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At least 973 records · Page 54Linked to original sources
PubMed1997

Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure.

Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterized resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36-52 weeks of indinavir (IDV)/zidovudine (ZDV)/lamivudine (3TC), IDV, or ZDV/3TC. After 1 year of therapy, viral RNA levels in LN of individuals remained detectable but were log10 = 4 lower than in subjects on the triple drug regimen with interruption of therapy or in those treated with ZDV/3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies indicate that pronounced and sustained suppression of plasma viremia by a potent antiretroviral combination is associated with low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens of virus in the lymph nodes.

Anti-HIV Agents↗
PubMed1999

Non-active site changes elicit broad-based cross-resistance of the HIV-1 protease to inhibitors.

Three high level, cross-resistant variants of the HIV-1 protease have been analyzed for their ability to bind four protease inhibitors approved by the Food and Drug Administration (saquinavir, ritonavir, indinavir, and nelfinavir) as AIDS therapeutics. The loss in binding energy (DeltaDeltaG(b)) going from the wild-type enzyme to mutant enzymes ranges from 2.5 to 4.4 kcal/mol, 40-65% of which is attributed to amino acid substitutions away from the active site of the protease and not in direct contact with the inhibitor. The data suggest that non-active site changes are collectively a major contributor toward engendering resistance against the protease inhibitor and cannot be ignored when considering cross-resistance issues of drugs against the HIV-1 protease.

Binding Sites↗
PubMed2001

Differential effects of HIV-1 protease inhibitors on dendritic cell immunophenotype and function.

Recent findings show that human immunodeficiency virus (HIV)-1 protease inhibitors designed to specifically inhibit the aspartic protease of HIV-1 nonetheless exert various effects on immune cell function in vitro and in vivo. Dendritic cells (DC), central players of the immune system, express several aspartic proteases that are important for DC function. In the present study, we demonstrate that all of the HIV-1 protease inhibitors tested affect DC maturation. In addition, saquinavir had a strong inhibitory effect on the T-cell stimulatory capacity of mature DC. In contrast, indinavir had only a slight effect on DC induced T-cell proliferation and allowed efficient transduction of DC with a replication-incompetent HIV-1 vector designed for DC-based immunotherapy. HIV-1 protease inhibitors that have little or no effect on DC function may be preferable for combination with immunotherapy for HIV/AIDS.

Cell Division↗
PubMed2003

HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk.

Accelerated bone resorption leading to osteopenia and osteoporosis has been noted in human immunodeficiency virus (HIV) seropositive, treatment-naive patients, but it may be greatly increased in incidence in those receiving highly active anti-retroviral therapies that incorporate certain protease inhibitors (PI). The pathophysiology of these processes is unclear. We have documented the induction of the primary cytokine responsible for osteoclast differentiation and bone resorption, the receptor activator of nuclear factor kappa B ligand (RANKL), in T cells exposed to soluble HIV-1 envelope glycoprotein gp120. Using a murine osteoclast precursor cell line as well as primary human osteoclast precursors, we demonstrate that pharmacologic levels of two PIs that are linked clinically to osteopenia, ritonavir and saquinavir, abrogate a physiological block to RANKL activity, interferon-gamma-mediated degradation of the RANKL signaling adapter protein, TRAF6 (tumor necrosis factor receptor-associated protein 6) in proteasomes. In contrast, indinavir and nelfinavir, PIs that may promote or stabilize bone formation in vivo, had no impact on this system. These findings offer a molecular basis for the acceleration of bone resorption by certain PIs and provide the first example of clinically useful drugs that can interfere with the cross-talk between RANKL and interferon-gamma via the proteasome. They also suggest a novel therapeutic approach to HIV osteopenia through modulation of these two molecules.

Animals↗
PubMed1999

Analysis of the discontinuation of protease inhibitor therapy in routine clinical practice.

We evaluated the frequency of and reasons for discontinuation of protease inhibitor therapy in a cohort of HIV-infected patients in a prospective observational study. We included 230 HIV-infected patients who had started protease inhibitor therapy between November 1996 and July 1997. Mean baseline CD4 count was 138 cells/microl and HIV-RNA 4.5 log10. Forty-five percent of patients had prior AIDS and 77% had been treated with nucleoside analogues. Saquinavir-treated patients were at a less advanced stage of HIV disease. Overall, 41.3% of patients discontinued therapy, and their last HIV-RNA measured higher than that of patients who continued therapy: 4.07 vs. 2.70 log10 (p < 0.0001). Reasons for discontinuation of therapy were poor adherence (including abandonment) (18.6%), drug intolerance (12.1%), virological failure (7%) and physician decision (3.5%). In a multivariate model, factors associated with drug discontinuation were not taking indinavir (OR 0.26, 95% CI 0.12-0.59) and being pretreated with nucleoside analogues (OR 3.42, 95% CI 1.58-7.42). We concluded that in routine clinical practice a high proportion of patients discontinued protease inhibitors during the first 6 months of therapy, the main reason being the patient's own decision (abandonment or poor adherence). Psychological support and counselling are warranted in patients when initiating protease inhibitor therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2002

CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro.

1. The aim was to identify the major metabolites of saquinavir (SQV) from human hepatic microsomal incubations and the CYP isoform(s) responsible. 2. Ten fractions containing various metabolites were separated by isocratic reversed-phase HPLC and characterized by HPLC, mass spectrometry and NMR. 3. Metabolites were either mono- or di-hydroxylated derivatives of SQV. Fast-atom bombardment and electrospray MS showed that hydroxylation was predominantly situated on the decahydroisoquinoline ring. A major metabolite (M4) was rigorously identified as 6-equatorial-hydroxy SQV. 4. Metabolism of saquinavir to all metabolites was inhibited by the CYP3A4-selective inhibitor ketoconazole (IC50 = 0.55 +/- 0.12 microM). Other isoform-selective inhibitors were non-inhibitory. The protease inhibitors ritonavir, indinavir and nelfinavir potently inhibited SQV metabolism in hepatic microsomes with IC50 = 0.025 +/- 0.004, 0.82 +/- 0.26 and 0. 58 +/- 0.14 microM, respectively. 5. Saquinavir metabolism correlated with immunochemically determined CYP3A4 levels and testosterone 6beta-hydroxylation, but it failed to correlate with either immunochemically determined CYPIA2 levels or marker activities for CYP1A2, 2C9 or 2E1. 6. Heterologously expressed CYP3A4 metabolized saquinavir with a similar metabolic profile to that of human liver microsomes. 7. Km, and Vmax for total SQV metabolism were 0.61 +/- 0.19 microM and 1.82 +/- 1.13 nmol mg(-1) min(-1), respectively. 8. The extensive involvement of hepatic CYP3A4 in the metabolism of saquinavir predicts high intrinsic clearance of saquinavir. Inhibitors of CYP3A4 such as other protease inhibitors will substantially increase the bioavailability of saquinavir.

Adult↗
PubMed1999

Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor-experienced persons.

The efficacy of sequential protease inhibitor therapy was studied in 16 human immunodeficiency virus (HIV) 1-infected persons in whom saquinavir with multiple nucleoside reverse transcriptase (RT) inhibitors (NRTI) had failed. Nelfinavir plus two NRTIs (new or continued) resulted in minimal (0.59 log RNA copies/mL) and transient (8 weeks) suppression of plasma HIV RNA levels. Rapid failure was surprisingly associated with baseline presence of protease gene mutation L90M (P=.04) in the absence of D30N and with RT mutations D67N (P<.01), K70R/S (P=.02), and K219Q/W/R/E (P<.01). Ten patients were subsequently switched to indinavir plus nevirapine and 2 NRTIs, resulting in a median 1.62 log reduction in plasma HIV RNA, with 3 patients maintaining 400 copies/mL for 24 weeks. These results suggest that nelfinavir may have limited utility after saquinavir failure, particularly without potent concomitant therapy. Combining an NRTI with a new protease inhibitor for rescue may improve response.

Adult↗
PubMed1999

In vitro and in vivo anticandidal activity of human immunodeficiency virus protease inhibitors.

Highly active antiretroviral therapy that includes human immunodeficiency virus (HIV) aspartyl protease inhibitors (PIs) causes a decline in the incidence of some opportunistic infections in AIDS, and this decline is currently attributed to the restoration of specific immunity. The effect of two PIs (indinavir and ritonavir) on the enzymatic activity of a secretory aspartyl protease (Sap) of Candida albicans (a major agent of mucosal disease in HIV-infected subjects) and on growth and experimental pathogenicity of this fungus was evaluated. Both PIs strongly (>/=90%) and dose dependently (0.1-10 microM) inhibited Sap activity and production. They also significantly reduced Candida growth in a nitrogen-limited, Sap expression-dependent growth medium and exerted a therapeutic effect in an experimental model of vaginal candidiasis, with an efficacy comparable to that of fluconazole. Thus, besides the expected immunorestoration, patients receiving PI therapy may benefit from a direct anticandidal activity of these drugs.

AIDS-Related Opportunistic Infections↗
PubMed1999

Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir.

Current treatments for human immunodeficiency virus (HIV) require uninterrupted drug administration because they are unable to reconstitute the immune response and do not affect the viral reservoir. Ten patients were treated during acute HIV infection before complete Western blot (WB) seroconversion with the combination of hydroxyurea, didanosine, and indinavir. This treatment was associated with the normalization of some immune parameters and functions. No loss of naive CD4 T lymphocytes was observed, and recovery of up to 35% of naive CD8 T lymphocytes occurred in several weeks. A vigorous HIV-specific T helper response (stimulation index >8) was observed in 7 of 8 patients treated before complete WB seroconversion but in only 1 of 5 controls treated after seroconversion. In addition, a limited latent viral reservoir (<0.02-0.5 infectious units/106 cells) was documented in quiescent peripheral blood lymphocytes after treatment initiated before complete WB seroconversion.

Anti-HIV Agents↗
PubMed2000

Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection.

T-cell responses were evaluated prospectively in 41 patients with acute human immunodeficiency virus type 1 (HIV-1) infection (30 untreated and 11 receiving zidovudine, lamivudine, and indinavir) and in 38 uninfected adults. By 6-12 months, treated patients had significantly greater median Candida and tetanus lymphoproliferative responses (stimulation index [SI], 76 and 55, respectively) than did untreated patients (SI, 7 and 6, P=.02 and.001, respectively), and the responses of treated patients surpassed those of uninfected adults (SI, 19 and 32, P= .002 and .101, respectively). Unlike the patients in the untreated group, the patients in the treated group mounted a 6-fold increased HIV-1 p24 response (SI increase, 1.0 to 5.7, P= .01) within 3 months. HIV-1-specific cytotoxicity remained detectable in most treated patients. Thus, combination therapy administered within 3-4 months of infection was associated with improved T-cell memory responses that were distinct from those of untreated patients. The amplified HIV-1-specific T-cell responses may help maintain cytotoxic activities.

Acute Disease↗
PubMed2000

In vitro activity of human immunodeficiency virus protease inhibitors against Pneumocystis carinii.

Since 1996, the introduction of protease inhibitors (PIs) has led to a dramatic decrease of human immunodeficiency virus-related Pneumocystis carinii pneumonia. This effect is clearly due, in large part, to the induction of immune reconstitution by highly active antiretroviral therapy (HAART). However, it is conceivable that PIs had other beneficial effects, including direct activity against Pneumocystis. In this study, the occurrence of specific aspartyl proteases in Pneumocystis is described. These protease targets seemed to be affected in vitro by antiretroviral PIs. These data suggest intriguing implications for the possible antipneumocystis benefit of receiving indinavir, ritonavir, nelfinavir, or saquinavir during HAART.

Animals↗
PubMed2000

Methods for investigation of the relationship between drug-susceptibility phenotype and human immunodeficiency virus type 1 genotype with applications to AIDS clinical trials group 333.

Use of human immunodeficiency virus (HIV) drug-resistance testing in therapeutic decision making may be aided by understanding the relationship between results of genotypic and drug-susceptibility phenotypic assays. We investigated this relationship by applying 3 different statistical methods-cluster analysis, recursive partitioning, and linear discriminant analysis-to results for 72 patients followed in the Adult AIDS Clinical Trials Group (ACTG) protocol 333. ACTG 333 was a multicenter, randomized trial comparing 2 formulations of saquinavir (SQV) to indinavir (IDV) in patients with extensive hard-gel SQV experience. Data include protease amino acid sequences and 50% inhibitory concentrations for SQV and IDV at baseline. The 3 methods give similar results showing the association of mutations at codons 10, 63, 71, and 90 with in vitro resistance to IDV and SQV. Recursive partitioning is especially useful because it can identify interactions among mutations at different codons and accommodates many types of data as well as missing observations.

Adult↗
PubMed2000

The danish protease inhibitor study: a randomized study comparing the virological efficacy of 3 protease inhibitor-containing regimens for the treatment of human immunodeficiency virus type 1 infection.

The Danish Protease Inhibitor (PI) Study has enrolled 318 human immunodeficiency virus (HIV)-infected, PI-naive patients for the purpose of comparing 3 PI-containing regimens for the treatment of HIV infection. The regimens include 2 nucleoside analogues in combination with indinavir (Idr), ritonavir (Rtv), or Rtv and saquinavir (Rtv/Sqv). Similar percentages of patients in the 3 study arms achieved reduced levels (</=20 copies/mL) of HIV RNA. In the area under the curve minus baseline analyses, a better response was found in the Rtv/Sqv arm than in the Rtv arm. No difference was found when comparing Rtv/Sqv with Idr and Rtv with Idr. Patients in the 3 arms had comparable increases in CD4 cell counts. At 72 weeks of follow-up, there was no statistical difference between arms for the primary study end point (</=20 HIV RNA copies/mL); however, some of the additional analyses indicated an advantage for the Rtv/Sqv arm, especially when compared with the Rtv arm.

Adolescent↗
PubMed2001

Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years.

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.

Cohort Studies↗
PubMed2001

Long-term protease inhibitor-containing therapy results in limited improvement in T cell function but not restoration of interleukin-12 production in pediatric patients with AIDS.

This study investigated whether immune restoration occurred in 26 human immunodeficiency virus (HIV) type 1-infected children treated first with indinavir for 16 weeks and then with combination antiretroviral therapy for >2 years. Compared with baseline, a significant, although modest, decrease in virus loads (maximum median, -0.86 log(10)) and increase in the number of CD4(+) lymphocytes, especially naive cells, were observed at several time points after 2 years. A maximum of 7% of treated children achieved undetectable viremia. There was a marked increase in the proliferative response and skin reactivity to recall antigens. However, responses to an HIV antigen remained depressed, and the production of interleukin-12 remained unchanged and abnormally low. The magnitude of virus suppression did not correlate with these measures of functional immune reconstitution. These findings suggest that long-term nonsuppressive antiretroviral therapy can induce limited improvement in immune function in pediatric AIDS patients and that the effect of suppressive treatments should be investigated.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Anti-human immunodeficiency virus drugs are ineffective against Pneumocystis carinii in vitro and in vivo.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) recently have been reported to be active against Pneumocystis carinii in cell culture. Twelve anti-HIV drugs were analyzed for their effects against rat P. carinii by an ATP cytotoxicity assay. Indinavir and saquinavir exhibited slight anti-P. carinii activity at concentrations above those that can be clinically achieved in serum; other PIs and nucleoside and nonnucleoside reverse-transcriptase inhibitors were inactive against the organism. Anti-HIV drugs, alone or in combination, did not materially reduce the organism count in the treatment of P. carinii pneumonia in immunosuppressed mice. Thus, anti-HIV drugs have little or no activity against P. carinii in these in vitro and in vivo systems. Caution should be used when interpreting reports of the susceptibility of P. carinii to anti-HIV drugs on the basis of in vitro testing only.

Administration, Oral↗
PubMed2003

A review of low-dose ritonavir in protease inhibitor combination therapy.

The pharmacokinetics of protease inhibitors center around the microsomal enzyme cytochrome P-450 3A4. As a potent inhibitor of this enzyme, ritonavir can increase the bioavailability and half-life of coadministered protease inhibitors. Evidence suggests that increased exposure to protease inhibitors is clinically relevant. Antiretroviral treatment with low-dose ritonavir-boosted lopinavir, indinavir, and saquinavir has durable virological activity and shows impressive immune reconstitution. Although tolerable in most cases, gastrointestinal side effects, hepatotoxicity, and blood lipid abnormalities remain relevant issues. Additional study will elucidate the advantages and disadvantages of twice-daily, low-dose ritonavir-boosted regimens and determine whether once-daily regimens based on this principle will have a lasting role in clinical practice.

Antiretroviral Therapy, Highly Active↗
PubMed2004

Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles?

Levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c), as well as the TC:HDL-c ratio, were compared in patients receiving different antiretroviral therapy regimens. Patients receiving first-line regimens including protease inhibitors (PIs) had higher TC and TG levels and TC : HDL-c ratios than did antiretroviral-naive patients; patients receiving 2 PIs had higher levels of each lipid. Ritonavir-containing regimens were associated with higher TC and TG levels and TC : HDL-c ratios than were indinavir-containing regimens; however, receipt of nelfinavir was associated with reduced risk of lower HDL-c levels, and receipt of saquinavir was associated with lower TC : HDL-c ratios. Patients receiving nonnucleoside reverse-transcriptase inhibitors had higher levels of TC and LDL-c than did antiretroviral-naive patients, although the risk of having lower HDL-c levels was lower than that in patients receiving a single PI. Efavirenz was associated with higher levels of TC and TG than was nevirapine.

Adult↗