Brigitte P. Griffith

A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease

A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2,3-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy.

efficacy and Safety of Delavirdine Mesylate With Zidovudine and Didanosine Compared With Two-drug Combinations of These Agents in Persons With Hiv Disease With Cd4 Counts of 100 to 500 cells/mm3 (actg 261)

To evaluate the antiretroviral activity of delavirdine mesylate, a non-nucleoside reverse transcriptase inhibitor of HIV-1, we performed a phase II, randomized, double-blind, multicenter trial comparing the three-drug combination of delavirdine with zidovudine and didanosine to two-drug combinations of these drugs. Patients with CD4 cell counts between 100 and 500 cells/mm3 without prior or <6 months of monotherapy with zidovudine or didanosine were randomized to one of four arms and observed on a follow-up basis for 48 weeks. In total, 544 patients were evaluated. In those assigned to the three-drug regimen, mean short-term (weeks 4-12) and long-term (weeks 40-48) change in CD4 cells from baseline were 49.3+/-8.1 and 65.4+/-13.4 cells/mm3, respectively; mean short-term and long-term HIV-1 RNA changes from baseline were -1.13 log10+/-0.12 and -0.73+/-0.12 copies/ml, respectively. These responses in CD4 cell counts and HIV-1 RNA levels were better in comparisons with each of the two-drug arms at all study points; however, differences were not consistently significant. Gastrointestinal side effects were experienced by 33% of patients (178 of 544), and 30% (121 of 407) receiving delavirdine experienced rash, only one case of which was severe. In this study, therapy with delavirdine + zidovudine + didanosine was safe and showed modest, but not always significant, antiviral activity and CD4 cell count benefit compared with two-drug regimens with these agents. Key

Mechanisms of Injury to the Central Nervous System Following Experimental Cytomegalovirus Infection

A guinea pig model was used to determine the mechanisms of injury to the central nervous system by cytomegalovirus. Focal, well-contained, histopathologic responses included the microglial nodule without residua, and the ependymitis with focal residual glial scarring. Higher virus dose infection in the brain resulted in inflammatory necrosis with an astrocytic response to injury. However, monocytes and microglia were the predominant responding cells of host defense. A vasogenic pathogenesis was suggested by the involvement of the vascular endothelium, and separately by central nervous system vasculitis, demonstrated here for the first time in this model. Hence, our studies suggest four potential mechanisms of injury to the central nervous system by cytomegalovirus: viral cytopathology, inflammatory mediators from cells of the monocyte series, two separate types of vascular impairment, and astroglial scarring.

Evolution of Genotypic Resistance Algorithms and Their Impact on the Interpretation of Clinical Trials: An OPTIMA Trial Substudy

Abstract Purpose: The outdated rules of older HIV genotypic resistance algorithms can affect virologic responses. This study was designed to determine how often these incorrect resistance interpretations affect analyses of long–term clinical trials, antiretroviral (ARV) choices, and HIV disease progression rates. Method: Baseline VIRCO virtual phenotypes (VVP) from patients screened in 2001–2002 for OPTIMA were compared to 2005 Stanford HIV resistance database algorithm (HIVDB–10/05, version 4.1.4) interpretations of the HIV–1 pol sequences. Drugs were called discordant if resistant by one algorithm and sensitive by the other. Results: Of 2,341 drug comparisons, 501 (21.4%) were discordant, affecting 140 (86.4%) of 162 screened patients. NRTI/NtRTIs were more discordant than NNRTIs and PIs (38.6% vs. 4.3% vs. 12.8%; p < .0001). Sixty-nine (53%) patients were placed on ≥2 drugs reported as sensitive by VVP but resistant by HIVDB–10/05; they had higher than expected rates of disease progression and a similar time to first event or death as patients on ARVs classified as resistant by both algorithms (p = .61). Conclusions: Underestimation of drug resistance by older genotypic algorithms resulted in using ARVs incorrectly thought to be sensitive and in higher than expected rates of HIV disease progression. The use of older genotypes to interpret long–term clinical trials should account for this underestimation, because results may be different if viral sequences are interpreted with newer algorithms.

Comparison of enzyme-linked immunosorbent and indirect immunofluorescence assays for the detection of human T-cell lymphotropic virus type-I antibodies in sera from rural Haiti

Serum samples were obtained from 340 healthy individuals without evidence of neurologic disease living in rural Haiti. Sera were screened for antibodies to human T-cell lymphotropic virus type I (HTLV-I) using two commercially available enzyme immunoassays (EIA) and by an indirect immunofluorescence assay (IFA) using a mixture of uninfected H9 cells and HTLV-I-infected MT-2 cells. Repeatedly positive samples were confirmed by Western blot (WB). Results with the two EIA systems were concordant and detected 13 positive samples, each of which was confirmed by WB. Only 9 (69%) of 13 WB-positive sera were detected by IFA, and four additional samples, positive by IFA, could not be confirmed by WB. The prevalence of HTLV-I seropositivity in this selected rural Haitian population was 3.8% (13 of 340).

Persistence and expression of herpes virus in guinea pig B and T spleen cells.

Summary The role of spleen lymphocytes in acute and latent guinea pig herpes-like virus (GPHLV) infection and the in vitro susceptibility of the lymphocytes to GPHLV were explored. Macrophage-, B-cell-, and T-cell-enriched populations obtained from infected guinea pigs were examined for infectious GPHLV. During acute infection, virus was first detected in the macrophage and B-cell fractions, whereas, infectious virus was only evident in the T-cell fraction 5 days or more after inoculation. During latent infection, infectivity titers in the B fractions were consistently higher than in the T fractions. In both the B and the T lymphocytes derived from latently infected guinea pigs, virus was expressed only after in vitro cultivation or cocultivation with susceptible cells. Lymphocytes infected in vitro did not support GPHLV replication, although latent infection of lymphocytes with GPHLV was readily accomplished in vivo. We thank Christine Cote for excellent technical assistance. This research was partially supported by a Research Training Grant 5 T32 AI 07018 from the Institute of Allergy and Infectious Diseases, National Institutes of Health, and by the Medical Research Service of the Veterans Administration.

Immunoblot analysis of the humoral immune response to cytomegalovirus in non-pregnant and pregnant guinea pigs

SummaryThe temporal appearance of antibodies to guinea pig cytomegalovirus (CMV) proteins was examined in pregnant and non-pregnant guinea pigs by immunoblotting. Antibodies to 12 guinea pig CMV proteins appeared in a defined time course during primary infection and were detected at a later time and in lower concentrations in pregnant than in non-pregnant guinea pigs.

Monocyte-mediated immunosuppression in chronic multiple sclerosis: implications for therapy

The goal of immunotherapy in multiple sclerosis (MS) is to halt disease progression by correcting an immunologic abnormality. The experiments described here sought an abnormality of immunoregulation. Specifically, the immunosuppressive activity of adherent monocytes in an in vitro assay of immunoglobulin-secreting cells was tested. Although the peak response was slightly lower, the induction, development and shutdown of the response by MS cells reproduced that of control cells. Most importantly, adherent monocytes from patients with MS exerted the same maximal suppression as did monocytes from controls. Further experiments are required to determine if the adherent monocyte is an appropriate target for immunotherapy in MS.