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Biomedical subjects

W L Drew

Publications and source records attributed to W L Drew.

At least 37 records · Page 2Linked to original sources
PubMed1997

Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial.

BACKGROUND: Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with the acquired immunodeficiency syndrome (AIDS). If left untreated, it may lead to progressive destruction of retinal tissue and blindness. Cidofovir is a nucleotide analogue of cytosine that has potent, prolonged in vitro and in vivo activity against herpesviruses, including many CMV isolates that are resistant to ganciclovir and foscarnet. OBJECTIVE: To determine whether intravenous cidofovir delays progression of previously untreated CMV retinitis. DESIGN: Randomized, controlled trial comparing immediate with deferred cidofovir treatment. Patients in the deferred treatment group were eligible to receive cidofovir after progression of CMV retinitis was documented by retinal photography. SETTING: Eight academic medical centers and an independent center that read retinal photographs. PATIENTS: 48 patients with AIDS and previously untreated peripheral CMV retinitis who were randomly assigned to immediate (n = 25) or deferred treatment (n = 23). INTERVENTION: Intravenous cidofovir, 5 mg/kg of body weight, once weekly for 2 weeks and then once every other week. To minimize nephrotoxicity, oral probenecid and intravenous hydration with normal saline were administered with each cidofovir infusion. MEASUREMENTS: Progression of CMV retinitis was assessed by bilateral, full-field retinal photographs that were read by an ophthalmologist who was masked to treatment assignment. Incidence of side effects, changes in visual acuity, effect on CMV shedding in urine and blood, and mortality were also assessed. RESULTS: The median time to progression of CMV retinitis was 22 days (95% CI, 10 to 27 days) in the deferred treatment group and 120 days (CI, 40 to 134 days) in the immediate treatment group (P < 0.001). Neutropenia (15%) and proteinuria (12%), both asymptomatic, were the most common serious adverse events considered to be possibly related to cidofovir. Cidofovir treatment was discontinued in 10 of 41 patients (24%) because of protocol-defined treatment-limiting nephrotoxicity. Transient reactions to probenecid, including mild to moderate constitutional symptoms or nausea, occurred in 23 of 41 patients (56%) and were dose limiting in 3 (7%). CONCLUSIONS: Cidofovir was efficacious in delaying progression of previously untreated CMV retinitis. Treatment was associated with manageable side effects; strict adherence to monitoring of renal function before cidofovir was administered and concomitant administration of probenecid and saline hydration appeared to minimize drug-related nephrotoxicity.

AIDS-Related Opportunistic Infections↗
PubMed1997

Diagnosis of cytomegalovirus (CMV) polyradiculopathy and documentation of in vivo anti-CMV activity in cerebrospinal fluid by using branched DNA signal amplification and antigen assays.

Branched chain DNA assay (bDNA), cytomegalovirus (CMV) antigen assay, and cerebrospinal fluid (CSF) viral culture were studied for their utility in the diagnosis of CMV polyradiculopathy and for documenting in vivo antiviral effects. CMV was demonstrated in 15 of 16 patients by bDNA assay, 15 of 16 by CMV antigen assay, and 11 of 15 by CSF culture. When clinical criteria and results of the other two assays were used as reference standards, the sensitivity of bDNA was 94% and 100% and the specificity 95.2% and 100%; the CMV antigen assay sensitivity was 94% and 100% and specificity was 85.7% and 100%. Nine (90%) of 10 patients with polyradiculopathy and follow-up CSF culture showed a drop in CMV DNA after treatment; however, only 2 (20%) improved clinically. These results suggest that bDNA and antigen assays may be useful methods for the diagnosis of CMV polyradiculopathy, but treatment failures may not be due to inadequate antiviral activity.

Antigens, Viral↗
PubMed1997

The safety and efficacy of adefovir dipivoxil, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults: a randomized, double-blind, placebo-controlled trial.

Adefovir dipivoxil is a novel nucleotide analogue with several promising in vitro anti-human immunodeficiency virus (HIV) characteristics. To evaluate the safety and efficacy of adefovir dipivoxil monotherapy, a randomized, double-blind, placebo-controlled study was initiated involving 72 subjects with moderately advanced HIV disease. Subjects were randomly assigned in a 2:1 ratio to receive adefovir dipivoxil or placebo as a once-daily oral dose for 6 weeks, followed by 6 weeks of open-label adefovir dipivoxil. Two dose levels were studied (125 mg and 250 mg). Adefovir dipivoxil was determined to be safe and well-tolerated when administered for 12 weeks. At week 6, changes in absolute CD4 T cell levels and HIV-1 RNA levels were significantly greater with adefovir dipivoxil than with placebo. These effects were sustained through 12 weeks of treatment. As determined by standard RNA sequencing techniques, only 1 of the 24 subjects who received adefovir dipivoxil (125 mg/day) developed any genotypic change from baseline.

Adenine↗
PubMed1997

A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS.

The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031). Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004). For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively). Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were -1.84 versus -0.34 (P = .042). Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting. Cidofovir therapy provided significant benefits in lesion healing, virologic effect, and pain reduction.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease.

In a human immunodeficiency virus-infected subject, cytomegalovirus (CMV) isolated 9 months after the patient began oral ganciclovir prophylaxis was resistant to ganciclovir and cidofovir and contained mutations in both UL97 and Pol coding regions. At 1 year, retinitis developed, which progressed despite intravenous ganciclovir followed by foscarnet and then cidofovir. A subsequent buffy coat virus isolate was resistant to all three drugs and contained new mutations in UL97 and Pol. By individually transferring the observed mutations to laboratory strain AD169, it was shown that a mutation at codon 603 of UL97 conferred resistance to ganciclovir, a mutation at codon 412 of Pol conferred resistance to both ganciclovir and cidofovir, and a mutation at codon 802 of Pol conferred resistance to ganciclovir and foscarnet. This case illustrates the development of multidrug resistance during prolonged exposure to antiviral therapy for CMV and cross-resistance arising from point mutations in the CMV Pol gene.

AIDS-Related Opportunistic Infections↗
PubMed1997

Cytomegalovirus gB genotype distribution differs in human immunodeficiency virus-infected patients and immunocompromised allograft recipients.

Cytomegalovirus isolates can be grouped into 4 gB and 2 gH genotypes. gB genotypes were studied in patients infected with human immunodeficiency virus (HIV) and in allograft transplantation recipients. In allograft recipients, the distribution of gB 1, -2, -3, and -4 in leukocytes and urine, respectively, was 36%, 21%, 43%, and 0% and 39%, 30%, 17%, and 13%. However, in leukocytes of HIV-infected patients with <100/microL CD4 cells, gB1 was found significantly less often than in allograft recipients (11% vs. 36%) but gB2 was more frequent (56% vs. 21%; P < .05). The decreased incidence of gBl and increased incidence of gB2 compared with allograft recipients was also seen in urine of HIV-infected patients and reflected the distribution seen in leukocytes. gB4 was found significantly more often (P < .05) in semen than in leukocytes of HIV-infected patients with < 100/microL CD4 cells. gB1-4 genotypes were similar in patients with < 100/microL CD4 cells with or without retinitis.

AIDS-Related Opportunistic Infections↗
PubMed1997

Quantification of cytomegalovirus DNA in peripheral blood leukocytes by a branched-DNA signal amplification assay.

Quantification of cytomegalovirus (CMV) DNA in blood may aid in the identification of patients at highest risk for developing CMV disease, the evaluation of new therapeutics, and the prompt recognition of drug-resistant CMV strains. A branched-DNA (bDNA) assay was developed for the reliable quantification of CMV DNA in peripheral blood leukocytes. The bDNA assay allowed for the highly specific and reproducible quantification of CMV DNA in clinical specimens. Furthermore, the bDNA assay was at least as sensitive as culture techniques and displayed a nearly 3 log10 dynamic range in quantification. Changes in CMV DNA levels measured by the bDNA assay in a human immunodeficiency virus-positive patient undergoing therapy were consistent with CMV culture, antigen, and genotype results and correlated with disease progression and resistance markers. The bDNA assay for the quantification of CMV DNA may provide a useful tool that can be used to aid physicians in monitoring disease progression, evaluating therapeutic regimens, and recognizing viral resistance and drug failure.

AIDS-Related Opportunistic Infections↗
PubMed1996

Summary of the International Consensus Symposium on Advances in the Diagnosis, Treatment and Prophylaxis and Cytomegalovirus Infection.

CMV infection and CMV disease can be difficult to differentiate and the diagnosis is usually based on a compatible clinical picture and the results of a diagnostic test for CMV. The only exception to this rule is in HIV-infected patients where fundoscopy is sufficient to diagnose CMV retinitis. Of the current diagnostic tests, qualitative and quantitative PCR, branched DNA and Hybrid Capture, are the most promising. The pp65 antigenemia assay has the disadvantage of being more labor-intensive than the DNA based tests. Preliminary data show that a positive qualitative PCR in a HIV-infected patient has a predictive value for the development of CMV retinitis. However, of the patients positive by qualitative PCR, those with high viral loads in quantitative PCR were at the greatest risk of CMV disease. This might make it possible to identify with great certainty the patients who will go on to develop CMV retinitis, thereby decreasing the number of patients eligible for preemptive or prophylactic therapy and increasing the cost-benefit of this therapeutic measure. Quantitative test might also be useful in monitoring response to therapy, but randomized trials comparing the test are needed. Prophylactic antiviral agents should not be used in seronegative transplant recipients receiving organs from seronegative donors. In high-risk transplant recipients, ganciclovir should be used. CMV vaccines are useful for the protection of babies from CMV seronegative mothers against congenital CMV disease. It also may be useful in seronegative transplant recipients receiving a seropositive donor organ, although the benefit of chemo prophylaxis may surpass that of vaccine. HIV-infected patients with CMV retinitis who relapse under either ganciclovir or foscarnet benefit from subsequent combination therapy, rather than switching to the other drug. However, the cost is high in terms of quality of life. Intravitreal therapy for CMV retinitis is very efficacious, suggesting that drug delivery is a problem in systemic therapy. However, intravitreal therapy does not protect against the development of CMV retinitis in the contralateral eye or from CMV disease elsewhere. Therefore, systemic therapy should be added. CMV disease of the CNS should be diagnosed early and treated agressively, possible with combination therapy. A diagnosis of CMV disease should be based on a compatible clinical picture and the demonstration of CMV in CSF by DNA or antigen assays which are more sensitive than culture.

Animals↗
PubMed1996

Susceptibility of human cytomegalovirus to cidofovir is unchanged after limited in vivo exposure to various regimens of drug.

Cidofovir [1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine] susceptibility among 29 paired pre- and post-cidofovir exposure isolates from 22 patients enrolled in phase I/II clinical trial, GS-92-101, was determined. This trial was designed to evaluate the safety and antiviral effects of cidofovir in patients with AIDS and asymptomatic shedding of human cytomegalovirus (HCMV) in semen with no evidence of end-organ HCMV disease and no prior anti-HCMV therapy. These patients received a median cumulative dose of 30 mg/kg (range, 3-67) administered over a median of 8 weeks (range, 2-38). The IC50 values of preexposure isolates ranged from <0.5 to 1.85 and for postexposure isolates from <0.5 to 2 uM. Thus, no significant changes in cidofovir susceptibilities have been noted for HCMV during the various regimens of cidofovir administrated in this clinical trial.

Adult↗
PubMed1995

Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. Syntex Cooperative Oral Ganciclovir Study Group.

BACKGROUND: Cytomegalovirus retinitis, a sight-threatening infection associated with the acquired immunodeficiency syndrome (AIDS), currently requires lifelong intravenous treatment. An effective oral treatment would be an important advance. METHODS: We compared oral with intravenous ganciclovir in an open-label, randomized study in patients with AIDS and newly diagnosed, stable cytomegalovirus retinitis (the disease was stabilized by three weeks of treatment with intravenous ganciclovir). Sixty subjects were randomly assigned to maintenance therapy with intravenous ganciclovir at a dose of 5 mg per kilogram of body weight daily, and 63 to maintenance therapy with oral ganciclovir at a dose of 3000 mg daily. The subjects were followed for up to 20 weeks, with photography of the fundi conducted every other week. The photographs were evaluated at the completion of the study by an experienced grader who was unaware of the subjects' treatment assignments. RESULTS: Efficacy could be evaluated in 117 subjects; photographs were ungradable for 2 of the 117. On the basis of the masked assessment of photographs from 115 subjects, the mean time to the progression of retinitis was 62 days in those given intravenous ganciclovir and 57 days in those given oral ganciclovir (P = 0.63; relative risk [oral vs. intravenous], 1.08; 95 percent confidence interval for the difference in means, -22 to +12 days). On the basis of funduscopy by ophthalmologists who were aware of the subjects' treatment assignments, the mean time to progression was 96 days in subjects given intravenous ganciclovir and 68 days in subjects given oral ganciclovir (P = 0.03; relative risk [oral vs. intravenous], 1.68; 95 percent confidence interval for the difference in means, -45 to -11 days). Survival, changes in visual acuity, the incidence of viral shedding, and the incidence of adverse gastrointestinal events were similar in the two groups. Neutropenia, anemia, intravenous-catheter-related adverse events, and sepsis were more common in the group given intravenous ganciclovir. CONCLUSIONS: Oral ganciclovir is safe and effective as maintenance therapy for cytomegalovirus retinitis and is more convenient for patients to take than intravenous ganciclovir.

AIDS-Related Opportunistic Infections↗
PubMed1995

Failure of high-dose oral acyclovir to suppress CMV viruria or induce ganciclovir-resistant CMV in HIV antibody positive patients.

Ninety-three symptomatic HIV antibody positive patients were randomized to receive zidovudine (ZDV) 600 mg/day and acyclovir (ACV) 4,800 mg orally per day versus ZDV 600 mg/day plus placebo. Urine was obtained at 3-month intervals and cultured for cytomegalovirus (CMV) in diploid fibroblast cells. The percent of urine specimens positive for CMV was 7.1% in the ZDV group and 5.8% in the ZDV plus ACV group (p = 0.55); 27% of patients had at least one urine culture positive for CMV while taking ZDV, versus 20% of patients taking the combination of ZDV plus ACV (p = 0.52). We conclude that ACV at a dosage of 4,800 mg/day does not suppress CMV excretion in urine of symptomatic HIV antibody positive patients taking concurrent ZDV. Use of ACV did not appear to induce resistance of CMV to ganciclovir since the ID50 of isolates from the two treatment groups did not differ.

Acyclovir↗
PubMed1995

(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analogue.

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, is a novel antiviral nucleotide analogue with potent in vitro and in vivo activity against cytomegalovirus (CMV) and other herpesviruses. Thirty-one human immunodeficiency virus-seropositive patients with asymptomatic CMV excretion were evaluated in a phase I/II study with 2 regimens of cidofovir: cidofovir alone at doses of 0.5, 1.0, 3.0, or 10.0 mg/kg/week (20 patients) and cidofovir at 3.0, 5.0, or 7.5 mg/kg with concomitant oral probenecid, saline prehydration, extended dosing intervals, and drug interruption for proteinuria (19 patients). Prolonged and dose-dependent anti-CMV effect was observed with all cidofovir regimens > or = 3.0 mg/kg. The dose-limiting toxicity of cidofovir was dose- and schedule-dependent nephrotoxicity. Four of 20 patients had serum creatinine levels > or = 2.0 mg/dL after a mean cumulative exposure of 14.8 mg/kg cidofovir alone; however, none of 19 patients receiving the modified regimen had elevated creatinine (mean cidofovir exposure, 32.2 mg/kg). The clinical efficacy of cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease.

AIDS-Related Opportunistic Infections↗
PubMed1995

Frequency of UL97 phosphotransferase mutations related to ganciclovir resistance in clinical cytomegalovirus isolates.

Cytomegalovirus (CMV) isolates from subjects who received ganciclovir therapy were tested for susceptibility to ganciclovir by a plaque reduction assay. Results were correlated with restriction enzyme and sequence analysis of the CMV UL97 phosphotransferase gene. Of the 30 isolates, 20 had one or more mutations in UL97 affecting amino acid encoding at codons 460, 520, or 591-596. All 20 were resistant to ganciclovir, with an IC50 of > 6.0 microM (range, 6.7-50.0). The remaining 10 isolates had no mutations at these loci; 8 were susceptible to ganciclovir while the other 2 were borderline resistant (IC50s, 6.6 and 7.2 microM). None of 40 control CMV isolates from untreated subjects contained any amino acid changes at these loci. The three most common mutations at codons 460, 594, and 595 were detected by restriction digest analysis in 16 (80%) of 20 isolates and in 16 (73%) of 22 isolates with ganciclovir IC50s > 6.0 microM. These results indicate that the majority of ganciclovir-resistant clinical isolates contain diagnostically useful mutations in UL97.

Amino Acid Sequence↗
PubMed1994

Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS.

(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a nucleotide analogue with potent in vitro and in vivo activity against a broad range of herpesviruses, including acyclovir-resistant herpes simplex virus (HSV). A patient with severe acyclovir-resistant perineal HSV infection received intravenous HPMPC at 5 mg/kg/week, with concomitant oral probenecid and prehydration, and had 95% healing after four infusions. The patient developed a hypersensitivity reaction to probenecid and discontinued HPMPC after the fourth infusion. Recurrence of the perineal lesions 2 weeks later prompted initiation of an oral desensitization program to probenecid and enabled the patient to resume therapy. The lesions again responded to infusions of HPMPC, but the drug was discontinued before complete healing because of transient nephrotoxicity (proteinuria, 2+; creatinine, 1.7 mg/dL). HPMPC is a potent antiviral agent that holds promise as a potential treatment for acyclovir-resistant HSV infection.

AIDS-Related Opportunistic Infections↗