The efficacy and tolerance of zidovudine (250 mg six-hourly) alone or in combination with acyclov... more The efficacy and tolerance of zidovudine (250 mg six-hourly) alone or in combination with acyclovir (800 mg six-hourly) as maintenance therapy was studied in a double-blind, placebo-controlled trial in 397 patients. One hundred and thirty patients with acquired immune deficiency syndrome (AIDS) post-opportunistic infection (post-OI) were randomised to either therapy and have been followed up for one year. Two hundred AIDS-related complex (ARC) patients and 67 AIDS patients with Kaposi's sarcoma (KS) were also randomised to placebo for the initial 24 weeks and data for the first 6 months are available so far. Patients in the ARC and KS groups who developed opportunistic infections could be removed from the study and given open label zidovudine.
Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromi... more Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromised hosts. The pain associated with herpes zoster is the most debilitating complication of the disease. It can be described as acute pain and post-herpetic neuralgia or zoster associated pain (ZAP). The latter definition encompasses pain from the onset of disease through its resolution and provides a convenient analytic tool for evaluation of antiviral therapy. A heuristic examination of ZAP historical data suggests the existence of three phases of pain resolution: the acute, subacute and chronic phases. The subacute and chronic phases comprise the post-herpetic neuralgia (PHN) stage. Common analytic methods, such as a Kaplan-Meier survival function or a Cox's model, have been used to assess the pain. However, such approaches do not adequately allow for phase comparison. Notably, in the clinical trial setting the comparison of specific treatment effects on the latter stages of pain are of the greatest medical relevance since this is the most debilitating phase of the illness. In order to incorporate the phase-specific information in the modelling of time to cessation of ZAP, we assumed the hazard function was a stepwise constant. Utilizing the full likelihood function, we obtained the maximum likelihood estimate for the transition times (that is, change-points), and other parameters of medical importance. The standard error of the change-point estimates were obtained through a bootstrapping method. The asymptotic properties of the parameter estimates are also discussed. Hence, the rates of pain resolution across all phases can be examined in order to precisely define the existence of multiple phases. In addition, the covariates effect can be examined across phases and populations, thereby allowing us to translate potential efficacy of a standard therapy to different populations. These results can be utilized in the design of clinical trials or in targeting the outcome for a specific phase while controlling for the effect of other variables.
Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromi... more Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromised hosts. The pain associated with herpes zoster is the most debilitating complication of the disease. It can be described as acute pain and post-herpetic neuralgia or zoster associated pain (ZAP). The latter definition encompasses pain from the onset of disease through its resolution and provides a convenient analytic tool for evaluation of antiviral therapy. A heuristic examination of ZAP historical data suggests the existence of three phases of pain resolution: the acute, subacute and chronic phases. The subacute and chronic phases comprise the post-herpetic neuralgia (PHN) stage. Common analytic methods, such as a Kaplan-Meier survival function or a Cox's model, have been used to assess the pain. However, such approaches do not adequately allow for phase comparison. Notably, in the clinical trial setting the comparison of specific treatment effects on the latter stages of pain are of the greatest medical relevance since this is the most debilitating phase of the illness. In order to incorporate the phase-specific information in the modelling of time to cessation of ZAP, we assumed the hazard function was a stepwise constant. Utilizing the full likelihood function, we obtained the maximum likelihood estimate for the transition times (that is, change-points), and other parameters of medical importance. The standard error of the change-point estimates were obtained through a bootstrapping method. The asymptotic properties of the parameter estimates are also discussed. Hence, the rates of pain resolution across all phases can be examined in order to precisely define the existence of multiple phases. In addition, the covariates effect can be examined across phases and populations, thereby allowing us to translate potential efficacy of a standard therapy to different populations. These results can be utilized in the design of clinical trials or in targeting the outcome for a specific phase while controlling for the effect of other variables.
Pain is the most frequent and disabling complication of herpes zoster. The analysis of pain sever... more Pain is the most frequent and disabling complication of herpes zoster. The analysis of pain severity data is complicated by the nonlinear rate of resolution. Further, three distinct phases characterize pain resolution-acute, subacute, and chronic. Using two clinical trial datasets as the bases for analyses, the rates of baseline pain resolution were computed across each of three phases and compared for age, severity of pain at onset, and number of lesions at baseline. The results defined transition points of 24.4 Ϯ 3.34 for the subacute phase and 110.3 Ϯ 11.9 days for the chronic phase. The model demonstrated a treatment effect of valiciclovir (VACV) during the subacute phase as compared to acyclovir (ACV) ( P ϭ 0.006) and supports effects of age, baseline pain and number lesions on pain cessation rates in the acute phase. This model verifies three phases of zoster pain and delineates the impact of treatment and other factors on the phase-specific rates of pain cessation.
In 1994, an international group of interested clinicians and biostatisticians met to discuss the ... more In 1994, an international group of interested clinicians and biostatisticians met to discuss the design of clinical trials in herpes zoster. They agreed that trials in herpes zoster should have prospectively agreed definitions of all outcome measures and plans for data analysis. In immunocompetent individuals, in whom pain is the major outcome measure, trials should only include patients over the age of 50 years, and for those recruited within 72 h of rash onset, should be designed to demonstrate superiority of any new therapy over existing antivirals. The primary endpoint should be time to cessation of pain for at least 4 weeks and, for the purposes of statistical analysis of its duration, the pain associated with herpes zoster ought to be considered as a continuum. All other variables, including the incidence of post-herpetic neuralgia and effects upon quality of life should be considered as secondary end-points. Evaluation of treatment effects on primary endpoints should be based upon an intent-totreat (ITT) analysis and subgroup analysis should be used only to support the findings of the ITT analysis. These elements of good study design should be borne in mind in the evaluation of current and future trails of antiviral drugs in herpes zoster.
Forty-one strains of Bacteroides fragilis, 20 strains of other Bacteroides species and 14 strains... more Forty-one strains of Bacteroides fragilis, 20 strains of other Bacteroides species and 14 strains of other genera were examined by the indirect immunofluorescent assay (IFA) using anticapsular serum. The sixty-one Bacteroides strains were 'O' serotyped by direct agglutination tests using absorbed antisera raised against 23 strains, each with a different 'O' antigenic determinant. All 41 B. fragilis strains tested were positive by IFA with the anticapsular serum, but apart from one strain of B. distasonis, none of the remaining 19 strains of other bacteroides, i.e. B. thetaiotaomicron, B. distasonis, B. vulgatus, B. ovatus, B. melaninogenicus group and B. ureolyticus, and none of the 14 other bacterial species examined were positive. The majority of strains of saccharolytic bacteroides tested reacted with one of the 23 'O' antisera and were designated as a specific 'O' serotype; a few Bacteroides strains had multiple agglutination reactions indicating the presence of multiple antigenic determinants. All 'O' serotypes gave positive IFA tests with their homologous 'O' antisera. Common capsular determinants and 'O' antigenic determinants appear to exist on the same strains of B. fragilis. Serological typing of B. fragilis and related species would be useful in epidemiological studies.
A double-blind, randomised trial of acyclovir versus placebo was conducted in 31 patients with in... more A double-blind, randomised trial of acyclovir versus placebo was conducted in 31 patients with initial and 85 patients with recurrent genital herpes. 17 patients with initial and 42 with recurrent disease were treated with 200 mg acyclovir by mouth five times a day for 5 days, and the remaining patients received matching placebo. In patients with initial genital herpes shedding virus acyclovir significantly reduced the duration of viral shedding, itching, and pain, the time to crusting and complete healing, and new lesion formation compared with controls. In patients with recurrence disease acyclovir significantly reduced the duration of viral shedding, time to complete healing, and new lesion formation. The reported incidence of adverse events was similar in both acyclovir and placebo groups. Oral acyclovir is effective and well tolerated in patients with initial and recurrent genital herpes and can be used in outpatient therapy.
A double-blind, randomized, placebo-controlled trial of 5% acyclovir ointment was carried out for... more A double-blind, randomized, placebo-controlled trial of 5% acyclovir ointment was carried out for thirty-one episodes of herpes labialis in thirteen patients experiencing severe, frequent recurrences. In addition, these patients continued to use acyclovir ointment or placebo for the treatment of twenty-two further episodes. Treatment was initiated by the patients as soon as possible after onset of prodromal symptoms, and continued five times a day for 5 days. It was found that acyclovir ointment shortened the duration of lesions only by about one day, but it greatly increased the number of abortive lesions resulting from early application. Acyclovir ointment is well tolerated and appears to modify the course of severe recurrent herpes labialis when therapy is initiated by the patient during the prodrome.
Immunocompromised patients are at high risk of developing herpes simplex virus infections caused ... more Immunocompromised patients are at high risk of developing herpes simplex virus infections caused by reactivation of the virus. Intravenous and oral formulations of acyclovir have been shown to prevent most of these infections during the major at-risk periods when given prophylactically. Immunocompetent patients may also experience reactivation of herpes simplex virus leading most often to recurrent genital or labial infections. For those patients who experience frequent attacks, oral acyclovir can prevent most recurrences and is well tolerated when given as continuous suppressive therapy. Bei Patienten mit beeinträchtigter Immunität besteht ein hohes Risiko für Herpes simplex Virus-Infektionen durch Reaktivierung des Virus. Es hat sich gezeigt, daß durch prophylaktische Gabe der intravenösen oder oralen Zubereitungsform von Aciclovir die meisten dieser Infektionen während der Phasen des größten Risikos verhütet werden können. Bei immunkompetenten Patienten treten ebenfalls durch Reaktivierung des Herpes simplex Virus Infektionen auf, die sich am häufigsten als rezidivierender Herpes genitalis oder labialis manifestieren. Bei Patienten, die sehr häufig Herpes-Schübe durchmachen, kann durch eine kontinuierliche orale Suppressionstherapie mit Aciclovir das Auftreten von Rezidiven weitgehend verhindert werden.
Eighteen asymptomatic men with persistent human immunodeficiency virus type 1 (HIV-1) p24 antigen... more Eighteen asymptomatic men with persistent human immunodeficiency virus type 1 (HIV-1) p24 antigenemia were treated with zidovudine 250-500 mg (+/- acyclovir 800 mg) 6-hourly for 4-12 weeks, and thereafter with zidovudine 500 mg (+/- acyclovir 1600 mg) 12-hourly for 92 weeks. Six additional HIV-1 p24 antigenemic subjects were treated with zidovudine 500 mg 12-hourly for 76 weeks. Disease progression occurred in 4 subjects, despite sustained reduction of serum HIV-1 p24 antigen levels: Pneumocystis carinii pneumonia was diagnosed after 60, 80, 90 and 93 weeks, respectively. The median CD4+ cell count of these 4 men at study entry was 0.2 x 10(9)/l, and it declined to 0.07 x 10(9)/l at the moment AIDS was diagnosed. In 20 subjects no disease progression occurred. The median CD4+ cell count of these 20 men at study entry was 0.4 x 10(9)/l and it was 0.45 x 10(9)/l at the end of the study period. Median serum HIV-1 p24 antigen levels at the end of the study period were 42% lower than at study entry in these 20 subjects. In 5/20 men, an initial decline was followed by a rise in antigen levels to above pretreatment value. Treatment with zidovudine was well tolerated. Anemia caused symptoms in 3/24 men, but prolonged leucopenia or neutropenia did not occur. None developed clinical or convincing biochemical evidence of zidovudine-associated myopathy.
The efficacy and tolerance of zidovudine (250 mg six-hourly) alone or in combination with acyclov... more The efficacy and tolerance of zidovudine (250 mg six-hourly) alone or in combination with acyclovir (800 mg six-hourly) as maintenance therapy was studied in a double-blind, placebo-controlled trial in 397 patients. One hundred and thirty patients with acquired immune deficiency syndrome (AIDS) post-opportunistic infection (post-OI) were randomised to either therapy and have been followed up for one year. Two hundred AIDS-related complex (ARC) patients and 67 AIDS patients with Kaposi's sarcoma (KS) were also randomised to placebo for the initial 24 weeks and data for the first 6 months are available so far. Patients in the ARC and KS groups who developed opportunistic infections could be removed from the study and given open label zidovudine.
Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromi... more Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromised hosts. The pain associated with herpes zoster is the most debilitating complication of the disease. It can be described as acute pain and post-herpetic neuralgia or zoster associated pain (ZAP). The latter definition encompasses pain from the onset of disease through its resolution and provides a convenient analytic tool for evaluation of antiviral therapy. A heuristic examination of ZAP historical data suggests the existence of three phases of pain resolution: the acute, subacute and chronic phases. The subacute and chronic phases comprise the post-herpetic neuralgia (PHN) stage. Common analytic methods, such as a Kaplan-Meier survival function or a Cox's model, have been used to assess the pain. However, such approaches do not adequately allow for phase comparison. Notably, in the clinical trial setting the comparison of specific treatment effects on the latter stages of pain are of the greatest medical relevance since this is the most debilitating phase of the illness. In order to incorporate the phase-specific information in the modelling of time to cessation of ZAP, we assumed the hazard function was a stepwise constant. Utilizing the full likelihood function, we obtained the maximum likelihood estimate for the transition times (that is, change-points), and other parameters of medical importance. The standard error of the change-point estimates were obtained through a bootstrapping method. The asymptotic properties of the parameter estimates are also discussed. Hence, the rates of pain resolution across all phases can be examined in order to precisely define the existence of multiple phases. In addition, the covariates effect can be examined across phases and populations, thereby allowing us to translate potential efficacy of a standard therapy to different populations. These results can be utilized in the design of clinical trials or in targeting the outcome for a specific phase while controlling for the effect of other variables.
Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromi... more Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromised hosts. The pain associated with herpes zoster is the most debilitating complication of the disease. It can be described as acute pain and post-herpetic neuralgia or zoster associated pain (ZAP). The latter definition encompasses pain from the onset of disease through its resolution and provides a convenient analytic tool for evaluation of antiviral therapy. A heuristic examination of ZAP historical data suggests the existence of three phases of pain resolution: the acute, subacute and chronic phases. The subacute and chronic phases comprise the post-herpetic neuralgia (PHN) stage. Common analytic methods, such as a Kaplan-Meier survival function or a Cox's model, have been used to assess the pain. However, such approaches do not adequately allow for phase comparison. Notably, in the clinical trial setting the comparison of specific treatment effects on the latter stages of pain are of the greatest medical relevance since this is the most debilitating phase of the illness. In order to incorporate the phase-specific information in the modelling of time to cessation of ZAP, we assumed the hazard function was a stepwise constant. Utilizing the full likelihood function, we obtained the maximum likelihood estimate for the transition times (that is, change-points), and other parameters of medical importance. The standard error of the change-point estimates were obtained through a bootstrapping method. The asymptotic properties of the parameter estimates are also discussed. Hence, the rates of pain resolution across all phases can be examined in order to precisely define the existence of multiple phases. In addition, the covariates effect can be examined across phases and populations, thereby allowing us to translate potential efficacy of a standard therapy to different populations. These results can be utilized in the design of clinical trials or in targeting the outcome for a specific phase while controlling for the effect of other variables.
Pain is the most frequent and disabling complication of herpes zoster. The analysis of pain sever... more Pain is the most frequent and disabling complication of herpes zoster. The analysis of pain severity data is complicated by the nonlinear rate of resolution. Further, three distinct phases characterize pain resolution-acute, subacute, and chronic. Using two clinical trial datasets as the bases for analyses, the rates of baseline pain resolution were computed across each of three phases and compared for age, severity of pain at onset, and number of lesions at baseline. The results defined transition points of 24.4 Ϯ 3.34 for the subacute phase and 110.3 Ϯ 11.9 days for the chronic phase. The model demonstrated a treatment effect of valiciclovir (VACV) during the subacute phase as compared to acyclovir (ACV) ( P ϭ 0.006) and supports effects of age, baseline pain and number lesions on pain cessation rates in the acute phase. This model verifies three phases of zoster pain and delineates the impact of treatment and other factors on the phase-specific rates of pain cessation.
In 1994, an international group of interested clinicians and biostatisticians met to discuss the ... more In 1994, an international group of interested clinicians and biostatisticians met to discuss the design of clinical trials in herpes zoster. They agreed that trials in herpes zoster should have prospectively agreed definitions of all outcome measures and plans for data analysis. In immunocompetent individuals, in whom pain is the major outcome measure, trials should only include patients over the age of 50 years, and for those recruited within 72 h of rash onset, should be designed to demonstrate superiority of any new therapy over existing antivirals. The primary endpoint should be time to cessation of pain for at least 4 weeks and, for the purposes of statistical analysis of its duration, the pain associated with herpes zoster ought to be considered as a continuum. All other variables, including the incidence of post-herpetic neuralgia and effects upon quality of life should be considered as secondary end-points. Evaluation of treatment effects on primary endpoints should be based upon an intent-totreat (ITT) analysis and subgroup analysis should be used only to support the findings of the ITT analysis. These elements of good study design should be borne in mind in the evaluation of current and future trails of antiviral drugs in herpes zoster.
Forty-one strains of Bacteroides fragilis, 20 strains of other Bacteroides species and 14 strains... more Forty-one strains of Bacteroides fragilis, 20 strains of other Bacteroides species and 14 strains of other genera were examined by the indirect immunofluorescent assay (IFA) using anticapsular serum. The sixty-one Bacteroides strains were 'O' serotyped by direct agglutination tests using absorbed antisera raised against 23 strains, each with a different 'O' antigenic determinant. All 41 B. fragilis strains tested were positive by IFA with the anticapsular serum, but apart from one strain of B. distasonis, none of the remaining 19 strains of other bacteroides, i.e. B. thetaiotaomicron, B. distasonis, B. vulgatus, B. ovatus, B. melaninogenicus group and B. ureolyticus, and none of the 14 other bacterial species examined were positive. The majority of strains of saccharolytic bacteroides tested reacted with one of the 23 'O' antisera and were designated as a specific 'O' serotype; a few Bacteroides strains had multiple agglutination reactions indicating the presence of multiple antigenic determinants. All 'O' serotypes gave positive IFA tests with their homologous 'O' antisera. Common capsular determinants and 'O' antigenic determinants appear to exist on the same strains of B. fragilis. Serological typing of B. fragilis and related species would be useful in epidemiological studies.
A double-blind, randomised trial of acyclovir versus placebo was conducted in 31 patients with in... more A double-blind, randomised trial of acyclovir versus placebo was conducted in 31 patients with initial and 85 patients with recurrent genital herpes. 17 patients with initial and 42 with recurrent disease were treated with 200 mg acyclovir by mouth five times a day for 5 days, and the remaining patients received matching placebo. In patients with initial genital herpes shedding virus acyclovir significantly reduced the duration of viral shedding, itching, and pain, the time to crusting and complete healing, and new lesion formation compared with controls. In patients with recurrence disease acyclovir significantly reduced the duration of viral shedding, time to complete healing, and new lesion formation. The reported incidence of adverse events was similar in both acyclovir and placebo groups. Oral acyclovir is effective and well tolerated in patients with initial and recurrent genital herpes and can be used in outpatient therapy.
A double-blind, randomized, placebo-controlled trial of 5% acyclovir ointment was carried out for... more A double-blind, randomized, placebo-controlled trial of 5% acyclovir ointment was carried out for thirty-one episodes of herpes labialis in thirteen patients experiencing severe, frequent recurrences. In addition, these patients continued to use acyclovir ointment or placebo for the treatment of twenty-two further episodes. Treatment was initiated by the patients as soon as possible after onset of prodromal symptoms, and continued five times a day for 5 days. It was found that acyclovir ointment shortened the duration of lesions only by about one day, but it greatly increased the number of abortive lesions resulting from early application. Acyclovir ointment is well tolerated and appears to modify the course of severe recurrent herpes labialis when therapy is initiated by the patient during the prodrome.
Immunocompromised patients are at high risk of developing herpes simplex virus infections caused ... more Immunocompromised patients are at high risk of developing herpes simplex virus infections caused by reactivation of the virus. Intravenous and oral formulations of acyclovir have been shown to prevent most of these infections during the major at-risk periods when given prophylactically. Immunocompetent patients may also experience reactivation of herpes simplex virus leading most often to recurrent genital or labial infections. For those patients who experience frequent attacks, oral acyclovir can prevent most recurrences and is well tolerated when given as continuous suppressive therapy. Bei Patienten mit beeinträchtigter Immunität besteht ein hohes Risiko für Herpes simplex Virus-Infektionen durch Reaktivierung des Virus. Es hat sich gezeigt, daß durch prophylaktische Gabe der intravenösen oder oralen Zubereitungsform von Aciclovir die meisten dieser Infektionen während der Phasen des größten Risikos verhütet werden können. Bei immunkompetenten Patienten treten ebenfalls durch Reaktivierung des Herpes simplex Virus Infektionen auf, die sich am häufigsten als rezidivierender Herpes genitalis oder labialis manifestieren. Bei Patienten, die sehr häufig Herpes-Schübe durchmachen, kann durch eine kontinuierliche orale Suppressionstherapie mit Aciclovir das Auftreten von Rezidiven weitgehend verhindert werden.
Eighteen asymptomatic men with persistent human immunodeficiency virus type 1 (HIV-1) p24 antigen... more Eighteen asymptomatic men with persistent human immunodeficiency virus type 1 (HIV-1) p24 antigenemia were treated with zidovudine 250-500 mg (+/- acyclovir 800 mg) 6-hourly for 4-12 weeks, and thereafter with zidovudine 500 mg (+/- acyclovir 1600 mg) 12-hourly for 92 weeks. Six additional HIV-1 p24 antigenemic subjects were treated with zidovudine 500 mg 12-hourly for 76 weeks. Disease progression occurred in 4 subjects, despite sustained reduction of serum HIV-1 p24 antigen levels: Pneumocystis carinii pneumonia was diagnosed after 60, 80, 90 and 93 weeks, respectively. The median CD4+ cell count of these 4 men at study entry was 0.2 x 10(9)/l, and it declined to 0.07 x 10(9)/l at the moment AIDS was diagnosed. In 20 subjects no disease progression occurred. The median CD4+ cell count of these 20 men at study entry was 0.4 x 10(9)/l and it was 0.45 x 10(9)/l at the end of the study period. Median serum HIV-1 p24 antigen levels at the end of the study period were 42% lower than at study entry in these 20 subjects. In 5/20 men, an initial decline was followed by a rise in antigen levels to above pretreatment value. Treatment with zidovudine was well tolerated. Anemia caused symptoms in 3/24 men, but prolonged leucopenia or neutropenia did not occur. None developed clinical or convincing biochemical evidence of zidovudine-associated myopathy.
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