Faculty Bibliography

Objective: To determine the safety and duration of antiviral activity of IDV + ZDV + 3TC. Methods: Randomized, double-blind study comparing IDV 800mg q8h + ZDV 200mg q8h + 3TC 150mg q12h or IDV 800mg q8h or ZDV 200mg q8h + 3TC 150mg q12h in 97 adult patients with HIV infection, greater than or equal to 20,000 copies/ml of serum HIV RNA (Roche PCR kit assay), 50-400 CD4 cells/mm(3), greater than or equal to 6 months of prior ZDV therapy, and no previous use of 3TC or protease inhibitors. Results: At baseline, median HIV RNA was 41,130 copies/ml, median CD4 was 142 cells/mm(3), and median prior ZDV experience was 31 months. After up to 52 weeks of follow-up, 90 of 97 patients continue on study. One patient withdrew for an adverse event (grade 2 nausea). Nine patients had clinical nephrolithiasis, eight of whom were on indinavir containing study arms. All nine patients continued study medications; two underwent indinavir dose reduction. Nine patients had neutropenia, anemia, nausea, or headache requiring ZDV/3TC dose reduction. A summary of available viral load data is shown: (table: see text) Median HIV RNA log(10) decreases at 24 and 44 weeks; -2.2 and -2.2 (IDV+ZDV+3TC), -0.7 and -0.9 (IDV), and -0.6 and -0.2 (ZDV+3TC). Median CD4 changes from baseline (cells/mm(3)) at 24 and 44 weeks; +126 and +218 (IDV+ZDV+3TC), +105 and +158 (IDV) and +14 and +14 (ZDV+3TC). Conclusions: IDV + ZDV +3TC is a generally safe, well-tolerated regimen with potent antiretroviral activity and CD4 cell increases that are sustained for at least 44 weeks

Objective: To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine. Design: A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units. Patients: 398 adults who had HIV-1 infection, had 350 or fewer CD4(+) T lymphocytes/mm(3), and had had more than 6 months of previous nucleoside therapy. Intervention: 1) Either nevirapine or placebo (200 mg/d for 2 weeks, then 400 mg/d thereafter) and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing greater than or equal to 60 kg). Measurements: CD4(+) T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA; HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites. Results: After 48 weeks of study treatment, the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% CI, 7% to 29%; P = 0.001), a 0.32 log(10) lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (CI, 0.05 to 0.59 log(10) infectious units per million cells; P = 0.023), and a 0.25 log(10) lower mean plasma HIV-1 RNA level (CI, 0.03 to 0.48 log(10) RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [CI, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference. Conclusions: Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens

Immune responses provoked by human immunodeficiency virus (HIV) infection ultimately are insufficient to control the disease and do not include strong lymphocyte-proliferative responses to HIV antigens or antibodies to many viral epitopes. A randomized double-blind, placebo-controlled trial evaluated the immunogenicity of recombinant HIV envelope vaccine (rgp160) in HIV-infected subjects with > or = 400/mm3 CD4 T cells. Controls received hepatitis B vaccine. Of subjects receiving rgp160, 98% developed lymphocyte-proliferative responses to the immunogen, 33% to a different envelope protein, and 56% and 60% to p24 and p66, respectively. All doses of vaccine (20, 80, 320, 1280 microgram) induced new responses. New antibodies to epitopes on rgp160 developed only in recipients of higher doses of rgp160. CD4 T cell percentages declined less rapidly in recipients of rgp160 than in controls. Vaccination of HIV-infected subjects with rgp160 results in cellular and humoral immune responses to HIV that infection itself had not stimulated

We have investigated the ability of human immunodeficiency virus (HIV)-infected cells to kill uninfected CD4+ lymphocytes. Infected peripheral blood mononuclear cells were cocultured with autologous 51Cr-labeled uninfected cells. Rapid death of the normal CD4-expressing target population was observed following a brief incubation. Death of blood CD4+ lymphocytes occurred before syncytium formation could be detected or productive viral infection established in the normal target cells. Cytolysis could not be induced by free virus, was dependent on gp120-CD4 binding, and occurred in resting, as well as activated, lymphocytes. CD8+ cells were not involved in this phenomenon, since HIV-infected CEMT4 cells (CD4+, CD8- cells) mediated the cytolysis of uninfected targets. Reciprocal isotope-labeling experiments demonstrated that infected CEMT4 cells did not die in parallel with their targets. The uninfected target cells manifested DNA fragmentation, followed by the release of the 51Cr label. Thus, in HIV patients, infected lymphocytes may cause the depletion of the much larger population of uninfected CD4+ cells without actually infecting them, by triggering an apoptotic death

Objective: To investigate the effect of lymphocyte activation on CD8-mediated suppression of HIV replication. Methods: CD4 and CD8 cells from HIV+ and HIV- donors were positively selected. The CD4 cells were stimulated and superinfected with HIV and the two cell populations were cocultured at various CD8:CD4 ratios. In addition to determining the concentration of p24 in the resultant supernatants, a fixed volume of each coculture was analyzed by three-color flow cytometry. Results: CD8 cells from healthy, infected donors are capable of powerfully suppressing vital replication regardless of whether they had been PHA stimulated. This suppression, however, was more powerful and less reversible using stimulated CD8 cells. In some cases CD8-mediated HIV suppression was more effective than 2 micromolar AZT, but often required both AZT and CD8 cells to completely shut off viral production. The CD8 cells from HIV negative donors also demonstrated antiviral activity but only when the CD8 cells were used at high CD8:CD4 ratios and were stimulated. The method of activation of the CD4 cells (PHA vs. anti-CD3) did not appear to play a role. Unstimulated CD8 cells from HIV negative donors in some cases could suppress viral replication in HIV negative allogeneic CD4 cell donors, but this was associated with CD4 cell death within the culture. Conclusion: The CD8 cells from HIV positive individuals possess the ability to powerfully suppress viral replication. This property can also be demonstrated using the CD8 cells from HIV negative donors, however it requires in vitro conditions that are probably not pertinent to the in vivo situation

Phase I dose-escalating trials of didanosine revealed dose-limiting toxicities, including pancreatitis, and established a total daily dose of 12.5 mg/kg/day as the maximum tolerated dose. Clinical and pharmacokinetic data of 61 patients from two trials were analyzed to further evaluate the risk of pancreatitis: 1 (6.3%) of 16 patients who received < 500 mg/day didanosine, 2 (13.3%) of 15 who received 500-750 mg/day, and 15 (50%) of 30 who received > 750 mg/day developed pancreatitis (P < .001). A relationship between risk of pancreatitis and steady-state plasma concentrations of didanosine and age was also observed, suggesting that knowledge of didanosine pharmacokinetics provided additional information regarding risk of toxicity. Further confirmation of these findings will be necessary to determine if the risk factors for pancreatitis remain the same at lower doses currently used

An HIV-1 envelope protein gp120-derived monomeric peptide (amino acid residues 419-439) and its homologous multiple chain peptide (MCP) construct were compared for immunogenicity in mice. The Abs stimulated by the MCP recognized epitopes on the MCP that were not present on the homologous monomer. The anti-419-439 MCP sera recognized a conformational determinant on the native envelope glycoprotein, as indicated by: 1) detection of native but not denatured recombinant envelope glycoprotein by ELISA and dot blot and 2) reaction with infected cell lines expressing gp120 on their surface as detected by flow cytometry. In contrast, the anti-monomer sera were highly specific for the monomer and recognized the envelope glycoprotein at lower titers. The low reactivity of the anti-monomer sera with the envelope glycoprotein was not decreased by denaturation. Reciprocally, murine antiserum to HIV-1 envelope glycoprotein gp160 recognized the MCP construct but not the homologous monomeric peptide. The data indicate that the MCP construct forms additional antigenic determinants not present on the homologous monomer, and that the anti-419-439 MCP Abs recognize a conformational determinant on the envelope glycoprotein not recognized by Abs against the homologous monomer. Furthermore, antisera against another envelope-derived MCP (amino acid residues 105-117) also recognize conformational determinants on the envelope glycoprotein, whereas antisera against the homologous monomeric peptide do not

Objective: To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir. Methods: Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60 mg/kg every 8h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90 mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day. Results: A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occuring at less-than-or-equal-to 2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses. Conclusion: in patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied

Changes in CD4 lymphocyte counts are widely used in monitoring human immunodeficiency virus (HIV)-infected patients for disease progression. However, random fluctuations may obscure clinically significant changes. CD4 cell counts from 1020 untreated subjects with asymptomatic HIV infection monitored by standardized methods for up to 2 years were assessed. The within-subject coefficient of variation averaged 25% but was higher in subjects with lower counts; in 6% of subjects the count was half or double the one obtained 8 weeks before. Proportionate rates of decline, which had negligible correlation with the baseline count, averaged 14.3%/year but varied considerably between subjects: An estimated 29% had increasing trends. Declines were greater in HIV p24-positive subjects and those with higher lymphocyte percentages or lower platelet counts or hemoglobin levels. With such high variation, changes between single counts should be interpreted cautiously. Using multiple counts and other markers may provide more precise assessment of immune status

Long-term follow-up of 44 patients with AIDS or AIDS-related complex (ARC) in a phase 1 trial of didanosine is reported. These patients were monitored for as long as 72 weeks (mean, 34 weeks) for toxicity and activity of didanosine. Pancreatitis and neuropathy, the major clinical toxicities, developed infrequently at the doses of didanosine (250-750 mg/d) employed during the latter part of the study. Consistent hematologic toxicity was not encountered; moreover, mean values for hematologic parameters such as hemoglobin concentration, white blood cell count, neutrophil count, lymphocyte count, and platelet count improved for up to 20-60 weeks. CD4 counts increased significantly through 10 weeks of therapy and in some patients remained at or above counts at enrollment for as long as 60 weeks. Serum concentrations of p24 antigen decreased significantly and remained at the decreased level for up to 48 weeks. An initial diagnosis of ARC (as opposed to AIDS), an initial CD4 count of > 100/mm3, and an increase in CD4 counts during the first 10 weeks of therapy were associated with a higher rate of survival and with lower rates of development of opportunistic infections and of other clinical manifestations of disease progression