Biomedical subjects

S A Spector

Publications and source records attributed to S A Spector.

At least 109 records · Page 6Linked to original sources

PubMed1994

Human cytomegalovirus-mediated enhancement of human immunodeficiency virus type-1 production in monocyte-derived macrophages.

Monocyte-derived macrophages were co-infected with human immunodeficiency virus (HIV), strain HIVBa-L, and human cytomegalovirus (HCMV) strain AD 169. HCMV enhanced the production of p24 antigen and infectious HIV, but HIV had no effect on HCMV production. In dually infected cultures HIV p24 antigen levels were increased 5- to 15-fold during the first 3 weeks of culture. This enhancement was observed both for cell-associated and extracellular p24 antigen from co-infected cells. The replication of macrophage-tropic clinical isolates of HIV were also enhanced by HCMV, but HCMV did not enable T cell-tropic viruses to replicate in macrophages. Conversely, HCMV clinical isolates from blood or urine were able to upregulate HIV production. Similar enhancement of HIV p24 antigen levels was observed with noninfectious, heat-inactivated HCMV, indicating that replication of HCMV in the macrophages was not necessary. Although replication was not required, the enhancing ability of HCMV was associated with the virus. Enhancement of HIV segregated with the HCMV pelleted virus particles and not the supernatant in stock virus. The fact that HCMV and HIV are detected in macrophages in persons with HIV infection highlights the importance of this system for studying interactions between HIV and HCMV in persons with HIV infection.

Cells, Cultured↗

PubMed1994

Dysregulation of cytokine expression in monocytes from HIV-positive individuals.

Because HIV may alter the production of inflammatory factors produced by monocytes, the expression of tumor necrosis factor alpha (TNF-alpha), tissue factor (TF), interleukin (IL)-1 beta, and IL-6 was evaluated in 47 HIV-seropositive persons and seronegative control subjects. RNA was extracted from freshly isolated lipopolysaccharide (LPS)-stimulated or unstimulated monocytes. Cytokine and TF expression was quantitated by dot blot hybridization or a reverse transcription polymerase chain reaction (RT-PCR). A significant depression of TF mRNA was observed in LPS-stimulated monocytes (66% less in AIDS, 20% less in AIDS-related complex (ARC), and 0% less in asymptomatic patients), whereas normal responses were observed for TNF-alpha, IL-1 beta, and IL-6. When constitutive expression was measured in unstimulated monocytes by RT-PCR, a differential pattern was also observed. TNF-alpha and IL-1 beta were positive in 85% of asymptomatic persons, compared with only 27% of ARC and 42% of AIDS patients. Expression of IL-6 was observed in lower proportions, 27-30%, with no significant differences among disease states. All samples were negative for TF. Thus, the regulation of inflammatory molecules is differentially altered in individuals with HIV infection. TF is preferentially down-regulated, compared with TNF-alpha, IL-1 beta, and IL-6, in LPS-stimulated monocytes as patients progress to AIDS. TNF-alpha and IL-1 beta are preferentially up-regulated, compared with IL-6 and TF, in unstimulated monocytes in asymptomatic persons, with a loss of up-regulation as patients progress to AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Human immunodeficiency virus type 1 infection of neonatal severe combined immunodeficient mice xenografted with human cord blood cells.

In these studies, neonatal C.B-17 severe combined immunodeficient (nSCID) mice were reconstituted with human cord blood leukocytes (hu-CBLs). The resulting hu-CBL-nSCID mice contained readily detectable human CD3+ T lymphocytes and CD20+ human B cells, and produced substantial levels of human IgM and IgG (including all subclasses). Human cells persisted in lymphoid organs and peripheral blood for at least 8 weeks, and CD4+ T cells outnumbered CD8+ T cells. Engraftment of human cells in peripheral lymphoid organs and blood was much greater than that seen in adult SCID mice grafted with adult peripheral blood leukocytes (PBLs). Hu-CBL-nSCID mice were susceptible to infection with laboratory-adapted and fresh clinical human immunodeficiency virus type 1 (HIV-1) isolates. Following infection with HIV-1, virus could be recovered by the coculture of spleen, lymph node, peritoneal cavity, liver, and plasma samples from hu-CBL-nSCID mice with fresh human peripheral blood mononuclear cells, and proviral copies were detectable following amplification using the polymerase chain reaction (PCR). HIV p24 core antigen levels in hu-CBL-nSCID mouse plasma were consistent with ongoing viral replication and high viral burdens. Rapid CD4+ T cell depletion occurred following infection with laboratory isolates of HIV-1 or a syncytium-inducing clinical isolate, but a non-syncytium-inducing clinical isolate caused expansion of CD8+ T cells, leading to an inversion of the CD4:CD8 ratio with only a transient decrease in CD4+ T cells. These results suggest that the hu-CBL-nSCID mouse system has unique features that mimic certain aspects of pediatric HIV infection, and distinguish it from other animal models of HIV infection, including the related hu-PBL-SCID model.

Animals↗

PubMed1994

Clinical significance of human immunodeficiency virus type 1 phenotypes in infected children.

Human immunodeficiency virus type 1 (HIV-1) isolates from perinatally infected infants and children were examined for syncytium-inducing (SI) capacity. All isolates from 14 infants < 1 year old had non-syncytium-inducing (NSI) HIV-1 phenotypes. Within their first year, 10 infants progressed to AIDS and 3 died. Of isolates from 26 children > 2 years old, 13 had SI HIV-1 phenotypes and 13 had NSI strains. Children with SI virus had significantly lower CD4+ cell counts standardized for age and were significantly older than those with NSI strains (P = .008 and .001, respectively); the effect of viral phenotype on CD4+ lymphocytes could not be detected independent of age. In another group, children with SI strains were more likely to show in vitro zidovudine resistance. Results suggest a biphasic response to HIV infection in children. Progression to AIDS may occur rapidly in infants with NSI HIV-1, but older children tend to have SI phenotypes and lower CD4+ lymphocyte counts and more often show zidovudine resistance.

CD4-Positive T-Lymphocytes↗

PubMed1994

Optimization of quantitative culture assay for human immunodeficiency virus from plasma. Plasma Viremia Group Laboratories of the AIDS Clinical Trials Group (National Institute of Allergy and Infectious Diseases).

Experimental conditions essential to a simple, reproducible, quantitative human immunodeficiency virus plasma assay were determined. Five parameters were evaluated: length of culture, reproducibility, assay dilution schema, washing procedures, and anticoagulant usage. The recommended quantitative plasma assay utilizes undiluted citrated plasma cultured with peripheral blood mononuclear cells for 14 days with fivefold dilutions and a medium change on day 1 with no washing.

Blood↗

PubMed1994

The effects of cytomegalovirus on human immunodeficiency virus replication in brain-derived cells correlate with permissiveness of the cells for each virus.

Human cytomegalovirus (HCMV) is commonly found in the brains of patients with AIDS and in some cases can be detected in the same cells as can human immunodeficiency virus type 1 (HIV-1). In this study, we analyzed the patterns of replication of HIV-1 and HCMV in singly infected cells and the effects of dual infection in human brain-derived cell lines of three different origins: neuroblastoma cell lines SK-N-MC and SY5Y; astrocytoma/glioblastoma cell lines U373-MG and Hs 683; and undifferentiated glioblastoma cell lines A172 and T98G. To bypass the restriction at the adsorption/penetration step in these CD4-negative cells, we used HIV-1 (amphotropic retrovirus) pseudotypes. These HIV-1 pseudotypes infected the majority of the cells in the cultures and expressed high levels of HIV-1 gene products in all except the SY5Y cells. The cell lines differed in the ability to support HCMV infection, but coinfection with HIV-1 had no effect on HCMV replication. The A172 cells were completely nonpermissive for HCMV gene expression, while HCMV replication in the singly infected T98G and SK-N-MC cell lines was restricted at the level of some early gene products. This resulted in complete and partial inhibition, respectively, of viral DNA synthesis. Dual infection of the A172, T98G, and SK-N-MC cells had no effect on HIV-1 replication. The other three cell lines, U373-MG, Hs 683, and SY5Y, were fully permissive for HCMV replication. In the U373-MG and Hs 683 cells, HCMV markedly inhibited the synthesis of HIV-1 gene products. In contrast, a transient stimulation of HIV-1 production followed by a repression was observed in the dually infected SY5Y cells. We conclude from these results that under conditions in which both HIV-1 and HCMV can undergo fully permissive infection, HCMV can repress HIV-1 gene expression. In cells in which HCMV replication is limited but HIV-1 replicates well, there is no effect on HIV-1 gene expression. However, activation of HIV-1, at least transiently, may occur in cells in which HIV-1 gene expression is limited. These studies suggest that a threshold level of some HIV-1 gene product(s) may obscure activation or promote repression of HIV replication by HCMV.

Antigens, Viral↗

PubMed1994

Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy.

Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine (AZT). Resistance developed as early as 1 week, indicating rapid turnover of the virus population. The development of resistance was associated with the loss of antiviral drug activity as measured by CD4 lymphocyte counts and levels of HIV p24 antigen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell culture, mutations at residues 108, 188, and 190 were also found in the patient isolates. Sequences from patient clones documented cocirculating mixtures of populations of different mutants. The most common mutation with monotherapy, tyrosine to cysteine at residue 181, was prevented from emerging by coadministration of AZT, which resulted in the selection of alternative mutations. The observations documented that, under selective drug pressure, the circulating virus population can change rapidly, and many alternative mutants can emerge, often in complex mixtures. The addition of a second RT inhibitor, AZT, significantly altered the pattern of mutations in the circulating population of HIV.

Antiviral Agents↗

PubMed1994

HIV therapy advances. Pediatric antiretroviral choices.

BACKGROUND: Zidovudine is the initial treatment of choice in HIV-infected children. Zalcitabine or didanosine may be used in children who do not respond adequately or who are intolerant of zidovudine. Several studies of the latter agents are reviewed. MONOTHERAPY STUDIES: Zalcitabine at 0.005 or 0.01 mg/kg three times a day was associated with stabilization of growth and a decline in p24 antigen levels in more than 50% of treated children. In a dose-ranging study of didanosine, 30% of children showed an increase in CD4 cell counts and gained weight. There was a correlation between the plasma didanosine concentration and an improvement in IQ (Intelligence Quotient) and p24 status. STUDIES ON COMBINATION THERAPY: In a 12-18 month trial of zidovudine/zalcitabine in 13 children, most gained weight and more than half showed improved CD4 cell counts. The combination of various doses of didanosine with zidovudine was associated with a reduction in viral titer, a significant increase in CD4 cell counts and a trend towards increased weight in many children. STUDY IN MOTHER TO INFANT TRANSMISSION: Zidovudine or placebo was administered to women throughout pregnancy and during labor and to their new-born infants up to 6 weeks of age. The infection rate for the zidovudine-treated group was 8.3% compared with 25.5% for the placebo group (P = 0.000056). CONCLUSION: Zalcitabine and didanosine are useful drugs in the treatment of HIV-infected children. Zidovudine is associated with a reduced rate of mother to infant viral transmission.

Body Weight↗

PubMed1994

Resistance to AZT and ddC during long-term combination therapy in patients with advanced infection with human immunodeficiency virus.

To ascertain whether combination therapy with zidovudine (AZT) and zalcitabine (ddC) delayed the emergence of AZT resistance, isolates of human immunodeficiency virus (HIV) were evaluated from 15 previously untreated patients with advanced HIV disease who received combination therapy. Eighteen sequential viral isolates were available from 15 patients who received > or = 6 months of combination therapy. Isolates from eight (73%) of 11 patients obtained between 24 and 48 weeks of therapy were AZT resistant [50% inhibitory concentration (IC50) > or = 0.45 microM; range, 0.45-2.0 microM]. Four of these eight patients yielded virus isolates that were highly AZT resistant (IC50 > 1.0 microM). No changes in ddC susceptibility were discerned. The median IC50 for ddC was 0.2 microM and ranged from 0.07 to 0.5 microM. The CD4 cell counts of patients with AZT-sensitive virus tended to have higher median areas under the curve (AUC) and greater increases compared with patients who had AZT-resistant virus. They also had higher means and ranges of the average CD4 cell counts at week 36 (p = 0.01) and week 48 (p = 0.04). These data would indicate that the previously described more sustained CD4 cell responses conferred by the addition of ddC to AZT therapy cannot be ascribed to delayed emergence of AZT resistance with combination therapy.

CD4-Positive T-Lymphocytes↗

PubMed1993

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex.

OBJECTIVE: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone. DESIGN: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared. SETTING: Outpatient clinics of 12 AIDS Clinical Trials Units. PATIENTS: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL). INTERVENTION: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine. MEASUREMENTS: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks). RESULTS: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels. CONCLUSIONS: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

AIDS-Related Complex↗

PubMed1993

Development and significance of zidovudine resistance in children infected with human immunodeficiency virus.

Decreasing susceptibility to zidovudine (ZDV) has been described in persons infected with human immunodeficiency virus (HIV) type 1 who are receiving ZDV therapy. However, the clinical significance of decreased ZDV susceptibility remains unclear. In this study, HIV isolates obtained from children with symptomatic HIV infection treated with ZDV were monitored for their susceptibility to the antiretroviral agent and correlated with disease progression. Using a peripheral blood mononuclear cell-based assay to measure ZDV susceptibility, we evaluated HIV isolates from 19 children (mean age, 6.8 years; range, 5 months to 12 years) during ZDV therapy for susceptibility to ZDV. Of the 19 children studied, 10 continued to have susceptible HIV strains during ZDV treatment, and 9 acquired resistant viruses. All eight isolates from children without previous exposure to ZDV were initially susceptible. After a median of 11 months of ZDV therapy, three (38%) of these eight children had acquired resistant HIV strains (defined as ZDV susceptibility > or = 10 mumol/L). Children with resistant strains had worse clinical outcomes than children whose viruses remained susceptible, as determined by a 50% decline in absolute CD4+ cell counts after 1 year of treatment, failure to thrive, or death. Children with resistant viruses who were given alternative antiretroviral therapy frequently responded to the new treatment with improved growth and stabilization of their HIV-related disease. These data suggest that, in HIV-infected children, ZDV-resistant HIV strains are associated with diminished drug efficacy and more rapid disease progression.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Virologic markers of human immunodeficiency virus type 1 in cerebrospinal fluid. The HIV Neurobehavioral Research Center Group.

As part of a longitudinal study, 265 cerebrospinal fluid (CSF) specimens from 204 human immunodeficiency virus type 1 (HIV-1)-seropositive subjects and 43 seronegative controls were evaluated. Of the 204 seropositive persons, 78 (38%) had > or = 1 CSF culture positive for HIV-1; the probability of being culture positive increased as the number of CSF samples obtained increased (P = .0018). Significantly correlated with culture positivity were elevations in CSF protein level (P = .014) and CSF white blood cell count (P = .001). Virus was more readily cultured from clarified CSF (89%, 42/47) than from the cellular fraction (30%, 14/47; P < .00001). Amplification of HIV-1 DNA by polymerase chain reaction (PCR) from 25 seropositive persons was positive in 9 (82%) of 11 culture-positive and in 4 (29%) of 14 culture-negative specimens, while amplification of viral RNA detected all 11 culture-positive and 9 (64%) of the 14 culture-negative CSF specimens. These data support the hypothesis that the development of HIV-1-associated neurocognitive disorders are not dependent solely on the presence of HIV-1 within the central nervous system.

Adult↗

PubMed1993

A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. AIDS Clinical Trials Group and Cytomegalovirus Cooperative Study Group.

This prospective, randomized, multicenter, controlled trial was designed to evaluate the efficacy and safety of intravenous ganciclovir for the treatment of peripheral cytomegalovirus (CMV) retinitis in patients with AIDS. Patients were randomly assigned to receive either immediate treatment, intravenous ganciclovir, 5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily for 14 weeks, or deferred treatment. Patients randomized to deferred treatment whose retinitis progressed were offered ganciclovir. Of the 22 patients randomized to deferred treatment who were included in the final analysis, 20 were found to have progressive CMV retinitis compared with 10 of the 13 randomized to immediate treatment. The median time to progression in the deferred treatment group, as determined by a masked fundus photography reading center, was 13.5 days compared with 49.5 days in the immediate treatment group (mean +/- SD, 19.3 +/- 4.1 vs. 66.4 +/- 14.0; P = .001, log rank test). These data indicate that ganciclovir delays the progression of CMV peripheral retinitis in persons with AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1993

A cross-sectional comparison of persons with syncytium- and non-syncytium-inducing human immunodeficiency virus.

The association between isolation of the syncytium-inducing (SI) phenotype of human immunodeficiency virus (HIV) and unfavorable clinical and immune status was evaluated in a cross-sectional study. Data on HIV phenotype were available for 341 of 878 persons entering clinical trials of antiretroviral therapies. Patients with SI virus were demographically similar to those with non-SI (NSI) virus but were more likely to have a diagnosis of AIDS and detectable circulating HIV p24 antigen. Patients with SI virus also had a lower CD4+ cell count and a higher serum level of beta 2-microglobulin. The association between phenotype and present status was explained statistically by CD4+ cell count. Phenotype, serum level of beta 2-microglobulin, and the presence of detectable p24 antigen were all independent predictors of present CD4+ cell count. The likelihood of finding SI virus increased with unfavorable virologic and immunologic parameters and varied with the amount of prior antiretroviral therapy.

Adult↗

PubMed1993

Pediatric human immunodeficiency virus infection in a low seroprevalence area.

Although increasing information is available regarding human immunodeficiency virus (HIV) infections of children in high seroprevalence areas, few data are available describing trends in low seroprevalence populations. In San Diego County approximately 1 in 1450 live births are to women infected with HIV as identified by nonlinked heel stick testing. Seventy-seven HIV-infected children were identified and followed in our clinics during the period 1983 to 1991, of whom 32 (42%) were infected perinatally, 32 (42%) were hemophiliacs and 13 (17%) were infected by blood transfusions. During the last 4 years of the study period (1988 to 1991), most (28 of 37, 76%), newly identified HIV-infected children less than 13 years old were perinatally infected. Of the 32 perinatally infected children 50% were Hispanic, 34% were Caucasian and 16% were African-American. The prospective vertical transmission rate was 16%. Twenty-nine (38%) of the HIV-infected children have a diagnosis of acquired immunodeficiency syndrome and 17 (22%) have died. Comparatively few of the HIV-infected hemophiliac patients (4 (12%)) have progressed to an acquired immunodeficiency syndrome diagnosis. The number of acquired immunodeficiency syndrome diagnoses declined in the last 2 years of the study as a result of fewer cases of Pneumocystis carinii pneumonia; 11 cases of P. carinii pneumonia were diagnosed in 1988 to 1989 compared with 4 cases in 1990 to 1991. Survival analysis for the perinatally infected group yielded a median survival of 9.2 years. The apparent trend in our data toward improved outcomes of children infected with HIV suggests the beneficial effects of early identification, antiretroviral treatment, and P. carinii pneumonia prophylaxis.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Early diagnosis of human cytomegalovirus disease in transplant recipients by DNA amplification in plasma.

Human cytomegalovirus (HCMV) infection in transplant recipients is often complicated by invasive visceral disease. The most reliable marker for HCMV disease is viremia, currently defined by detection of the virus in white blood cells. In this study we employed the polymerase chain reaction (PCR) to detect HCMV DNA in the plasma of transplant recipients. The utility of plasma PCR in the early diagnosis of active HCMV infection and disease was determined in 83 bone marrow transplant recipients and 6 kidney transplant recipients. All 46 patients who had a positive leukocyte culture were positive by plasma-PCR. PCR detection preceded culture isolation by a median interval of one week and remained positive for a longer period, with a median lag interval of two weeks in uncomplicated infection. Lack of PCR resolution predicted disease development in 11 patients and culture relapse in three. Of the 11 patients who were culture-negative but positive by plasma-PCR, 8 (73%) subsequently developed HCMV disease; 32 (74%) of 43 leukocyte culture-negative patients remained plasma PCR-negative, regardless of concomitant viral shedding in 11. In bone marrow transplant recipients, plasma PCR was associated with a positive predictive value of 60% for disease development and with a negative predictive value of 97%. PCR detection preceded disease development by a median interval of 3 weeks. Plasma PCR is a rapid, specific, and highly sensitive method for the early diagnosis of HCMV disease and should prove useful in guiding prophylactic therapy in transplant recipients.

Adolescent↗

PubMed1993

Functional status and well-being in a placebo-controlled trial of zidovudine in early symptomatic HIV infection.

To determine the effect of zidovudine on functional status and well-being in patients with early symptomatic human immunodeficiency virus (HIV) infection, 70 subjects in a randomized, placebo-controlled trial (ACTG Protocol 016) were observed for 1 year using a brief quality-of-life questionnaire. Thirty-four subjects were assigned to placebo and 36 subjects to zidovudine, 200 mg orally every 4 h (1,200 mg daily). Functional status and well-being were measured every 3 months using a 30-item self-administered questionnaire derived from health ratings from the Medical Outcomes Study. The mean changes from baseline for zidovudine versus placebo groups were compared using paired and two-sample t tests. Subjects receiving a placebo reported better quality of life compared to baseline than subjects receiving zidovudine at 24 weeks for all dimensions of well-being, including overall health, energy, mental health, health distress, pain, and quality of life. The difference between the two groups' changes from baseline for overall health was 11.5 points on a 100-point scale (p = 0.02), and 11.1 points for energy (0.002). There were no differences between changes from baseline along various dimensions of functional status (physical, social, role, and cognitive function). At 52 weeks both groups reported worse overall health than at baseline, and changes in scores were more similar for the two groups. Although zidovudine has previously been demonstrated to delay progression of disease for patients with mildly symptomatic HIV infection, early in treatment the net effect of a 1,200 mg daily dose of zidovudine may diminish patients' subjective well-being.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. A phase I/II study.

OBJECTIVE: To evaluate the safety and immunologic and antiviral effects of combination therapy with zidovudine and dideoxycytidine (ddC) in patients with advanced human immunodeficiency virus type 1 (HIV) infection. DESIGN: A phase I/II open-label, dose-ranging study. SETTING: Two AIDS Clinical Trials Group units. PATIENTS: Patients (56) with advanced HIV disease. INTERVENTIONS: Patients were randomly assigned to one of three paired regimens of zidovudine and ddC. We evaluated six dosing regimens, each involving oral administration of the study drugs at 8-hour intervals. MEASUREMENTS: Pharmacokinetics, toxicity, CD4 counts, p24 antigenemia and clinical end points. MAIN RESULTS: The median follow-up period was 40.6 weeks (range, 0.3 to 70 weeks). Neither drug affected the pharmacokinetic profile of the other. Episodes of serious hematologic toxicity were infrequent, occurring in only 17.9% of patients, and did not differ among the regimens (P = 0.15). Severe sensory peripheral neuropathy occurred in two patients (one patient each in regimens 1 and 4). One patient receiving regimen 4 died. The mean maximal increase in CD4 counts exceeded 109 cells/mm3, and 69% of patients receiving combinations containing 300 or 600 mg of zidovudine daily had an increase in CD4 counts of 50 cells/mm3 or greater. Regimens containing 600 mg of zidovudine daily (regimens 2 and 5) were also more likely to result in persistent increases in CD4 counts above pretreatment values than were the two lowest dose regimens (P = 0.003). The decline in CD4 counts was more rapid, and the suppression of the p24 antigenemia was less rapid and less sustained in patients receiving the lowest zidovudine dose alone (regimen 6). The addition of ddC to regimen 6 (regimen 3) resulted in a slower decline in the CD4 counts (P = 0.06). CONCLUSIONS: Combination therapy with zidovudine and ddC at the doses tested was well tolerated and did not result in toxicity. A daily oral dose of 150 mg of zidovudine appeared to produce a suboptimal effect on p24 antigenemia and CD4 counts. Combination therapy with ddC and higher doses of zidovudine produced greater and more persistent effects in patients with advanced HIV infection compared with other study regimens and with the results of previous trials of zidovudine monotherapy.

Adult↗