indinavir-sulfate and Viremia

We compared the response of two standard 3-drug regimens containing two-nucleoside reverse transcriptase inhibitor (Zidovudine +Lamivudine) plus either a protease inhibitor (PIs) (Indinavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTIs) (Efavirenz) among treatment-naïve or treatment-experienced HIV-infected persons. The obtained results will be compared to clinical trial findings. Through a retrospective study, we compared the virological and immunological response of 119 Tunisian HIV-1 infected patients (North Africa) who started for the first time/ in salvage use a triple antiretroviral treatment containing one NNRTI (group A1/group A2) or one PI (group B1/group B2). Viral load (VL) was analysed with Amplicor HIV-1 Monitor test and drug resistance mutations were examined by using two distinct line probe assays (LiPA). The analysis according to the received treatment showed an average of 0.45 log(10) drop in the mean VL among groups A2 and B2. For naïve patients, 62.5% of group A1 reached an undetectable VL versus 53.5% for group B1 (p < 0.001). With regard to the CD4 cell count change, we observed a mean increase of more than 65% versus baseline within group A1 in comparison with 42% for group B1 (p < 0.001). Genotypic resistance assays showed that patients of group A2 had significantly more resistance mutations than those of group B2 (2.66 vs. 0.75 (p = 0.0039)). Finally, 15 patients who were failing were switched to indinavir or efavirenz. When indinavir was replaced by efavirenz, we observed an increase in the plasma VL. With regard to the effects on immunological and virological outcome of patients using PIs or NNRTIs in a triple antiretroviral therapy, our observations in normal clinical practice supported the reported clinical trial findings but are not in favour of replacing indinavir by efavirenz in failing regimen.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cohort Studies; Cyclopropanes; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Oxazines; Retrospective Studies; Treatment Outcome; Tunisia; Viremia; Zidovudine

Toxicity and other drug adherence-related factors have contributed to decreased compliance to antiretroviral regimens amongst HIV-infected patients. Irregular therapy disruption causes loss of CD4 T cells, onset of drug resistance and rapid rebound of plasma viral load (VL). However, an appropriate choice of drugs and properly scheduled structured treatment interruptions (STIs) may limit VL rebound, maintain CD4 counts and minimize resistance.. We conducted a clinical study of STIs, RIGHT 901, involving 60 drug-naive patients with chronic HIV infection (CD4 >300, VL >10,000) randomized to receive didanosine-stavudine-indinavir (IDV group) or didanosine-stavudine-hydroxyurea (HU group), for 12 weeks. Subsequently, all patients were randomized again to start STI (short induction) or to continue the therapy for an additional 24 weeks before starting STI (long induction). Both groups underwent four STI cycles and then stopped therapy as long as viraemia remained below 10,000 copies/ml before reinitiating another four cycles of STI.. During continuous therapy VLs were suppressed at similar rates in both the HU and IDV groups, while a blunted CD4 count was documented in the HU group. Following the first stop median VL rebounded close to baseline values in both groups, however, during the following STI median VL rebound decreased in the HU group, while in the IDV group VL continued to rebound to values close to baseline, and the difference between the two groups was statistically significant. Moreover, patients treated with HU had a constant and stable CD4 increase during STI, whereas CD4 counts fluctuated in the IDV group, with sharp falls during treatment interruptions and partial CD4 recovery following treatment restart. Even in the presence of IDV resistance predisposing mutations at baseline, no genotypic change in the protease sequence was observed during STI. A relevant mutation in the reverse transcriptase sequence (K70R) emerged in one patient interrupting treatment after 36 weeks of continuous therapy and in one patient after four STI cycles. Side effects (no major events) were similar among groups.. An appropriate choice of STI schedule and regimens containing drugs less prone to resistance and/or able to prevent CD4 fluctuation may contribute to optimizing STI for chronically infected patients with respect to limiting viral rebound, improving CD4 counts and maintaining a resistance profile comparable to continuous highly active antiretroviral therapy.

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Didanosine; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; HIV-1; Humans; Hydroxyurea; Indinavir; Italy; RNA, Viral; Stavudine; Time Factors; Viral Load; Viremia

To provide insight into the dynamics and source of residual viremia in human immunodeficiency virus (HIV) patients successfully treated with antiretroviral therapy, 14 intensely monitored patients treated with indinavir and efavirenz sustaining HIV RNA at <50 copies/ml for >5 years were studied. Abacavir was added to the regimen of eight patients at year 5. After the first 9 months of therapy, HIV RNA levels had reached a plateau ("residual viremia") that persisted for over 5 years. Levels of residual viremia differed among patients and ranged from 3.2 to 23 HIV RNA copies/ml. Baseline HIV DNA was the only significant pretreatment predictor of residual viremia in regression models including baseline HIV RNA, CD4 count, and patient age. In the four of five patients with detectable viremia who added abacavir to their regimen after 5 years, HIV RNA levels declined rapidly. The estimated half-life of infected cells was 6.7 days. Decrease in activated memory cells and a reduction in gamma interferon production to HIV Gag and p24 antigen in ELISpot assays were observed, consistent with a decrease in HIV replication. Thus, in patients treated with efavirenz plus indinavir, levels of residual viremia were established by 9 months, were predicted by baseline proviral DNA, and remained constant for 5 years. Even after years of highly suppressive therapy, HIV RNA levels declined rapidly after the addition of abacavir, suggesting that productive infection contributes to residual ongoing viremia and can be inhibited with therapy intensification.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; DNA, Viral; HIV-1; Humans; Indinavir; Longitudinal Studies; Oxazines; RNA, Viral; Time Factors; Viremia

Evaluation of high active antiretroviral therapy (HAART) in human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) patients receiving combined antiretroviral therapy in China.. We initiated the first efficacy trial of zidovudine (AZT) 600 mg/d and lamivudine (3TC) 300 mg/d (brand name: Combivir) plus indinavir (2 400 mg/d) in 15 Chinese chronically infected with HIV in May 1999 at Beijing.. There was a rapid reduction of 2.7 log in the plasma viremia levels in 15 cases 3 months, after treatment, from a mean baseline of 90 743 copies/ml. The mean CD(4) cell counts increased by 67 cells/microliter from a baseline mean value of 471 cells/microliter and the mean CD(8) cell counts reduced by 192/microliter after 12 months of therapy. The ratio of CD(4)/CD(8) increased from 0.35 to 0.56. The average naive CD(4) cell (CD(45)RA + CD(62)L +) count and naive CD(8) cell (CD(45)RA + CD(62)L +) count increased 42 and 19/microliter respectively after one-year treatment. This drug regimen was well tolerated, with mild nausea in all, transient elevated serum bilirubin in three and kidney stone in two patients.. It is effective for the virus with different genotype. The results will form a scientific foundation for the development of therapeutic strategies for HIV infection in China.

Topics: Adult; Aged; Anti-HIV Agents; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; China; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Lymphocyte Count; Male; Middle Aged; RNA, Viral; Time Factors; Treatment Outcome; Viremia; Zidovudine

To evaluate the decay rate of cellular proviral HIV-DNA and viral replication in patients receiving highly active antiretroviral therapy (HAART) in the very early phase of infection.. Thirty-four patients treated with HAART and retrospectively selected for progressive decline of plasma viraemia up to undetectable levels (< 20 copies/ml), were stratified according to CD4+ cell count and plasma viraemia at base line: > 500 x 10(6) cells/l with < 5000 copies/ml (group 1) or with > 5000 copies/ml (group 2), > 5000 copies/ml with 300-500 x 10(6) cells/l (group 3) or with < 300 x 10(6) cells/l (group 4). Plasma HIV-RNA and proviral HIV-DNA were analysed at baseline and after 1, 2, 3, 6, 9 and 12 months of treatment.. After 1 year of treatment, a significant decrease of proviral DNA titre was observed in all patients and a decrease > 1 log was achieved in 24 of 29 subjects of the first three groups. The more pronounced decay of HIV-DNA (half-life 28 weeks) up to < 50 HIV-DNA copies/10(6) CD4+ cells was detected in patients of group 1. At the year's endpoint, five patients (four in group 1 and one in group 2) had < 20 HIV-DNA copies. However, HIV strains sensitive to antiretroviral drugs were isolated from peripheral lymphocytes of 16 out of 34 patients.. In patients with undetectable plasma viraemia after 1 year of HAART, the highest reduction of proviral DNA up to < 50 copies/10(6) CD4+ cells was obtained only in subjects in the early asymptomatic phase of infection. Nevertheless, a replication-competent virus can be detected in all phases of antiretroviral therapy.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Prospective Studies; Proviruses; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Stavudine; Viremia

Antiretroviral regimens containing HIV protease inhibitors suppress viremia in HIV-infected patients, but the durability of this effect is not known.. To describe the 3-year follow-up of patients randomly assigned to receive indinavir, zidovudine, and lamivudine in an ongoing clinical trial.. Open-label extension of a randomized, double-blind study.. Four clinical research units.. 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.. Indinavir, zidovudine, and lamivudine.. Safety assessments, HIV RNA levels, CD4 cell counts, and genotypic analyses.. 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%).. A three-drug regimen of indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of patients for at least 3 years.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Genotype; HIV; HIV Infections; Humans; Indinavir; Kidney Calculi; Lamivudine; Male; Middle Aged; RNA, Viral; Viral Load; Viremia; Zidovudine

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Daunorubicin; Didanosine; Drug Therapy, Combination; Herpesvirus 8, Human; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Sarcoma, Kaposi; Stavudine; Viremia

CD4 T cell responses were studied for >2 years in 27 zidovudine-experienced patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who received triple combination drug therapy with indinavir, zidovudine and lamivudine or zidovudine plus lamivudine or zidovudine alone for 24-42 weeks before switching to the three-drug therapy. Subjects initially given the three drugs had viremia suppressed to undetectable levels and increases in T cell proliferative and cytokine responses to microbial antigens through 2 years of follow-up. Patients receiving the triple-drug therapy after either indinavir or zidovudine-lamivudine treatment had similar increases in T cell responses only if they also had suppression of virus load. CD4 T cell reactivity to HIV-1 antigens was not restored. Prolonged indinavir-zidovudine-lamivudine treatment has significant but incomplete enhancing effects on CD4 T cell reactivity, which could be important in host control of microbial and persistent HIV-1 infections.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antigens, Bacterial; CD4-Positive T-Lymphocytes; Cell Division; Chemokines; Cytokines; Double-Blind Method; Female; HIV Antigens; HIV-1; Humans; Indinavir; Lamivudine; Male; Mitogens; RNA, Viral; Viremia; Zidovudine

Cell activation is essential for HIV infection. CD4+ T lymphocyte activation allows virus replication and CD8+ T lymphocyte activation may contribute to pathogenesis. We combined hydroxyurea, a cytostatic drug that inhibits cell activation and proliferation, with two drugs that inhibit HIV (didanosine and indinavir), to block the "cell activation-virus production-pathogenesis" cycle. HIV was strongly suppressed in treated patients, and the average CD4 count increased to 224/mm3. Compared with a matched group of patients who had declined antiretroviral treatment, treated patients had a significantly lower proportion of activated CD8+ T lymphocytes and a significantly higher number of naive CD8+ and CD4+ T lymphocytes. The proliferative responses to allogeneic and influenza virus antigens were increased in treated patients, and a defect in CD3-zeta expression, the signaling chain of the T cell receptor complex, was reversed. The use of a cytostatic drug was not detrimental to the immune system; on the contrary, the combination of antiviral and cytostatic treatment improved all of the immune parameters tested.

Topics: Anti-HIV Agents; CD3 Complex; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Indinavir; Lymphocyte Activation; Nucleic Acid Synthesis Inhibitors; Reverse Transcriptase Inhibitors; Viremia

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.

Topics: Adult; Anti-HIV Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cohort Studies; DNA, Viral; Drug Therapy, Combination; HIV Antibodies; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Prospective Studies; RNA, Viral; T-Lymphocyte Subsets; Viremia; Zidovudine

The impact of human immunodeficiency virus (HIV) protease inhibitors on hepatitis C (HCV) viremia was assessed in 19 patients infected with both HIV and HCV. HIV and HCV RNA levels were measured before and during treatment with protease inhibitors. Before treatment, mean levels of HCV RNA were 5.3 log for HCV RNA and 5.0 log for HIV RNA. CD4 lymphocyte counts were 63/mm3. After 6 weeks of treatment, a mean reduction of 2.1 log10 in HIV RNA (P < .001) and a mean (+/-SE) increase of 73 (+/-21) CD4 and 296 (+/-70) CD8 cells were observed (P < .05). In contrast, both HCV viremia (+0.4 log +/- 0.1) and alanine aminotransferase increased (P < .04). HCV RNA levels returned to baseline after 17 and 32 weeks of treatment. Thus, potent anti-HIV regimens with protease inhibitors may temporarily worsen HCV status despite improvement of HIV parameters.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Viremia

HIV infection accelerates natural course of HCV infection, but impact of antiretroviral treatment on HCV infection is not well known. The aim of this study is to compare the change of HCV viral load in patients on combination of 2 nucleoside analogues and in patients on combination of 2 nucleoside analogues and protease inhibitor. HCV and HIV viral load, lymphocyte CD4 counts, alanine aminotransferase (ALT) and aspartate amino transferase (AST) were measured before and 3 months after starting treatment in 2 groups: Group 1 (n = 15) treated with 2 nucleoside analogues and Group 2 (n = 15) treated with 2 nucleoside analogues and a protease inhibitor. Results show a significant increase in lymphocyte and a significant decrease in HIV viral load in the both group but no significant change in HCV viral load and in ALT and AST. In conclusion efficiency of anti-HIV therapy (combination of 2 nucleoside analogues with or without a protease inhibitor) doesn't seem to have any impact on the course of HCV viremia in HIV-coinfected patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Alanine Transaminase; Anti-HIV Agents; Aspartate Aminotransferases; CD4 Lymphocyte Count; Disease Progression; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Substance Abuse, Intravenous; Treatment Outcome; Viral Load; Viremia

HIV reservoirs are rapidly established after infection, and the effect of HAART initiated very early during acute infection on HIV reservoirs remains poorly documented, particularly in tissue known to actively replicate the virus. In this context, we used the model of experimental infection of macaques with pathogenic SIV to assess in different tissues: (i) the effect of a short term HAART initiated at different stages during acute infection on viral dissemination and replication, and (ii) the local concentration of antiviral drugs.. Here, we show that early treatment with AZT/3TC/IDV initiated either within 4 hours after intravenous infection of macaques with SIVmac251 (as a post exposure prophylaxis) or before viremia peak (7 days post-infection [pi]), had a strong impact on SIV production and dissemination in all tissues but did not prevent infection. When treatment was initiated after the viremia peak (14 days pi) or during early chronic infection (150 days pi), significant viral replication persists in the peripheral lymph nodes and the spleen of treated macaques despite a strong effect of treatment on viremia and gut associated lymphoid tissues. In these animals, the level of virus persistence in tissues was inversely correlated with local concentrations of 3TC: high concentrations of 3TC were measured in the gut whereas low concentrations were observed in the secondary lymphoid tissues. IDV, like 3TC, showed much higher concentration in the colon than in the spleen. AZT concentration was below the quantification threshold in all tissues studied.. Our results suggest that limited antiviral drug diffusion in secondary lymphoid tissues may allow persistent viral replication in these tissues and could represent an obstacle to HIV prevention and eradication.

Topics: Administration, Cutaneous; Administration, Oral; Animals; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; HIV Protease Inhibitors; Indinavir; Lamivudine; Macaca fascicularis; Male; Reverse Transcriptase Inhibitors; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Time Factors; Tissue Distribution; Viremia; Zidovudine

To evaluate the efficacy of postexposure prophylaxis with a combination of zidovudine (ZDV), lamivudine (3TC) and indinavir (IDV), after vaginal exposure to HIV.. : Experimental intravaginal exposure of female cynomolgus macaques to SIVmac251.. ZDV/3TC/IDV treatment was initiated 4 h after exposure and continued for 28 days. Groups of six animals received a placebo or a combination of oral ZDV (4.5 mg/kg), 3TC (2.5 mg/kg) and IDV (20 mg/kg) twice daily or subcutaneous ZDV (4.5 mg/kg) and 3TC (2.5 mg/kg) twice daily, and a higher dose of IDV (60 mg/kg) administered orally twice daily.. In the placebo group, all animals were infected. Antiretroviral association protected one of the six animals if all drugs were administered orally and four of the six animals if ZDV and 3TC were administered subcutaneously and IDV was given orally at triple dose. In infected animals, viremia was significantly delayed and lowered in treated animals than in animals given placebo, and high CD4 cell counts were maintained in the treated animals, at least in the medium term. Antiretroviral dosages made in macaques receiving the same treatments showed that protection efficacy could be linked to antiretroviral plasmatic concentration.. This study shows, for the first time in macaques, that the postexposure prophylaxis recommended for humans may be effective after vaginal exposure. Improvements in pharmacokinetic parameters significantly increased treatment efficiency.

Topics: Administration, Oral; Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Indinavir; Injections, Subcutaneous; Lamivudine; Macaca fascicularis; Sexually Transmitted Diseases, Viral; Simian Acquired Immunodeficiency Syndrome; Vagina; Viral Load; Viremia; Zidovudine

We compared immunovirological outcomes and toxicities of HAART regimens including LPV/r and IDV/r in antiretroviral naïve HIV-1 patients. We retrospectively selected 55 patients starting LPV/r and 52 starting IDV/r as first-line HAART. Immunovirological and metabolic parameters were recorded at baseline and every 3 months as were side effects, AIDS-defining events and deaths. Demographic characteristics and NRTIs included in the regimens were comparable. Both groups reached undetectable HIV-RNA plasma viremia from third month and maintained during follow-up. However, patients receiving IDV/r had a lower probability to obtain virological success (RH: 0.46). Patients receiving IDV/r patients showed a greater increase of total cholesterol (P = 0.01). Three patients on LPV/r and 21 on IDV/r discontinued the drug for toxicity, leading to a 8.40 higher risk of discontinuation in the latter group. In our clinical setting IDV/r showed to be less effective and more toxic than LPV/RTV as first-line HAART.

Topics: Adult; Antiretroviral Therapy, Highly Active; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Viremia

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).

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cognition Disorders; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Neuropsychological Tests; RNA, Viral; Time Factors; Viral Load; Viremia; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Oxazines; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Viral Load; Viremia; Zidovudine

OBJECTIVE To determine the rate of virological rebound and factors associated with rebound among patients on highly active antiretroviral therapy (HAART) with previously undetectable levels of viraemia. DESIGN An observational cohort study of 2444 patients from the EuroSIDA study. METHODS Patients were followed from their first viral load under 400 copies/ml to the first of two consecutive viral loads above 400 copies/ml. Incidence rates were calculated using person-years of follow-up (PYFU), Cox proportional hazards models were used to determine factors related to rebound. RESULTS Of 2444 patients, 1031 experienced virological rebound (42.2%). The incidence of rebound decreased over time; from 33.5 in the first 6 months after initial suppression to 8.6 per 100 PYFU at 2 years after initial suppression (P < 0.0001). The rate of rebound was lower for treatment-naive compared with treatment-experienced patients. In multivariate models, patients who changed treatment were more likely to rebound, as were patients with higher viral loads on starting HAART. Treatment-naive patients were less likely to rebound. Among pretreated patients, those who were started on new nucleosides were less likely to rebound. CONCLUSION The rate of virological rebound decreased over time, suggesting that the greatest risk of treatment failure is in the months after initial suppression. Treatment-naive patients were at a lower risk of rebound, but among drug-experienced patients, those who added new nucleosides had a lower risk of rebound, as were patients with a good immunological response.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Europe; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Treatment Failure; Viral Load; Viremia

Analysis of indinavir levels in HIV-positive patients indicated that drug concentrations in lymph node mononuclear cells (LNMCs) were about 25-35% of mononuclear cells in blood. To enhance lymphatic delivery of anti-HIV drugs, a novel drug delivery strategy was designed consisting of lipid-associated indinavir (50-80 nm in diameter) complexes in suspension for subcutaneous (SC) injection. Due to the pH-dependent lipophilicity of indinavir, practically all the drug molecules are incorporated into lipid phase when formulated at pH 7.4 and 5:1 lipid-to-drug (m/m) ratio. At pH 5.5, about 20% of drugs were found in lipid-drug complexes. Effects of lipid association on the time course of plasma indinavir concentrations were determined in macaques (Macaca nemestrina) administered with either soluble or lipid-associated formulation of indinavir (10 mg/kg, SC). Results yielded about a 10-fold reduction in peak plasma concentration and a 6-fold enhancement in terminal half-life (t1/2beta = 12 vs. 2 hours). In addition, indinavir concentrations in both peripheral and visceral lymph nodes were 250-2270% higher than plasma (compared with <35% with soluble lipid-free drug administration in humans). Administration of lipid-associated indinavir (20 mg/kg daily) to HIV-2287-infected macaques (at 30-33 weeks after infection) resulted in significantly reduced viral RNA load and increased CD4 T cell number concentrations. Collectively, these data indicate that lipid association greatly enhances delivery of the anti-HIV drug indinavir to lymph nodes at levels that cannot be achieved with soluble drug, provides significant virus load reduction, and could potentially reverse CD4 T cell depletion due to HIV infection.

Topics: Animals; CD4 Lymphocyte Count; Cholesterol; Disease Progression; HIV Infections; HIV Protease Inhibitors; HIV-2; Humans; In Situ Hybridization; Indinavir; Liposomes; Lymphoid Tissue; Macaca; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Viral Load; Viremia; Virus Replication

Highly active antiretroviral therapy (HAART) has been shown to have a beneficial effect on several opportunistic and other coinfections of HIV infected individuals. The effect of HAART on HCV coinfections is controversial. We describe the case of a patient, in whom a close temporal relationship between changes in HIV viremia, HCV viremia and ALT levels was observed. Longterm suppression of HIV replication by HAART was associated with a normalization of ALT levels and finally clearance of the HCV infection. Our data suggest that improved immune functions due to reductions of the HIV load led to a better control and finally resolution of the HCV infection in this patient.

Topics: Acute Disease; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Nevirapine; Viral Load; Viremia

Sustained elevations in CD4 cell counts commonly occur despite incomplete viral suppression with protease inhibitor-based antiretroviral therapy.. To determine the incidence and risk factors associated with return of CD4 cell count to pre-therapy levels in patients experiencing virologic failure of protease inhibitor therapy.. This is a clinic-based cohort study of HIV-infected adults who failed to maintain durable viral suppression on a protease inhibitor-based regimen.. Virologic failure was defined as persistent plasma HIV RNA level > 500 copies/ml. Immunologic failure was defined as return of CD4 cell count to pre-therapy levels.. A total of 291 patients experienced virologic failure on a protease inhibitor-based regimen and had a treatment-mediated CD4 cell increase above pre-therapy levels at the time of virologic failure. If patient data were censored at the time a successful salvage regimen was initiated, then the median time to immunologic failure after the onset of virologic failure was 3 years. If patient data were also censored at the time therapy was discontinued, then 36.8% of the cohort experienced immunologic failure after 3 years of continuous virologic failure. The change in viral load from a pre-treatment baseline, and not the absolute level of viremia achieved, was a strong and independent predictor of immunologic failure. Discontinuing therapy was associated with immunologic failure independent of viral load changes.. Reduction in T CD4+ cell numbers may eventually occur during prolonged virologic failure of a protease inhibitor-based regimen and is predicted by the degree of virologic suppression below a pre-therapy 'set-point'.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Disease Progression; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Ritonavir; RNA, Viral; Saquinavir; Time Factors; Treatment Failure; Viremia

This paper establishes a framework for understanding the complex relationships between HIV-1 genotypic markers of resistance to antiretroviral drugs and clinical measures of disease progression. A new classification scheme based on the probabilities of how new patients will respond to antiretroviral therapy given the available data is proposed as a method for distinguishing among groups of viral sequences. This approach draws from existing cluster analysis, discriminant analysis, and recursive partitioning techniques and requires a model relating genotypic characteristics to phenotypic response. A data set of 2,746 sequences and the corresponding Indinavir 50% inhibitory concentrations are described and used for illustrative purposes.

Topics: Amino Acid Sequence; Cluster Analysis; Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Inhibitory Concentration 50; Models, Genetic; Molecular Sequence Data; Multigene Family; Multivariate Analysis; Mutation; Phenotype; Predictive Value of Tests; Viremia

Recent advances in the ability to detect people at the early stages of HIV infection now permit the initiation of antiretroviral treatment before the full complement of antiviral immune responses has evolved. However, the influence of early treatment interventions on the developing anti-HIV immune response is unknown. This study investigates the impact of standard highly active antiretroviral therapy (HAART) during the primary stages of HIV infection on the plasma HIV-1 RNA level, CD4(+) and CD8(+) lymphocyte counts, and the CD8(+) cell anti-HIV response. Individuals treated with HAART within 6 months of infection showed dramatic and rapid reductions in HIV-1 RNA levels along with modest increases in CD4(+) cell number and decreases in CD8(+) cell numbers. A significant reduction in the level of CD8(+) cell noncytotoxic suppression of HIV replication was observed over time in most participants receiving HAART. Importantly, those individuals choosing not to receive therapy maintained low but detectable HIV-1 RNA levels and showed no reduction in their CD8(+) cell antiviral response. These results suggest that either continued antigenic challenge is required to sustain CD8(+) cell-mediated anti-HIV activity, or that HAART has some inhibitory effect on this important immunologic function during the early stages of infection.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Depression, Chemical; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hydroxyurea; Immunity, Cellular; Indinavir; Lamivudine; Lymphocyte Count; Male; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Treatment Refusal; Viral Load; Viremia; Zidovudine

Ten severely immunocompromised HIV-HCV co-infected patients were enrolled in a quantifiable HCV-RNA assay. Serum alanine aminotransferase, HCV-RNA levels and HIV viral loads were determined at baseline, at month three and at month six after initiation of a highly active antiretroviral therapy including an HIV protease inhibitor. HCV genotypes were determined using a line probe assay kit. Our results suggested that this therapy did not result in lower HCV viraemia, whatever the HCV genotypes, and probably had no effect on the outcome of chronic viral hepatitis C. As our patients were severely immunocompromised and their mean increase of CD4 cell counts was less than 50/mm(3), we cannot reach any conclusions about the impact of the improvement of immune status on the HCV-RNA load.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Hepacivirus; Hepatitis C; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load; Viremia; Virus Replication

To analyse cell membrane proteins (CMP) acquired by HIV-1 present in the plasma of asymptomatic patients, and their modifications after a cycle of highly active antiretroviral therapy (HAART) and interleukin (IL)-2.. Plasma samples from eight drug-naive asymptomatic subjects underwent immobilized antibody capture (IAC) to detect CMP on the surface of circulating HIV-1. The CMP considered were lymphocyte subset markers (CD45RA, CD45RO), activation markers (HLA-DR), adhesion molecules (LFA-3), costimulatory proteins (B7-2), lymph-node homing receptors (CD62L) and pro-apoptosis molecules (FasL). This analysis was repeated after one cycle of HAART + IL-2, after virus rebound.. LFA-3, followed by CD45RO and HLA-DR, are the most represented CMP on the surface of circulating virions in naive asymptomatic patients; CD45RA, CD62L, B7-2 and FasL are detected only occasionally. After rebound, a significant reduction of CD45RO and HLA-DR, but not of LFA-3, is observed on virions, whereas CD45RA and CD62L, as well as other molecules, are not affected, remaining almost undetectable.. Assuming that CMP on HIV-1 reflect the cellular origin of virions, activated T cells expressing CD45RO, HLA-DR, and LFA-3 may be the main source of HIV-1 in asymptomatic patients. After a cycle of HAART + IL-2, followed by therapy interruption, CD45RA and CD62L are detected on virions rarely, indicating that even during virus rebound, expanded naive T cells do not become a major target of virus replication. Furthermore, the presence of HLA-DR on rebound HIV-1 is decreased, consistent with decreased activation of the HIV-producing cells. More extensive investigation may clarify the significance of these findings with respect to pathogenesis.

Topics: Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; B7-2 Antigen; CD4 Lymphocyte Count; CD58 Antigens; Fas Ligand Protein; HIV Infections; HIV Protease Inhibitors; HIV-1; HLA-DR Antigens; Humans; Indinavir; Interleukin-2; L-Selectin; Lamivudine; Leukocyte Common Antigens; Membrane Glycoproteins; Membrane Proteins; Reverse Transcriptase Inhibitors; Stavudine; Viremia; Virion

Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.

Topics: Cohort Studies; DNA, Viral; Female; Genitalia; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Longitudinal Studies; Lymph Nodes; Male; Molecular Sequence Data; Randomized Controlled Trials as Topic; RNA, Viral; Time Factors; Viral Load; Viremia; Virus Replication; Zidovudine

A longitudinal study was conducted to evaluate the viral shedding present in cervicovaginal secretions of HIV-1-seropositive women receiving antiretroviral therapy. A total of 128 paired cervicovaginal and blood samples was obtained from 37 women during a median follow-up period of 21 months. A sensitive, competitive, polymerase chain reaction and a reverse transcription polymerase chain reaction were used for the simultaneous quantitation of HIV-1 proviral DNA and RNA in cervicovaginal cells and cell-free RNA in cervicovaginal secretions, as well as HIV-1 RNA in peripheral blood. The cumulative probability of detecting proviral DNA in genital secretions was significantly higher over time in women with detectable viremia than in women in whom HIV-1 RNA was persistently undetectable in plasma (< 50 copies/ml) (P = 0.028 by log-rank test). The presence and amount of proviral DNA, cell-associated RNA and cell-free RNA in the cervicovaginal secretions were positively correlated with the presence of detectable viremia or the number of HIV-1 RNA copies in plasma (Spearman rank correlation, 0.290, 0.279, and 0.305, respectively; all P < 0.01), but no correlation was found with the CD4+ cell count. In addition, vaginal infections were positively correlated with the detection of proviral DNA in cervicovaginal secretions (odds ratio, 2.60; 95% confidence interval, 1.07-5.70). However, the positive correlation between the presence and amount of HIV in cervicovaginal secretions and the viral load in plasma provides no assurance that HIV shedding does not occur in the genital tract of women with undetectable HIV-RNA in plasma.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Female; Genitalia, Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Longitudinal Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Statistics, Nonparametric; Viral Load; Viremia; Virus Shedding; Zidovudine

HIV-1 can persist in infected patients despite undetectable plasma viremia. To characterize the residual viral load, repetitive blood and tonsillar samples were collected from 11 HIV-1-positive individuals before and during 96 weeks of therapy with zidovudine, lamivudine, and indinavir. HIV-1 RNA in tonsils was quantified by RT-PCR and infectious HIV-1 provirus by the limiting dilution assay. Genotypic resistance analyses and biological characterization were performed on plasma virus, blood, and tonsillar isolates. Tonsillar infectious HIV-1 provirus and HIV-1 RNA declined by 2 and 3 log(10), respectively, but 10(3)-10(4) cells, less than 0.5% of the total body CD4(+) T cell population carrying infectious HIV-1 provirus, remained involved in active viral replication of drug-sensitive R5 viruses. Thus, the dominant HIV-1 residual infection consists of < or = 10(6) latently infected CD4(+) cells. Plasma HIV-1 RNA decline of > 1.5 log(10) during the first 2 weeks of therapy may indicate low levels of this latent reservoir. Whereas the reservoir of latently infected cells remains stable, actively replicating HIV-1 continuously declines during prolonged antiretroviral therapy. Thus, although viral eradication seems unlikely, antiretroviral therapy may induce an extended period of virologic latency in HIV-1-positive individuals.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Disease Progression; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Longitudinal Studies; Lymphoid Tissue; Phenotype; Proviruses; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Viral Load; Viremia; Virus Replication; Zidovudine

In HIV-infected patients having virologic suppression (plasma HIV RNA <50 copies/mL) with antiretroviral therapy, intermittent episodes of low-level viremia have been correlated with slower decay rates of latently infected cells and increased levels of viral evolution, but the clinical significance of these episodes is unknown.. To determine if HIV-infected patients with intermittent viremia have a higher risk of virologic failure (confirmed HIV RNA >200 copies/mL).. Retrospective analysis of subjects in well-characterized cohorts, the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998) and the Merck 035 trial (ongoing since March 1995).. Two hundred forty-one ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after 6 months of indinavir-zidovudine-lamivudine.. Association of intermittent viremia (plasma HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL) with virologic failure (2 consecutive plasma HIV RNA measures >200 copies/mL) in both study groups; evidence of drug resistance in 7 patients from the small (n = 13) study group with long-term follow-up.. Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had 2 consecutive HIV RNA values >50 copies/mL during the median 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks). Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort and 68% for the group not receiving triple-drug therapy throughout vs 55% for those who did (P =.25). Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95% confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95% CI, 0.59-2.79). Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs <2.5 copies/mL in those without (P =.15). Intermittent viremia occurred in 6 of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication (P =.03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance.. Intermittent viremia occurred frequently and was associated with higher levels of replication (Merck 035), but was not associated with virologic failure in patients receiving initial combination therapy of indinavir-zidovudine-lamivudine (ACTG 343 and Merck 035). In this population, treatment changes may not be necessary to maintain long-term virologic suppression with low-level or intermittent viremia.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Microbial; HIV; HIV Infections; Humans; Indinavir; Lamivudine; Predictive Value of Tests; Prevalence; Proportional Hazards Models; Retrospective Studies; RNA, Viral; Viral Load; Viremia; Virus Replication; Zidovudine

We have evaluated the use of an ultrasensitive reverse transcriptase (RT) activity assay to monitor plasma viremia in two human immunodeficiency virus type 1 (HIV-1) group O-infected patients treated with stavudine, lamivudine, and indinavir. After a initial decline in RT levels observed at 4 weeks of therapy, RT-based plasma viremia returned to baseline values at 28 or 44 weeks of treatment. The rebound in levels of RT activity was associated with the detection of phenotypic resistance to lamivudine and with the Met184Val mutation. Analysis of RT activity in plasma provides a sequence-independent means of monitoring virus loads in HIV-1 group O-infected patients.

Topics: Adult; Anti-HIV Agents; Female; Guinea; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Molecular Sequence Data; Spain; Stavudine; Viral Load; Viremia

Major T-cell receptor beta chain variable region (TCRBV) repertoire perturbations are temporally associated with the down-regulation of viremia during primary human immunodeficiency virus (HIV) infection and with oligoclonal expansion and clonal exhaustion of HIV-specific cytotoxic T lymphocytes (CTLs). To determine whether initiation of antiretroviral therapy (ART) or highly active antiretroviral therapy (HAART) during primary infection influences the dynamics of T-cell-mediated immune responses, the TCRBV repertoire was analyzed by semiquantitative polymerase chain reaction in serial blood samples obtained from 11 untreated and 11 ART-treated patients. Repertoire variations were evaluated longitudinally. Stabilization of the TCRBV repertoire was more consistently observed in treated as compared with untreated patients. Furthermore, the extent and the rapidity of stabilization were significantly different in treated versus untreated patients. TCRBV repertoire stabilization was positively correlated with the slope of HIV viremia in the treated group, suggesting an association between repertoire stabilization and virologic response to treatment. To test whether stabilization was associated with variations in the clonal complexity of T-cell populations, T-cell receptor (TCR) heteroduplex mobility shift assays (HMAs) were performed on sequential samples from 4 HAART-treated subjects. Densitometric analysis of HMA profiles showed a reduction in the number of TCR clonotypes in most TCRBV families and a significant decrease in the total number of clonotypes following 7 months of HAART. Furthermore, a biphasic decline in HIV-specific but not heterologous CTL clones was observed. This indicates that ART leads to a global reduction of CD8(+) T-cell oligoclonality and significantly modulates the mobilization of HIV-specific CTL during primary infection. (Blood. 2000;95:1743-1751)

Topics: Acute Disease; Anti-HIV Agents; Clone Cells; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Lymphocyte Activation; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; Saquinavir; T-Lymphocytes, Cytotoxic; Viremia; Zidovudine

Antiretroviral therapy increases the number of both CD4+ and CD8+ T cells in the blood of HIV-1-positive patients with advanced disease. In the present study, we have examined the kinetics of CD4+ and CD8+ T cell restoration in blood and lymphoid tissue in asymptomatic HIV-1-positive individuals with high CD4+ cell counts during highly active antiretroviral treatment. Tonsillar biopsies and blood samples were collected at baseline and at regular intervals during the following 48 weeks and from HIV-1-negative controls. Mononuclear cells from blood and tonsils were phenotyped and quantified by three-color flow cytometry. After 48 weeks of therapy, blood CD4+ cell counts in the HIV-1-infected group were comparable to those found in uninfected controls. Naive CD4+ T cells in blood increased during the initial 2 weeks in parallel with reduced plasma viremia. Both naive and memory CD4+ T cells in blood reached normal numbers by week 48, whereas the CD4+ naive/memory cell ratio in tonsils was within normal range throughout the study. The level of memory CD8+ T cells in blood declined during the first 8 weeks in parallel with a reduction in the tonsillar memory CD8+ T cells. Naive CD8+ T cells in the blood increased after 4 weeks, while the level of naive CD8+ T cells in tonsils remained unaltered. Our data indicate that in the early stages of HIV-1 infection antiretroviral therapy normalizes CD4+ cell counts and causes a decrease in the level of memory CD8+ cells in blood and lymphoid tissue, suggesting reduced CD8+ cell turnover in response to reduced viral replication.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunologic Memory; Indinavir; Lamivudine; Male; Palatine Tonsil; Reverse Transcriptase Inhibitors; T-Lymphocyte Subsets; Time Factors; Viremia; Zidovudine

To assess the prognostic role of proviral DNA in peripheral blood mononuclear cells (PBMC) of patients with undetectable viremia over long-term highly active antiretroviral therapy (HAART).. Eighty-two human immunodeficiency virus (HIV)-1-infected patients, free of acquired immunodeficiency syndrome (AIDS), received zidovudine plus lamivudine plus indinavir. Levels of plasma HIV-RNA, and PBMC proviral DNA and RNA unspliced (US) transcripts were evaluated by using competitive polymerase chain reaction (cPCR) assays, every 3 months over 1 year.. Among patients with undetectable viremia at baseline, 13 of 18 with CD4 cell count 350/mm3 or less and 12 of 16 with CD4 between 351 and 700/mm3, constantly maintained undetectable RNA levels; in these patients, a mean proviral DNA decrease of 0.67 6 0.7 and 1.03 6 0.53 log (P < 0.001), respectively, a significant decrease of RNA-US transcripts (P < 0.001), and significant correlations between decreases of proviral DNA and RNA-US transcripts (P = 0.008 and P < 0.001, respectively) were observed.. Proviral DNA quantitation permits the continued monitoring of HAART in patients with undetectable viremia.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; DNA, Viral; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Polymerase Chain Reaction; Proviruses; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viremia; Zidovudine

Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After the start of therapy, both subjects had declines in the levels of in vivo-activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1-specific CTL memory cells. With continued therapy, and continued suppression of viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining demonstrated that declining levels of in vivo-activated CTL activity were associated with a decrease in the expression of the CD38(+) activation marker. Transient increases in viral load during continued therapy were associated with increases in the levels of virus-specific CTLps in both individuals. The results were confirmed by measuring CTL responses to discrete optimal epitopes. These studies illustrate the dynamic equilibrium between the host immune response and levels of viral antigen burden and suggest that efforts to augment HIV-1-specific immune responses in subjects on HAART may decrease the incidence of virologic relapse.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Cytotoxicity, Immunologic; Drug Therapy, Combination; Epitopes, T-Lymphocyte; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunologic Memory; Indinavir; Lamivudine; Longitudinal Studies; Reverse Transcriptase Inhibitors; Stavudine; T-Lymphocytes, Cytotoxic; Viral Load; Viremia; Zidovudine

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Male; Stavudine; Viremia; Zidovudine

Topics: Adult; Flaviviridae; Hepatitis, Viral, Human; HIV Protease Inhibitors; HIV Seropositivity; Humans; Indinavir; RNA, Viral; Viremia

To study the effects of antiretroviral therapy on T cell activation in blood and tonsils from HIV-1 infected individuals in relation to CD4 cell count, plasma viremia, and infectious HIV-1 provirus.. A 48-week study of viral load and T cell subsets in blood and tonsils from 12 HIV-1-positive individuals with a mean CD4 cell number of 400 x 10(6) cells/l treated with a combination of zidovudine, lamivudine, and indinavir.. Tonsil biopsies and blood samples were collected at regular intervals. Lymphocytes were phenotyped and quantified by three-color flow cytometry; infectious provirus was quantified by a limiting dilution assay. HIV-1-negative individuals were included as controls.. The fraction of tonsillar CD8 T cells expressing CD69, CD38, or HLA-DR in the patients with suppressed virus replication declined to levels comparable with that in controls by 48 weeks and showed a strong positive correlation with tonsillar infectious provirus and plasma viremia. The level of CD4 T cell activation was within normal range in tonsils throughout the study. The fraction of HLA-DR+ cells within CD4 and CD8 T cells in blood declined rapidly in parallel with plasma viremia but remained slightly higher compared with that in uninfected individuals.. Antiretroviral therapy normalizes tonsillar CD8 T cell activation in HIV-1-positive individuals in parallel with suppression of viral replication, indicating reduced CD8 cell turnover. Normal tonsillar CD4 T cell activation suggests limited CD4 cell turnover in early HIV infection. Activated CD8 T cells in lymphoid tissue is superior to that in blood as an immunological marker for the virological response to antiretroviral therapy.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Adult; Anti-HIV Agents; Antigens, CD; Antigens, Differentiation; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; HIV Infections; HIV-1; HLA-DR Antigens; Humans; Indinavir; Lamivudine; Lymphocyte Activation; Male; Membrane Glycoproteins; NAD+ Nucleosidase; Palatine Tonsil; Proviruses; T-Lymphocyte Subsets; Time Factors; Viremia; Virus Replication; Zidovudine

To evaluate the clinical and biological impact of protease inhibitors on HIV-associated Kaposi's sarcoma.. A cohort of 10 patients included prospectively from April 1996 to June 1997 were studied in one institutional centre after initiation of protease inhibitors.. All patients but one (stable disease) had progressive Kaposi's sarcoma. Three out of 10 patients had stopped specific chemotherapy for Kaposi's sarcoma for more than 4 weeks, three were still under chemotherapy, and four had never received specific treatment of Kaposi's sarcoma. Plasma HIV viral load, human herpesvirus (HHV)-8 viraemia in peripheral blood mononuclear cells (PBMC), and CD4 cell count were sequentially assessed from the beginning of therapy. For six patients, a semiquantitative evaluation of HHV-8 viral load in the Kaposi's sarcoma lesions was performed during treatment using polymerase chain reaction.. After initiation of HIV triple therapy with protease inhibitors, we observed six complete responses, two partial responses, and two patients with progressive disease. All patients had undetectable plasma HIV viral load within 2 months of treatment. Undetectable HHV-8 viraemia in PBMC occurred in seven out of eight patients with partial or complete response and in none of the progressive patients. A decrease or negation of HHV-8 viral load in Kaposi's sarcoma lesions was observed in two complete responders.. Our results suggest that antiviral therapy with protease inhibitors are clinically efficient in HIV-associated Kaposi's sarcoma and that there exists a correlation between clinical response and negation of HHV-8 viraemia.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; Herpesvirus 8, Human; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sarcoma, Kaposi; Stavudine; Treatment Outcome; Viral Load; Viremia; Zalcitabine; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Evaluation; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Oxazines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Viremia; Zidovudine

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Antigens, CD; Antigens, Differentiation; CD8-Positive T-Lymphocytes; Child; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Membrane Glycoproteins; NAD+ Nucleosidase; Stavudine; Viremia

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Proviruses; Reverse Transcriptase Inhibitors; RNA, Viral; Viral Load; Viremia

To determine whether, as predicted by predator-prey dynamics, early withdrawal of antiretroviral therapy, i.e. when the number of CD4+ lymphocytes is still elevated, results in an overshoot of HIV-1 viraemia due to infection of increased numbers of available target cells at that time.. Five HIV-1-infected individuals were identified who discontinued antiretroviral therapy for various reasons after 8-19 days, and from whom stored serum samples obtained before, during, and shortly after treatment were available for measurement of HIV-1 RNA load. A mathematical model was designed to assess whether increased target cell availability could quantitatively explain the clinical observations.. After therapy withdrawal, increases in the HIV-1 RNA load to levels exceeding pretreatment values by log10 0.6-1.5 copies/ml were observed after 2-17 days in all four of the individuals who had treatment-induced increases in CD4+ cell counts at the time of therapy withdrawal. Increases in viraemia were maximal within a few days, and subsequently seemed to wane until the pretreatment equilibrium between virus and its target cells was attained. Mathematical modelling confirms that these transient increases in viraemia can be explained by increased availability of target cells at the time of therapy withdrawal.. Transient rises in HIV-1 viraemia do occur following early therapy withdrawal. These rises especially warrant consideration in short-term antiretroviral regimens for prevention of mother-to-child transmission, as are being studied in developing countries, since they could result in an increased transmission risk during the post-partum period through breast-feeding. This possibility needs to be investigated urgently.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Indinavir; Models, Biological; Nevirapine; Pyridines; Risk Factors; RNA, Viral; Substance Withdrawal Syndrome; Viral Load; Viremia; Zidovudine

In evaluating current combination drug regimens for treatment of human immunodeficiency virus (HIV) disease, it is important to determine the existence of viral reservoirs. After depletion of CD8 cells from the peripheral blood mononuclear cells (PBMCs) of both patients and normal donors, activation of patient CD4 lymphocytes with immobilized antibodies to CD3 and CD28 enabled the isolation of virus from PBMCs of six patients despite the suppression of their plasma HIV RNA to fewer than 50 copies per milliliter for up to 2 years. Partial sequencing of HIV pol revealed no new drug resistance mutations or discernible evolution, providing evidence for viral latency rather than drug failure.

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Coculture Techniques; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Immunologic Memory; Indinavir; Lamivudine; Lymphocyte Activation; Mutation; RNA, Viral; T-Lymphocyte Subsets; Viral Load; Viremia; Virus Activation; Virus Latency; Virus Replication; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; HIV; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Ritonavir; RNA, Viral; Thiazoles; Valine; Viremia

Some of the most dramatic reductions in HIV viremia have been observed among patients treated with indinavir sulfate (Crixivan). How the hypothesis that HIV protease maintains the infectious nature of the virus led to Merck's development of indinavir is discussed. Also examined are results of the early clinical studies on indinavir's safety and pharmacokinetics, and research into the dynamics of HIV replication and the mechanisms of resistance. Several studies are highlighted that demonstrate the effectiveness of indinavir in reducing plasma viremia and increasing CD4 cell counts, thus providing the basis for marketing approval. Descriptions of ongoing clinical trials of indinavir, both open and closed trials, are listed, including duration, end points, sites, and contacts.

Topics: CD4 Lymphocyte Count; Clinical Trials as Topic; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Pyridines; Viremia; Virus Replication

The results of small, rapid clinical trials, reported in January in newspapers and journals, have led to the discovery that the "turnover" of new virus in the body is far more rapid than previously believed. The findings suggest that the immune system might have the ability to recover if HIV reproduction could be stopped for a longer time, although the virus would not be eradicated. The new understanding of how HIV behaves in the body was made possible by new antiviral drugs and by the new blood test which measures plasma HIV RNA. The work validates the use of small, rapid trials, and emphasizes the problem of HIV developing resistance to drugs. The researchers emphasized the need to use combination treatments because the more drugs that are added, the less likely the virion will be resistant to all of them. The most important unanswered question about HIV disease may be how it progresses from early, asymptomatic infection to late-stage illness. The fear is that researchers will assume that the new understanding of HIV explains this and research could be prematurely downgraded due to the rush of enthusiasm from these new findings. The pro's and con's of the interpretations of the findings and suggestions of what should be studied are discussed. The impact of these findings will be on the strategy of research and development of new AIDS treatments.

Topics: Antiviral Agents; CD4 Lymphocyte Count; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nevirapine; Pyridines; Reverse Transcriptase Inhibitors; Viremia; Virus Replication

An overview of the Fourth International Workshop on HIV Drug Resistance held in 1995 is presented. Topics concern the dual resistance to AZT and 3TC, viral resistance to protease inhibitors, and recent laboratory findings on viral resistance patterns that have provided impetus for the design of clinical studies to evaluate rational combinations of protease inhibitors. VX-478, indinavir, and ritonavir study data are presented.

Topics: Antiviral Agents; Carbamates; CD4 Lymphocyte Count; Drug Resistance, Microbial; Furans; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Lamivudine; Pyridines; Quinolines; Ritonavir; Saquinavir; Sulfonamides; Thiazoles; Valine; Viremia; Zalcitabine; Zidovudine