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At least 19 recordsLinked to original sources
PubMed1996

Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group.

OBJECTIVE: To compare the safety and efficacy of 2 doses of lamivudine given in combination with zidovudine with continued zidovudine monotherapy. DESIGN: Double-blind, randomized, multicenter, comparative trial of 223 patients treated for 24 weeks. SETTING: Patients from 32 hospitals in Europe were enrolled throughout a 1-year period. PATIENTS: Adult human immunodeficiency virus type 1 (HIV-1)-positive, zidovudine-experienced ( > or = 24 weeks prior zidovudine) patients with CD4+ cell counts between 0.10 and 0.40 x 10(9)/L (100-400 cells/microL). INTERVENTION: Patients received either 200 mg of zidovudine every 8 hours, 150 mg of lamivudine every 12 hours plus zidovudine, or 300 mg of lamivudine every 12 hours plus zidovudine for 24 weeks. All patients were then allowed to receive zidovudine and open-label lamivudine combination therapy. Twelve patients withdrew because of adverse events during the 24-week treatment period. MAIN OUTCOME MEASURES: Efficacy was measured by evaluating immunological and viral load changes, and safety was assessed by evaluating clinical manifestations and laboratory indexes of toxic effects. RESULTS: Patients receiving low- or high-dose combination therapy had greater treatment effects compared with patients receiving continued zidovudine monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts (+0.04 vs +0.03 vs -0.02 x 10(9)/L, respectively; P < .001); log10 HIV-1 RNA as measured by the Roche assay (-0.96 vs -0.77 vs +0.07 copies/mL, respectively; P < .001) or log10 HIV-1 RNA measured by the quantitative nucleic acid sequence-based amplification assay (-0.59 vs -1.06 vs -0.02 copies/mL, respectively; P < .011); and immune-complex dissociated (ICD) p24 antigen (-74% vs -68% vs +27%, respectively; P < .001). There were no statistically significant differences in viral measurements, in CD4+ cell counts, or in safety profile between the groups receiving 2 doses of lamivudine in combination with zidovudine. The effects on CD4+ cell counts and ICD p24 antigen were sustained throughout 48 weeks for patients continuing combination therapy. Patients switching to combination therapy at week 24 showed improvement. CONCLUSION: In zidovudine-experienced HIV-1-infected patients, combination treatment with lamivudine and zidovudine is well tolerated and provides greater and more sustained increases in CD4+ cell counts and decreases in viral load than continued zidovudine monotherapy.

Adult↗
PubMed1999

Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter. PISCES (SV14604) Study Group.

BACKGROUND: This double-blind study evaluated treatment with zalcitabine-zidovudine, saquinavir-zidovudine, or saquinavir-zalcitabine-zidovudine on the health-related quality of life of HIV-infected adults with CD4 cell counts between 50 and 350 cells/mm3. METHODS: Nine hundred and ninety-three HIV-infected male or female quality of life substudy patients aged 18 years or older, with CD4 cell counts between 50 and 350 cells/mm3 naïve to antiretroviral therapy or with less than 16 weeks of zidovudine therapy, were randomly assigned to one of three daily regimens: zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (ddC/ZDV); saquinavir 600 mg and zidovudine 200 mg every 8 h (SQV/ZDV); or saquinavir 600 mg, zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (SQV/ddC/ZDV). The health-related quality of life was measured using the Medical Outcome Study HIV (MOS-HIV) Health Survey subscale and physical and mental health summary scores, and a global visual analogue scale (VAS) score. The primary health-related quality of life endpoints were the MOS-HIV physical and mental health summary scores. RESULTS: After 24 weeks of treatment, no statistically significant differences were observed between the three treatment groups on physical health and mental health summary scores (global test P = 0.118). After 48 weeks of treatment, statistically significant differences among the groups were observed for physical health and mental health summary scores (global test P = 0.020); no change in physical health summary scores from the baseline were seen in the triple combination therapy, whereas the ddC/ZDV combination therapy group showed decreases from baseline in physical health summary scores (P = 0.008). Six of the 10 individual MOS-HIV subscale scores and the VAS scores showed results consistent with the physical health summary endpoints after 48 weeks of therapy. No statistically significant differences in baseline to 48 week changes in MOS-HIV subscale or summary scores were seen between the ddC/ZDV and SQV/ZDV groups (P > 0.05). CONCLUSIONS: Patients on triple combination therapy maintained their quality of life over 48 weeks compared with significant decreases in the quality of life for ddC/ZDV combination therapy.

Adult↗
PubMed1999

Resistance mutations to zidovudine and saquinavir in patients receiving zidovudine plus saquinavir or zidovudine and zalcitabine plus saquinavir in AIDS clinical trials group 229.

The relationships among treatment regimens, plasma human immunodeficiency virus (HIV) RNA levels, and resistance mutations to saquinavir (codons 48 and 90) and zidovudine (codon 215) were examined in a cohort of 144 patients from the AIDS Clinical Trials Group 229 study. After 24-40 weeks of therapy, no patients who had received the two-drug combination (zidovudine plus saquinavir) had only codon 48 mutations, 45.8% had only codon 90 mutations, and 8.3% had both codon 48 and 90 mutations. Mutations developed by patients who had received the three-drug combination (zidovudine and zalcitabine plus saquinavir) were codon 48 alone in 1.4%, codon 90 alone in 33.3%, and both codons 48 and 90 in 4.2%. The difference between the groups showed a trend toward reduced mutations with three versus two drugs but did not reach significance (P=.11, two-sided chi2). Higher baseline HIV RNA levels correlated with the development of protease mutations. Mutations at codon 215 were present in 82% of all patients at baseline and in 87% after therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Greater and more rapid depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine+didanosine or zidovudine+zalcitabine) vs. single (zidovudine) nucleoside reverse transcriptase inhibitors.

BACKGROUND: Most toxicities associated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) are thought to result from mitochondrial toxicity. These toxicities include peripheral neuropathy, pancreatitis, lactic acidosis, and peripheral lipoatrophy. Unfortunately, there are no validated laboratory markers for clinically assessing, let alone predicting, the onset of mitochondrial toxicity associated with NRTI therapy. OBJECTIVES: To provide preliminary evidence of the potential clinical utility of an assay which has been developed for quantifying mitochondrial DNA (mtDNA) in clinical samples from HIV-infected patients. METHODS: A single-tube duplex real-time DNA-nucleic acid sequence-based amplification (NASBA) assay (Mitox, Primagen, Amsterdam, the Netherlands) was used to quantify mtDNA in cryopreserved peripheral blood mononuclear cells (PBMC) obtained from HIV-1-infected patients during their prior participation in a randomized placebo-controlled trial comparing zidovudine (ZDV) monotherapy with combinations of ZDV plus either dideoxycytidine (ddC) or didanosine (ddI) (the Delta trial). Patients were antiretroviral naïve prior to entering the trial. Samples obtained during the initial 48 weeks of treatment were tested. RESULTS: A significant decline of mtDNA, both in an intent-to-treat and in an as-treated analysis, was observed in patients treated with ZDV+ddC and ZDV+ddI, but not with ZDV alone, consistent with the results expected from the degree of mtDNA depletion described for each of these drugs in vitro. CONCLUSIONS: This single-tube duplex real-time DNA-NASBA assay was shown to measure mtDNA accurately in PBMC. Treatment with a combination of two NRTIs was associated with greater reductions in mtDNA than obtained for ZDV monotherapy. The relevance of these results in predicting treatment toxicity requires further evaluation.

Analysis of Variance↗
PubMed1995

Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no previous experience with zidovudine. AIDS Clinical Trials Group.

BACKGROUND: We conducted a trial to compare treatment with zidovudine or didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine. METHODS: Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, < or = 0.30 x 10(9)/L [300/microL]), or asymptomatic HIV (CD4 cell count, < or = 0.20 x 10(9)/L) received zidovudine, 500 mg/d of didanosine, or 750 mg/d of didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival. RESULTS: In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with didanosine was pancreatitis (dosage, 750 mg/d). CONCLUSIONS: In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine.

AIDS-Related Opportunistic Infections↗
PubMed1993

Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection.

OBJECTIVE: To assess safety, pharmacokinetics, and in-vivo virologic activity of five different combination regimens of zidovudine and didanosine compared with zidovudine alone in patients with human immunodeficiency virus type 1 (HIV-1) infection. DESIGN: Open-label, partially randomized, dose-ranging study. SETTING: University-affiliated, medical center clinics. PATIENTS: A total of 69 patients with HIV-1 infection, CD4+ cell counts fewer than 400 cells/mm3, and fewer than 121 days of previous zidovudine treatment. INTERVENTIONS: Fifty-five patients received combination therapy with zidovudine and didanosine, and 14 received zidovudine therapy alone (600 mg/d). Daily dosages in milligrams of zidovudine and didanosine, respectively, in the five combination groups were 150 and 90 mg, 300 and 334 mg, 600 and 334 mg, 300 and 500 mg, and 600 and 500 mg. MEASUREMENTS: CD4+ cell counts, HIV-1 RNA titers in plasma, and toxic effects. RESULTS: The combination regimens were associated with higher and more sustained increases in CD4+ cells than zidovudine alone, even after adjustment for initial CD4+ counts and previous zidovudine therapy (P < 0.001). The median increase in CD4+ cell counts was 166 cells/mm3 with combination therapy and 77 cells/mm3 with zidovudine alone (P = 0.001) and did not differ statistically among the five combination regimens. Human immunodeficiency virus type 1 RNA titers in plasma decreased in 15 (83%) of 18 combination-therapy recipients compared with 2 of 7 zidovudine-alone recipients (P = 0.017). No pharmacokinetic interactions were seen between zidovudine and didanosine. Toxicity rates were low among all treatment groups. A greater decrease in hemoglobin levels was seen with the regimen using zidovudine alone (-8 g/L) compared with combination regimens using the same zidovudine dose (-1.5 g/L, P = 0.03). CONCLUSIONS: Combination therapy with zidovudine and didanosine produced larger and more sustained increases in CD4+ cell counts, more frequent decreases in plasma HIV-1 RNA titers, and more stable hematologic status than zidovudine therapy alone. The effects of this combination on the progression of HIV disease merit further study, to provide information about clinical outcome, because this was a relatively small study based on surrogate markers of HIV-1 infection.

Adult↗
PubMed1994

Efficacy of zidovudine treatment in homosexual men with AIDS-related complex: factors influencing development of AIDS, survival and drug intolerance. Australian Zidovudine Study Group.

OBJECTIVES: To investigate (1) the efficacy and safety of zidovudine treatment in homo-/bisexual men with AIDS-related complex (ARC) and (2) factors associated with development of intolerance to zidovudine. DESIGN: A multicentre open-label study. SETTING: Australian public hospital system. SUBJECTS: A total of 235 homo-/bisexual men with ARC were enrolled. INTERVENTIONS: All subjects received 1200 mg zidovudine daily. MAIN OUTCOME MEASURES: Survival, incidence and time to development of AIDS and to development of haematological and clinical side-effects. RESULTS: Median time to development of AIDS was 61 weeks, significantly longer (P < 0.03) than the median of 22 weeks in a small control group of 12 untreated ARC subjects. Median survival from development of AIDS was 48 weeks, marginally longer than the 44 weeks in untreated historical AIDS controls. Anaemia requiring transfusion occurred in 113 subjects (48%). Significant differences in time to development of AIDS were found in favour of subjects not requiring transfusions (P < 0.001) with no weight loss (P = 0.004), and who received the full zidovudine dose (1200 mg) during the first 52 weeks of treatment (P = 0.021). Significantly longer median survival times from commencement of zidovudine were found in subjects with a baseline Karnofsky score > or = 90, baseline Hb > or = 13 g/dl, baseline CD4+ cell count > or = 50 x 10(6)/l, no weight loss during first year of treatment, and no or not more than one blood transfusion during treatment. The ability to tolerate full-dose zidovudine was best predicted by a baseline Hb > or = 13 g/dl. Zidovudine-intolerant subjects (defined as the development of either anaemia requiring transfusions, WCC 1000 x 10(6)/l or zidovudine-related myopathy) had a significantly shorter time to development of AIDS than zidovudine-tolerant subjects (P = 0.002). CONCLUSIONS: Zidovudine may benefit people with ARC by significantly postponing the development of AIDS. This benefit appears to be greater in those who do not develop clinical intolerance whilst receiving zidovudine. However, administration of zidovudine to subjects with ARC does not appear to contribute to improved survival after the development of AIDS. People with ARC who develop AIDS while receiving zidovudine, or who develop intolerance to zidovudine, should be considered immediately eligible for other antiretroviral therapies.

AIDS-Related Complex↗
PubMed1996

The impact of zidovudine compared with didanosine on health status and functioning in persons with advanced HIV infection and a varying duration of prior zidovudine therapy. AIDS Clinical Trials Group 116/117 Study Group.

The objective of this study was to compare the effects of zidovudine and didanosine on health-related quality of life in persons with advanced HIV infection and varying duration of prior zidovudine exposure. It was designed as a substudy nested in two similar placebo-controlled active-control-arm randomized trials, using sites of the AIDS Clinical Trials Group participating in the randomized trials of zidovudine versus didanosine (ACTG 116 and 117). The patients comprised 356 participants enrolled in ACTG 116 and 117. All had HIV infection and either a CD4 count of <200 cells/mm3, or a CD4 count of <300 cells/mm3 plus symptoms of HIV disease. Participants were randomized equally within strata defined by duration of prior zidovudine therapy, to receive didanosine sachets at a dose of 500 mg daily (334 mg in subjects weighing <60 kg) or 750 mg daily (500 mg in subjects weighting <60 kg) plus inactive capsules resembling zidovudine, or to receive zidovudine capsules at a dose of 600 mg daily plus inactive sachets resembling didanosine. The main outcome measures were self-reported health-related quality of life, healthcare utilization, disability, work and symptom impact. The results showed no differences in reported symptom impact or healthcare utilization, and most measures of disability were similar. In the group with more than 8 weeks of prior zidovudine therapy, several of the health status scale scores for ongoing participants were significantly better for didanosine recipients, but average differences were small. Use of several different approaches to combining health status and survival showed no differences in the overall quality-time experiences between the treatment groups. Individuals taking zidovudine, low-dose didanosine and high-dose didanosine experienced 33, 34 and 35 weeks, respectively, in at least the typical health state if they had fewer than 8 weeks of previous zidovudine therapy, and had 23, 23 and 26 weeks, respectively, if they had more than 8 weeks previous use of zidovudine. Results did not differ when data were analysed within strata ofpatients who had any versus no prior exposure to zidovudine, or AIDS versus non-AIDS status. In conclusion, functional status and health-related quality of life were substantially similar among persons receiving either zidovudine or didanosine, regardless of the duration of prior zidovudine treatment.

Adult↗
PubMed1996

Zidovudine phosphorylation after short-term and long-term therapy with zidovudine in patients infected with the human immunodeficiency virus.

BACKGROUND: Resistance of human immunodeficiency virus (HIV) to zidovudine (AZT) has been associated with mutations in the viral reverse transcriptase gene. However, recent studies suggest that host cellular factors such as a decreased thymidine kinase activity or an increased cellular P-glycoprotein expression may be important. This study compared concentrations of zidovudine monophosphate, zidovudine diphosphate, and zidovudine triphosphate with P-glycoprotein expression in peripheral blood mononuclear cells from patients receiving long-term (> 18 months) and short-term (< 2 months) zidovudine treatment. METHODS: Ten subjects in the short-term group and 11 subjects in the long-term group with CD4 counts between 300 and 500 received a single oral dose of zidovudine (200 mg) after a 24-hour washout period. Blood samples were collected at 0, 1, 2, 4, and 6 hours. Intracellular nucleotide concentrations were measured by a combined HPLC-radioimmunoassay method, and P-glycoprotein expression was determined by fluorescence activated cell sorting (FACS) analysis with use of the monoclonal mouse antibody MRK-16. RESULTS: Zidovudine monophosphate was the predominant compound, accounting for 73.4% +/- 7.1% (SD) of the total phosphates in the long-term treatment group and 74.2% +/- 15.0% (SD) in the short-term group. Zidovudine diphosphate accounted for 13.3% +/- 3.3% (SD) in the long-term group and 12.5% +/- 6.6% (SD) in the short-term group. Zidovudine triphosphate accounted for 13.4% +/- 4.1% (SD) in the long-term group and 13.5% +/- 8.3% (SD) in the short-term group. Mean peak concentrations for the active zidovudine triphosphate were 0.04 +/- 0.02 (SD) pmol/10(6) cells in both groups. Comparison of the individual zidovudine phosphate concentrations and P-glycoprotein expression revealed no significant difference in the two patient populations. CONCLUSIONS: These data suggest that intracellular phosphorylation does not change over time and that zidovudine does not select for P-glycoprotein expressing cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group.

A randomized controlled study was done to determine whether initial combination therapy with zidovudine and zalcitabine or zidovudine and didanosine would delay the emergence of zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with <300 CD4 cells/mm3 and <4 weeks of prior zidovudine therapy were randomized to zidovudine, zidovudine plus zalcitabine, or zidovudine plus didanosine. Combination therapy did not delay the emergence of zidovudine-resistant virus isolates. However, combination therapy resulted in a significant increase in CD4 cells through 72 weeks compared with zidovudine monotherapy and a greater and more sustained decline in serum HIV-1 RNA. Although this trial was not designed as a clinical end-point study, patients assigned to zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned to zidovudine monotherapy.

Adult↗
PubMed1996

Lamivudine plus zidovudine compared with zalcitabine plus zidovudine in patients with HIV infection. A randomized, double-blind, placebo-controlled trial. North American HIV Working Party.

OBJECTIVE: To compare the safety and activity of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine in patients with moderately advanced human immunodeficiency virus (HIV) infection who had received zidovudine. DESIGN: A multicenter, randomized, double-blind, three-arm, 24-week study with a blinded extension through at least 52 weeks. SETTING: 21 sites in the United States, Canada, and Puerto Rico. PATIENTS: 254 patients who had received zidovudine (median duration of previous therapy, 20 months) and had absolute CD4+ cell counts of 100 to 300 cells/mm3. INTERVENTIONS: Patients were randomly assigned to receive one of three regimens: 150 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (low-dose lamivudine group); 300 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (high-dose lamivudine group); or 0.75 mg of zalcitabine plus 200 mg of zidovudine three times daily (zalcitabine group). MEASUREMENTS: Immunologic activity was assessed primarily by changes in absolute CD4+ cell counts; virologic activity was assessed by changes in plasma HIV RNA levels as measured by reverse transcriptase polymerase chain reaction. Safety of the treatment regimens was assessed through the reporting of adverse events. RESULTS: 78% of patients completed 24 weeks of study treatment, and 63% of patients completed 52 weeks of study treatment. Changes in absolute CD4+ cell counts were significantly better for the low-dose and the high-dose lamivudine groups than for the zalcitabine group (median changes at 52 weeks were +42.5 cells/mm3 in the low-dose lamivudine group, +23.33 cells/mm3 in the high-dose lamivudine group, and -29.58 cells/mm3 in the zalcitabine group). Suppression of plasma HIV RNA levels was similar for all groups (median changes at 52 weeks were -0.48 log10 copies/mL in the low-dose lamivudine group, -0.51 log10 copies/mL in the high-dose lamivudine group, and -0.39 log10 copies/mL in the zalcitabine group). No significant differences in safety were seen among the three regimens, although the low-dose lamivudine regimen appeared to be better tolerated than the others. CONCLUSIONS: In patients with HIV infection who had previously received zidovudine, 150 mg of lamivudine plus zidovudine resulted in greater immunologic evidence of benefit than did 0.75 mg of zalcitabine plus zidovudine and was better tolerated than 300 mg of lamivudine plus zidovudine.

Adult↗
PubMed1997

Zidovudine monotherapy versus zidovudine plus zalcitabine combination therapy in HIV-positive persons with CD4 cell counts 300-500 cells/mm3: a double-blind controlled trial. The M50003 Study Group Coordinating and Writing Committee.

OBJECTIVE: To assess the safety and clinical and immunological activity of zalcitabine/zidovudine combination therapy compared with zidovudine monotherapy in persons with no or limited antiretroviral experience and CD4 counts of 300-500 cells/mm3. DESIGN AND SETTING: A double-blind controlled multi-centre study conducted in specialist human immunodeficiency virus (HIV) care centres in Spain, Portugal and Australia. Participants were randomized at study entry to zidovudine (200 mg three times daily) plus zalcitabine (0.75 mg three times daily) or matched placebo. The primary end point was the proportion of patients with CD4 above baseline value at 24 months. The secondary end points were time to AIDS/death, quality of life (by MOS-30) and safety. RESULTS: The study was terminated prematurely following the results of the Delta and ACTG 175 studies. Two-hundred and fifty-six patients entered the protocol of whom all but 15 were treatment naive. One hundred and twenty-seven patients commenced zidovudine and 129 commenced a combination of zidovudine/zalcitabine. The median duration of follow-up was 634 days with a median time on blinded therapy of 500 days. Using the last available CD4 count data, 32.4% randomized to zidovudine and 65.1% randomized to zidovudine/zalcitabine remained above baseline at study close (P < 0.001). No significant differences were observed in the time taken for CD4 count to return to baseline. Over 104 weeks, median CD4 counts rose in the combination group from 399 to 509 cells/mm3 whereas those randomized to zidovudine fell from 410 to 374 cells/mm3. Only 12 AIDS events and two deaths (both accidental) occurred during the study with no differences between groups. No differences in quality of life were observed. Adverse events were the cause of treatment discontinuation in 8.6% of patients with no differences between treatment arms. A further 8.2% of patients were lost to follow-up. At least one adverse event (all severities, all relationships) was experienced by 80.3% of patients randomized to zidovudine and 79.8% of patients on combination. Peripheral neuropathy (all grades) was reported in 10.1% of patients randomized to the combination and 3. 1% in the zidovudine arm (P = 0.026). Oral ulcers were reported in 7.8% and 4.7% of combination and zidovudine monotherapy arms, respectively. Neutropenia was more common in the zidovudine group (22%) than the combination group (14%). CONCLUSIONS: Combination of zidovudine/zalcitabine as initial therapy maintains CD4 count above commencement levels in a significantly greater proportion of patients than zidovudine monotherapy. In persons with CD4 counts > or = 300 cells/mm3 inclusion of zalcitabine with zidovudine does not increase the incidence of adverse events or adversely affect quality of life.

Adult↗
PubMed1996

Viral load, viral phenotype modification, zidovudine susceptibility and reverse transcriptase mutations during the first 6 months of zidovudine monotherapy in HIV-1-infected people.

We studied 14 zidovudine-naive, HIV-1-infected patients attending an infectious diseases clinic in Milan during zidovudine therapy for 6 months. We monitored CD4 cell counts, immune complex-dissociated p24 antigen, viral phenotype and viral load in plasma. The virus infecting a subset of patients was examined for zidovudine susceptibility and zidovudine resistance-associated mutations. A significant correlation was established between the increase in the CD4 cell count and the decrease in viral load (Spearman's coefficients < -0.5). Patients who were p24 antigen positive had a higher viral load (P < 0.005 at baseline and after 6 months of therapy). Patients with non-syncytium-inducing (NSI) virus had higher CD4 cell counts over time than those with syncytium-inducing (SI) virus. We also examined the viral load in relation to viral phenotype. The median viral load in patients with NSI virus was higher than in SI controls at baseline, but not after 3 and 6 months of therapy. Sequential isolates of HIV-1 were obtained from nine patients and tested for resistance to zidovudine by monitoring the drug susceptibility and the reverse transcriptase-encoding sequence. Amino acid changes at codons 70 and 215 were present in some but not all isolates with zidovudine-resistant phenotype in vitro. It was possible to perform a correlation between zidovudine susceptibility and zidovudine-associated pol gene mutations only at the 6-month time point (Spearman's coefficient = 0.076). SI phenotype was associated with the development of a decreased zidovudine susceptibility. A correlation between zidovudine-associated pol gene mutations and SI phenotype was detected at the 6-month time point.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group.

OBJECTIVE: To compare safety and efficacy of lamivudine-zidovudine combination therapy with zidovudine monotherapy in treating human immunodeficiency virus type 1 (HIV-1)-infected, antiretroviral therapy-naive patients. DESIGN: Double-blind, randomized, multicenter, comparative trial of 129 patients throughout 24 weeks followed by 24 weeks of open-label lamivudine in combination with zidovudine. SETTING: Outpatients from 14 hospitals in Belgium, France, Germany, Spain, and the United Kingdom were enrolled within 6 months. PATIENTS: HIV-1-positive, antiretroviral-naive ( < or = 4 weeks prior zidovudine use) patients aged atleast 18 years with CD4+ cell counts between 0.10 x 10(9)/L and 0.40 x 10(9)/L (100-400/microL). INTERVENTION: Patients received either 300 mg of lamivudine every 12 hours in combination with 200 mg of zidovudine every 8 hours for 24 weeks or zidovudine monotherapy for 24 weeks. All patients were then allowed to receive zidovudine in combination with open-label lamivudine (300 mg every 12 hours). MAIN OUTCOME MEASURES: Efficacy was assessed by changes in CD4+ cell counts beta 2-microglobulin, neopterin, HIV-1 immune-complex dissociated (ICD) p24 antigenemia, and HIV-1 viral load. Safety was assessed by incidence of adverse clinical events and defined laboratory-measured toxic effects. RESULTS: Combination therapy showed superior treatment effects compared with monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts (increase of 0.08 x 10(9)/L vs 0.02 x 10(9)/L; P < .001), ICDp24 (-88% vs -49%; P = .04), cellular viremia (-1.27 vs -0.20 log10 median tissue-culture infected dose [TCID50] per 10(6) peripheral blood mononuclear cells; P = .001), and viral load measured by HIV-1 RNA polymerase chain reaction using a Roche method (-1.33 vs -0.57 log10 copies/mL; P = .001) or an immune-capture method (-0.6 vs -0.14log10 copies/mL; P = .008). Observed changes were sustained to 48 weeks for patients continuing to receive combination therapy. Patients switching to receive combination therapy at week 24 showed improvements in CD4+ cell count and viral load to week 48. Mutation results suggested that mutations associated with zidovudine resistance may have developed more slowly over the first 24 weeks in patients receiving combination therapy. In contrast, mutations associated with lamivudine resistance appeared to develop rapidly, despite sustained antiviral treatment effect. However, the number of patients evaluated for genotypic changes was small, and confirmation of these results is needed in larger studies. No statistically significant differences in incidence or severity of clinically manifested or laboratory-measured toxic effects were noted between treatment groups. CONCLUSIONS: The combination of lamivudine and zidovudine results in a potent and sustained antiviral effect in antiretroviral-naive patients that is superior to that observed with zidovudine monotherapy.

Adult↗
PubMed2006

Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study.

CONTEXT: Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. OBJECTIVE: To compare the efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. DESIGN, SETTING, AND PATIENTS: A 2 x 2 factorial randomized clinical trial with peripartum (single-dose nevirapine vs placebo) and postpartum infant feeding (formula vs breastfeeding with infant zidovudine prophylaxis) interventions. In Botswana between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomized from 4 district hospitals. Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month through age 18 months. INTERVENTION: All of the mothers received zidovudine 300 mg orally twice daily from 34 weeks' gestation and during labor. Mothers and infants were randomized to receive single-dose nevirapine or placebo. Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). MAIN OUTCOME MEASURES: Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. RESULTS: The 7-month HIV infection rates were 5.6% (32 infants in the formula-fed group) vs 9.0% (51 infants in the breastfed plus zidovudine group) (P = .04; 95% confidence interval for difference, -6.4% to -0.4%). Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed) vs 86 infants (15.1% breastfed plus zidovudine) (P = .60; 95% confidence interval for difference, -5.3% to 2.9%). Cumulative infant mortality at 7 months was significantly higher for the formula-fed group than for the breastfed plus zidovudine group (9.3% vs 4.9%; P = .003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P = .21). CONCLUSIONS: Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIV-free survival at 18 months. These results demonstrate the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00197587.

Anti-HIV Agents↗
PubMed1994

Long-term persistence of zidovudine resistance mutations in plasma isolates of human immunodeficiency virus type 1 of dideoxyinosine-treated patients removed from zidovudine therapy.

Zidovudine (3'-azido-2',3'-dideoxythymidine)-resistant isolates of human immunodeficiency virus type 1 (HIV-1) were previously demonstrated in zidovudine-treated AIDS patients. The genetic linkage of multiple mutations characteristic of zidovudine resistance as well as dideoxyinosine resistance were demonstrated by examining clones of viral reverse transcriptase after polymerase chain reaction amplification of plasma culture DNA. The zidovudine resistance mutations persisted at seven time points from 4 patients for 5-22 months despite cessation of zidovudine therapy (and while patients underwent dideoxyinosine therapy). One patient's plasma virus isolate at 14 months possessed a genotype doubly resistant to zidovudine and dideoxyinosine. Virus recovered from four time points showed intermediate to high levels of zidovudine resistance. As these genotypes were mainly derived from plasma culture, the zidovudine-resistant virus appears to persist and replicate well in vivo after cessation of zidovudine therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Changes in plasma HIV-1-RNA viral load and CD4 cell counts, and lack of zidovudine resistance among pregnant women receiving short-course zidovudine.

OBJECTIVE: To describe changes in HIV-1 plasma viral load (VL) and CD4 cell counts and to assess zidovudine resistance associated with a short course of oral zidovudine during late pregnancy. METHODS: From April 1996 to February 1998 in Abidjan, Côte d'Ivoire, 280 HIV-1-seropositive women were randomly assigned at 36 weeks' gestation to receive zidovudine (300 mg) or placebo twice a day, and then one tablet every 3 h from the onset of labor until delivery. Blood samples obtained every 2 weeks until delivery, then at 2 and 4 weeks, and 3 or 6 months after delivery were tested from selected women based on duration of therapy for plasma VL and CD4 cell counts, and samples from 20 women in the zidovudine group were tested by DNA sequencing for the presence of zidovudine resistance mutations. RESULTS: In the zidovudine group, the median reduction in plasma VL (log(10) copies/ml) was -0.48 after 2 weeks (P = 0.02 versus placebo), -0.48 after 4 weeks (P = 0.06), -0.80 after 6 weeks (P = 0.29) of treatment, -0.12 at delivery (P = 0.11), +0.21 at 2 weeks (P = 0.83), +0.17 at 4 weeks (P = 0.69), and +0.21 at 3 months (P = 0.56) postpartum. Median CD4 cell counts were higher in the zidovudine than in the placebo group after 2, 4, and 6 weeks of treatment (P < 0.05). No mutations associated with zidovudine resistance were identified in any of the samples tested. CONCLUSION: These findings suggest that a short course of zidovudine has no adverse HIV-1 virological consequences for the mother.

Anti-HIV Agents↗
PubMed2000

Semen and serum pharmacokinetics of zidovudine and zidovudine-glucuronide in men with HIV-1 infection.

STUDY OBJECTIVE: To characterize the concentration-time profiles of zidovudine and zidovudine-glucuronide in semen and serum of men infected with the human immunodeficiency-1 virus (HIV-1). DESIGN: Open-label observational study. SETTING: University-affiliated teaching hospital and research center. PATIENTS: Four asymptomatic HIV-1-infected men. INTERVENTIONS: Zidovudine administration was followed by an 8-hour intensive pharmacokinetic study on day 1. Over the next 8 days, a dose administration and timed single-sample strategy was employed to determine serum and semen concentration time profiles simultaneously. MEASUREMENTS AND MAIN RESULTS: Zidovudine and zidovudine-glucuronide concentrations were uniformly higher in semen than in serum except at 1 hour after the dose. The median area under the curve ratio (semen AUC0-48:serum AUC0-infinity) was 3.31 for zidovudine and 15.04 for zidovudine-glucuronide. CONCLUSION: Zidovudine and zidovudine-glucuronide reach high levels in seminal plasma relative to serum. The virologic, pharmacodynamic, and public health implications of distribution to this compartment require further study.

Adolescent↗