Viral resistance testing: practical issues and future opportunities - interview with Thomas Merigan, M.D. Interview by John S. James.
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Anti-HIV Agents↗
Biomedical subjects
T Merigan
Publications and source records attributed to T Merigan.
Human immunodeficiency virus reverse transcriptase codon 215 mutations diminish virologic response to didanosine-zidovudine therapy in subjects with non-syncytium-inducing phenotype.
Eight zidovudine-experienced subjects received zidovudine and didanosine for 30 weeks followed by 30 weeks of didanosine monotherapy. At study entry, plasma from 4 subjects had human immunodeficiency virus RNA pol T215Y/F mutant and 4 had codon 215 wild type. All 8 subjects had non-syncytium-inducing virus phenotype. Sustained 10-fold decreases in plasma RNA levels were seen only in subjects who initially had 215 wild type RNA, despite the development of a T215Y/F mutation during combination therapy. Virologic and immunologic benefits were maintained in this group with didanosine monotherapy. No subject developed a pol L74V codon mutation. Significant differences in plasma virus load and CD4 cell responses were seen in this zidovudine-didanosine combination pilot study relative to codon 215 genotype.
Acquired Immunodeficiency Syndrome↗
The tolerability and pharmacokinetics of N-butyl-deoxynojirimycin in patients with advanced HIV disease (ACTG 100). The AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases.
Twenty-nine patients were enrolled in a phase I dose-escalating tolerance trial of N-butyl-deoxynojirimycin, an alpha-glucosidase I inhibitor that inhibits human immunodeficiency virus (HIV)-1 replication by altering glycosylation of gp120. Dosing was begun at 8 mg/kg/day and subsequent doses were 16, 32, 48, and 64 mg/kg/day. The maximum tolerated dose was not achieved because of slow accrual and because the study was stopped after the finding of cataracts in initial long-range rat toxicology studies. These cataracts were later shown to be transient and not found in other animals. The most common side effects were gastrointestinal, with diarrhea and flatulence occurring in most subjects, which seemed to partially improve on a modified diet that excluded complex carbohydrates. Grade III elevations in liver function tests were seen in two patients. Grade III leukopenia and neutropenia were seen in seven patients, but were only severe enough in two to require discontinuation. No significant trends in CD4 cell counts or HIV-1 p24 levels were noted.
1-Deoxynojirimycin↗
Safety, pharmacokinetics, and antiviral response of CD4-immunoglobulin G by intravenous bolus in AIDS and AIDS-related complex.
To assess the safety, pharmacokinetics, and antiviral effects of intravenous recombinant CD4 immunoglobulin G (CD4-IgG), a 12-week Phase One study with an optional maintenance phase was performed. Twenty-two subjects with advanced human immunodeficiency virus (HIV) infection were enrolled; 15 subjects completed the initial 12 weeks. CD4-IgG doses were 30, 100, or 300 micrograms/kg weekly; 1,000 micrograms/kg once, twice, or three times per week; or 3,000 micrograms/kg twice weekly. Serum concentrations of CD4-IgG increased linearly with dose, with average peak serum concentrations of 22 micrograms/ml with 1,000 micrograms/kg. CD4-IgG was well tolerated; one patient had self-limited tachycardia and flushing associated with CD4-IgG therapy. No changes were seen in CD4 cell counts, hematologic or coagulation studies, serum chemistries, HIV p24 antigen titers, or plasma HIV titers. No subject developed anti-CD4 antibodies. HIV isolates from five patients had IC90 values that were higher than the peak concentrations of CD4-IgG achieved in those patients. Additional studies that achieve higher CD4-IgG concentrations are necessary to evaluate the antiviral activity of this compound.
AIDS-Related Complex↗
Individualization of therapy using viral markers.
Early intervention with a combination of drugs is generally accepted as the way forward in the management of HIV infection. In general, combination therapy should include agents that demonstrate additive or synergistic activity, do not have similar side-effect profiles, and avoid cross-resistance. Use of these criteria will no doubt lead to the development of more effective combinations. However, it is well known that patients respond to therapy in very different ways. A number of trials have provided clear examples of the individualized nature of patient responses to therapy and have also demonstrated that the use of measures such as viral load and CD4 cell count, in conjunction with phenotypic and genotypic characterization of emerging viral strains, may significantly enhance our ability to predict disease progression. A number of methods are becoming available to quantify accurately viral load, and new methodologies such as the Affymetrix chip-sequencing technique will allow quick detection of genotypic alterations known to be associated with disease progression, such as the appearance of resistance mutations. These developments now enable us to conduct clinical trials to assess the impact of an individualized approach to therapy, i.e., the changing of treatment regimens based on the identification of resistance markers, changes in viral load and CD4 cell count, and conversion from non-syncytium-inducing to syncytium-inducing phenotype. It is hoped that studies conducted in the near future will show that an approach of gaining maximal benefit from one treatment regimen before moving on to another, as a result of genotypic or viral load markers, will prevent destruction of the immune system and will ultimately prolong the well-being and survival of patients with HIV infection.
Antiviral Agents↗
Zidovudine and dideoxycytidine differ in their effects on human immunodeficiency virus-induced pathologic activation of the immune system. AIDS Clinical Trial Research Group 047.
When zidovudine and dideoxycytidine (ddC) were given on schedules of 1 week on drug and 1 week off, results differed substantially in effects on HIV (human immunodeficiency virus type 1)-induced immune activation. Zidovudine (200 mg every 4 h) caused marked lowering toward normal of serum neopterin and beta 2-microglobulin within 1 week. This effect was lost within 1 week off zidovudine. Intermittent ddC (0.03 mg/kg every 4 h) had a smaller 1-week effect but had a delayed cumulative suppressive effect on HIV-associated immune activation that was not seen with intermittent zidovudine therapy. Zidovudine and ddC given in alternating weeks had synergistic effects in the first 10 weeks (e.g., early and rapid reduction followed by cumulatively greater effects on immune cell activation). The identical sawtooth effect of intermittent zidovudine was also evident in serum HIV p24 antigen levels. This is consistent with the hypothesis that the increased serum levels of the immune activation markers seen in HIV infection reflect stimulatory effects of HIV viral components on immune system cells.
Acquired Immunodeficiency Syndrome↗
2',3'-dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients.
We administered the antiviral agent 2',3'-dideoxycytidine (ddC) to HIV-infected patients with either ARC or AIDS as part of the AIDS Clinical Treatment Group protocol 012 and serially evaluated them with neuropathic symptom questionnaires, neurologic examinations, nerve conduction studies, and quantitative sensory testing (QST). All patients treated with high-dose ddC (0.06 and 0.03 mg/kg every 4 hours) developed a painful, predominantly sensory peripheral neuropathy, with a mean onset of 7.7 weeks, which reached severe intensity over several days. Abnormalities of vibration QST threshold preceded clinical symptoms. Treatment with 0.01 mg/kg every 4 hours produced a similar neuropathy, although of milder severity, later onset (mean, 9.3 weeks), and slower progression. In these patients, the onset of clinical symptoms and QST abnormalities were coincident. Only two of six patients treated with 0.005 mg/kg every 4 hours developed clinical or laboratory evidence of neuropathy; in both cases it was very mild and delayed in onset (26 weeks). All patients treated with high-dose ddC reported progression of symptoms (coasting) for 2 to 3 weeks following discontinuation of therapy. This study documents a painful sensory neuropathy resulting from treatment with ddC. With high-dose treatment, only the rapidity of onset and progression differentiated it from the distal, predominantly sensory neuropathy of AIDS.
HIV Infections↗
Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient.
This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam. Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. Zidovudine concentrations were determined by radioimmunoassay. Oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p = 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p = 0.25), and 1.38 h versus 1.15 h (p = 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h, p = 0.16). The mean pharmacokinetic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Intermittent, alternating, and concurrent regimens of zidovudine and 2'-3' dideoxycytidine in the LP-BM5 murine induced immunodeficiency model.
The murine retrovirus-induced immunodeficiency model, LP-BM5, was used to evaluate the efficacy of intermittent and alternating regimens of zidovudine (azido-2'-3'dideoxythymidine; AZT) and 2'-3' dideoxycytidine (ddC) compared with continuous and concurrent therapy. Intermittent oral AZT therapy was less effective in protecting mice inoculated with LP-BM5 virus than was continuous oral AZT therapy. Continuous oral ddC therapy (80 mg/kg/day) increased survival time an average of 3.5 weeks (P less than .001) compared with that in untreated LP-BM5-infected mice. Alternating weekly AZT and ddC therapy, which increased survival time 3.5 weeks (P less than .001), was more effective than either therapy administered intermittently, although not additive or synergistic. Concurrent AZT and ddC therapy was no more effective than continuous AZT therapy alone in this model, with a 4.4-week increase in survival time (P less than .001).
Administration, Oral↗
Human cytomegalovirus glycoprotein-receptor interactions.
The HCMV envelope glycoprotein having a molecular weight of 86 kd, gH, has been shown to react with a 92 kd protein that can be extracted from HEL fibroblasts. This HCMV-gp86 membrane receptor appears to be present on the surface of both HCMV-permissive and HCMV-non-permissive cells, suggesting that there are factors in addition to viral attachment governing the intracellular replicative process. Another HCMV envelope glycoprotein (gp130/55; gB homologue) binds predominantly to a 31 kd protein with minor bands at 180, 96, and 90 kd. HCMV-gp86 does not bind to the principal gp130/55 receptor.
Antibodies, Monoclonal↗
Clinical trials of combination therapies for HIV infection. Discussion.
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Acquired Immunodeficiency Syndrome↗
Cytomegalovirus infection and abnormal T-lymphocyte subset ratios in homosexual men.
T-helper:T-suppressor cell ratios of 1 or less were found in 2 of 42 homosexual men without antibodies to cytomegalovirus but in 33 of 67 homosexual men with antibodies (p less than 0.001). Of 34 men without antibody who were followed prospectively, 12 became seropositive for cytomegalovirus and all 12 developed helper: suppressor ratios of less than 1.0. These ratios remained at 1 or less for an average of 9.6 months but persisted for 15 months or more in 3 men. None of the men in the prospective study developed antibodies to the acquired-immunodeficiency-syndrome-associated retrovirus. These results indicate that in the homosexual men studied, abnormally low T-lymphocyte helper: suppressor ratios occurred almost exclusively in those who were infected with cytomegalovirus, and in those prospectively followed low ratios did not reflect contact with the syndrome-associated retrovirus. Abnormal ratios were rarely seen in men who had never been exposed to cytomegalovirus. Thus, cytomegalovirus infection may be an important cofactor in the immunologic disorders leading to the acquired immunodeficiency syndrome.
Antibodies, Viral↗
Phase I evaluation of a synthetic mutant of beta-interferon.
A synthetic mutant of beta-interferon, produced by recombinant DNA technology, was prepared with serine substituted for the naturally occurring cysteine at amino acid 17. This molecule, after purification to homogeneity, was evaluated in 23 patients with cancer for tolerated doses, safety, and pharmacokinetics. Each patient was begun on twice weekly administration, one dose i.m., then an identical dose i.v. Doses, escalated weekly, were tolerated by 9 of 12 patients at 100 X 10(6) units i.m., 11 of 14 patients at 100 X 10(6) units i.v., and 8 of 10 patients receiving i.v. doses of 200 X 10(6) units. Fever (greater than or equal to 38.9 degrees C), the commonest cause for ceasing dose escalation, occurred in 11 of 13 patients who developed limiting i.v. toxicity and 6 of 11 who developed limiting i.m. toxicity. Patients who did not have progressive cancer after completion of dose escalation received five consecutive daily doses at their maximum tolerated single dose by each route, i.m. and i.v. These two 5-day treatments were given without difficulty. All patients treated with 300 X 10(6) units or less, i.m. (n = 13) or i.v. (n = 10), were able to receive five daily doses without limiting toxicity. Peak serum titers occurred immediately after i.v. administration and declined in an exponential manner thereafter. Despite absence of measurable titers in serum after i.m. injection, fever and significant (P less than 0.05) depression of WBC and platelet counts, serum calcium, and serum cholesterol occurred (prestudy to maximum tolerated dose). An immunoglobulin antibody to beta-interferon, detected by enzyme-linked immunoabsorbent assay, developed in 17 of 23 patients. Neutralizing activity (titer 10(2] was found in only 1 of 23 patients. No immune-mediated sequelae (symptomatic or renal) were identified. Further Phase I and II trials with this molecule will determine whether it will prove to have a better therapeutic index or different spectrum of therapeutic activity from alpha-interferon or gamma-interferon.
Adult↗
Collaborative phase I-II study of recombinant DNA-produced leukocyte interferon (clone A) in metastatic breast cancer, malignant lymphoma, and multiple myeloma.
Fifty-two patients with advanced cancer received sequentially escalating doses of 3 to 50 million units of recombinant DNA-produced alpha interferon by daily intramuscular injection. There were 23 patients with metastatic breast cancer, 17 patients with nodular poorly differentiated lymphocytic lymphoma, and 12 patients with multiple myeloma. Complete and partial remissions were obtained in 35 percent of patients with nodular poorly differentiated lymphoma, whereas rare activity was found in breast cancer and multiple myeloma. Dose-limiting toxicity occurred in patients receiving 36 million units or more and consisted of fatigue/asthenia, weight loss, and elevation of transaminase levels, requiring frequent interruption, reduction in dose, or cessation of treatment. Hematologic toxicity was rarely a limiting factor, but myelosuppression was severe in some patients with multiple myeloma. All toxicities were reversible on discontinuation of treatment. Antibodies to recombinant leukocyte A interferon were seen infrequently but may adversely affect therapy.
Adult↗
Regulation of expression of class II major histocompatibility antigens on human peripheral blood monocytes and Langerhans cells by interferon.
Although normal peripheral blood monocytes from different individuals are primarily DR+ (L243), they vary in the mean expression of L243 and the percentage of cells with detectable Leu-10 (DC/DS) and L03 (D). All three species of human recombinant IFNs enhance Ia expression on normal peripheral blood monocytes; however, r-IFN-gamma is much more effective in enhancing the expression of these three class II antigens in vitro than r-IFN-beta or r-IFN-alpha A. In addition, r-IFN-gamma has a more profound effect on the expression of Leu-10 (DC/DS), an antigen critical for presentation in autologous MLR, than on L243 (DR). Adherent monocytes cultured for 5 days develop macrophage characteristics and become strongly positive for all three of these class II antigens without further manipulation. Isolated skin Langerhans cells which are thought to be antigen presenting cells in the epidermis are also strongly positive for all three of these Ia antigens and are unaffected by IFN treatment. Therefore, this early interferon effect on cell surface expression may be the result of enhancing the maturation of monocytes to mature antigen presenting cells.
Adult↗
Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients.
Sixteen patients with advanced cancer were treated with recombinant-DNA-produced pure leukocyte A interferon (IFLrA) intramuscularly in doses ranging from 3 to 198 X 10(6) units. with interval periods of 72 to 96 hours between doses. At the two lowest doses of 3 and 9 million units, there was a cross-over evaluation between IFLrA and partially pure leukocyte interferon (IFN-C) produced from human cells. THe maximum observed serum concentration of IFLrA measured by enzyme immunoassay and bioassay increased with increasing doses. The mean serum concentrations of IFLrA and IFN-C were similar. Clinical effects produced by IFLrA and IFN-C were similar, including fever, chills, myalgias, headache fatigue, and reversible leukopenia and granulocytopenia. Eight patients had transient and mild numbness of the hands or feet, or both. Three patients developed low titers of antibody to IFLrA, Seven of 16 patients showed objective evidence of tumor regression during the study.
Adult↗
Inhibition of lymphoma hybrids by human interferon.
A set of stable mouse-human hybrids was constructed from the neoplastic lymphocytes from a patient with nodular lymphoma and from another with chronic lymphocytic leukaemia. Both patients had shown a clinical response to human leucocyte interferon. The same interferon preparation inhibited the growth rate of 14 out of 17 established hybrid cell lines. This system provides evidence of a direct growth inhibitory effect of interferon on neoplastic B lymphocytes. Such a system could be used to predict the sensitivity of a patient's tumour before therapy.
Aged↗