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Background: Percutaneous, mechanical closure of defects of the atrial septum fails to completely resolve shunting in up to 20% of cases. Little is known about the factors associated with device failure. Methods: We measured the left atrial opening (X), right atrial opening (Z), tunnel length (Y), septum secundum, device-septum primum separation, and tunnel compressibility of the patent foramen ovale (PFO) in 301 patients with cryptogenic neurological events, PFO anatomy, and severe Valsalva shunting (Spencer Grade 5–5+). All patients then underwent percutaneous closure with the GORE®HELEX Septal Occluder device and were evaluated at 3 months for residual shunt by transcranial Doppler (TCD). Results: Severe residual Valsalva shunt (TCD Grade 5–5+) was found at 3 months in 21 of 301 (7%) patients. X, Y, and Z were associated with failure with a high degree of statistical significance, whereas the width of the septum secundum, device-septum primum separation, and tunnel compressibility were not. An unanticipated finding was that 14 of 35 (40%) patients sized with a large balloon failed compared with 9 of 280 (3%) sized with a small balloon (P < 0.0001). In the multivariate logistic regression model, X (P = < 0.0001) and balloon size (P < 0.0001) were both strong predictors of failure. Conclusions: In an intracardiac echocardiography-defined PFO population, characterized by severe baseline Valsalva shunt and a high incidence of persistent (rest) shunting, association of six intracardiac measurements to closure device failure by multivariate logistic regression showed that the width of the left atrial opening was a strong predictor of residual shunting. An unanticipated finding was that use of a large sizing balloon was also strongly associated with failure. (J Interven Cardiol 2012;25:304–312)

Background: Ideally, percutaneous, mechanical closure of defects of the atrial septum should completely resolve shunt. To achieve this goal, more information is needed about the factors associated with device failure. Methods: Consecutive patients with cryptogenic neurological events who had severe baseline Valsalva shunt (Spencer Grade 5–5+) and intracardiac echocardiography (ICE) defined patent foramen ovale (PFO) who underwent percutaneous PFO closure with the GORE® HELEX Septal Occluder device were evaluated for residual 3-month shunt by transcranial Doppler (TCD). Results: We closed 315 PFO patients with the HELEX devices: 15, 20, 25, 30 mm devices in 19, 138, 150, and 8 patients, respectively. Severe residual Valsalva shunt (TCD Grade 5–5+) at 3 months occurred in 23 of 315 (7%) of all patients and in 2 of 108 (2%), 5 of 86(6%), and 16 of 121 (13%) patients with none, Grade 4, and Grade 5–5+ baseline rest shunt, respectively (P = 0.002). At 3 months, rest shunting was essentially abolished by closure. The percent of patients with severe residual Valsalva shunt was also related to device size: 15 mm (0%), 20 mm (4%), 25 mm (10%), and 30 mm (25%) (P = 0.008) and to atrial septal aneurysm. All of these variables were independent predictors of failure by multivariate logistic regression. Conclusions: In an ICE-defined PFO population characterized by severe baseline Valsalva shunt and a high incidence of persistent (rest) shunting, the GORE® HELEX Septal Occluder device effectively reduces both provoked and persistent shunt. The causes of device failure are multifactorial. Larger devices perform less reliably suggesting the need for size-specific modifications to improve closure of more severe defects. (J Interven Cardiol 2011;24:366–372)

There are substantial difficulties involved in carrying out clinical studies of recurrent herpes labialis, since the disease has a rapid onset, short-lasting viral shedding period and is rapidly self-healing. The aim of this paper was to critically assess published reports of episodic treatment of herpes labialis and to review biological and methodological problems involved in such studies. Limited, but statistically significant, results have been shown with topical antivirals, such as acyclovir and penciclovir, improving healing times by approximately 10%. Orally administrated antivirals, such as valaciclovir and famciclovir, have subsequently found clinical use. However, these two oral medications have different profiles in phase 3 studies. Famciclovir showed additional improvement of efficacy in terms of lesion healing time, but no effect on prevention of ulcerative lesions, while valaciclovir appeared to have similar efficacy to that of acyclovir cream on lesion healing, but some additional efficacy with respect to prevention of ulcerative lesions. A formulation of acyclovir/hydrocortisone showed further improvement in prevention of ulcerative lesions, while retaining efficacy with respect to lesion healing.

BACKGROUND Multiple studies of the use of acyclovir for the treatment of herpes labialis have suggested that the nominal efficacy of the topical formulation is the result of inadequate penetration of the drug into the target site of infection, the basal epidermis. METHODS We developed a low-voltage, wireless, hand-held, computer-controlled, iontophoretic applicator to enhance the skin penetration of topical acyclovir in the treatment of herpes labialis. We performed a multicenter, placebo-controlled, clinic-initiated, pilot trial of a single, topical, iontophoretic application of 5% acyclovir cream for the episodic treatment of herpes labialis among 200 patients with an incipient cold sore outbreak at the erythema or papular/edema lesion stage. RESULTS The median classic lesion healing time (aborted lesions were assigned a value of 0 h) was 1.5 days shorter for the active treatment group than for the vehicle group (113 h vs. 148 h; P = .02). In the subgroup of patients who presented with lesions in the erythema stage, the median classic lesion healing time was 3 days shorter for the acyclovir group, compared with the control group (49 h vs. 120 h; P < .03), and the acyclovir group tended to have more aborted lesions than did the control group (46% vs. 24%; P = .10). CONCLUSIONS Single-dose topical iontophoresis of acyclovir appears to be a convenient and effective treatment for cold sores and merits further clinical investigation.

Background. Imiquimod is currently approved for the treatment of genital warts and has been shown to decrease recurrences of genital herpes in the guinea pig model of genital herpes. Therefore, we evaluated the safety and potential of topical imiquimod to decrease the rate of recurrence in humans with a history of recurrent herpes labialis. Methods. Forty-seven subjects with recurrent herpes labialis applied imiquimod 5% ( ) or vehicle cream n p 30 ( ) to recurrent lesion(s) on days 1, 3, and 5 of the study (day 1 of observation occurred within 48 h after n p 17 recurrence of lesion). Subjects were seen at the study centers between each dose and 3 days after application of the final dose or until resolution of the lesion. Results. After application to recurrent lesions, local erythema, edema, scabbing and/or flaking, pain, burning, and maximal lesion size were significantly greater in the imiquimod group than in the vehicle group. The study was terminated early because of severe local adverse events that occurred in 5 recipients of imiquimod. The median time until the next recurrence was, however, increased from 50 days in the vehicle group to 91 days in the imiquimod group ( ). P p .018 Conclusions. Application of imiquimod 5% cream to herpes labialis lesions was associated with a delay in the time to the first recurrence after treatment, but severe local inflammation occurred in some individuals.

Time-to-event curves analyzed by Cox proportional hazards regression are commonly used to describe the outcome of drug studies. This methodology has the advantage of using all available information, including patients who fail to complete the trial, such as in cancer chemotherapy or human immunodeficiency virus antiviral treatment studies. The goal of treatment in such studies may be to prevent the development of a complication, for example, Pneumocystis carinii pneumonia, and to describe the likelihood of this complication's developing in the treatment group compared to the control group. The hazard ratio describes the relative risk of the complication based on comparison of event rates.

Valaciclovir (Valtrex) 2 g twice daily for 1 day was recently approved in the United States for treatment of cold sores. In order to apply more clinically relevant assumptions to the analysis, we examined the effect of differ- ent missing data and endpoint assumptions on apparent valaciclovir efficacy. Results of each analysis demonstrate statistically significant increases in the proportion of subjects whose cold sores were aborted with valaciclovir compared with placebo, and significant decreases in healing times for subjects with cold sore lesions who were treated with valaciclovir compared with placebo. These exploratory analyses provide evidence of the robustness of the results to differing missing data assumptions and show that use of more clinically relevant endpoint assumptions increases the magnitude of some therapeutic responses. We also introduce a new measure that combines the two observed drug effects (reduced lesion duration, increased aborted lesions) into a single endpoint that captures the global benefit of the drug to the patient.

Acyclovir cream has been available for the treatment of herpes labialis in numerous countries outside the United States for over a decade. Evidence for its efficacy comes from a few small clinical trials conducted in the 1980s. To examine more comprehensively the efficacy and safety of this formulation, we conducted two independent, identical, parallel, randomized, double-blind, vehicle-controlled, large-scale multicenter clinical trials. Healthy adults with a history of frequent herpes labialis were recruited from the general population, screened for eligibility, randomized equally to 5% acyclovir cream or vehicle control, given study medication, and told to self-initiate treatment five times daily for 4 days beginning within 1 h of the onset of a recurrent episode. The number of patients who treated a lesion was 686 in study 1 and 699 in study 2. In study 1, the mean duration of episodes was 4.3 days for patients treated with acyclovir cream and 4.8 days for those treated with the vehicle control (hazards ratio [HR] = 1.23; 95% confidence interval [CI], 1.06 to 1.44; P = 0.007). In study 2, the mean duration of episodes was 4.6 days for patients treated with acyclovir cream and 5.2 days for those treated with the vehicle control (HR = 1.24; 95% CI, 1.06 to 1.44; P = 0.006). Efficacy was apparent whether therapy was initiated “early” (prodrome or erythema lesion stage) or “late” (papule or vesicle stage). There was a statistically significant reduction in the duration of lesion pain in both studies. Acyclovir cream did not prevent the development of classical lesions (progression to vesicles, ulcers, and/or crusts). Adverse events were mild and infrequent.

Immunopathology is recognized as an important component of infectious disease manifestations, and corticosteroids have been used as an adjunct to antimicrobial therapy for a variety of conditions. Antiviral therapy of herpes labialis has been shown to result in only a small reduction in the time to healing and the duration of pain. To determine if topical application of a combination product containing 5% acyclovir and 1% hydrocortisone (ME-609) could provide benefit to herpes labialis patients, 380 immunocompetent adults with a history of herpes labialis were exposed to experimental UV radiation (UVR) to induce a recurrence. On day 2, just before the appearance of the majority of lesions (“delayed” lesions), subjects were randomized to receive active medication or vehicle control six times per day for 5 days. Overall, 120 of 380 patients developed delayed classical lesions, of whom 50 of 190 (26%) had been treated with ME-609 and 70 of 190 (37%) had received placebo (a reduction of 29% [ P = 0.02]). Healing time, measured as the time to normal skin, was reduced by treatment with ME-609 (9.0 days for treated patients versus 10.1 days for the controls [ P = 0.04]). There was a trend toward a reduction in the maximum lesion size in the ME-609 recipients compared to that in the controls (43 versus 60 mm 2 , respectively [ P = 0.07]). The treatment had no effect on lesion pain, but ME-609 treatment reduced the number of patients with moderate or severe tenderness. Compared to treatment with a placebo, treatment with the combination antiviral-immunomodulatory cream provided benefit to patients with experimental UVR-induced herpes labialis, reducing classical lesion incidence, healing time, lesion size, and lesion tenderness. ME-609 is a novel product that merits further evaluation as a treatment for cold sores.

Background Two randomized, double-blind, parallel-group clinical trials were conducted in Europe and North America to compare the efficacy and safety of topical 1 percent penciclovir cream with a placebo cream. Methods A total of 4,573 immunocompetent people with a history of recurrent herpes simplex labialis, or HSL, with three or more episodes a year that typically manifested as classical lesions, were enrolled and prospectively dispensed medication—either 1 percent penciclovir in a cetomacrogol cream base or a matching placebo. Patients self-initiated treatment and were required to apply study medication six times per day for the first day and every two hours while awake for four consecutive days. Results Of 4,573 enrolled patients, 3,057 initiated treatment (1,516 with penciclovir and 1,541 with placebo). Combined data from two trials revealed that penciclovir recipients lost classical lesions 31 percent faster than did placebo recipients (hazard ratio, or HR, = 1.31; 95 percent confidence interval, or CI, 1.20 to 1.42; P = .0001) and experienced 28 percent faster resolution of lesion pain (HR = 1.28; 95 percent CI, 1.17 to 1.39; P = .0001). Significant benefits were achieved with penciclovir use whether treatment was initiated in the early stages ( P = .001) or later stages ( P = .0055). Conclusions The largest data set currently available on the treatment of recurrent HSL revealed that penciclovir cream significantly outperformed the placebo in healing classical lesions and resolution of pain. Clinical Implications The authors found that penciclovir cream positively affects recurrent HSL, and dose frequency is vital to topical treatment. Even when penciclovir was applied late, it was effective in favorably altering the course of recurrent HSL.

Resiquimod, a Toll-like receptor 7 and 8 agonist, stimulates production of cytokines that promote an antigen-specific T helper type 1 acquired immune response. Animal and phase II human trials showed posttreatment efficacy in reducing recurrent herpes lesion days and/or time to first recurrence. Three phase III randomized, double-blind, vehicle-controlled trials of topical resiquimod to reduce anogenital herpes recurrences were conducted in healthy adults with ≥4 recurrences within the prior year. Participants applied resiquimod 0.01% gel or vehicle gel 2 times per week for 3 weeks to each recurrence for 12 months. Trials 1 and 2 had 2:1 resiquimod-vehicle randomization. Trial 3 had 1:1:1 randomization for resiquimod and 500 mg valacyclovir orally twice daily for 5 days (RESI-VAL), resiquimod and oral placebo (RESI-PLA), and vehicle and oral placebo (VEH-PLA). The median time to first recurrence was similar for resiquimod and vehicle (trial 1, 60 and 56 days, P = 0.7; trial 2, 54 and 48 days, P = 0.47; trial 3, 51 [RESI-VAL], 55 [RESI-PLA], and 44 [VEH-PLA] days, P = not significant [NS]). The median time to healing of initial treated recurrence was longer for resiquimod (trial 1, 18 compared to 10 days, P < 0.001; trial 2, 19 compared to 13 days, P = 0.16; trial 3, 14 [RESI-VAL], 16 [RESI-PLA], and 8 [VEH-PLA] days, P < 0.001). In trials 1 and 2, moderate to severe erythema and erosion/ulceration at the application site were more common in resiquimod recipients. In conclusion, no posttreatment efficacy of resiquimod 0.01% gel was observed. Increased application site reactions and initial recurrence healing time are consistent with resiquimod-induced cytokine effects.

Herpes simplex viruses (HSVs) can cause a variety of infections, including genital herpes. Despite effective antiviral therapy, HSV infections remain a significant worldwide public health problem. Vaccines offer the best hope for controlling spread and limiting HSV disease. This article discusses the pathogenesis and immunobiology of mucocutaneous HSV infections, summarizes the spectrum of diseases caused by HSV, and provides a review of the field of HSV vaccine research. This article also discusses what might be realistically expected of a vaccine intended for control of genital herpes and explores the question of whether a vaccine that is effective in controlling genital HSV disease might also be effective in controlling nongenital HSV disease. The efficacy of such vaccines for the full spectrum of HSV disease will eventually determine the timing and targeting of immunization, ranging from selective immunization in preadolescence to universal childhood immunization as part of the routine childhood regimen.

Three doses of famciclovir were tested for treatment of experimental ultraviolet radiation (UVR)-induced herpes labialis. Patients received 125, 250, or 500 mg of famciclovir or placebo 3 times a day for 5 days beginning 48 h after UVR exposure, a model of early episodic intervention. Of 248 patients irradiated, 102 developed lesions while on treatment. There were no significant differences between groups in the number of lesions. The mean maximal lesion size was reduced in a dose-proportional manner: 139, 105, 77, and 55 mm2 for the placebo and 125-, 250-, and 500-mg famciclovir groups, respectively (P=.040, linear regression). Median time to healing was faster in the 500-mg famciclovir group than in the placebo group, both by investigator (4 vs. 6 days, 33% reduction, P=.010) and patient assessment (3.0 vs. 5.8 days, 48% reduction, P=.008) analyses. These findings suggest that evaluation of higher drug doses for herpes labialis treatment is warranted.

Genital warts are a common sexually transmitted disease caused by human papillomavirus. Imiquimod is a novel immune-response modifier capable of inducing a variety of cytokines, including interferon alfa, tumor necrosis factor-alpha, as well as interleukins 1, 6, and 8. In animal models imiquimod has demonstrated antiviral, antitumor, and adjuvant activity. In vitro, imiquimod has no antiviral or antitumor activity.Our purpose was to determine the safety and efficacy of topical imiquimod for the treatment of external genital warts.This prospective double-blind, placebo-controlled, parallel design clinical trial was performed in three outpatient centers, a public health clinic, a university-based clinic, and a private practice. One hundred eight patients with external genital warts (predominantly white men) were entered into the trial. Fifty-one patients were randomly selected to receive 5% imiquimod cream; 57 patients were randomly chosen to receive placebo cream. Study medication was applied three times weekly for up to 8 weeks. Patients whose warts cleared completely were observed for up to 10 weeks to determine recurrence rates.In the intent-to-treat analysis, the warts of 37% (19 of 51) of the imiquimod-treated patients and 0% (0 of 57) of the placebo group cleared completely (p0.001). In addition, many patients experienced a partial response. A reduction in baseline wart area of 80% or more was observed in 62% of imiquimod-treated patients (28 of 45) and 4% of the placebo group (2 of 50) (p0.001); a 50% reduction or more in wart area was noted in 76% of imiquimod-treated patients (34 of 45) and 8% of placebo recipients (4 of 50) (p0.001). Of imiquimod-treated patients whose warts cleared completely and who finished the 10-week follow-up period, 19% (3 of 16) experienced recurrences of warts. Imiquimod-treated patients experienced a significantly greater number of local inflammatory reactions than the placebo group. Symptoms and signs associated with the local inflammatory reactions included itching (54.2%), erythema (33.3%), burning (31.3%), irritation (16.7%), tenderness (12.5%), ulceration (10.4%), erosion (10.4%), and pain (8.3%). There were no differences in systemic reactions or laboratory abnormalities between treatment groups.Topical 5% imiquimod cream appears to have a significant therapeutic effect in the treatment of external genital warts.

A topical 3% foscarnet cream formulation was evaluated for its ability to treat experimental UV radiation (UVR)-induced herpes labialis in a double-blind study. Healthy adult volunteers with a history of sunlight-induced herpes labialis were randomly assigned at four centers to receive either foscarnet cream (n = 152) or a vehicle control (n = 150). Following measurement of the minimal erythematous dose (MED), the subjects' lips were exposed to 4 MEDs of UV light. Subjects applied the cream on the UVR-exposed area approximately eight times daily beginning immediately after UVR exposure and continuing for 7 days, or until all lesions had a minimum of 4 days of treatment. There were no significant differences between groups in the percentages of subjects that developed any lesion, aborted lesions (did not progress beyond a papule), immediate lesions (developed within 48 h of UVR), or delayed classic lesions (developed 48 h to 7 days after UVR). Treatment with foscarnet significantly reduced the mean lesion area (49 versus 81 mm2; P = 0.01), the maximum lesion area (80 versus 141 mm2; P = 0.01), and the time to healing (P = 0.03) of the delayed classic lesions (n = 78). There was also a trend for a decrease in the mean duration of these lesions (156 versus 191 h; P = 0.08) and the duration of pain (3.9 versus 4.3 days; P = 0.06) in foscarnet-treated subjects. There were no clinically significant adverse reactions. These data suggest that topical foscarnet can be efficacious and deserves further evaluation for the treatment of herpes labialis.

To investigate potential immunologic mechanisms of resistance to recurrent herpes simplex labialis, we assayed serum antibody titers and cultured peripheral blood mononuclear cell (PBMC) cytokine production among patients with a history of frequent episodes (H+S+), herpes simplex virus (HSV)-seropositive individuals without a history of herpes labialis (H-S+) and HSV-seronegative persons (H-S-). In addition, H+S+ patients were exposed to experimental ultraviolet radiation (UVR) on the lips and the immunologic assay results compared among those who developed experimental lesions and those who did not. H+S+ patients were found to have higher median serum titers of HSV antibody and trends to lower levels of HSV-specific PBMC IFN-gamma and IL-2 than H-S+ control patients (123 vs 66, P = 0.04; 424 vs 548 pg/ml, P = 0.08; 14 vs 26 pg/ml, P = 0.14, respectively). Correlation of the results with the occurrence of experimental lesions showed the inverse: the subgroup of H+S+ patients with UVR-induced lesions had lower titers of antibody and trends to higher levels of IFN-gamma and IL-2 than H+S+ patients who could not be induced (93 vs 149, P = 0.02; 501 vs 347 pg/ml, P = NS; 26 vs 11 pg/ml, P = NS, respectively). The size and duration of UVR-induced lesions showed positive correlations with IFN-gamma and IL-2 levels (r = 0.60-0.67, P = 0.02-0.04). Although the small number of patients limited the power of this study, the overall pattern of the findings suggests that a Th1-like cytokine response (IFN-gamma and IL-2 production) may be associated with resistance to naturally occurring episodes of herpes labialis. The development and severity of experimental UVR-induced herpes labialis appears to be regulated differently and may involve an immunopathologic mechanism.

The naturally occurring polyphenolic biopolymer SP-303 has in vitro activity against both HSV-1 and HSV-2, including strains that are resistant to acyclovir. Nine AIDS patients with acyclovir-unresponsive mucocutaneous herpes simplex virus infection were treated with thrice daily topical SP-303T ointment in an open-label pilot study. Although a transient decrease in lesion size was observed in 4 patients during study drug therapy, and 3 patients sustained a quantitative decrease in virus burden, neither complete healing nor cessation of virus shedding occurred in any patient. Seven patients complained of pain or burning upon application of the study ointment, causing 1 patient to terminate the study. In summary, application of SP-303T ointment effected no significant improvement in the clinical course of 9 AIDS patients with acyclovir-unresponsive HSV infection.

The medical literature was reviewed and 11 clinical trials of prophylactic topical or peroral acyclovir for the suppression of recurrent herpes simplex labialis were identified. The results of these trials showed that prophylactic topical acyclovir was mostly ineffective, but that prophylactic peroral acyclovir, in doses ranging from 400 to 1,000 mg/day, reduced the frequency of herpes labialis during treatment by 50-78%. The reduction in the frequency of episodes of herpes labialis with acyclovir prophylaxis is less than the suppressive effect that has been reported for herpes genitalis (50-78% vs. 80-90%). In trials of prophylactic acyclovir for herpes labialis induced by experimental ultraviolet radiation, 26% of induced lesions developed within 48 hours of radiation exposure ("immediate" lesions) and, in contrast to "delayed" lesions that developed 2-7 days post-irradiation, were not suppressed by the antiviral compound. It is proposed that these treatment-unresponsive immediate lesions have an atypical pathogenesis, possibly involving latency of herpes simplex virus in the labial epithelium, and that these may be responsible for the apparent difference between herpes labialis and genitalis in the degree of benefit from prophylactic acyclovir therapy.

Prior pilot studies support the use of antiviral medications with topical corticosteroids for herpes simplex labialis (HSL). ME-609 (Xerese, Xerclear) is a combination of 5% acyclovir and 1% hydrocortisone developed for the topical treatment of HSL.The primary study end point was the prevention of ulcerative HSL lesions.In all, 2437 patients with a history of HSL were randomized to self-initiate treatment with ME-609, 5% acyclovir in ME-609 vehicle, or ME-609 vehicle (placebo) at the earliest sign of a cold sore recurrence. Cream was applied 5 times/d for 5 days. A total of 1443 patients experienced a recurrence and initiated treatment with ME-609 (n = 601), acyclovir (n = 610), or placebo (n = 232).Of patients receiving ME-609, 42% did not develop an ulcerative lesion compared with 35% of patients receiving acyclovir in ME-609 vehicle (P = .014) and 26% of patients receiving placebo (P.0001). In patients with ulcerative lesions, healing times were reduced in the ME-609 and acyclovir groups compared with placebo (P.01 for both). The cumulative lesion area for all lesions was reduced 50% in patients receiving ME-609 compared with the placebo group (P.0001). There were no differences among groups in the number of patients with positive herpes simplex virus cultures. The side-effect profile was similar among treatments.The study did not contain a group treated with a topical corticosteroid alone.ME-609 prevented progression of cold sores to ulcerative lesions and significantly reduced the cumulative lesion area compared with acyclovir and placebo. ME-609 treatment offers additional therapeutic benefit compared with therapy with topical acyclovir alone.

Background Treatment of herpes simplex labialis (HSL) has been associated with modest benefits. This difficulty results from the rapid resolution of the disease accomplished by the immune system, which narrows the window of therapeutic opportunity. The immune response is also responsible for important clinical manifestations, including oedema and pain. The dual role of immune responses (protection, pathology) is well recognized in other infectious diseases. The addition of corticosteroids to antimicrobial agents has been associated with improvement in some of these diseases. Objective We evaluated the combination of oral valacyclovir plus topical clobetasol compared to placebo for recurrent HSL. Methods Eighty-one subjects were screened, randomized, and dispensed medication (valacyclovir 2 g orally twice daily φορ 1 day and clobetasol gel 0.05% twice daily for 3 days). Forty-two patients developed a recurrence and initiated treatment. Results There were more aborted lesions in the valacyclovir–clobetasol arm compared to placebo–placebo (50% vs.15.8%, P = 0.04). Combination therapy reduced the mean maximum lesion size (9.7 vs. 54 mm2, P = 0.002) and the mean healing time of classical lesions (5.8 vs. 9.3 days, P = 0.002). We created a composite statistic, area-under-the-curve (AUC) of classical lesion size versus time. There was a reduction in the AUC in the combination arm compared with placebo (23 vs. 193 mm2, P

Topical antiviral chemotherapy has a number of potential advantages over systemic drug delivery for the treatment of cutaneous herpes simplex virus infections, including convenience; higher target tissue drug levels and greater efficacy; and specific targeting of the drug to the site of infection, with reduced cost and reduced exposure of the remainder of the body to drug side effects. Realization of these possibilities has been slow in part because of the paucity of ‘active’ topical drug formulations with effective penetration-enhancing agents and a technical barrier - our failure as yet to measure drug levels in the epidermis, which could guide formulation development. Recent success with a topical treatment for herpes simplex labialis should stimulate continued laboratory and clinical research in this field.

In a double-blind, randomized, patient-initiated clinical trial, 174 nonimmunocompromised patients with a history of virus-culture-confirmed herpes simplex labialis were treated with acyclovir capsules, 400 mg five times daily for 5 days, or placebo capsules. For 97% of the patients, treatment started within 1 h of the first sign or symptom of a recurrence. The frequency of positive lesion virus cultures was significantly lower among acyclovir-treated subjects (29/114, 25%) than among placebo-treated subjects (29/60, 48%; P = .004). Drug treatment did not affect the development of lesions, measured by the frequency of macular and papular (aborted) lesions and mean maximum lesion size. However, acyclovir hastened lesion resolution among the patients who could start treatment in the prodrome or erythema lesion stage. For this group, the mean duration of pain was reduced by 36% (P = .02) and the mean healing time to loss of crust by 27% (P = .03). Thus, oral acyclovir alleviated some of the clinical manifestations of herpes simplex labialis.

In a double-blind, randomized, patient-initiated treatment study at five medical centers, 301 immunocompetent patients experiencing a recurrence of herpes labialis were treated with topical 15% idoxuridine (IDU) in dimethyl sulfoxide (DMSO), 80% DMSO control solution, or 2% DMSO control solution. IDU did not prevent the development of lesions but significantly accelerated lesion resolution in comparison with the combined control groups. For the total population, the mean duration of pain was reduced by 1.3 days (35%, P = .01) and the mean healing time to loss of crust by 1.7 days (21%, P = .004). Analysis of subpopulations revealed that the beneficial activity of the treatment was concentrated among the patients who began treatment in the prodrome or erythema lesion stage. For these patients, the mean duration of pain was reduced by 1.8 days (42%, P = .08) and the mean healing time to loss of crust by 3.3 days (38%, P less than .001). If only patients with classic herpes lesions (vesicle, ulcer, or crust formation) were considered, there was a greater drug effect on the duration of pain (reduction by 2.6 days, 49%; P = .03) and the mean healing time to normal skin was significantly shortened (reduction by 2.3 days, 23%; P = .004). Adverse reactions to the medication were minimal.

Approximately 20% to 40% of the population experience recurrent herpes labialis caused by herpes simplex virus type 1 (HSV-1). Since there is no cure, patients typically use antiviral therapy to treat outbreaks as they occur. A large proportion of patients self-administer topical antiviral therapies at the onset of symptoms, but lack of efficacy, frequent dosing, and inconvenient long-term treatment regimens have made the use of oral antiviral therapies more common. Valacyclovir is currently the only oral antiviral approved for the treatment of herpes labialis in immunocompetent individuals. The pharmacokinetic/pharmacodynamic profile of famciclovir suggests that it could be utilized for episodic treatment for immunocompetent individuals as well.A recent study comparing single-dose vs. single-day bid famciclovir and placebo in the treatment of herpes labialis demonstrated single-dose famciclovir to be as efficacious as single-day bid dosing in time to healing of lesions and more efficacious than single-day bid famciclovir in time to resolution of pain and tenderness. Both were statistically superior to placebo. When results of this study were compared with recently published results of other frequently prescribed treatments, single-dose famciclovir appeared to produce similar or better improvements in healing time and duration of pain.Single-dose famciclovir appears to be an effective, convenient therapy for recurrent herpes labialis. The convenience of single-dose therapy may lead to better overall management of the condition.

Background The brief period of viral replication in recurrent herpes labialis lesions suggests shorter therapeutic regimens are a logical episodic treatment strategy. Objective We sought to assess the efficacy and safety of single-dose and single-day famciclovir treatments. Methods In all, 701 randomly assigned patients self-initiated therapy with famciclovir (1500 mg once [single dose] or 750 mg twice a day for 1 day [single day]) or placebo within 1 hour of onset of the prodromal symptoms of an episode of herpes labialis. Lesion healing was monitored by diaries and frequent clinic visits. Results Median healing times of primary (first to appear) vesicular lesions in the famciclovir single-dose, famciclovir single-day, and placebo groups were 4.4, 4.0, and 6.2 days, respectively. There was no significant difference between the famciclovir regimens. Adverse events in the famciclovir groups were similar to placebo. Limitations The active arms of this trial were not directly compared to other antiviral regimens. Conclusion Single-dose famciclovir reduced time to healing of herpes labialis lesions by approximately 2 days compared with placebo.

A number of important risk factors for the acquisition of HSV-2 have been established including female gender, black or Hispanic ethnic origin, HIV infection, age, and increased number of sexual partners. Transmission is influenced by a number of biological factors such as sexual behavior, use of condoms, duration of relationships, and knowledge of a partner's serologic status. Vertical transmission (transmission of HSV from mother to neonate) is potentially life-threatening; neonatal HSV infection is associated with significant morbidity and mortality. The valaciclovir transmission study provides evidence that an antiviral agent can interrupt the transmission of a viral sexually transmitted disease between serologically discordant sexual partners. This review explores the importance of the cofactors that affect transmission, and makes recommendations on considerations for the prophylactic use of antiviral agents for the prevention of transmission in other patient populations.

Oral valacyclovir is better absorbed than oral acyclovir, increasing acyclovir bioavailability three- to fivefold. This provides the opportunity to explore whether high systemic acyclovir concentrations are effective in the treatment of cold sores (herpes labialis). Two randomized, double-blind, placebo-controlled studies were conducted. Subjects were provided with 2 g of valacyclovir twice daily for 1 day (1-day treatment), 2 g of valacyclovir twice daily for 1 day and then 1 g of valacyclovir twice daily for 1 day (2-day treatment), or a matching placebo and instructed to initiate treatment upon the first symptoms of a cold sore. In study 1, the median duration of the episode (primary endpoint) was reduced by 1.0 day ( P = 0.001) with 1-day treatment and 0.5 days ( P = 0.009) with 2-day treatment compared to placebo. Similarly, the mean duration of the episode was statistically significantly reduced by 1.1 days with 1-day treatment and 0.7 days with 2-day treatment compared to placebo. The proportion of subjects in whom cold sore lesion development was prevented and/or blocked was increased by 6.4% ( P = 0.096) with 1-day treatment and 8.5% ( P = 0.061) with 2-day treatment compared to placebo. The time to lesion healing and time to cessation of pain and/or discomfort were statistically significantly reduced with valacyclovir compared to placebo. In study 2, results similar to those in study 1 were obtained. AEs were similar across treatment groups. These studies provide evidence supporting a simple, 1-day valacyclovir treatment regimen for cold sores that is safe and effective. The 1-day valacyclovir regimen offers patients a unique and convenient dosing alternative compared to available topical therapies.

An effective prophylactic vaccine would help control the spread of genital herpes.We conducted two double-blind, randomized trials of a herpes simplex virus type 2 (HSV-2) glycoprotein-D-subunit vaccine with alum and 3-O-deacylated-monophosphoryl lipid A in subjects whose regular sexual partners had a history of genital herpes. In Study 1, subjects were seronegative for herpes simplex virus type 1 (HSV-1) and HSV-2; in Study 2, subjects were of any HSV serologic status. At months 0, 1, and 6, subjects received either vaccine or a control injection and were evaluated for 19 months. The primary end point was the occurrence of genital herpes disease in all subjects in Study 1 and in HSV-2-seronegative female subjects in Study 2.A total of 847 subjects who were seronegative for both HSV-1 and HSV-2 (268 of them women, in Study 1) and 1867 subjects who were seronegative for HSV-2 (710 of them women, in Study 2) underwent randomization and received injections. Vaccination was well tolerated and elicited humoral and cellular responses. Overall, the efficacy of the vaccine was 38 percent in Study 1 (95 percent confidence interval, -18 to 68 percent; 15 cases occurred in the vaccine group and 24 in the control group), and efficacy in female subjects was 42 percent in Study 2 (95 percent confidence interval, -31 to 74 percent; 9 cases occurred in the vaccine group and 16 in the control group). In both studies, further analysis showed that the vaccine was efficacious in women who were seronegative for both HSV-1 and HSV-2: efficacy in Study 1 was 73 percent (95 percent confidence interval, 19 to 91 percent; P=0.01), and efficacy in Study 2 was 74 percent (95 percent confidence interval, 9 to 93 percent; P=0.02). It was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at base line or in men.These studies suggest that the glycoprotein D vaccine has efficacy against genital herpes in women who are seronegative for both HSV-1 and HSV-2 at base line but not in those who are seropositive for HSV-1 and seronegative for HSV-2. It had no efficacy in men, regardless of their HSV serologic status.

There are 3 new topical treatments for herpes labialis that have either been approved by the US Food and Drug Administration (penciclovir cream [Denavir] and n-docosanol cream [Abreva]) or recently undergone extensive clinical evaluation (acyclovir cream). The relative efficacy of these products is unknown.To compare the efficacy of penciclovir cream, acyclovir cream, n-docosanol cream, and acyclovir ointment in an experimental animal model of cutaneous herpes simplex virus type 1 (HSV-1) disease.The backs of guinea pigs were infected with HSV-1 using a vaccination instrument. Active treatments and corresponding vehicle controls were applied for 3 to 5 days beginning 24 hours after inoculation.After completion of treatment, the animals were killed and the severity of the infection assessed from the number of lesions, the total lesion area, and the lesion virus titer.Penciclovir cream effected modest reductions in lesion number (19%), area (38%), and virus titer (88%) compared with its vehicle control, and each of these differences was significantly greater (P.05) than the reductions effected by acyclovir ointment (0%, 21%, and 75%, respectively). The acyclovir cream effect (reductions of 4%, 28%, and 77%, respectively) was less than that of penciclovir cream, and this difference was confirmed by 2 additional head-to-head experiments. Two experiments with n-docosanol cream failed to show statistically significant differences by any parameter between n-docasonol cream and vehicle control-treated sites or between n-docosanol and untreated infection sites.In this model, the efficacy of penciclovir cream was greater than acyclovir cream, acyclovir cream was greater than or equal to acyclovir ointment, and acyclovir ointment was greater than n-docosanol cream. Since our model was designed to evaluate compounds that function primarily through antiviral activity, the negative findings with n-docosanol in these studies do not exclude that it might work clinically through other mechanisms.

Resiquimod (R-848), a topically active immune response modifier, induced production of interferon-a and interleukin-12 in cultured blood mononuclear cells and decreased genital herpes recurrences in an animal model. In this study, 52 patients with frequently recurrent genital herpes applied topical resiquimod gel 0.01% (twice or thrice weekly) or 0.05% (once or twice weekly) or vehicle gel to herpes lesions for 3 weeks. During the 6-month observation period after treatment, median days to first recurrence in the pooled resiquimod group was 169 days, compared with 57 days for the vehicle group (P = .0058). In all, 32% of resiquimod-treated patients completed the observation period without a recurrence, compared with 6% of vehicle-treated patients (P = .039). Resiquimod 0.05% twice weekly produced dose-limiting inflammation at the lesion sites, but the other regimens were well tolerated. Application of resiquimod to genital herpes lesions appeared to reduce the frequency of recurrences.

To investigate the efficacy of corticosteroids for the treatment of herpes labialis, we compared famciclovir (Famvir, 500 mg 33/day po [per os] for 5 days) and topical fluocinonide (0.05% Lidex Gel 33/day for 5 days) with famciclovir and topical vehicle control for experimental ultraviolet radiation‐induced herpetic recurrences. We irradiated 49 volunteers, and 29 (60%) of 48 developed signs or symptoms of a recurrence. They self-initiated treatment, and we were able to evaluate them. There was a trend in the combination group toward more aborted lesions, compared with those who received antiviral therapy alone (7 [41%] of 17 vs. 1 [8%] of 12; ). Combination therapy significantly reduced the median maximum lesion P= .09 size (48 vs. 162 mm 2 ; ) and the number of patients who experienced lesion pain (10 P= .02 [59%] of 17 vs. 12 [100%] of 12; ). Adverse events were minimal. Corticosteroids in P= .02 combination with an antiviral agent may be safe and beneficial for episodic treatment of herpes labialis. Larger studies are needed to confirm these findings.

Publisher Summary This chapter presents a guinea pig model of herpes skin infection. The animals used in this model are female Hartley outbred albino guinea pigs, of 500 g each. Each of them are injected with about 0.24 ml of 50 mg ketamine/ml plus 10 mg xylazine/ml, subcutaneous (s.c.), high on the back between the shoulder blades, by using a tuberculin syringe with a 25 G 5/8 in needle. After 5–10 minutes, the animals are sedated. The dorsal skin of the anesthetized animals are infected with HSV-1 in four quadrants with 10 well-spaced activations of a vaccination instrument in each quadrant. Ideally, the infection in each quadrant develops over the course of four days into 10 small, well-spaced circles of six lesions in each circle for a total of 60 lesions per area. The virus is harvested from the skin and the amount present is determined in a plaque assay. The clinical parameters for each drug versus placebo pair are total lesion number, total lesion area, and virus titer. Histology of a cutaneous HSV-1 lesion, 72 hours after inoculation of the skin, shows that the infection primarily involves the epidermal layer in the skin with focal epidermal destruction, leukocytic infiltration of the epidermis and adjacent dermis, and cytologic changes in infected epidermal cells typical for HSV. The infection is confined to the skin of the animal's back. Food and water intake are normal and general health is maintained. Any lethargy or abnormal behavior on the part of a guinea pig is usually associated with an overdose of or reaction to anesthesia rather than systemic infection.

A meta-analysis of 8 randomized trials (1792 patients, 2947 patient-years of follow-up) showed that acyclovir (or = 3200 mg/day) offered a significant survival benefit (P = .006 by log-rank test) in human immunodeficiency virus (HIV) infection. The treatment effect did not vary significantly in patient subgroups of different CD4 cell counts, hemoglobin levels, age, race, and sex, and with or without AIDS diagnosis. Acyclovir treatment (hazard ratio, 0.78; 95% confidence interval [CI], 0.65-0.93), higher CD4 cell count (P.001), higher hemoglobin level (P.001), and younger age (P.001) reduced the hazard of mortality. Acyclovir decreased herpes simplex virus infections (odds ratio [OR], 0.28; 95% CI, 0.21-0.37) and varicella-zoster virus infections (OR, 0.29; 95% CI, 0.13-0.63) but not cytomegalovirus disease or mortality from lymphoma or Kaposi's sarcoma. A survival advantage was seen specifically in studies with high incidence of clinical herpesvirus infections (or = 25% per year). Given the wide confidence intervals, the small effect in low-risk patients, and recent changes in HIV therapeutics, the results should be interpreted cautiously, but the meta-analysis supports the importance of pathogenetic interactions between herpesviruses and HIV.

Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Imiquimod is a new agent, an immune-response modifier, that has been demonstrated to have potent in vivo antiviral and antitumor effects in animal models. The present prospective, multicenter, double-blind, randomized, vehicle-controlled trial evaluated the efficacy and safety of daily patient-applied imiquimod for up to 16 weeks for the treatment of external genital warts. Wart recurrence was investigated during a 12-week treatment-free follow-up period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94 (52%) patients treated with 5% imiquimod cream, 13 of 90 (14%) patients treated with 1% imiquimod cream, and 3 of 95 (4%) vehicle-treated patients; the differences between the groups treated with vehicle and imiquimod were significant ( P < 0.0001). For subjects who completed the follow-up period, recurrence rates after a complete response were 19% (9 of 48 patients) in the 5% imiquimod cream group, 17% (2 of 12) in the 1% imiquimod cream group, and 0% (0 of 3) in the vehicle-treated group. There were no systemic reactions, although local skin reactions (generally of mild or moderate severity) were common, particularly in the 5% imiquimod cream group. Local reactions caused two patients to discontinue treatment. The most frequently reported local skin reactions were erythema, excoriation or flaking, and erosion. Patient-applied 5% imiquimod cream is effective for the treatment of external genital warts and has a favorable safety profile.

Carrie A Sailer1, Spotswood L Spruance2, Christopher M Hull11Department of Dermatology, 2Department of Medicine, Division of Infectious Diseases, University of Utah, Salt Lake City, USAAbstract: Current antiviral therapies for herpes simplex labialis primarily reduce healing time. Since the host immune response also plays a role in both controlling recurrent infection as well as producing clinical symptoms, new studies are showing efficacy using topical corticosteroids. This review will evaluate the safety and efficacy of 5% acyclovir–1% hydrocortisone cream (Xerese™[US], Xerclear®[Europe]) for treatment of patients with herpes simplex labialis. A large, randomized, double-blind, placebo-controlled study recently demonstrated that treatment with 5% acyclovir–1% hydrocortisone cream significantly decreased the percentage of ulcerative lesions, reduced lesion healing time, and decreased mean lesion area compared with both topical acyclovir alone and vehicle.Keywords: herpes labialis, herpes simplex virus, HSV, acyclovir, hydrocortisone, ME-609, Xerese, Xerclear

Women with culture-proven Chlamydia trachomatis cervical infection were randomized to receive either ofloxacin (300 mg) or doxycycline (100 mg), orally twice daily for 7 days. All 56 had negative cultures 5 to 9 days after treatment. Four weeks after treatment, 26 (93%) of 28 ofloxacin-treated patients and all 22 doxycycline-treated patients were cured. We conclude that 300 mg of ofloxacin given twice daily for 7 days provides effective therapy for chlamydial infection of the cervix.

Objective To compare valacyclovir hydrochloride with acyclovir in the treatment of recurrent genital herpes infection. Design A multicenter, double-blind, placebo-controlled, randomized, parallel-design study. Setting University clinics (dermatology, gynecology, and infectious diseases) and private practices. Patients One thousand two hundred patients with recurrent genital herpes simplex infections. Interventions Patients self-initiated oral therapy with 1000 mg of valacyclovir hydrochloride twice daily, 200 mg of acyclovir 5 times daily, or placebo for 5 days. Main Outcome Measures Resolution of all signs and symptoms of recurrent genital herpes infection. Results Both drugs were significantly more effective than placebo in speeding resolution of herpetic episodes (median duration, 4.8, 4.8, and 5.9 days, respectively); the hazards ratios for valacyclovir and acyclovir vs placebo were 1.66 (95% confidence interval [CI], 1.38-2.01) and 1.71 (95% CI, 1.41-2.06) (both P P Conclusions Twice-daily valacyclovir was as effective and well tolerated in the treatment of recurrent genital herpes simplex virus infection as 5-times-daily acyclovir. Therefore, valacyclovir could prove a useful alternative to acyclovir when convenience of dosing or compliance issues are the prime considerations in treatment.

Background: Stavudine is a promising antiretroviral agent, but its clinical efficacy has not been determined. Objective: To evaluate the clinical effect of stavudine (2',3'-didehydro-3'-deoxythymidine) monotherapy in patients with human immunodeficiency virus (HIV) infection. Design: Randomized, controlled, double-blind trial. Setting: 56 outpatient clinics in private practices, universities, and contract research organizations in the United States, France, and Italy. Patients: 822 HIV-infected adults who had 50 to 500 CD4 + cell/mm 3 and had previously received at least 6 months of zidovudine treatment. Intervention: Monotherapy with peroral stavudine capsules or peroral zidovudine capsules. Measurements: The primary end point was clinical progression, which was defined as all occurrences of acquired immunodeficiency syndrome (AIDS)-defining events or death. Results: Patients receiving stavudine reached clinical end points at a rate of 26 per 100 person-years, compared with 32 per 100 person-years for patients receiving zidovudine (relative risk, 0.75 [95% Cl, 0.58 to 0.98]; P = 0.03). The risk for death alone was 26% lower in the stavudine group than in the zidovudine group, but the comparison was not statistically significant (relative risk, 0.74 [Cl, 0.53 to 1.02]; P = 0.066). The benefit of stavudine therapy was seen in all CD4 + cell strata (≤100 cells/mm 3 , 101 to 300 cells/mm 3 , and >300 cells/mm 3 ) and clinical stages of HIV disease (asymptomatic, symptomatic, and AIDS). Four weeks after treatment began, CD4 + cell counts were 30 cells/mm 3 higher in the stavudine group than in the zidovudine group; this difference was sustained for 96 weeks (P < 0.001). Nausea and vomiting were more common in patients receiving zidovudine (P < 0.01), and neuropathy occurred more frequently in those receiving stavudine (12% in the stavudine group compared with 4% in the zidovudine group; P < 0.001). Neuropathy resolved completely in many patients (63%) after interruption of stavudine treatment; these patients could resume stavudine therapy at a lower dose. Conclusions: Stavudine was well tolerated and delayed progression of HIV disease in patients who had previously received 6 or more months of zidovudine treatment. Benefits were apparent in all CD4 + cell strata and clinical stages of HIV disease. Stavudine is an important agent to consider for trials of combination chemotherapy.

Background: Valaciclovir, the 1-valyl ester of acyclovir, has provided a peroral acyclovir bioavailability 3 to 5 times that of acyclovir itself and is rapidly and completely converted to acyclovir by the liver. Accordingly, valaciclovir has the same antiviral activity as acyclovir, but the potential for enhanced clinical activity and/or less frequent administration because of its superior pharmacokinetics. Methods: We conducted a double-blind, placebo-controlled, patient-initiated clinical trial of peroral valaciclovir, 500 or 1000 mg, or matching placebo tablets twice daily for 5 days for the acute treatment of 1 episode of recurrent herpes genitalis among 987 otherwise healthy volunteers. Results: Both doses of valaciclovir were equally effective. Patients receiving the lower dose of valaciclovir experienced a median episode length of 4.0 days compared with 5.9 days for those receiving placebo treatment (hazard ratio, 1.9; 95% confidence interval [CI], 1.6-2.3). Valaciclovir therapy increased the proportion of patients in whom the development of vesicular and ulcer-ative lesions was prevented in comparison with placebo treatment: 31% vs 21% (relative risk, 1.5; 95% CI, 1.1-1.9). Valaciclovir therapy accelerated the resolution of pain (hazard ratio, 1.8; 95% CI, 1.5-2.1) and the time to cessation of viral shedding (hazard ratio, 2.9; 95% CI, 2.1-3.9). Adverse reactions among the valaciclovir groups were comparable with those of the placebo group. Conclusions: Valaciclovir therapy provided a clinically significant benefit to patients that included shortening of the duration of lesions, the duration of pain or discomfort, and the duration of virus shedding. In addition, this study, to our knowledge, provides the first convincing demonstration that antiviral therapy can prevent lesion development. These results should prompt a reconsideration of the role that episodic treatment plays in the management of recurrent herpes genitalis. Arch Intern Med. 1996;156:1729-1735

OBJECTIVE To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. DESIGN Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. SETTING Outpatient clinics at 19 tertiary care medical centers. PATIENTS 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. INTERVENTION Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). MEASUREMENTS Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)--defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. RESULTS Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% Cl, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; Cl, 1.1 to 4.4). CONCLUSIONS This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.

OBJECTIVE To assess the effect of recombinant human erythropoietin (r-HuEPO) on anemia in patients with the acquired immunodeficiency syndrome (AIDS) who are receiving zidovudine therapy. DESIGN Combined analysis of four 12-week, randomized, double-blind, controlled clinical trials. SETTING Multiple centers in the United States. PATIENTS Two hundred and ninety-seven anemic (hematocrit < 30%) patients with AIDS who were receiving zidovudine therapy. Of the 297 patients, 255 were evaluable for efficacy, but all patients were included in analysis of safety. INTERVENTION Patients were randomly assigned to receive either r-HuEPO (100 to 200 U/kg body weight) or placebo, intravenously or subcutaneously, three times per week for up to 12 weeks. MEASUREMENTS Changes in mean hematocrit, transfusion requirement, and quality of life. RESULTS Sixty-nine percent of patients had endogenous serum erythropoietin levels less than or equal to 500 IU/L, and 31% had erythropoietin levels greater than 500 IU/L. In patients with low erythropoietin levels (< or equal to 500 IU/l), r-HuEPO therapy decreased the mean number of units of blood transfused per patient when compared with placebo (3.2 units and 5.3 units, respectively; P = 0.003) and increased the mean hematocrit from the baseline level (4.6 percentage points and 0.5 percentage points, respectively; P