A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I)

BACKGROUND: No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. OBJECTIVE: To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DESIGN: Randomized, open-label, multi-center. SETTING: Fifteen HIV clinical research centers. PATIENTS: Two-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts > or = 200 x 10(6)/l and HIV-1 RNA > or = 10,000 copies/ml (bDNA assay), modified to 5000 copies/ml. INTERVENTION: d4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MEASUREMENTS: Primary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA < or = 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. RESULTS: For HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, -0.204 to 0.036; P= 0.213], with 49% and 47% respectively achieving < or = 50 copies/ml at 48 weeks (90% CI, -0.134 to 0.096; P = 0.834). Median change in CD4 cell counts at 48 weeks was +227 x 10(6)/l and +198 x 10(6)/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 x 10(6)/l versus 110 x 10(6)/l; P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. CONCLUSIONS: These results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.     

A randomized, comparative study of lamivudine plus stavudine, with indinavir or nelfinavir, in treatment-experienced HIV-infected patients

OBJECTIVE: To compare adherence and clinical outcome with two modalities of highly active antiretroviral therapy (HAART), in HIV-infected patients. DESIGN: Randomized, open-label, prospective study. SETTING: Tertiary care centre in Spain. PATIENTS: A total of 112 non-naive HIV-infected patients, recruited from March 1998 through August 1998, were studied. INTERVENTIONS: Triple drug therapy with stavudine and lamivudine, plus indinavir or nelfinavir. MAIN OUTCOME MEASURES: Adherence, side-effects, and immunological, virological, and clinical efficacy of treatment were assessed at 3-month intervals. RESULTS: After a median follow-up of 9 months, 32% of patients in the indinavir group versus 50% of those in the nelfinavir group showed adequate adherence in all clinical appointments (P= 0.0559). Adherence was superior in the nelfinavir group in every visit. After 6 months of treatment 48% of subjects in the indinavir group and 70% of those in the nelfinavir group exhibited adequate adherence (P= 0.0311). After 9 months 35% of patients in the indinavir group and 59% of those in the nelfinavir group showed adequate adherence (P= 0.0291). Side-effects provoked discontinuation of treatment in 34% of patients in the indinavir group and 12% of patients in the nelfinavir group (P= 0.0073). Immunological and virological efficacy were similar in both groups. CONCLUSIONS: Adherence to a HAART regimen with stavudine plus lamivudine plus nelfinavir was superior to a regimen with stavudine plus lamivudine plus indinavir. Side-effects provoked more discontinuation of treatment in the indinavir group than in the nelfinavir group.     

The efficacy of combined zidovudine and lamivudine compared with that of combined zidovudine,lamivudine and nelfinavir in asymptomatic and early symptomatic HIV-infected children

In this 6-month prospective study, we compared the efficacy of two treatment regimens: double-drug therapy with zidovudine (ZDV) and lamivudine (3TC) and triple-drug therapy with ZDV plus 3TC plus nelfinavir (NFV), in the treatment of asymptomatic and early symptomatic HIV-infected children. Twenty-five children were enrolled in this study and were divided into 2 groups: group A, consisting of 13 children who were given ZDV+3TC; group B, consisting of 12 children who were given ZDV+3TC+NFV. Serial determinations of weight, CD4-cell count, HIV RNA or plasma viral load (VL) and complete blood counts (CBC), liver function tests (LFT), blood urea nitrogen (BUN) tests, creatinine and serum amylase tests were performed at study entry and at 1, 3 and 6 months. The side-effects of drugs were recorded. Over the 6-month period, the median weight increase in group B (24%) was higher than in group A (2%). The median CD4-cell count increase from baseline in group B (94.5%) was better than in group A (9.4%). The reduction of VL below baseline in group B (1.2 log10; 20.8%) was also better than in group A (0.72 log10; 13.8%). However, these differences were not statistically significant (p>0.05). Both combination regimens could not completely suppress HIV RNA below detectable limits (<400 copies/ml). Both groups tolerated the regimens well; no side-effects or toxicities occurred. The efficacy levels of triple-drug therapy (ZDV+3TC+NFV) and double-drug therapy (ZDV+3TC) were not different. There were no side-effects and no deaths during the 6-month study period.     

高效抗逆转录病毒治疗15例人类免疫缺陷病毒感染者一年总结

目的 首次报道我国于1999年5月开始对人类免疫缺陷病毒（HIV）－1感染者的规范化高效抗逆转录病毒治疗。方法 用齐多夫定＋拉米夫定（AZT＋3TC,商品名：双汰芝）联合硫酸茚地那韦（indinavir,商品名：佳息患）对15例HIV感染或艾滋病患者进行为期1年的治疗。随访指标为病毒载量和T淋巴细胞亚群分析。结果 15例随访1年,用药3个月后HIV－1 RNA平均值至198拷贝／ml,比治疗前的90743RNA拷贝／ml下降2.7log。用药后12个月CD4细胞计数平均增加67个／μl,CD8细胞计数平均减少192个／μl,CD4／CD8比例从0．35增加到0．56,15例中2例未作T淋巴细胞亚群分类,13例治疗后3、6、9、12个月CD4^ 童贞细胞（CD45RA＋CD62L＋）数呈现平稳上升趋势,在治疗1年时平均升高42个／μl。而CD8^ 童贞细胞（CD45RA＋CD62L＋）数平均升高19个/μl。所有患者用药后出现消化道反应,3例出现一过性黄疸,2例出现泌尿系结石。结论 与国外临床报道的治疗效果相一致,15例HIV－1不同阶段感染者经治疗后病毒载量水平明显降低,CD4平均细胞数有所增加,在具有不同病毒基因亚型的病例显示同样的治疗效果。     

Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine

OBJECTIVES: To compare the efficacy and safety of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. DESIGN: Two multicenter, open-label, randomized 24-week studies. METHODS: Adults HIV-1 infection, HIV-1 RNA greater than 10000 copies/ml, and no prior lamivudine or protease inhibitor therapy were eligible. In a pilot study (Study A), patients received indinavir at 800 mg every 8 h, 1000 mg every 12 h, or 1200 mg every 12 h. In a subsequent study (Study B), patients received indinavir at 800 mg every 8 h or 1200 mg every 12 h. All subjects received zidovudine (300 mg) and lamivudine (150 mg) every 12 h. An intent-to-treat analysis was used. RESULTS: In Study A, which enrolled 88 patients, neither HIV-1 RNA nor CD4 cell responses differed significantly between treatment groups at 24 weeks when corrected for multiple comparisons. Study B enrolled 433 patients, but was prematurely discontinued when interim analysis suggested greater efficacy of three-times-daily indinavir. Of the first 87 patients reaching week 24, HIV-1 RNA was less than 400 copies/ml in 91% receiving three-times-daily versus 64% receiving two-times-daily indinavir (P < 0.01). CONCLUSION: Three-times-daily indinavir appears more efficacious than two-times-daily dosing when administered with zidovudine and lamivudine. Two-times-daily indinavir dosing should only be considered in situations characterized by favorable pharmacokinetic drug-drug interactions.     

3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine

BACKGROUND: Antiretroviral regimens containing HIV protease inhibitors suppress viremia in HIV-infected patients, but the durability of this effect is not known. OBJECTIVE: To describe the 3-year follow-up of patients randomly assigned to receive indinavir, zidovudine, and lamivudine in an ongoing clinical trial. DESIGN: Open-label extension of a randomized, double-blind study. SETTING: Four clinical research units. PATIENTS: 33 HIV-infected, zidovudine-experienced patients with serum HIV RNA levels of at least 20,000 copies/mL and CD4 counts ranging from 50 to 400 cells/mm3. INTERVENTION: Indinavir, zidovudine, and lamivudine. MEASUREMENTS: Safety assessments, HIV RNA levels, CD4 cell counts, and genotypic analyses. RESULTS: After 3 years of follow-up, 21 of 31 contributing patients (68% [95% CI, 49% to 83%]) had serum viral load levels less than 500 copies/mL. Twenty of 31 (65% [CI, 45% to 80%]) had levels less than 50 copies/mL. The median increase in CD4 count from baseline was 230 cells/mm3 (interquartile range, 150 to 316 cells/mm3). Nephrolithiasis occurred in 12 of 33 patients (36%). CONCLUSION: A three-drug regimen of indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of patients for at least 3 years.     

Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive HIV-infected individuals with CD4 cell counts between 50 and 250/mm3

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p<0. 0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.     

Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine

OBJECTIVE: To assess virological and immunological responses and toxicity in subjects receiving combination antiretroviral therapy. DESIGN: Six-year follow-up of a single arm of a randomized study of combination antiretroviral therapy. METHODS: HIV-infected, zidovudine-experienced patients originally randomized to receive indinavir, zidovudine, and lamivudine had HIV RNA levels and CD4 cell counts assessed over 6 years. Information was collected by questionnaire from subjects who discontinued the study regimen before 6 years. Both on-study and post-study responses were assessed. RESULTS: Of 33 subjects, 16 (48%) discontinued before 6 years of follow-up. After 6 years, 16 (53%) and 14 (47%) of 30 contributing subjects had HIV RNA levels < 500 and < 50 copies/ml, respectively, and the median increase in CD4 cell count from baseline for 28 contributing subjects was 268 x 10(6) cells/l. Treatment-limiting nephrolithiasis occurred in four subjects. Of the 16 subjects who discontinued the study, 12 had post-study questionnaire data available and seven had HIV RNA < 500 copies/ml on a post-study regimen. In an exploratory analysis combining both on-study and post-study data at approximately 6 years, 26 (79%) and 19 (58%) of 33 had HIV RNA levels < 500 and < 50 copies/ml, respectively, and the median increase in CD4 cell count from baseline was 344 x 106 cells/l. CONCLUSIONS: Antiretroviral therapy with indinavir, zidovudine, and lamivudine suppressed HIV viremia and produced continued CD4 cell increases in a majority of subjects for 6 years. Most subjects who discontinued study medications had HIV RNA levels suppressed on post-study therapy. Though based on a small group, this study demonstrates the durable effects of antiretroviral therapy.     

Zidovudine/lamivudine/abacavir plus tenofovir in HIV-infected naive patients: a 96-week prospective one-arm pilot study

We evaluated a single-class quadruple nucleoside/nucleotide regimen in a 96-week prospective one-arm pilot study in adult HIV-infected naive patients with CD4 >100 cells/microl. Standard zidovudine/lamivudine/abacavir and tenofovir doses were given. Virologic efficacy was evaluated by intent-to-treat (ITT), switch = failure and on-treatment (OT) analyses. A total of 54 patients were included (median CD4 count 254 cells/microl, VL 79,706 copies/ml). A median drop in VL of 2 log at 14 days and >3 log since week 12 was observed. A total of 34/54 (63%) patients (ITT) and 34/39 (87%) patients (OT) had VL <50 copies/ml at 96 weeks. Four (7%) patients switched therapy due to adverse events, 5 (9%) had virologic failure, and 1 died. Similar efficacy results were observed irrespective of baseline VL (> or <5 log) or CD4 cells (> or <250/microl). A median CD4 gain of +223 cells/microl was achieved. K65R + 41L + 219Q were detected in one patient at virologic failure. Only two patients presented fat loss on clinical evaluation. A decrease in total cholesterol (p = 0.007) and LDLc (p = 0.016) was observed. Our data suggest that zidovudine/lamivudine/abacavir plus tenofovir is a simple, effective, and well-tolerated NNRTI/PI-sparing regimen, even for patients with high viral loads. Larger trials comparing this option with standard initial antiretroviral regimens should be conducted.     

Low risk of adefovir resistance in lamivudine-resistant chronic hepatitis B patients treated with adefovir plus lamivudine combination therapy: two-year follow-up

BACKGROUND/AIMS: We studied the long-term efficacy (median follow-up of 28 months) of adefovir (ADV) in combination with lamivudine (LAM) in 132 LAM-resistant Japanese patients with chronic genotype C-dominant hepatitis B virus (HBV) infection. METHODS: The viral response (undetectable HBV-DNA by PCR assay) and the predictor of viral response were evaluated. The emergence of ADV-resistant mutants was investigated during the combination therapy. RESULTS: The cumulative probability of viral response was 69% at 12 months, and 81% at 24 months. Multivariate analysis identified baseline HBe antigen status (P=0.0001), aspartate aminotransferase level (AST) (P=0.001) and HBV-DNA level (P=0.002) as determinants of viral response to treatment. At the beginning of ADV therapy, substitutions at rtA181 (rtA181T and rtA181S) were identified in 3 patients (2.3%). In the remaining 129 patients, the rtM204 mutants were identified at baseline, and two (1.6%) of the 129 patients developed new ADV-resistant mutants; one was rtA181S and another was rtA181T plus rtN236T mutation. CONCLUSIONS: Adefovir and lamivudine combination therapy effectively suppressed viral replication and maintained the efficacy well in LAM-resistant patients with chronic HBV infection. Genotypic analysis indicated that the emergence of ADV-resistant mutants is rare, at least over a period of 2 years, in patients with combination therapy.     

Effect of lamivudine in HIV-infected persons with prior exposure to zidovudine/didanosine or zidovudine/zalcitabine

Nucleoside analog-based regimens remain an integral component of combination therapy for use in both antiretroviral treatment-naive and experienced HIV-infected patients. To further define treatment responses to new antiretroviral therapy in patients with long-term experience to dual nucleoside analog therapy (zidovudine [ZDV] plus didanosine [ddI] or ZDV plus zalcitabine [ddC]), 325 subjects derived from the AIDS Clinical Trials Group (ACTG) 175 trial were randomized to three different combination regimens: (1) continuation of ZDV + ddI or ZDV + ddC (continuation arm), (2) addition of 3TC to ZDV + ddI or ZDV + ddC (addition arm), or (3) a switch to ZDV + 3TC therapy (switch arm). Both the addition and switch arms sustained significantly greater short-term (baseline to week 4) mean CD4+ cell count increases compared with the continuation arm (+36, +28 versus -4 cells/mm3; p = 0.012) and long-term CD4+ cell count responses (baseline to weeks 40/48: +32, +19 versus -9 cells/mm3; p = 0.003). Superior short-term (baseline to week 8) mean decreases in plasma HIV RNA (p < 0.001) were achieved by both the addition and switch arms (0.53 log10 and 0.54 log10 copies/ml, respectively) compared with the continuation arm (0.13 copies/ml) whereas no differences in long-term virologic suppression were observed (p = 0.30). At week 48, no differences were observed in the proportions of subjects who had HIV RNA levels below 500 copies/mL: 18% of subjects in each treatment arm (3-way p = 1.0). Overall, the treatments were well tolerated and only nine subjects (3%) died or developed one or more AIDS-defining events. While this study confirms the intrinsic antiretroviral activity of 3TC, only modest marker changes and limited short-term viral suppression are seen with incremental addition of the drug. The current approach of using 3TC in maximally suppressive regimens is preferred.     

Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients

OBJECTIVES: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine. METHODS: Plasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach. RESULTS: Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level-time curve up to 8 h and plasma half-life were 0.42 micromol/l (CV 57.5%), 9.51 micromol/l (CV 47.3%), 29.56 micromol/l x h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 micromol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017. CONCLUSIONS: Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.     

Cytomegalovirus viremia in HIV-infected patients treated with zidovudine

We followed the course of cytomegalovirus (CMV) viremia in 65 patients treated with zidovudine for symptomatic HIV-1 infection. Blood samples were tested for the presence of CMV before initiation of treatment and every 3 months thereafter. 13 patients (20%) showed a positive CMV viremia at initiation of treatment. After 3 months of therapy, only 2 patients (3%) remained viremic. However, the frequency of CMV viremia increased from the 6th month of treatment and 28 (43%) of our patients showed a persistence of, or conversion to, positive viremia during the course of treatment. CMV viremia was associated with a decline in the patients' clinical state in 79% of the cases. In contrast, among the 37 patients, who remained negative for CMV viremia, 73% did not show a progression of the HIV-associated disease. The results suggest that CMV viremia could be considered as a useful marker for HIV-associated disease and its progression as well as for the efficacy of therapy.     

Adherence, side effects and efficacy of stavudine plus lamivudine plus nelfinavir in treatment-experienced HIV-infected patients

OBJECTIVES: To evaluate adherence, side effects and efficacy of a modality of highly active antiretroviral therapy (HAART) in HIV-infected patients. METHODS: In a cohort, prospective study, 65 previously treated patients received stavudine plus lamivudine plus nelfinavir. Fifty-three participants (81%) had a history of intravenous drug use. Patients were evaluated at 3-month intervals. The association of adherence with demographic variables, hepatitis C virus infection, number of stopped antiretroviral regimens, HIV RNA level, CD4 cell count, and adverse effects to drugs was assessed. RESULTS: After a median follow-up of 12 months, 30 participants (46%) showed adequate adherence in all visits. An association was observed between adherence and female sex: 18 of 47 men (38%) vs. 12 of 18 women (67%) presented adequate adherence in all visits (P=0. 0416). An association was also observed between adherence and low baseline HIV RNA level (P=0.0229). Discontinuation of treatment took place because of refusal to take medication in 11 participants (17%) and because of side effects in seven participants (11%). Undetectable HIV RNA level was achieved in 26 patients (40%) at 3 months and in lower percentages at months 6, 9 and 12. CONCLUSIONS: Overall adherence to the employed HAART regimen was poor. Female sex and low baseline HIV RNA were associated with better adherence. Refusal to take medications and side effects were the main reasons to stop therapy. At 3 months' follow-up, virological efficacy was achieved in 40% of patients.