Intermittent tuberculosis treatment for patients with isoniazid intolerance or drug resistance.

SETTING: Twenty tuberculosis (TB) clinics in the United States and Canada. OBJECTIVE: To evaluate the efficacy and safety of a 6-month intermittent regimen of rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB) in human immunodeficiency virus (HIV) negative patients with culture-confirmed pulmonary or extra-pulmonary tuberculosis and either isoniazid (INH) resistance or INH intolerance. DESIGN: Patients were enrolled in a single-arm clinical trial to receive intermittent dosing after at least 14 initial daily doses of RMP+PZA+EMB. Treatment was continued twice (BIW) or thrice weekly (TIW) per physician/patient preference for a total of 6 months, with 2 years of follow-up for relapse after treatment. RESULTS: From 1999 to 2004, 98 patients were enrolled, 78 with reported INH resistance and 20 with INH intolerance. BIW dosing was used in 77 and TIW in 21. Study treatment was completed in 73 (74%). Reasons for discontinuation were hepatic adverse events (n= 12), other adverse effects (n= 3) and other reasons (n= 10). Failure (n= 1) and relapse (n= 2) occurred in 3 (3.5%, 95%CI 1.2-9.8) of 86 patients eligible for efficacy analysis, all occurring in patients with cavitary, acid-fast bacilli smear-positive pulmonary TB. CONCLUSIONS: Intermittent RMP+PZA+EMB appears to be effective in HIV-negative patients, but the regimen is poorly tolerated, possibly due to the prolonged use of PZA. Alternative regimens of lower toxicity are needed.

Reasons for non-participation in an international multicenter trial of a new drug for tuberculosis treatment.

SETTING: Clinical trials can provide a high standard of patient care and contribute to scientific knowledge; however, only a fraction of the patients screened participate and receive treatment as part of a trial. OBJECTIVE: To explore reasons why patients were not enrolled in an international tuberculosis (TB) treatment trial and to compare experiences among study sites. DESIGN: An analysis of reasons why patients were not enrolled was conducted among patients screened for a TB clinical trial at 26 sites in North and South America, Africa, and Europe. RESULTS: Staff at study sites screened 1119 potential candidates for the trial: 61% (n = 686) were not enrolled due to 1) failure to meet eligibility criteria (n = 405, 59%), 2) site's decision (n = 168, 24%), or 3) candidate's choice (n = 113, 16%). Study staff recorded a total of 144 reasons for why they believed patients chose not to participate, including concerns over research (28%), conflicts with work or school (21%), and lifestyle and family issues (20%). Socio-demographic and geographic factors also influenced participation. CONCLUSION: Increased evaluation of screening outcomes and of specific interventions, such as improved education and communication about trial procedures, may increase the efficiency of screening and enrollment in clinical trials.

Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium.

BACKGROUND: Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin. The US Public Health Service Study 22 compared a once-weekly regimen of isoniazid and rifapentine with twice weekly isoniazid and rifampin in the continuation phase (the last 4 months) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients. This report concerns only the HIV-seropositive part of the trial, which has ended. The HIV-seronegative part will stop follow-up in 2001. METHODS: Adults with culture-positive, drug-susceptible pulmonary tuberculosis who completed 2 months of four-drug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase) were randomly assigned 900 mg isoniazid and 600 mg rifapentine once weekly, or 900 mg isoniazid and 600 mg rifampin twice weekly. All therapy was directly observed. Statistical analysis used univariate, Kaplan-Meier, and logistic and proportional hazards regression methods. FINDINGS: 71 HIV-seropositive patients were enrolled: 61 completed therapy and were assessed for relapse. Five of 30 patients in the once-weekly isoniazid/rifapentine group relapsed, compared with three of 31 patients in the twice-weekly isoniazid/rifampin group (log rank chi2=0.69, p=0.41). However, four of five relapses in the once-weekly isoniazid/rifapentine group had monoresistance to rifamycin, compared with none of three in the rifampin group (p=0.05). Patients who relapsed with rifamycin monoresistance were younger (median age 29 vs 41 years), had lower baseline CD4 cell counts (median 16 vs 144 microL), and were more likely to have extrapulmonary involvement (75% vs 18%, p=0.03) and concomitant therapy with antifungal agents (75% vs 9%, p=0.006). No rifamycin monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled to date. INTERPRETATION: Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly isoniazid/rifapentine continuation-phase regimen. Until more effective regimens have been identified and assessed in clinical trials, HIV-seropositive people with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine regimen.

Lack of correlation between human herpesvirus-6 infection and the course of human immunodeficiency virus infection.

Human herpesvirus-6 (HHV-6) and human immunodeficiency virus (HIV) are both tropic for CD4+ lymphocytes. To determine whether HHV-6 infection affects the susceptibility to or the course of HIV infection, HHV-6 titers were measured by an anticomplement immunofluorescence assay in serum of three groups of homosexual or bisexual men: (1) those with AIDS (n = 78), (2) those with HIV-associated lymphadenopathy (LAS; n = 81), and (3) those who were HIV-seronegative (n = 55). Early and late serum samples were available for 45 men with LAS (median interval 49 months). Men with early LAS did not differ from HIV-seronegative men in either the percentage that were HHV-6-seropositive or in the distribution of titers. There was a significantly lower percentage of seropositives in AIDS patients than in the other two groups (P less than .01). LAS patients who progressed to AIDS did not differ in percentage seropositivity or distribution of titers from nonprogressors. HHV-6 titers tended to decrease over time. HHV-6 titers late in LAS were similar to those in AIDS patients. These findings suggest that it is unlikely that previous exposure to HHV-6 either predisposes to or affects the course of HIV infection.

Deterioration in immunologic status of human immunodeficiency virus (HIV)-infected homosexual men with lymphadenopathy: prognostic implications.

Changes in immunologic parameters were followed in members of a cohort of human immunodeficiency virus (HIV)-positive homosexual or bisexual men with lymphadenopathy and were analyzed for differences between those who have and those who have not progressed to the acquired immunodeficiency syndrome (AIDS) (progressors, nonprogressors). T helpers and the Th/Ts ratio were lower in progressors than in nonprogressors both at entry into the study and at the latest visit. T suppressors were not different in the two groups at entry but were higher in nonprogressors at the latest visit. Evaluation of the patterns of change over time showed that T helpers and Th/Ts ratios tended to decrease over time in both nonprogressors and progressors, while T suppressors increased in nonprogressors and decreased in progressors. Although progressors had a greater deterioration in immunologic parameters over time, nonprogressors also had significant deterioration when compared with controls. Based on the respective percentages of men with abnormal or normal T helpers or Th/Ts ratio at entry who have already progressed to AIDS, we would conservatively estimate, considering their latest T helpers and Th/Ts ratio, that at least an additional 16 (32%) of our nonprogressors will develop AIDS in the next 5 years.

A six-year follow-up of HIV-infected homosexual men with lymphadenopathy. Evidence for an increased risk for developing AIDS after the third year of lymphadenopathy.

Seventy-five homosexual men with generalized lymphadenopathy for at least three months (lymphadenopathy syndrome [LAS]), subsequently shown to be seropositive for antibody against human immunodeficiency virus, were enrolled in a prospective study in Atlanta in 1982 and 1983. As of Nov 30, 1987, twenty-two (29%) of the 75 were known to have developed acquired immunodeficiency syndrome (AIDS) three to 60 months after enrollment and five to 69 months after onset of LAS. The six-year cumulative incidence of AIDS, by Kaplan-Meier survival analysis, was 38%. The cumulative incidence in years 4, 5, and 6 (30%) was significantly higher than in years 1, 2, and 3 (11%), suggesting that the risk for AIDS increases after the third year of LAS and that many more study participants will eventually develop AIDS. A precipitous decline in the T-helper cell count frequently heralds the diagnosis of AIDS; this decrease appears to occur at different times after the onset of LAS in different persons. The four-year cumulative incidence of AIDS following observations of T-helper cell counts less than 200/mm3, 200 to 299/mm3, 300 to 399/mm3, and 400/mm3 or greater was 84%, 41%, 25%, and 18%, respectively; these data are important for determining prognosis in the individual patient as well as for determining the suitability of candidates and baseline data for drug trials.

Micromethod for assaying reverse transcriptase of human T-cell lymphotropic virus type III/lymphadenopathy-associated virus.

A micromethod for assaying the reverse transcriptase enzyme of human T-cell lymphotropic virus type III/lymphadenopathy-associated virus in cocultures of clinical specimens for viral isolation was developed and compared with the macromethod in use. Ultracentrifuged, pelleted, and solubilized viral culture supernatants were transferred into either tubes (macromethod) or microtiter plates (micromethod) and incubated with tritiated enzyme substrate. Trichloroacetic acid-precipitated DNA was collected on individual filter papers with a Millipore filtration manifold (macromethod) or on filter sheets using a semiautomated cell harvester (micromethod). Filters were then placed in scintillation fluid and counted on a beta scintillation counter. Results of the micromethod significantly correlated to those of the macromethod, with a linear relationship between the two. The cutoffs for positivity based on the mean + 2 standard deviations for a set of known negative specimens (n = 19) was 4,973 cpm for the micromethod compared with 5,336 for the macromethod. The intrarun and interrun variations were comparable for both methods. There was a 67% increase in the maximal daily number of specimens which could be run (100 versus 60) as well as a reduction in reagent use. In summary, the micromethod utilizing a semiautomated cell harvester is comparable to the existing macromethod in accuracy and is an improvement due to savings in time and reagents.

Effects of exposure to factor concentrates containing donations from identified AIDS patients. A matched cohort study.

We compared recipients of eight lots of factors VIII and IX voluntarily withdrawn from distribution because one donor was known to have subsequently developed the acquired immunodeficiency syndrome with a nonexposed cohort matched by age, sex, and factor use. The factor VIII recipient cohorts did not differ in prevalence of antibody to human immunodeficiency virus (HIV) (exposed, 75%; nonexposed, 86%), T-cell subset numbers (median: exposed, 619 T-helper cells per cubic millimeter; nonexposed, 659 T-helper cells per cubic millimeter), T-helper to T-suppressor ratios, or immunoglobulin levels. Exposed individuals had higher levels of immune complexes by C1q binding and staphylococcal binding assays and lower responses to phytohemagglutinin and concanavalin A. However, only the staphylococcal binding assay values were outside the normal range for our laboratory. Factor IX recipient cohorts did not differ in HIV antibody prevalence (exposed, 30%; nonexposed, 40%) or any immune tests. Although exposed and nonexposed individuals did not differ from each other in a clinically meaningful fashion at initial testing, both the exposed and nonexposed cohorts had high rates of HIV seroprevalence. Market withdrawals were clearly insufficient means of limiting the spread of HIV in hemophilic patients; however, the currently available methods of donor screening and viral inactivation of blood products will prevent continued exposure within this population.

Investigations of budgerigar fledgling disease virus.

The DNA of a papovavirus associated with budgerigar fledgling disease was purified and cloned into plasmid pBR322. The genome was circular and approximately 5.1 kilobases long. Physical mapping of the genome with restriction endonucleases revealed little similarity to simian virus 40 or polyomavirus DNA. Transformation trials using murine 3T3 cells were negative. Attempts to characterize proteins were unsuccessful due to the apparent close association of the virus and host cell components.

Mycoplasma challenge studies in budgerigars (Melopsittacus undulatus) and chickens.

An upper respiratory condition that resulted in 20% mortality in a flock of yellow-naped Amazon parrots was apparently caused by a concomitant infection of mycoplasmas and bacteria. Mycoplasma gallisepticum (MG), M. iowae, and an unidentified mycoplasma were isolated from the affected parrots. Budgerigars were experimentally infected with a parrot strain of MG designated MG(P) 1669 as well as with the R strain of MG and the F10-2 strain of M. synoviae (MS). Air-sac lesions were evident in all groups of challenged budgerigars, and MS and MG were cultured from the tracheas, air sacs, and lungs of the budgerigars up to 5 weeks postexposure. Serological findings were ambiguous and therefore considered unreliable. White leghorn and commercial broiler chickens challenged with the MG(P) 1669 isolate did not exhibit any significant air-sac lesions relative to the controls. However, MG was cultured from both groups of experimentally infected birds. Eight weeks after exposure, the white leghorns were seropositive to all MG antigens used in the agglutination test.

A light and electron microscopic examination of budgerigar fledgling disease virus in tissue and in cell culture.

Morphological changes induced by a newly described avian virus in budgerigar (Melopsittacus undulatus) tissues were examined with light and electron microscopes. Infected cells viewed with the light microscope were found to have enlarged nuclei containing marginated chromatin. Cytoplasmic contents were frequently clear in appearance. Tissues affected included skin, feather, follicle, kidney, uropygial gland, crop, lung, liver, heart, bone marrow, spleen and brain. Serum from infected birds contained viral particles. No tumours were found in affected birds. Electron microscopy demonstrated viral particles that were naked, predominantly icosehedral, and 42-49 nm in diameter. Occasional elongate forms of the virions were seen in kidney tissue. Small groups of virions were occasionally enclosed within nuclear and cytoplasmic membranes. Viral particles were observed in chicken embryo fibroblast cultures 18 hours post-inoculation. The particles first appeared in swollen nuclei and subsequently were found in the cytoplasm of more senescent cells. Cytoplasmic disruption and swollen rough endoplasmic reticulum were also observed in infected cells. Negatively stained preparations of the fluid from infected chicken embryo fibroblast cultures contained typical cubic viral particles as well as elongate forms similar to those seen in excised tissue preparations.

Characterization of a papovavirus isolated from fledgling budgerigars.

A virus suspected of causing high death rates in fledgling budgerigars in Georgia and Texas aviaries was isolated in budgerigar embryo fibroblasts inoculated with tissue homogenates from affected birds. Virus was most easily recovered from tissues containing many intranuclear inclusion bodies. Cytopathic effect on fibroblasts of all four isolates was characterized by a swollen nucleus followed by rounding and detachment of the affected cell from the monolayer. Properties suggesting the B-931 isolate belongs to the papovaviridae family are (1) presence of DNA; (2) insensitivity to treatment with CHCl3; and (3) presence of cubic viral particles 42 to 49 nm in diameter in the nucleus of infected chicken embryo fibroblasts. The isolate did not hemagglutinate erythrocytes of chickens, turkeys, budgerigars, guinea pigs, or type O humans and was basically stable against heating and freeze-thawing. An examination of fledgling budgerigars from infected aviaries demonstrated that sick birds carried more virus than healthy birds.

A viral disease of fledgling budgerigars.

Fledgling budgerigars from aviaries in Georgia and Texas were reported to have high rates of mortality. Affected birds died acutely and exhibited abdominal distention and reddening of the skin. Postmortem lesions were hydropericardium, enlarged heart and liver with areas of necrosis, and swollen, congested kidneys. Histologic examination of a variety of tissues revealed cells with enlarged nuclei containing inclusions. Electron micrographs revealed the presence of viral particles 42 to 49 nm in diameter in the nuclei of epithelial cells of the renal tubule.