Showing papers on "Zidovudine published in 2003"

Comparison of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection

Abstract: BackgroundThe optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. MethodsThis multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen. ResultsA total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard...

Comparison of Four-Drug Regimens and Pairs of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection

Abstract: BACKGROUND It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens. METHODS In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir. RESULTS A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21). CONCLUSIONS There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice.

Toxicity of Nucleoside Analogues Used to Treat AIDS and the Selectivity of the Mitochondrial DNA Polymerase

Abstract: Incorporation of nucleoside analogues by the mitochondrial DNA polymerase has been implicated as the primary cause underlying many of the toxic side effects of these drugs in HIV therapy. Recent success in reconstituting recombinant human enzyme has afforded a detailed mechanistic analysis of the reactions governing nucleotide selectivity of the polymerase and the proofreading exonuclease. The toxic side effects of nucleoside analogues are correlated with the kinetics of incorporation by the mitochondrial DNA polymerase, varying over 6 orders of magnitude in the sequence zalcitabine (ddC) > didanosine (ddI metabolized to ddA) > stavudine (d4T) >> lamivudine (3TC) > tenofovir (PMPA) > zidovudine (AZT) > abacavir (metabolized to carbovir, CBV). In this review, we summarize our current efforts to examine the mechanistic basis for nucleotide selectivity by the mitochondrial DNA polymerase and its role in mitochondrial toxicity of nucleoside analogues used to treat AIDS and other viral infections. We will also discuss the promise and underlying challenges for the development of new analogues with lower toxicity.

Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers.

Abstract: Although children born to HIV-infected (HIV+) women receiving antiretroviral therapy during pregnancy show virtually no adverse clinical effects at birth, the antiretroviral nucleoside analog drugs are known to damage nuclear and mitochondrial DNA. In this study, biomarkers of mitochondrial toxicity and genotoxicity have been examined in a well-characterized sample set consisting of infants born to HIV-uninfected (HIV-) mothers (n = 30), and HIV- infants (n = 20) born to HIV-infected (HIV+) mothers who received either no antiretroviral therapy (n = 10) or zidovudine (3'-azido-3'-deoxythymidine [AZT]) during pregnancy (n = 10). DNA from cord blood leukocytes and peripheral blood leukocytes taken at 1 and 2 years of age was examined for loss of mitochondrial DNA (mtDNA) and telomere integrity. Telomere length, a measure of nuclear DNA damage, was the same in all infants at birth and at age 1 year. The quantity of mtDNA was assessed relative to nuclear DNA using a polymerase chain reaction-based chemiluminescence detection (PCR-CID) method that determined mitochondrial D Loop gene copies relative to nuclear 18S RNA gene copies by comparison with a standard curve. MtDNA quantity was expressed as a ratio of gene copy numbers. In infants of uninfected mothers (AZT-/HIV-) at the three time points, the ratios were 442 to 515, whereas in infants of untreated AZT-/HIV+ mothers the ratios were 261 to 297, and in infants of AZT-treated (AZT+/HIV+) mothers the ratios were 146 to 203. At all three time points, differences between the AZT-/HIV- group and the two HIV+ groups were statistically significant (p <.05), and differences between the AZT-/HIV+ and AZT+/HIV+ groups were also statistically significant (p <.05), demonstrating that AZT exposure causes a persistent depletion of mtDNA. The study shows that children of HIV+ mothers are at risk for mitochondrial damage that is further increased in infants of mothers receiving AZT during pregnancy.

Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants.

Abstract: Background: The perinatal prophylactic administration of zidovudine is associated with rapidly reversible macrocytic anemia in infants. However, a recent study suggests that there may be more persistent inhibition of hematopoietic stem cells. Objective: To study hematopoiesis in uninfected infants, born to HIV-1 seropositive mothers, including those exposed and those not exposed to perinatal zidovudine alone or in combination. Methods: Longitudinal study, from 0 to 18 months, of hemoglobin, platelets, poly- nuclear neutrophils, total lymphocytes, and CD4+ and CD8+ lymphocytes in more than 4000 infants of the French Perinatal Study. Modeling of repeated measures and non-linear evolution with age, with models combining natural cubic B-splines and random effects. Results: The hemoglobin level was transiently reduced in newborns exposed to zidovudine. Multivariate analysis taking into account age, prematurity, geographical origin, maternal drug use and maternal CD4 cell count, indicated that levels of the three other lineages were slightly lower until age 18 months in exposed than not exposed infants (P , 0.0001 for each lineage).There was a negative relationship between the duration of exposure and each hematological variable. Combinations of antiretroviral treatments were associated with larger decreases than monotherapy up to 15 months of age. Similar, but less pronounced, patterns were found for the CD4+ and CD8+ subpopulations of lymphocytes. Conclusions: Zidovudine administered during the perinatal period may result in a small but significant and durable effect on hematopoiesis up to the age of 18 months.

Breast Cancer Resistance Protein (BCRP/ABCG2) Induces Cellular Resistance to HIV-1 Nucleoside Reverse Transcriptase Inhibitors

Abstract: Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP- binding cassette transporters, which induce multidrug resistance in cancer cells. We found that a high level of BCRP expression in CD4+ T cells conferred cellular resistance to human immunodeficiency virus type-1 (HIV-1) nucleoside reverse transcriptase inhibitors. The cell line MT-4/DOX 500 was established through the long-term culture of MT-4 cells in the presence of doxorubicin (DOX) and had reduced sensitivity to not only DOX but also zidovudine (AZT). MT-4/DOX 500 cells showed reduced intracellular accumulation and retention of DOX and increased ATP-dependent rhodamine 123 efflux. The cells were also resistant to several anticancer agents such as mitoxantrone, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, and 7-ethyl-10-hydroxycamptothecin. AZT was 7.5-fold less inhibitory to HIV-1 replication in MT-4/DOX 500 cells than in MT-4 cells. Furthermore, the anti-HIV-1 activity of lamivudine was severely impaired in MT-4/DOX 500 cells. In contrast, the antiviral activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors was not affected in the cells. MT-4/DOX 500 cells expressed glycosylated BCRP but not P-glycoprotein (ABCB1), multidrug resistance protein 1, 2, or 4 (ABCC1, -2, or -4), or lung resistance-related protein. In addition, the BCRP-specific inhibitor fumitremorgin C completely abolished the resistance of MT-4/DOX 500 cells to AZT as well as to DOX. An analysis for intracellular metabolism of AZT suggests that the resistance is attributed to the increase of ATP-dependent efflux of its metabolites, presumably AZT 5'-monophosphate, in MT-4/DOX 500 cells.

Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level.

Abstract: Objectives: It has been proposed that the contribution of nucleoside-analogue reverse transcriptase inhibitor (NRTI) therapy to subcutaneous fat wasting involves adipose tissue-specific mitochondrial DNA toxicity. We have investigated the relationships between NRTI therapy, adipocyte mitochondrial DNA content, evidence of toxicity in adipose tissue and fat wasting in Caucasian male Western Australian HIV Cohort study participants. Methods: Longitudinal mixed effects analysis of fat wasting was undertaken in individuals receiving initial stavudine- or zidovudine-containing highly active antiretroviral therapy (HAART) (n=49, 149 DEXA measurements). Adipocyte mitochondrial DNA (mtDNA) depletion was also assessed according to current NRTI therapy in 92 subcutaneous fat biopsies from 69 HIV-positive individuals and seven healthy controls, and results were correlated with fat wasting among a subset of patients with biopsy data receiving initial stavudine- or zidovudine-containing HAART (n=22, 103 DEXA measurements). Confocal microscopy was performed in 22 biopsy samples obtained before and after initiating/switching NRTI therapy. Results: Stavudine therapy was associated with more severe adipocyte mitochondrial DNA depletion (P<0.001) and fat wasting over time (P=0.002) compared with zidovudine therapy in independent analyses. Among patients with concurrent biopsy and longitudinal DEXA data, fat wasting was associated with duration of NRTI therapy (P=0.001) and adipocyte mtDNA copies/cell (P=0.01). In this analysis, the significant association between choice of stavudine versus zidovudine and fat wasting (P=0.03) was lost after adjustment for the effect of mtDNA depletion (P=0.13). Confocal analysis provided direct evidence of a relationship between severity of adipose tissue toxicity and mitochondrial DNA depletion. No significant effects of HIV protease inhibitor therapy were detected in these analyses. Conclusions: Severity of subcutaneous fat wasting is primarily determined by choice of NRTI therapy (stavudine versus zidovudine) and by duration of exposure to the relevant NRTI. At the cellular level, evidence is provided that this effect manifests through NRTI-induced mitochondrial DNA depletion.

Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals.

Abstract: Objectives: Nucleoside analog reverse transcriptase inhibitors (NRTI) are used in virtually all anti-HIV regimens. Clinical response depends on the intracellular formation of the pharmacologically active triphosphate moiety. Our objective was to quantify the pharmacological characteristics of zidovudine and lamivudine triphosphate in HIV-infected individuals. Methods: Peripheral blood mononuclear cells were obtained at multiple planned intervals from antiretroviral-naive adults participating in a study of zidovudine, lamivudine and indinavir, and triphosphate levels were determined by immunoassay and high-performance liquid chromatography/mass spectrometry. Plasma HIV-RNA, CD4 cell counts, and plasma drug concentrations were collected over 18 months. Data were analysed using non-parametric, regression and time-to-event methods. Results: Thirty-three subjects were evaluated. The estimated half-lives of zidovudine and lamivudine triphosphate were 7 and 22 h, respectively. Triphosphate concentrations were elevated in individuals with low baseline CD4 cell counts. Triphosphate concentrations in women were higher than in men by 2.3 and 1.6-fold for zidovudine and lamivudine, respectively. Women reached an HIV-RNA level under 50 copies/ml twice as fast as men. Zidovudine triphosphate above 30 fmol/10 6 cells was independently predictive of the time to under 50 copies/ml. Lamivudine triphosphate above 7017 fmol/10 6 cells was independently predictive of a longer virological response. Indinavir concentrations were related to antiviral responses in univariate analyses. Conclusion: Zidovudine and lamivudine triphosphate concentration thresholds were independently associated with the antiviral activity of zidovudine, lamivudine, and indinavir. The significantly elevated triphosphate concentrations in women and individuals with low baseline CD4 cell counts, groups that historically experience high rates of serious NRTI toxicities, provide a hypothesis for the pathogenesis of these events.

Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy.

Abstract: ObjectiveTo investigate potential mitochondrial toxicity in HIV-uninfected infants exposed to highly active antiretroviral therapy (HAART) in utero and/or neonatal zidovudineDesignA prospective observational study performed in a tertiary referral center for HIV-infected women and their infants an

Severe cutaneous reactions associated with the use of human immunodeficiency virus medications.

Abstract: Patients infected with human immunodeficiency virus are highly susceptible to adverse dermatological reactions to specific medications. Severe cutaneous conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis are associated with high morbidity and, notably for toxic epidermal necrolysis, high mortality. Although overall mortality from human immunodeficiency virus has dramatically declined owing to highly active antiretroviral therapy, these antiretroviral regimens have been associated with a wide spectrum of severe cutaneous reactions. We reviewed case reports and clinical trials in the English literature on Medline® (1966 to 2001) and Aidsline® (1980 to 2000) to determine the prevalence of Stevens-Johnson syndrome and toxic epidermal necrolysis attributable to the current FDA approved antiretroviral medications. We identified a total of approximately 50 patients who had Stevens-Johnson syndrome andlor toxic epidermal necrolysis associated with the use of 5 antiretroviral medications: 2 nucleoside reverse transcriptase inhibitors, zidovudine (2 patients) and didanosine (1 patient); 1 non-nucleoside reverse transcriptase inhibitor, nevirapine (42 patients); and 2 protease inhibitors, indinavir (1 patient) and amprenavir (an unspecified number within the 1% of over 1400 patients experiencing severe life-threatening reactions). Of the reports that specified the onset time of adverse reaction after initiation of treatment, 86% (19/22) of patients experienced reactions within 4 weeks. Ten of the approximately 50 patients were diagnosed with Stevens-Johnson syndrome or toxic epidermal necrolysis, due to specific antiretroviral medication, or a combination of medications identified by either resolution upon withdrawal, consistent biopsy findings or a positive rechallenge. The remainder of the identified patients were reported in articles lacking data regarding drug administration, reaction history or other details.

Randomized, controlled, 48-week study of switching stavudine and/or protease inhibitors to combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients.

Abstract: Objective: HIV-1 protease inhibitors (versus no protease inhibitors) and stavudine (versus zidovudine) are independently associated with a higher risk of lipoatrophy in HIV-infected patients. We sought to determine whether the revision of stavudine and/or protease inhibitor-containing regimens to combivir/abacavir would result in prevention and/or reversibility of lipoatrophy in HIV-1-infected patients. Design: The investigation was a prospective, randomized, controlled, open-label study. Subjects: The subjects included 37 HIV-1-infected individuals with stable undetectable HIV-1 loads who were taking a regimen containing either stavudine or zidovudine with lamivudine and a protease inhibitor. Intervention: Subjects were randomized to continue therapy or switch stavudine to zidovudine and protease inhibitor to abacavir, such that the universal switch regimen was combivir (zidovudine/lamivudine) and abacavir. Main Outcome Measures: Total body, leg, and arm fat mass was measured at baseline, 24 weeks, and 48 weeks using whole-body dual-energy x-ray absorptiometry. Single-cut L4 computed tomography and assays of multiple metabolic parameters were also performed. Results: There was an average gain in fat mass of 0.009 kg/(leg.mo) in switch patients versus a loss of 0.010 kg/(leg.mo) in controls (p =.04, on-treatment analysis) over 48 weeks. Significant arm fat restoration was observed in patients who switched regimens, with an average gain of 0.014 kg/(arm.mo) (p =.004), whereas controls did not have a significant change from baseline. Analyses of percentage changes in arm and leg fat masses showed similar findings. No significant effects on intraabdominal fat, blood lipid levels, glycemic indices, and lactate levels were detected, although most baseline mean values were normal in study subjects. Combivir/abacavir maintained virological control in all but one case, and three (13.6%) of 22 individuals had adverse reactions to abacavir therapy. Conclusions: A switch to combivir/abacavir therapy was associated with objective evidence of limb fat-sparing and fat restoration compared with continued treatment with stavudine and/or protease inhibitor.

Antiretroviral therapy in HIV-2-infected patients: changes in plasma viral load, CD4+ cell counts, and drug resistance profiles of patients treated in Abidjan, Côte d'Ivoire.

Abstract: Objective To describe changes in plasma viral load, CD4+ cell counts, and drug resistance profiles of HIV-2-infected patients receiving antiretroviral (ARV) therapy in Abidjan, Cote d'Ivoire. Methods Consecutive blood samples were collected from 18 HIV-2-infected ARV-naive patients who had received ARV therapy in the UNAIDS drug access initiative (UNAIDS-DAI) in Abidjan between August 1998 and July 2000. Changes in HIV-2 plasma viral load, CD4+ cell counts, and genotypic and phenotypic drug resistance testing were determined. Results At baseline, 11 (61%) of the 18 patients initiated highly active antiretroviral therapy (HAART) and seven (39%) received dual therapy. No significant change in median viral load was observed at 2 months (P = 0.09), at 6 months (P = 0.06), and at 12 months of therapy (P = 0.26). No significant increase in CD4+ cell counts was observed at 12 months (P = 0.10). All four patients on indinavir-containing HAART had undetectable viral loads at 2-4 months of therapy. However, none of seven patients on nelfinavir-containing HAART had a substantial decrease in viral load. Viruses from 14 patients were analyzed, 12 of which (86%) had at least one primary resistance mutation that is known to confer resistance to HIV-1 virus. Three patients had the multi-drug-resistant mutation, Q151M, two of whom showed reduced susceptibility to zidovudine, didanosine, stavudine and zalcitabine. Conclusion Our limited findings show that nelfinavir-containing regimens may have limited virologic benefit to HIV-2-infected patients.

Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients.

Abstract: Objectives: To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype. Design and methods: DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPARg, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype. Results: Stavudine-based HAART recipients (n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARgamma (53.9% of control, P=0.021), UCP2 (62.2% of control, P=0.024) and UCP3 (51.8% of control, P=0.047) mRNA compared with controls. Zidovudine-based HAART recipients (n=7) also displayed significant mtDNA depletion (34.45% of control, P=0.031), increased mitochondrial protein mass (5.7-fold of control, P=0.009), and markedly increased UCP1 (18-fold of control, P=0.009) mRNA. Elevated UCP1 mRNA expression was found to be associated with non-stavudine (zidovudine or abacavir), protease inhibitor (PI)-containing HAART (95-fold of non-stavudine, non-PI-containing HAART, P=0.006). Conclusion: Differential effects of stavudine and zidovudine therapy on mtDNA depletion and expression of adipocyte differentiation markers PPARgamma and UCP2 were observed, consistent with increased adipose tissue toxicity associated with stavudine therapy. Increased UCP1 mRNA, a marker of brown adipose tissue phenotype, was associated with non-stavudine, PI-containing HAART, and may represent an adaptive response to the increased fatty acid flux associated with PI therapy, and may contribute to the increased resting energy expenditure reported in such patients.

A Novel Genetic Pathway of Human Immunodeficiency Virus Type 1 Resistance to Stavudine Mediated by the K65R Mutation

Abstract: Stavudine (d4T) and zidovudine (AZT) are thymidine analogs widely used in the treatment of human immunodeficiency virus type 1 (HIV-1)-infected persons. Resistance to d4T is not fully understood, although the selection of AZT resistance mutations in patients treated with d4T suggests that both drugs have similar pathways of resistance. Through the analysis of genotypic changes in nine recombinant viruses cultured with d4T, we identified a new pathway for d4T resistance mediated by K65R, a mutation not selected by AZT. Passaged viruses were derived from treatment-naive persons or HIV-1(HXB2) and had wild-type reverse transcriptase (RT) or T215C/D mutations. K65R was selected in seven viruses and was associated with a high level of enzymatic resistance to d4T-triphosphate (median, 16-fold; range, 5- to 48-fold). The role of K65R in d4T resistance was confirmed in site-directed mutants generated in three different RT backgrounds. Phenotypic assays based on recombinant single-cycle replication or a whole-virus multiple replication cycle were unable to detect d4T resistance in d4T-selected mutants with K65R but detected cross-resistance to other nucleoside RT inhibitors. Four of the six viruses that had 215C/D mutations at baseline acquired the 215Y mutation alone or in association with K65R. Mutants having K65R and T215Y replicated less efficiently than viruses that had T215Y only, suggesting that selection of T215Y in patients treated with d4T may be favored. Our results demonstrate that K65R plays a role in d4T resistance and indicate that resistance pathways for d4T and AZT may not be identical. Biochemical analysis and improved replication assays are both required for a full phenotypic characterization of resistance to d4T. These findings highlight the complexity of the genetic pathways of d4T resistance and its phenotypic expression.

Human immunodeficiency virus-associated polymyositis: A longitudinal study of outcome

Abstract: Objective To determine the clinical course and optimum treatment of human immunodeficiency virus (HIV)–associated myositis. Methods Sixty-four patients attending a county outpatient HIV/acquired immunodeficiency syndrome facility were referred for the presence of elevated creatine kinase (CK) levels or muscle weakness. Patients underwent neurologic and rheumatologic evaluation, electromyography, and muscle biopsy after exclusion for recreational drug or alcohol use, metabolic/endocrine disorders, zidovudine therapy, and other infections. Results Thirteen patients (20%) had biopsy-proven myositis. The median duration of HIV infection prior to diagnosis of myositis was 4.3 years (range 0–11 years). Six patients had concomitant diffuse infiltrative lymphocytosis syndrome. There was no correlation of severity of weakness, stage of HIV infection, or retroviral treatment with the CK level at diagnosis. Eight patients received prednisone (60 mg/day) with 5 attaining complete resolution of myositis. The remaining 3 patients received immunosuppressive therapy (azathioprine or methotrexate and intravenous immunoglobulin) and had normalization of strength and CK. Four patients had spontaneous resolution of their myositis without treatment. Conclusion HIV-associated myositis occurs at any stage of HIV infection, has a relatively good prognosis, responds well to immunosuppressive therapy, and has little evidence of adverse outcome on the HIV infection.

Low efficacy and high frequency of adverse events in a randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine.

Abstract: BACKGROUND Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear. METHODS Randomized, controlled, open-label trial of 180 antiretroviral drug-naive HIV-infected patients allocated to a regimen of abacavir, stavudine and didanosine (A/S/D, n = 60), ritonavir and saquinavir (R/S 400/400 mg twice daily; n = 60) or nelfinavir and nevirapine (N/N 1250/200 mg twice daily; n = 60); the latter two in combination with lamivudine and zidovudine. The primary endpoint was HIV plasma RNA < or = 20 copies/ml after 48 weeks. RESULTS At baseline, the median CD4 cell count was 161 x 106 cells/l (range, 0-920) and the HIV RNA was 5.0 log10 copies/ml (range, 2.7-6.7). At 48 weeks, 43% in the A/S/D arm had a HIV RNA < or = 20 copies/ml, compared with 69% in the N/N arm (P < 0.01) and 62% in the R/S arm (P < 0.05). In a multivariate analysis, the A/S/D arm had an odds ratio of obtaining a viral load of < or = 20 copies/ml at week 48 of 0.25 [95% confidence interval (CI) 0.10-0.59] versus N/N and 0.53 (95% CI, 0.33-0.83) versus R/S. The A/S/D arm had a particularly poor outcome in patients with higher viral load and AIDS at baseline: 63% had to discontinue A/S/D (any drug). Side effects were more frequent in the A/S/D arm and included neuropathy 27%, suspicion of hypersensitivity 12%, and increase in lactate accompanied by systemic symptoms 8%. CONCLUSION The A/S/D regimen had a low efficacy and a high frequency of adverse events and cannot be recommended.

Changes in CSF and plasma HIV-1 RNA and cognition after starting potent antiretroviral therapy

Abstract: The authors assessed CSF and plasma HIV-1 RNA and neuropsychological test performance (composite neuropsychological test Z score [NPZ-4]) in 25 HIV-1-infected subjects 4 and 8 weeks after beginning potent antiretroviral therapy that included a protease inhibitor. In the 14 subjects who entered the study on no antiretroviral treatment, NPZ-4 improvement was associated with decline in CSF HIV-1 RNA at both visits (p = 0.001 and p = 0.02), and those treated with zidovudine or indinavir had greater improvement in NPZ-4 at both visits compared to those treated with other drugs (p = 0.003 and p = 0.01).

Risk factors for pediatric human immunodeficiency virus-related malignancy.

Abstract: ContextAlthough cancers occur with increased frequency in children with human immunodeficiency virus (HIV) infection, the specific clinical, immunological, and viral risk factors for malignancy have not been identified.ObjectiveTo identify risk factors for malignancy among HIV-infected children.Design, Setting, and PatientsA multicenter case-control study of children with HIV at 26 institutions participating in the Pediatric Oncology Group. Forty-three case patients with a new malignancy and 74 control patients without a malignancy were matched based on the duration of their infection. Patients were enrolled between January 1992 and July 1998.Main Outcome MeasuresClinical and laboratory factors assessed as putative risk factors included demographic characteristics, HIV characteristics, prior antiretroviral treatment, and CD4 cell count. Coviral infections with Epstein-Barr virus (EBV), cytomegalovirus, and human herpesvirus 6 were assessed by semiquantitative polymerase chain reaction assays and serological testing.ResultsCase malignancy diagnoses included 28 non-Hodgkin lymphoma, 4 B-cell acute lymphoblastic leukemia, 1 Hodgkin disease, 8 leiomyosarcoma, 1 hepatoblastoma, and 1 schwannoma. Epstein-Barr virus viral load of more than 50 viral genome copies per 105 peripheral blood mononuclear cells was strongly associated with cancer risk but only for children with CD4 cell counts of at least 200/µL (odds ratio [OR], 11.33; 95% confidence interval [CI], 2.09-65.66, P<.001). High EBV viral load was not associated with cancer for children with CD4 cell counts of less than 200/µL (OR, 1.12; 95% CI, 0.13-9.62; P = .99). Zidovudine antiretroviral therapy did not confer a significant protective effect for either the high (OR, 0.81; 95% CI, 0.22-3.09; P = .77) or the low CD4 cell count groups (OR, 0.27; 95% CI, 0.04-1.46; P = .16). The route of HIV infection was not associated with increased cancer risk.ConclusionsRoute of infection, demographic characteristics, and zidovudine use were not associated with the development of malignancy in HIV-infected children. High viral burden with EBV was associated with the development of malignancy in HIV-infected children although the effect was modified by CD4 cell count. The pathogenesis of HIV-related pediatric malignancies remains unclear and other contributing risk factors can be elucidated only through further study.

Choroid plexus controls brain availability of anti-HIV nucleoside analogs via pharmacologically inhibitable organic anion transporters.

Abstract: Objective: In AIDS, early suppression of the viral load in the central nervous system is critical for the efficacy of antiretroviral therapy, in order to prevent the emergence of a reservoir of resistant strains of virus, and brain impairment in late stages of the infection. The blood-cerebrospinal fluid (CSF) interface (i.e. the choroidal epithelium) constitutes the most direct route to reach the ventricular meningeal and perivascular infected macrophages, and may modulate the cerebral biodisposition of antiretroviral drugs through various transport systems. Our aim was to address nucleoside drug transfer specifically across the blood-CSF interface, and identify the possible mechanisms involved in their transport. Methods: Drug influx and efflux were measured using an in vitro cellular model that reproduces the barrier and transport properties of the blood-CSF interface in vivo. Transport mechanisms were investigated by competition studies. Results: The CSF influx rate of zidovudine was the highest, although moderate, followed by that of stavudine. The permeability coefficients of the other drugs tested were low. Zidovudine influx into the CSF is independent of thymidine transport systems, and more importantly is limited by an efflux mechanism. This efflux involves an apical (CSF-facing) carrier belonging to the solute carrier (Slc) 22 family of organic anion transporters, and can be inhibited by a therapeutic concentration of benzbromarone. Conclusions: The demonstration and characterization of this efflux mechanism is the basis for the development of specific inhibitory agents in view to increase the delivery of antiretroviral nucleoside analogs to the brain.

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

Abstract: 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.

Mitochondrial:Nuclear DNA Ratios in Peripheral Blood Cells from Human Immunodeficiency Virus (HIV)–Infected Patients Who Received Selected HIV Antiretroviral Drug Regimens

Abstract: Mitochondrial:nuclear DNA (mtDNA:nDNA) ratios in blood cells were investigated in relation to selected human immunodeficiency virus antiretroviral drug regimens. Patients (n = 214) continually received a regimen consisting of either (1) saquinavir (SAQ) + ritonavir (RTV) + either nevirapine (NVP) or lamivudine (3TC) (n=32) or (2) SAQ+RTV (+/- either NVP or 3TC) + either stavudine (d4T) (n=127), didanosine (ddI) (n=19), d4T+ddI (n=21), or zidovudine (ZDV) (n=15), for >/=4 months. NVP- or 3TC-only regimens were associated with median mtDNA:nDNA ratios that were significantly higher than those for ddI- and d4T+ddI-containing regimens (P<.01) but that were not significantly higher than those for d4T- or ZDV-containing regimens. Patients received thymidine analogue- and/or ddI-containing regimens for a shorter time (median, 14 vs. 24 months; P<.01). Because of survivor-bias effect, these results may represent a conservative estimate of these nucleosides' effect on mtDNA.

Lipid changes in patients initiating efavirenz- and indinavir-based antiretroviral regimens.

Abstract: Purpose: To evaluate nonfasting lipid levels in a large cohort of patients on three HAART regimens: efavirenz + zidovudine + lamivudine (EFV+ZDV+3TC), efavirenz + indinavir (EFV+IDV), and indinavir + zidovudine + lamivudine (IDV+ZDV+3TC). Method: Nonfasting lipid levels were analyzed from a large randomized multicenter treatment trial for HIV-infected patients initiating HAART. Treatment evaluations were carried out at prescribed intervals, and data were recorded and analyzed. Assessment was limited to high-density lipoprotein (HDL) and total cholesterol. Results: The results demonstrate an increase in the total cholesterol, ranging from 23 to 57 mg/dL, in the three combinations of HAART therapy. The increase was most significant in the EFV+IDV arm where the effects appear to be additive. HDL cholesterol also increased in all three arms, but the greatest increase was in the two groups containing EFV. In all three arms, the HDL cholesterol increased significantly in women while increases in men wer...

Low rate of genotypic Hiv-1 drug-resistant strains in the Senegalese government initiative of access to antiretroviral therapy

Abstract: Objective: To monitor the prevalence of antiretroviral (ARV)-resistant HIV-1 viruses and the genotypic mutations in patients enrolled in the Senegalese initiative for access to antiretroviral treatment (ART) Methods: A total of 80 patients with a virological follow-up of at least 6 months were selected 68 were ART-naive and 12 ART-experienced Genotypic resistance to ARV was studied at baseline for a random subset of patients and at each rebound in plasma viral load during ART by sequencing the protease and reverse transcriptase genes Results: At baseline 66 patients received highly active antiretroviral therapy (HAART) [2 nucleoside reverse transcriptase inhibitors (NRTIs)+1 protease inhibitor (PI) (n=64) or 2 NRTIs +1 non-nucleoside reverse transcriptase inhibitor (NNRTI) (n=2)] and 14 patients (175%) started with a dual therapy because of ongoing antitubercular therapy or efficient previous bitherapy for the ART-experienced patients The emergence of drug-resistant viruses (n=13) during follow-up was more frequent in ART-experienced patients than in ART-naive patients 417 versus 118% resistant viruses emerged at comparable follow-up periods a median of 178 and 183 months respectively In patients receiving zidovudine and lamivudine in their drug regimen resistance to lamivudine was more frequent than to zidovudine Two of the three patients with viruses resistant to Pls acquired mutations associated with cross- resistance Strikingly five (39%) of the 13 patients developed resistances to drugs that they had never received (n=3) or that they received 18 or 36 months ago (n=2) Didanosine/stavudine pressure had selected zidovudine-resistant viruses in four patients and indinavir had selected a nelfinavir-resistant virus in one patient Conclusion: In contrast to other reports from developing countries where patients had received ARVs in an uncontrolled manner our study showed that implementation of HAART together with good clinical biological and logistical monitoring can reduce the emergence of resistant strains in Africa (authors)

Fat distribution and metabolic abnormalities in HIV-infected patients on first combination antiretroviral therapy including stavudine or zidovudine: role of physical activity as a protective factor.

Abstract: Objective: To compare body composition, serum lipid profile, parameters of insulin secretion and endocrine measurements in HIV-1-infected patients whose first combination antiretroviral regimen differed only in a nucleoside reverse transcriptase inhibitor (NRTI). Design and setting: Cross-sectional study in an AIDS clinic of a university hospital. Patients: One-hundred-and-fifty HIV-infected patients on long-term first highly active antiretroviral therapy including stavudine (n=75) or zidovudine (n=75). Main outcome measure: Fat wasting was assessed by physical examination. Regional fat distribution was estimated using calliper measurements of skinfold thickness at four sites. Central adiposity was assessed by measurement of waist-hip ratio. Fasting glucose, insulin, triglyceride, cholesterol and its fractions, testosterone, follicle stimulating hormone, luteinizing hormone levels, CD4 cell count and HIV viral load were determined. Daily caloric intake and physical activity level were also calculated. Results: Total body fat was significantly lower in patients taking stavudine, whereas the lean body mass was not statistically different amongst both groups. Ninety-four patients (62.7%; 95% Cl: 54.9-70.4%) had fat redistribution, being isolated lipoatrophy in 20 (13.3%; 95% Cl: 7.9-18.8%), isolated lipohypertrophy in 33 (22.0%; 95% Cl: 15.4-28.6%) and mixed syndrome in 41 (27.3%; 95% Cl: 20.2-34.5%). There were not statistically significant differences between stavudine- and zidovudine-treated patients with respect to the overall prevalence of fat redistribution syndromes (P=0.34). The prevalence of lipoatrophy (OR=1.86; 95% Cl: 0.58-6.33, P=0.37), lipohypertrophy (OR=0.65; 95% Cl: 0.25-1.69, P=0.45) and mixed syndromes (OR=1.05; 95% Cl: 0.43-2.54, P=0.93) was not statistically different in both groups of patients. The only independent predictor for the appearance of mixed syndrome and lipoatrophy was sedentarism (OR=4.418; 95% Cl: 1.565-12.472, P=0.005) and (OR=4.515; 95% Cl: 1.148-17.761, P=0.03), respectively. Independent predictors of lipohypertrophy were age (OR=1.138; 95% Cl: 1.061-1.220, P<0.0001) and prior AIDS (OR=0.305; 95% Cl: 0.100-0.931, P=0.04). There were no statistically significant differences between stavudine and zidovudine-based groups with respect to metabolic and hormonal parameters. Conclusion: The use of stavudine or zidovudine in the context of the first combination antiretroviral therapy is not associated either with an increased likelihood of lipid or gonadal hormones abnormalities, and although there was a trend to a lesser body fat content in the stavudine group, there was no increase in the overall likelihood of fat redistribution syndromes with respect to zidovudine group. Physical activity is a protective factor for the development of fat redistribution syndromes.

Triple Nucleoside Combination Zidovudine/Lamivudine/Abacavir Versus Zidovudine/Lamivudine/Nelfinavir as First-Line Therapy in HIV-1-infected Adults: A Randomized Trial

Abstract: ObjectiveTo compare the efficacy and safety of a triple nucleoside combination to a protease inhibitor-containing triple regimen as first-line antiretroviral therapy (ART) in HIV-1-infected patient...

Kinetics of Lymphocyte Proliferation during Primary Immune Response in Macaques Infected with Pathogenic Simian Immunodeficiency Virus SIVmac251: Preliminary Report of the Effect of Early Antiviral Therapy

Abstract: The aim of this study was to evaluate the kinetics of lymphocyte proliferation during primary infection of macaques with pathogenic simian immunodeficiency virus (SIV) and to study the impact of short-term postexposure highly active antiretroviral therapy (HAART) prophylaxis. Twelve macaques were infected by intravenous route with SIVmac251 and given treatment for 28 days starting 4 h postexposure. Group 1 received a placebo, and groups 2 and 3 received combinations of zidovudine (AZT), lamivudine (3TC), and indinavir. Macaques in group 2 received AZT (4.5 mg/kg of body weight), 3TC (2.5 mg/kg), and indinavir (20 mg/kg) twice per day by the oral route whereas macaques in group 3 were given AZT (4.5 mg/kg) and 3TC (2.5 mg/kg) subcutaneously twice per day, to improve the pharmacokinetic action of these drugs, and a higher dose of indinavir (60 mg/kg). The kinetics of lymphocyte proliferation were analyzed by monitoring 5-bromo-2′-deoxyuridine (BrdU) uptake ex vivo and by fluorescence-activated cell sorting analysis. HAART did not protect against SIV infection but did strongly impact on virus loads: viremia was delayed and lowered during antiviral therapy in group 2, with better control after treatment was stopped, and in group 3, viremia was maintained at lower levels during treatment, with virus even undetectable in the blood of some macaques, but there was no evidence of improved control of the virus after treatment. We provide direct evidence that dividing NK cells are detected earlier than dividing T cells in the blood (mostly in CD45RA− T cells), mirroring plasma viremia. Dividing CD8+ T cells were detected earlier than dividing CD4+ T cells, and the highest percentages of proliferating T cells coincided with the first evidence of partial control of peak viremia and with an increase in the percentage of circulating gamma interferon-positive CD8+ T cells. The level of cell proliferation in the blood during SIV primary infection was clearly associated with viral replication levels because the inhibition of viral replication by postexposure HAART strongly reduced lymphocyte proliferation. The results and conclusions in this study are based on experiments in a small numbers of animals and are thus preliminary.

Alternation of antiretroviral drug regimens for HIV infection. A randomized, controlled trial.

Abstract: Background: Mathematical modeling has suggested that alternating antiretroviral regimens while patients' viral load remains suppressed would minimize HIV resistance mutations. Objective: To compare alternation of antiretroviral regimens with the current standard of switching regimens after viral load rebound. Design: Randomized, multicenter, open-label, pilot trial. Setting: 15 outpatient HIV clinics in Spain and Argentina. Patients: 161 HIV-1-infected, antiretroviral-naive persons. Intervention: Patients were assigned to continuously receive stavudine, didanosine, and efavirenz (standard of care, regimen A) or zidovudine, lamivudine, and nelfinavir (standard of care, regimen B) until virologic failure, or to alternate between those two regimens every 3 months while viral load was suppressed (regimen C). Measurements: Time to virologic failure, percentage of patients with undetectable plasma viremia over 48 weeks, CD4 and CDS cell counts, adverse events, emergence of drug resistance, drug adherence, and quality of life. Results: Patients receiving standard-of-care regimens A and B did not differ. Virologic failure over 48 weeks was delayed in the alternating therapy group compared with the pooled standard-of-care group (incidence rate, 1.2 events/1000 person-weeks [95% Cl, 0.3 to 3.6 events/1000 person-weeks] vs. 4.8 events/1000 person-weeks [Cl, 2.9 to 7.4 events/1000 person-weeks]; P = 0.01). Genotypic drug resistance emerged in 79% of patients in the standard-of-care group who experienced on-therapy treatment failure. Patients in the standard-of-care and alternating therapy groups had similar CD4 cell counts, frequency of adverse events, reported drug adherence, and quality of life. Conclusions: Virologic outcome was better with alternating therapy than with the current standard of care, while adverse events and adherence were similar. The strategy of alternating therapy merits further investigation.