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Biomedical subjects

R W Shafer

Publications and source records attributed to R W Shafer.

At least 55 records · Page 3Linked to original sources
PubMed1995

Temporal trends and transmission patterns during the emergence of multidrug-resistant tuberculosis in New York City: a molecular epidemiologic assessment.

To ascertain the role of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis transmission on multidrug-resistant (MDR) tuberculosis (TB) emergence in New York City, medical records, drug susceptibilities, and restriction fragment length polymorphisms (RFLPs) of TB cases at a city hospital between two 9-month periods (1987-1988 and 1990-1991) were reviewed. The proportion of TB patients with MDRTB increased from 10% (27/267) to 17% (38/222; P = .03). Among MDRTB patients of known HIV status, the proportion with HIV increased from 16% (3/19) to 58% (22/38; P = .006). HIV-infected MDRTB patients were more likely than the seronegative ones to have initial MDRTB (88% vs. 56%; P = .03). Among 56 MDR cases with RFLP results, 12 had unique patterns; 44 belonged to one of six clusters. During 1990-1991, 27 (75%) of 36 MDRTB patients were infected with strains isolated from HIV-seronegative patients during 1987-1988. The increase in MDRTB caused by transmission from immunocompetent to immunocompromised persons underscores the urgency of TB control in populations with increasing HIV prevalence.

Adolescent↗
PubMed1995

New virologic tools for the design and analysis of clinical trials.

While a large number of candidate drugs and drug combinations are being evaluated for treating human immunodeficiency virus (HIV) infection, clinicians are confronted by the problem of how to optimally use those antiretroviral drugs already approved for clinical use. While new techniques are being developed for studying HIV pathogenesis, clinicians are asking whether these new techniques can be used to develop improved strategies for treating the HIV-infected individual. In the current issue of the Journal, Kojima et al. from the National Cancer Institute (NCI) used two research techniques to analyze the results of a phase I/II study comparing alternating versus simultaneous therapy with zidovudine and didanosine. The authors used a quantitative polymerase chain reaction (PCR) assay for measuring plasma virus RNA and a selective PCR assay for detecting specific HIV reverse transcriptase (RT) drug-resistance mutations. Their study demonstrates the potential for effective combination therapy if drugs are optimally combined and suggests that assays for measuring HIV burden and HIV drug resistance can be used to better understand the results of preliminary clinical trials. In addition, their study raises questions about the potential role for measurements of virus burden and the detection of HIV drug resistance in larger clinical trials and clinical practice.

Antiviral Agents↗
PubMed1995

Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. The AIDS Clinical Trials Group 143 Virology Team.

Plasma human immunodeficiency virus (HIV) type 1 RNA levels, CD4 lymphocyte changes, and drug resistance were studied in HIV-infected patients with 200-500 CD4 lymphocytes/microL who received zidovudine and didanosine combination therapy for 2 years. Among 35 patients, 10 had sustained and 16 had transient > 10-fold reductions in HIV RNA: 9 did not have 10-fold HIV RNA reductions. Only patients with sustained HIV suppression maintained increased CD4 cell counts for 2 years (370 to 501 cells/microL; P = .006). Patients with transient HIV suppression were more likely to develop drug-resistant HIV strains (12/16 vs. 5/19, P = .01) and reverse transcriptase (RT) mutations (4.5 vs. 2.5/strain; P = .02) than were patients with sustained or no HIV suppression. Zidovudine resistance occurred with RT mutations at codons 41, 67, 70, 215, and 219. Multidrug resistance occurred with mutations at codons 62, 75, 77, 116, and 151. Mutations occurred at codons 60, 68, 118, 210, and 228 in > or = 4 patients each. Heterogeneity exists among individual virologic responses to zidovudine and didanosine combination therapy. HIV resistance mechanisms during combination therapy appear more complex than reported with monotherapy.

Amino Acid Sequence↗
PubMed1995

Quantitative analysis of syncytium-inducing and non-syncytium-inducing virus in patients infected with human immunodeficiency virus type 1.

Among 75 consecutive human immunodeficiency virus type 1 (HIV-1)-infected patients with moderate and advanced immunosuppression, those harboring syncytium-inducing (SI) HIV-1 had a lower CD(4+)-cell count (145 versus 278 cells per microliter, P < 0.001) and 10-fold-higher virus titers than patients with non-SI HIV-1 (398 versus 39 infectious units per 10(6) CD4+ lymphocytes; P < 0.001). In patients with SI virus, the mean titer of SI virus, determined with a quantitative MT-2 cell assay, was 135 SI infectious units per 10(6) CD4+ lymphocytes. Virus titer correlated inversely with CD(4+)-cell count in patients with SI (r = -0.67) but not non-SI (r = -0.29) virus.

CD4-Positive T-Lymphocytes↗
PubMed1994

Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy.

OBJECTIVE: To determine the frequency and pattern of development of specific drug resistance mutations for human immunodeficiency virus (HIV) reverse transcriptase in patients switched from zidovudine to didanosine therapy and to examine the relation of the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene to CD4+ T-cell changes and virus burden. DESIGN: Retrospective analysis of all patients enrolled at Stanford University in protocols where patients were switched from zidovudine to didanosine monotherapy. SETTING: A university hospital. PATIENTS: 64 patients infected with HIV who were switched from zidovudine to didanosine monotherapy. Patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex, or were asymptomatic (mean [+/- SD] starting CD4+ T-cell count of 129 +/- 88 cells/mm3). MEASUREMENTS: Serial serum specimens were tested for the didanosine resistance mutation at codon 74 of the HIV reverse-transcriptase gene and for a zidovudine resistance mutation at codon 215 using selective polymerase chain reactions (PCR). Serum HIV RNA levels were determined by quantitative PCR. CD4+ T-cell counts were determined at serial time points. RESULTS: By 24 weeks of didanosine therapy, the proportion of patients with the didanosine resistance mutation at codon 74 increased from 0% to 56% (36 of 64). In contrast, the proportion of patients with the zidovudine resistance mutation at codon 215 decreased from 84% at the start to 59% after 24 weeks of didanosine therapy (a 25% decrease, 95% lower CI, 15%; P < 0.0001). Patients who developed the codon 74 mutation had a greater decrease in CD4+ T cells after the development of the mutation than did patients without the mutation (P < 0.001). In addition, after 24 weeks of didanosine, patients who developed the codon 74 mutation had a greater serum HIV RNA burden than patients who remained wild type (did not have the mutation) at codon 74 (225,000 compared with 82,400 HIV RNA copies/mL serum; P = 0.01). CONCLUSIONS: Among patients infected with HIV who had advanced disease and were switched from zidovudine to didanosine therapy, more than one half developed the didanosine resistance mutation at codon 74 by 24 weeks of didanosine therapy. Patients who developed the codon 74 mutation had a greater decline in CD4+ T cells after the development of the mutation and had a greater serum virus burden than did patients without the codon 74 mutation.

CD4-Positive T-Lymphocytes↗
PubMed1994

Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations.

Drug resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol mutations of HIV-1 strains from patients treated for 1 year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine resistance or a zidovudine resistance pol mutation at codon 215 (P = .6). In contrast, a ddI resistance mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P < .001). Two patients receiving combination therapy developed resistance to zidovudine and ddI; they had HIV strains with amino acid mutations at codons 62, 75, 77, 116, and 151. Combination therapy with zidovudine and ddI selects for zidovudine-resistant HIV-1 strains lacking a ddI resistance mutation and for multidrug-resistant strains containing novel pol mutations.

Amino Acids↗
PubMed1994

HIV-1 syncytium-inducing phenotype, virus burden, codon 215 reverse transcriptase mutation and CD4 cell decline in zidovudine-treated patients.

The variable rate of disease progression in HIV-1-infected patients treated with zidovudine may be related to certain viral characteristics, such as, antiviral drug resistance, virus burden, and viral syncytium-inducing (SI) capacity. Thirty-two HIV-1-infected patients treated with zidovudine (mean of 34 months) were studied to determine the relationship of SI phenotype and the codon 215 pol gene mutation (a marker of zidovudine resistance) to virus burden and CD4 cell decline. Patients with SI strains and the codon 215 mutation in their proviral DNA had a 54% decline in CD4 cells and a virus burden of 21,480 proviral DNA copies/10(6) CD4 cells. In contrast, patients with non-SI (NSI) strains and wild-type at codon 215 had a 10% increase in CD4 cells and had a viral burden 1/46 that of patients with SI and the 215 mutation. Among patients with NSI strains, changes in CD4 cells depended on the presence of the codon 215 mutation (-160 CD4 cells/microliters), compared with those wild-type at codon 215 (+28 CD4 cells/microliters) (p < 0.01). There was a concordant rise in virus burden between proviral DNA and plasma HIV RNA depending on HIV phenotype and genotype. Using multiple linear regression, SI phenotype and the codon 215 mutation were found to independently predict CD4 cell decline and increased virus burden in zidovudine-treated patients.

CD4-Positive T-Lymphocytes↗
PubMed1993

Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection.

BACKGROUND: In the United States there have been recent outbreaks of multidrug-resistant tuberculosis. These outbreaks have primarily involved persons infected with the human immunodeficiency virus (HIV). METHODS: We collected clinical information on 17 patients seen at a New York City hospital who had repeatedly positive cultures for Mycobacterium tuberculosis. Analysis of restriction-fragment--length polymorphisms (RFLPs) was performed on serial isolates of M. tuberculosis obtained from these patients. RESULTS: Six patients had isolates that remained drug-susceptible, and the RFLP patterns of these isolates did not change over time. Eleven patients had isolates that became resistant to antimicrobial agents. The RFLP patterns of the isolates from six of these patients remained essentially unchanged (two strains showed one additional band) despite the development of drug resistance. In five other patients, however, the RFLP patterns of the isolates changed dramatically at the time that drug resistance was detected. The change in the RFLP pattern of the isolate from one patient appeared to be the result of contamination during processing in the laboratory. In the remaining four patients, all of whom had advanced HIV disease, the clinical and microbiologic evidence was consistent with the presence of active tuberculosis caused by a new strain of M. tuberculosis. CONCLUSIONS: Resistance to antituberculous drugs can develop not only in the strain that caused the initial disease, but also as a result of reinfection with a new strain of M. tuberculosis that is drug-resistant. Exogenous reinfection with multidrug-resistant M. tuberculosis can occur either during therapy for the original infection or after therapy has been completed.

AIDS-Related Opportunistic Infections↗
PubMed1993

Zidovudine susceptibility testing of human immunodeficiency virus type 1 (HIV) clinical isolates.

Traditional antiviral susceptibility testing methods using cell lines can be applied to no more than about 30% of clinical HIV isolates (Larder et al., 1989a; Fenyo et al., 1989). We tested the cell-free supernatant from low passage clinical HIV isolates using donor peripheral blood mononuclear cells (PBMC). Drug susceptibility was assessed by measuring the effect of increasing zidovudine (ZDV) concentrations on HIV P24 antigen production. Susceptibility results were obtained on 24/27 consecutive clinical isolates and 6/6 laboratory isolates. The mean IC90 of isolates from untreated patients was 0.008 microM ZDV (range: 0.002-0.038). The IC90s of isolates from ZDV-treated patients ranged from 0.007 to greater than 10 microM ZDV. All isolates with an IC90 < 0.1 microM ZDV had a wild type sequence at codon 215 of the HIV pol gene; 11/12 isolates with an IC90 > 0.1 microM ZDV had a mutation at codon 215 (P < 0.001). Among 16 ZDV-treated patients, there was a modest correlation between the change in CD4 count from the start of ZDV treatment and the IC90 of the patient's isolate following treatment (r = 0.51). Susceptibility testing using donor PBMC can be a sensitive means of testing a broad range of clinical HIV isolates.

Base Sequence↗
PubMed1993

A mutation in human immunodeficiency virus reverse transcriptase and decline in CD4 lymphocyte numbers in long-term zidovudine recipients.

A nested polymerase chain reaction assay was used to define the sequence of a specific codon, amino acid 215, of the human immunodeficiency virus (HIV) pol gene in DNA from peripheral blood mononuclear cells (PBMC) and viral RNA from serum from 38 patients treated with zidovudine for > or = 2 years. After treatment for a mean of 34 months, 17 patients with sequences with a codon 215 mutation had a mean 50% decrease in CD4 cells, compared with 21 patients with sequences wild-type at codon 215, who had a mean 11% increase in CD4 cells (P < .0001). Patients with a mutation at 215 had a ninefold higher provirus burden in PBMC. Detection of the codon 215 mutation in plasma viral RNA preceded detection of the mutation in DNA from PBMC and decline in CD4 cells. The appearance of a mutation at codon 215 in the HIV reverse transcriptase gene in patients receiving zidovudine may be a marker for impending immunologic decline.

CD4-Positive T-Lymphocytes↗
PubMed1992

Mycobacterium xenopi, Mycobacterium fortuitum, Mycobacterium kansasii, and other nontuberculous mycobacteria in an area of endemicity for AIDS.

Between 1981 and 1990, cultures of specimens from 86 patients at State University of New York-Health Sciences Center at Brooklyn were positive for nontuberculous mycobacteria other than Mycobacterium avium/Mycobacterium intracellulare complex or Mycobacterium gordonae. The most common species isolated were Mycobacterium xenopi (33), Mycobacterium fortuitum (28), Mycobacterium kansasii (7), and Mycobacterium chelonae (6). Thirty-five patients (41%) had clinical and/or serological evidence of human immunodeficiency virus (HIV) infection. Patients from whom M. xenopi and M. kansasii were isolated were significantly more likely to be infected with HIV than were the remaining patients in this series. Most of the mycobacterial isolates were cultured from respiratory secretions. However, extrapulmonary infections with M. fortuitum, M. xenopi, M. kansasii, Mycobacterium terrae, and Mycobacterium scrofulaceum did occur among the HIV-infected patients.

Adolescent↗
PubMed1991

Relapse of tuberculosis in a patient with the acquired immunodeficiency syndrome despite 12 months of antituberculous therapy and continuation of isoniazid.

A 33-year-old man with AIDS and pleuro-pulmonary tuberculosis was treated with a combination of antituberculous medications for 12 months and with continuation of isoniazid. A total of 2 months after completing combination therapy the patient developed fever, malaise, and anorexia. Mycobacterial blood cultures grew M. tuberculosis and the patient improved with the readministration of rifampicin and pyrazinamide. Phage typing of the patient's isolates of M. tuberculosis confirmed that he had experienced a relapse and not a reinfection. The patient had received 5 months of his treatment while hospitalised. We believe he was compliant with therapy outside the hospital because he attended all of his clinic appointments. Follow-up studies of HIV-infected patients with tuberculosis are therefore needed.

Acquired Immunodeficiency Syndrome↗
PubMed1991

HIV prevalence, immunosuppression, and drug resistance in patients with tuberculosis in an area endemic for AIDS.

From October 1987 to June 1988, we attempted to determine the prevalence of HIV infection among patients hospitalized with tuberculosis and the extent of immunosuppression among those tuberculosis patients infected with HIV. Of 178 consecutive patients, 18-65 years of age, who were hospitalized with newly diagnosed, previously untreated tuberculosis, 46% (82 out of 178) had clinical or serological evidence of HIV infection, 30% (54 out of 178) were HIV-seronegative, and 24% (42 out of 178) could not be assessed for the presence of HIV infection. Among the HIV-seropositive patients without an AIDS-defining diagnosis by non-tuberculous criteria, the median CD4 lymphocyte (CD4) count was 133 x 10(6) cells/l (range: 11-677 x 10(6]; among the HIV-seronegative patients, the median CD4 count was 613 x 10(6) cells/l (range: 238-1614 x 10(6); P less than 0.001). Among the HIV-seropositive patients, those with disseminated tuberculosis (median CD4 = 79 x 10(6) cells/l) and those with pulmonary tuberculosis who had radiographic evidence of mediastinal or hilar adenopathy (median CD4 = 45 x 10(6) cells/l) had the most severe CD4 depletion, whereas those with localized extrapulmonary tuberculosis (median CD4 = 242 x 10(6) cells/l) and those with pulmonary tuberculosis without adenopathy (median CD4 = 299 x 10(6) cells/l) were less severely immunosuppressed. Of the 178 patients, 6% (11 out of 178) were infected with strains of Mycobacterium tuberculosis resistant to both isoniazid and rifampin.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection.

The annual number of cases of culture-proven extrapulmonary tuberculosis (TB) at our hospital increased from 47 cases in 1983 to 113 cases in 1988. At least 43% (199) of 464 consecutive patients with extrapulmonary TB during this 6-year period were infected with the human immunodeficiency virus (HIV); since HIV serologic testing was not performed routinely the true HIV prevalence is likely to be higher. Of the HIV-infected patients, 59% were intravenous drug users, 31% were Haitian, 3% were homosexual males, 1% were perinatally-infected infants, and 6% did not have a known risk factor for HIV infection. Ninety-eight percent of the HIV-infected patients were black (84%) or hispanic (14%). The HIV-infected patients were more likely than the control patients to have either disseminated, genitourinary, intra-abdominal, mediastinal, or concurrent pulmonary TB. Fever was nearly universal among the HIV-infected patients, but was absent in about one-third of the control patients. Among untreated HIV-infected patients, disease progression was rapid and nearly always fatal. Among HIV-infected patients who received treatment, the response to therapy, as judged by hospital survival and time to defervescence, was similar to that of the control patients. Despite the extensive tuberculous dissemination among the HIV-infected patients, the diagnosis of TB was difficult and often delayed. In addition to the decrease in tuberculin reactivity and the atypical chest radiograph patterns, there was a need to consider other HIV-related infections in the differential diagnosis. Although sputum specimens grew M. tuberculosis in greater than 90% of the HIV-infected patients in whom they were obtained, sputum AFB stains were positive in less than 50%. Blood and urine specimen cultures were positive in 56% and 77% of the HIV-infected patients in whom these specimens were obtained, but did not provide a means of early diagnosis. Cerebrospinal fluid and pleural fluid were abnormal in nearly all patients with involvement of these sites but were rarely AFB-positive and were, therefore, only suggestive of TB. Procedures such as biopsies and aspirates of peripheral lymph nodes, visceral lymph nodes, liver, and bone marrow provided the highest immediate diagnostic yields with rates between 50% and 90%. These procedures must be considered early in the course of illness in HIV-infected patients with suspected extrapulmonary TB due to the rapidly progressive nature of this often fatal but usually treatable infection.

Acquired Immunodeficiency Syndrome↗