Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy.
(17/1109)
Efavirenz, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, is a promising addition to the antiretroviral armamentarium. Efavirenz levels and HIV-1 RNA levels were measured in cerebrospinal fluid (CSF) and plasma of 10 HIV-1-infected patients taking efavirenz, 600 mg daily, in combination with other antiretroviral medications. Efavirenz was detected in the CSF at a mean concentration of 35.1 nM (range, 6. 6-58.9 nM), which was above the IC95 for wild-type HIV-1. The mean CSF-to-plasma ratio was 0.61% (range, 0.26%-0.99%). CSF HIV-1 RNA levels were ascertained in 9 of the patients; all were <400 copies/mL after a mean of 26 weeks on therapy. Eight of the 9 patients had no detectable virus in plasma. These results indicate that efavirenz is present in the CSF at low levels and is effective in suppressing CSF viral levels when used in combination therapy. (+info)
Phenotypic changes in drug susceptibility associated with failure of human immunodeficiency virus type 1 (HIV-1) triple combination therapy.
(18/1109)
The emergence of drug-resistant human immunodeficiency virus type 1 is a frequent cause of failure of combination therapies comprising reverse transcriptase and protease inhibitors. Rational design of salvage therapies requires new methods to assess drug susceptibility. A novel phenotypic drug susceptibility assay was developed and used to measure the drug susceptibilities of viruses obtained from 2 patients treated with zidovudine, lamivudine, and nelfinavir. Results showed that phenotypic drug resistance may be detectable before virus load rebound, treatment failure does not always imply viral resistance to all drugs in a treatment regimen, and persons with similar antiviral treatment histories and clinical courses may have different phenotypic drug resistance profiles at the time that treatment fails. (+info)
Hepatitis B virus (HBV) mutations associated with resistance to lamivudine in patients coinfected with HBV and human immunodeficiency virus.
(19/1109)
Mutations associated with hepatitis B virus (HBV) resistance to lamivudine have not been extensively addressed in human immunodeficiency virus (HIV)-HBV coinfection. We have studied the HBV polymerase sequences from nine coinfected patients who experienced HBV recurrence while under lamivudine treatment. In seven of these nine patients, Met(550), belonging to the highly conserved YMDD motif, was mutated to Val and was associated with a substitution of Met for Leu(526) in each case. In the two remaining patients, we found a Met(550)-to-Ile change that was associated in only one case with a Leu(526)-to-Met mutation. No mutation was observed in three control patients not receiving lamivudine. This study demonstrates the emergence of particular genetic profiles in HBV-HIV-coinfected patients experiencing a loss of control of HBV infection despite high doses of lamivudine. (+info)
Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine.
(20/1109)
Lamivudine is a nucleoside analog with activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Patients coinfected with HIV and HBV may have hepatitis flares when lamivudine therapy is discontinued or when resistance of HBV to lamivudine emerges. This retrospective, descriptive study conducted in three tertiary care medical centers describes patients coinfected with HIV type 1 and HBV who presented with a spectrum of clinical and subclinical hepatitic responses to lamivudine withdrawal or resistance. One patient had fulminant hepatic failure and a second patient had subclinical hepatitis when lamivudine therapy was discontinued and a more efficacious antiretroviral regimen was substituted. Three patients had flares of hepatitis after 13 to 18 months of lamivudine therapy. Lamivudine withdrawal or emergence of lamivudine-resistant mutants in patients coinfected with HIV and HBV may result in severe hepatitis. Clinicians caring for patients with coinfection with HIV and HBV should be aware of the possibility that a hepatitis B flare may occur in previously asymptomatic carrier patients. (+info)
Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP.
(21/1109)
Of all of the nucleoside inhibitors approved by the FDA for treatment of AIDS, (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is the only one with the unnatural (-)-beta-L configuration. The fluorinated derivative (-)-beta-2', 3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and its triphosphate form have also been reported to have excellent antiretroviral activity against HIV-1 reverse transcriptase (RT). Preliminary results of clinical trials suggest that (-)-FTC is 6- to 10-fold more potent than 3TC. However, the molecular mechanism for the observed enhanced clinical potency of (-)-FTC to inhibit viral replication is not understood. The present mechanistic studies used a transient kinetic approach and were designed to compare the incorporation of 3TC-TP and (-)-FTC-TP into DNA by HIV-1 RT and illuminate key features that may play a role in the differential potency. Here we show that (-)-FTC-TP is incorporated 10-fold more efficiently than 3TC-TP during HIV-1 RT-catalyzed RNA-dependent DNA synthesis. The enhanced incorporation efficiency of (-)-FTC-TP may be a key mechanistic feature that, in part, is responsible for the enhanced potency of (-)-FTC observed in ongoing clinical trials. (+info)
Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids.
(22/1109)
An important component of triple-drug anti-AIDS therapy is 2', 3'-dideoxy-3'-thiacytidine (3TC, lamivudine). Single mutations at residue 184 of the reverse transcriptase (RT) in HIV cause high-level resistance to 3TC and contribute to the failure of anti-AIDS combination therapy. We have determined crystal structures of the 3TC-resistant mutant HIV-1 RT (M184I) in both the presence and absence of a DNA/DNA template-primer. In the absence of a DNA substrate, the wild-type and mutant structures are very similar. However, comparison of crystal structures of M184I mutant and wild-type HIV-1 RT with and without DNA reveals repositioning of the template-primer in the M184I/DNA binary complex and other smaller changes in residues in the dNTP-binding site. On the basis of these structural results, we developed a model that explains the ability of the 3TC-resistant mutant M184I to incorporate dNTPs but not the nucleotide analog 3TCTP. In this model, steric hindrance is expected for NRTIs with beta- or L- ring configurations, as with the enantiomer of 3TC that is used in therapy. Steric conflict between the oxathiolane ring of 3TCTP and the side chain of beta-branched amino acids (Val, Ile, Thr) at position 184 perturbs inhibitor binding, leading to a reduction in incorporation of the analog. The model can also explain the 3TC resistance of analogous hepatitis B polymerase mutants. Repositioning of the template-primer as observed in the binary complex (M184I/DNA) may also occur in the catalytic ternary complex (M184I/DNA/3TCTP) and contribute to 3TC resistance by interfering with the formation of a catalytically competent closed complex. (+info)
Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults.
(23/1109)
Today's antiretroviral combination regimens can induce significant and sustained decreases in human immunodeficiency virus (HIV)-RNA levels, allowing the immune system to recover. To what extent immune reconstitution is possible and what factors determine the outcome have thus far not been resolved. We studied 19 subjects, treated for 2 years with protease inhibitor-containing triple therapy, who had a strong suppression of HIV-RNA levels. CD4+ T-cell numbers increased from medians of 170 to 420x106 cells/L, but in a number of subjects T-cell numbers did not further increase after week 72, without having reached normal values. Long-term CD4+ T-cell change was mainly caused by a slow but continuous increase in naive CD4+ T cells (CD45RA+CD62L+) and was predicted by the baseline number of these cells. Our data indicate that long-term immunological recovery is gradual, even during strong suppression of viral replication, not always complete, and dependent on the preexisting level of naive CD4+ T cells. (+info)
Highly active antiretroviral treatment initiated early in the course of symptomatic primary HIV-1 infection: results of the ANRS 053 trial.
(24/1109)
Highly active antiretroviral treatment (HAART) was given early to 64 patients with symptomatic primary human immunodeficiency virus (HIV)-1 infection. At the time of analysis, patients had been followed up for 9-21 months. No patient had died or developed an AIDS-defining event. Survival analysis showed that by month 21 the proportion of patients with plasma HIV-1 RNA <50 copies/mL was 72% (95% confidence interval, 58%-95%) in intention-to-treat analysis. After 18 months of treatment, 50% of the patients with undetectable plasma HIV-1 RNA also had undetectable HIV-1 RNA in peripheral blood mononuclear cells (PBMC). Only 1 of 3 patients had undetectable HIV-1 RNA in lymphoid tissue, while all patients had quantifiable HIV-1 DNA both in PBMC and lymphoid tissue. The median CD4 lymphocyte increase from baseline was 230 cells/microL. These preliminary results support the use of HAART in patients with primary HIV-1 infection. (+info)