details the increasing incidence of herpes simplex virus infection in the United States and summarizes the data regarding the safety and efficacy of chronic and acute antiviral therapy with acyclovir. It additionally establishes the validity of psychosocial intervention as an adjunct to pharmacologic therapy for patients with recurrent genital herpes.

Fungal infections in immunocompromised individuals.

This article examines the expression of fungal infections seen with different immunodeficiency states and discusses how the sequential appearance of different diseases serves as a harbinger of clinical disease progression. The effect of an immunocompromised state on the medical history, physical findings, and natural history of fungal infections are discussed. The appearance and increased frequency of rare fungal infections, made possible by immunosuppression, are highlighted.

Safety and efficacy of thymopentin in zidovudine (AZT)-treated asymptomatic HIV-infected subjects with 200-500 CD4 cells/mm3: a double-blind placebo-controlled trial.

Thymopentin, 50 mg subcutaneously (s.c.) 3 times per week, was evaluated in a double-blind, randomized, placebo-controlled trial of zidovudine (AZT)-treated asymptomatic human immunodeficiency virus (HIV)-infected subjects with 200-500 CD4 cells/mm3 at entry. The 352 subjects were prestratified by prior AZT use into stratum I (235 subjects, > 6 months AZT at entry) and stratum II (117 subjects, < or = 6 months AZT at entry). Clinical end points, CD4 cell counts, serum p24, serum immune complex dissociated (ICD) p24, and safety variables were evaluated through 48 weeks, using an intent-to-treat analysis. The two strata were analyzed individually because they yielded different clinical outcomes, with a statistically significant treatment-by-stratum interaction. In stratum I (mean, 16 months AZT at entry) two AIDS or death events occurred in thymopentin and 10 in placebo recipients (p = 0.024; relative risk (RR) estimate, 4.9 [95% confidence limit (CI), 1.1 to 22.2]). There were three AIDS-related complex (ARC), AIDS, or death events in thymopentin and 18 in placebo recipients [p = 0.001; RR estimate, 5.9 (95% CI, 1.7 to 20.0)]. In stratum II (mean, 3 months AZT at entry), four AIDS or death events occurred in thymopentin and none in placebo recipients (p = 0.11), and four ARC, AIDS, or death events occurred in thymopentin and two in placebo recipients (p = 0.79). The treatment groups did not differ significantly with respect to changes in CD4 counts or p24 antigen levels or with respect to clinical adverse experiences or laboratory abnormalities. Thus, AZT-experienced placebo-treated subjects had relatively high progression rates to AIDS or death and to ARC, AIDS, or death, and these rates were reduced by thymopentin treatment. In contrast, placebo-treated subjects with little prior AZT experience had low progression rates; these were not significantly changed by thymopentin treatment. There was no increase in the incidence of adverse reactions with thymopentin.

Management of human immunodeficiency virus-associated malignancies.

A number of malignancies which have been seen with other immunodeficiency diseases have appeared in patients immunosuppressed by the human immunodeficiency virus (HIV) infection. These include Kaposi's sarcoma, lymphomas, superficially spreading basal cell carcinomas, and squamous cell carcinomas. The fact that Kaposi's sarcoma is the most common of these malignancies and is seen almost exclusively among homosexual men remains an enigma. The dermatological treatment of Kaposi's sarcoma includes observation, surgical excision, radiation therapy, interlesional chemotherapy, and topical liquid nitrogen. When the disease becomes more aggressive, systemic chemotherapy, using a combination of chemotherapeutic agents, will often slow disease progression. It is essential that the chemotherapy be given in a dose that will slow the course of the malignancy, but will not further immunosuppress the patient. The treatment of lymphomas in HIV-infected patients has been less than satisfactory, with a high mortality rate. Aggressive therapy of these lymphomas using combination therapy has been the most successful in increasing survival.

The AIDS epidemic.

The nature of the clinical presentation of HIV infection continues to evolve over time. New cutaneous (e.g., seborrheic dermatitis, onychomycosis, and tinea pedis) and systemic (e.g., Aspergillus fumigatus and Penicillium marneffei) opportunistic fungal infections can now be added to the classic clinical markers for progressive HIV infection, such as Kaposi's sarcoma, Pneumocystis carinii pneumonia, Mycobacterium avium intercellulare infections, and cryptococcal meningitis. The fact that the appearance of many of these fungal diseases is directly correlated with the patient's CD4 cell count is a valuable tool for ongoing clinical evaluation. Although systemic manifestations characterize a progression from asymptomatic HIV infection to AIDS, many of the signs of disease progression are cutaneous. Prophylaxis against many of the potentially life-threatening systemic opportunistic infections associated with HIV positivity has had a positive impact on the life expectancy of patients with AIDS.

Severe opportunistic infections in AIDS patients with late-stage disease.

BACKGROUND: Clinicians caring for patients who have acquired immunodeficiency syndrome (AIDS) need to be aware of the wide variety of infectious diseases that can occur. Although Pneumocystis carinii pneumonia (PCP) is the most common AIDS-defining infection, other opportunistic infections associated with advanced immunodeficiency can develop after an initial diagnosis. METHODS: To ascertain AIDS-defining opportunistic infections that developed at the time of or after an AIDS diagnosis, and intensive chart review was conducted for 45 homosexual men with AIDS who died from 1990 through 1992. Time to death after first occurrence of these infections was also determined. RESULTS: The most common opportunistic infection occurring as the initial AIDS-defining illness was PCP (31 percent). The most common opportunistic infection occurring as a secondary disease was cytomegalovirus (CMV) disease (40 percent), followed by disseminated Mycobacterium avium complex (33 percent) and invasive candidiasis (31 percent). Each of these latter infections was associated with a poor prognosis (median time to death < or = 8 months). CONCLUSIONS: Diseases caused by CMV, disseminated M. avium complex, and invasive candidiasis were uncommon presenting manifestations of AIDS but were common secondary diseases that tended to be associated with limited survival. With increasing survival and a declining incidence of PCP as a result of medical therapy, other severe opportunistic infections might become increasingly recognized.

Long-term suppression of recurrent genital herpes with acyclovir. A 5-year benchmark. Acyclovir Study Group.

BACKGROUND AND DESIGN: This multicenter trial (19 sites) was initiated in 1984 in more than 1100 immunocompetent individuals with a history of frequently recurring genital herpes (mean, > or = 12 episodes per year). The first year of this suppressive therapy trial was placebo controlled, with acyclovir being provided for episodic treatment in both groups. Thereafter, patients were treated with open-label acyclovir suppressive therapy on a long-term basis (400 mg twice daily) to continue to assess its long-term safety and efficacy. Complete data are available on 389 of the 430 patients who began the fifth year of the study. RESULTS: Patients were seen quarterly for review of diaries and clinical laboratory evaluations. The percentage of patients recurrence free for any 3-month quarter of the fifth year ranged from 86% to 90%. The mean annual number of recurrences per patient declined from 1.7 during the first year to 0.8 during the fifth year of suppressive therapy. The frequency of false prodromes has also decreased over time. More than 20% of the patients receiving suppressive therapy for 5 years have been recurrence free the entire time. The duration of herpetic outbreaks during suppressive therapy has not changed. CONCLUSION: This study extends the safety and efficacy profile of oral acyclovir in the suppression of genital herpes to 5 years. The majority of the patients were recurrence free on an annual basis during suppressive therapy. Therapy was well tolerated. Acyclovir usage was not associated with serious side effects or cumulative toxicity.

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 Kaposi's 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.

Continuous five-year treatment of patients with frequently recurring genital herpes simplex virus infection with acyclovir.

This study presents data relative to the efficacy and safety following the continuous use of oral acyclovir in the treatment of genital herpes over a 5-year period. In this study, 1,146 patients (53% males; 47% females) were originally enrolled. These included patients with a history of frequently recurring genital herpes (mean > 12 episodes per year). During the first year, patients were randomized between those receiving 400 mg of acyclovir twice daily and an equal number receiving placebo. Additionally, acyclovir was utilized for episodic treatment (ES) in both groups. Thereafter, patients received open-label acyclovir suppressive therapy for the remainder of the study period. Complete data are available on 389 patients who completed the fifth year of therapy. All the participants who completed the fifty year of the study had completed either 4 or 5 years of daily suppressive acyclovir therapy. During the first year, a significant decrease in the frequency of recurrences in patients receiving continuous acyclovir (SS) was noted as compared to the placebo group (1.7 vs. 12.5 recurrences; P < 0.0001). From year one to the end of year three, a progressive decrease in the frequency of recurrences was noted in both groups. Yet, those patients who had received SS for the full 3 years had significantly fewer recurrences than those who had received ES in the first year (P = 0.05). During years four and five, the decrease in frequency of recurrences between the ES and SS groups was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance of CD4+ cells by thymopentin in asymptomatic HIV-infected subjects: results of a double-blind, placebo-controlled study.

OBJECTIVE: To assess the efficacy and safety of thymopentin in HIV-infected patients who had not yet developed AIDS. DESIGN: Patients were stratified into asymptomatic or symptomatic groups and randomized to receive either thymopentin (50 mg) or placebo, subcutaneously, double-blind for 24 or 52 weeks, three times a week. SETTING: Patients were enrolled at three sites (two hospital clinics and one private practice). PATIENTS: Of 91 HIV-seropositive patients (52 asymptomatic and 39 symptomatic) from whom HIV could be isolated from peripheral blood, 45 were enrolled for 24 weeks and 46 for 52 weeks of double-blind evaluation. MAIN OUTCOME MEASURES: Virological, immunological and clinical evaluations were performed before and during treatment. RESULTS: Thymopentin-treated asymptomatic patients had more CD4+ cells, as demonstrated by a greater area under the percentage CD4+ cells curve (P = 0.03) and a shorter median time to a 20% increase in percentage of CD4+ cells (P = 0.04) in the first 24 weeks, with similar trends in the 52-week study. By 24 weeks no asymptomatic thymopentin-treated and two placebo-treated patients (9.1%, Kaplan-Meier estimate) had progressed to constitutional symptoms (P = 0.12; two-tailed Wilcoxon-Gehan test), with only one further progression in a placebo-treated patient in the subset followed for 52 weeks. Symptomatic patients receiving thymopentin or placebo were similar in both CD4+ cell levels and disease progression (two progressions to AIDS in each group). No serious adverse effects attributable to thymopentin were observed. CONCLUSIONS: These results, if confirmed, indicate that thymopentin, by maintaining CD4+ cells, could slow or arrest immune decline and consequent disease progression at the asymptomatic stage of HIV infection.