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PubMed2006

Viral factors correlate with hepatitis B e antigen seroconverson in patients with chronic hepatitis B.

BACKGROUND/AIMS: Seroconversion (SC) from hepatitis B envelope antigen (HBeAg) to anti-HBe usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. However, the role of viral factors in the development of SC remains largely unknown. We thus comprehensively studied these factors in 25 patients with sustained HBeAg SC and seven control patients with sustained loss of HBeAg. METHODS: We determined viral factors in serum samples obtained 1 year before, 6 months before, 3 months before, at the time of, 6 months after and 1 year after HBeAg SC or HBeAg loss. Precore A1896 and basal core promoter T1762/A1764 mutants were determined by polymerase chain reaction (PCR)-based assays. Serum HBV levels were determined by a real-time PCR assay. RESULTS: We found that decline of serum viral load, frequently accompanied by hepatitis exacerbation, occurred within 1 year before HBeAg SC. The proportions of precore and BCP mutations also increased gradually throughout the process of HBeAg SC. The virologic features were similar between HBeAg SC group and HBeAg loss group. Before HBeAg SC or loss, genotype B patients had higher serum viral loads and lower proportions of BCP mutation compared with genotype C patients. CONCLUSION: Our findings suggested that viral factors correlate with the development of sustained HBeAg SC or loss.

Adolescent↗
PubMed2005

Transient rebounds of HIV plasma viremia are associated with the emergence of drug resistance mutations in patients on highly active antiretroviral therapy.

BACKGROUND: There are very few and contradictory data about the consequences of 'blips', transient rebounds of HIV viremia. We assessed the emergence of new drug resistance mutations during blips among HIV-infected patients on HAART from a cohort in which we found no association between blips and virological failure. METHODS: Seventeen patients with blips were selected from 330 patients under HAART for over 48 weeks according to these criteria: (1) presence of only one blip, viremia < or =1000copies/ml preceded by two consecutive visits and followed by one visit showing undetectable viremia; (2) therapy adherence > or =95%; (3) availability of frozen sera. RESULTS: HIV RNA could be extracted and amplified from five patients. In another two patients only the protease region could be amplified. Drug mutations in either the retrotranscriptase or protease genes, not detected at baseline, were observed in six patients at the blip. None of the patients showed detectable viremia during a median (range) follow-up after the blip of 120 (36-156) weeks. CONCLUSIONS: Transient rebounds of viremia in patients on HAART are associated with the emergence of new drug resistant HIV variants. In spite of it, virological failure is not observed after a median follow-up of over 2 years.

Adolescent↗
PubMed2003

P-glycoprotein in blood CD4 cells of HIV-1-infected patients treated with protease inhibitors.

OBJECTIVE: Many factors are involved in the virological failure of antiretroviral treatments such as low pharmacological plasma levels of drugs, poor adherence to therapy and emergence of viral resistance. P-glycoprotein (P-gp) has been demonstrated to play a role in multidrug resistance in the therapy of solid tumours, haematological malignancies and Plasmodium falciparum infection. HIV-1 protease inhibitors (PIs) have been described to be substrates of P-gp. In vitro and in vivo studies performed in mice have demonstrated that P-gp may affect the oral bioavailability and intracellular accumulation of PIs. P-gps have been detected on peripheral CD4 blood cells in HIV-1-infected, but antiretroviral-naive patients. METHOD: We quantified P-gp expression and performed functional tests of P-gp activity in the CD4 cells in HIV-1-infected patients, with and without virological failure, treated with PIs, and in healthy patients (control group). RESULT: Out of the 18 HIV-infected patients studied, P-gp expression and function were found in the CD4 cells of six patients (four of 10 without, and two of eight with virological failure). Out of the 43 healthy patients studied, P-gp expression and function were found in the CD4 cells of 11 patients (26%). We found P-gp in peripheral CD4 cells of patients treated with PIs, with and without virological failure, within the same frequency than in antiretroviral naive patients or than in non HIV-infected patients. CONCLUSIONS: P-gp expression in peripheral CD4 blood cells does not seem to be enhanced by PI treatment and does not seem to be linked particularly to virological failures. These facts do not preclude of the role of P-gp on PI absorption or efficacy in other compartments of the body such as gut, lymph nodes or brain in HIV-1 PI-treated patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort.

BACKGROUND AND METHODS: The Sydney Blood Bank Cohort consists of a blood donor and eight transfusion recipients who were infected before 1985 with a strain of human immunodeficiency virus type 1 (HIV-1) with a deletion in the region in which the nef gene and the long terminal repeat overlap. Two recipients have died since 1994, at 77 and 83 years of age, of causes unrelated to HIV infection; one other recipient, who had systemic lupus erythematosus, died in 1987 at 22 years of age of causes possibly related to HIV. We present longitudinal immunologic and virologic data on the six surviving members and one deceased member of this cohort through September 30, 1998. RESULTS: The five surviving recipients remain asymptomatic 14 to 18 years after HIV-1 infection without any antiretroviral therapy; however, the donor commenced therapy in February 1999. In three recipients plasma concentrations of HIV-1 RNA are undetectable (<200 copies per milliliter), and in two of these three the CD4 lymphocyte counts have declined by 9 and 30 cells per cubic millimeter per year (P=0.3 and P=0.5, respectively). The donor and two other recipients have median plasma concentrations of HIV-1 RNA of 645 to 2850 copies per milliliter; the concentration has increased in the donor (P<0.001). The CD4 lymphocyte counts in these three cohort members have declined by 16 to 73 cells per cubic millimeter per year (P<0.001). In the recipient who died after 12 years of infection, the median plasma concentration of HIV-1 RNA was 1400 copies per milliliter, with a decline in CD4 lymphocyte counts of 17 cells per cubic millimeter per year (P=0.2). CONCLUSIONS: After prolonged infection with this attenuated strain of HIV-1, there is evidence of immunologic damage in three of the four subjects with detectable plasma HIV-1 RNA. The CD4 lymphocyte counts appear to be stable in the three subjects in whom plasma HIV-1 RNA remains undetectable.

Adult↗
PubMed2004

A trial of three antiretroviral regimens in HIV-1-infected children.

BACKGROUND: Depletion of CD4 T-cell counts or progression of human immunodeficiency virus (HIV) disease occurs rapidly in children, but few data address the efficacy of aggressive therapy for HIV-infected children. METHODS: We evaluated the safety, tolerability, and activity of three regimens of antiretroviral therapy in a multicenter, open-label, phase 1-2 trial. Children infected with HIV type 1 (HIV-1) were stratified at entry according to age--three months or younger (early therapy) or older than three months (delayed therapy)--and assigned sequentially to one of three regimens. Children continued to receive treatment for up to 200 weeks if the plasma HIV-1 RNA level was less than 1000 copies per milliliter by 16 weeks. RESULTS: Plasma HIV-1 RNA levels fell from a median of 5.3 log copies per milliliter (range, 3.3 to 6.4 log copies per milliliter) at baseline to less than 1000 copies per milliliter at 16 weeks in 32 of 52 infants (62 percent). Plasma HIV-1 RNA levels were below 400 copies per milliliter at 48 weeks in 26 infants (50 percent) and at 200 weeks in 23 infants (44 percent). An intention-to-treat analysis revealed that significantly more children who received stavudine, lamivudine, nevirapine, and nelfinavir had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 48 weeks (83 percent) and 200 weeks (72 percent) than children who received reverse-transcriptase inhibitors alone (P=0.001 and P=0.01, respectively). Fewer infants in the delayed-therapy group than in the early-therapy group (30 percent vs. 60 percent) had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 200 weeks (P=0.03). Treatment-associated adverse effects were infrequent. CONCLUSIONS: In this phase 1-2 trial involving HIV-1-infected children, an age of three months or younger at the initiation of therapy and treatment with stavudine, lamivudine, nevirapine, and nelfinavir were associated with improved long-term viral suppression. Larger, randomized trials are required to define the optimal time to initiate therapy and the optimal regimen for these infants.

Anti-Retroviral Agents↗
PubMed2005

Development of HIV with drug resistance after CD4 cell count-guided structured treatment interruptions in patients treated with highly active antiretroviral therapy after dual-nucleoside analogue treatment.

BACKGROUND: For patients with human immunodeficiency virus (HIV) infection, structured treatment interruption (STI) is an attractive alternative strategy to continuous treatment, particularly in resource-restrained settings, because it reduces both side effects and costs. One major concern, however, is the development of resistance to antiretroviral drugs that can occur during multiple cycles of starting and stopping therapy. METHODS: HIV genotypic drug resistance was investigated in 20 HIV-infected Thai patients treated with highly active antiretroviral therapy (HAART) and CD4 cell count-guided STI after dual nucleoside reverse-transcriptase inhibitor (NRTI) treatment. Resistance was tested at the time of the switch from dual-NRTI treatment to HAART and when HAART was stopped during the last interruption. RESULTS: After STI, one major drug-resistance mutation occurred (T215Y), and, in the 4 samples with preexisting major mutations (D67N [n=2], K70R [n=2], T215Y [n=2], and T215I [n=1]), the mutations disappeared. All mutations in the HIV protease gene were minor mutations already present, in most cases, before STI was started, and their frequency was not increased through STI, whereas the frequency of reverse-transcriptase gene mutations significantly decreased after the interruptions. After the 48-week study period, no patients had virological failure. Long-term follow-up (108 weeks) showed 1 case of virological failure in the STI arm and 1 in the continuous arm. No virological failure was seen in patients with major mutations. CONCLUSIONS: Major HIV drug-resistance mutations were not induced through CD4 cell count-guided treatment interruptions in HIV-infected patients successfully treated with HAART after dual-NRTI therapy.

Adult↗
PubMed2006

Rate of viral evolution and risk of losing future drug options in heavily pretreated, HIV-infected patients who continue to receive a stable, partially suppressive treatment regimen.

BACKGROUND: Many treatment-experienced, HIV-infected patients who have limited therapeutic options for complete viral suppression continue to receive a partially suppressive treatment regimen pending the availability of at least 2 new antiretroviral drugs. The major risk of this approach is ongoing viral evolution and the loss of future drug options. METHODS: Antiretroviral-treated subjects with incomplete viral suppression were sampled from a clinic-based cohort. Inclusion criteria were receipt of a stable treatment regimen for > or = 120 days, a plasma HIV RNA load of > 500 copies/mL, and > or = 1 resistance mutation. Phenotypic and genotypic resistance testing was performed every 4 months. RESULTS: The 106 patients who were eligible for the study had a median of 3 observations during a median of 11.3 months. An estimated 23% and 18% developed at least 1 new nucleoside analogue and 1 new protease inhibitor mutation at 1 year, respectively. An estimated 30% lost the phenotypic equivalent of 1 susceptible drug at 1 year. A lower number of total mutations at baseline was a significant predictor of developing a new nucleoside analogue mutation (P=.01). At 1 year, the probability that an existing mutation would become undetectable using population-based sequencing was 32%. There was a higher rate of change at nonresistance codons than at codons known to be associated with drug resistance. CONCLUSIONS: Heavily pretreated patients with HIV infection who remain on a partially suppressive regimen have a measurable risk of losing future drug options, particularly those patients who have few baseline mutations. Resistance mutations vary over time, which suggests that the results of any single resistance test may not be representative of all mutations selected by a given treatment regimen.

Anti-HIV Agents↗
PubMed2004

Hypokalaemia and paralysis in the Thai population.

BACKGROUND: Hypokalaemia with paralysis is a syndrome common in Thailand. This syndrome may result from hypokalaemic periodic paralysis (HypoPP), thyrotoxic periodic paralysis (TPP) or distal renal tubular acidosis (dRTA). We prospectively investigated the nature of this syndrome in afflicted Thai patients. METHODS: Blood and urine samples were collected from 47 patients during attacks for multiple biochemical and thyroid function tests. A long acid loading test was performed in all euthyroid patients. Mutation analyses were done in all HypoPP and TPP patients. RESULTS: Of the subjects, 34 completed the study. Of those, 11 (32%), eight (24%) and 15 (44%) had TPP, dRTA and HypoPP, respectively. Patients with dRTA and TPP were older than those with HypoPP. Males were more prevalent than females in HypoPP and TPP; the reverse was true for dRTA. Two-thirds of the HypoPP cases were sporadic. The majority of the HypoPP and dRTA patients resided in northeastern Thailand. Of the 11 TPP patients, nine (82%) had no previous thyroid disease. Moreover, four out of 11 patients (36%) had subtle clinical signs of hyperthyroidism; three of eight dRTA patients had renal stones, nephrocalcinosis or both. Only two patients had metabolic acidosis at the time of presentation. No common mutations were found in the HypoPP and TPP patients. CONCLUSIONS: In most of our patients, HypoPP is sporadic and not associated with the common mutations reported previously. Clinical clues that can assist in differentiating between the causes of hypokalaemia and paralysis are age at onset, gender and geographic region residence of the patients. However, the absence of previous histories of thyroid disease or overt thyrotoxicosis, and of stone disease/nephrocalcinosis or metabolic acidosis does not exclude the diagnosis of TPP or dRTA.

Adult↗
PubMed1996

Effectiveness of 3TC in HIV clinical trials may be due in part to the M184V substitution in 3TC-resistant HIV-1 reverse transcriptase.

OBJECTIVE: To measure the extent of HIV resistance to (-)-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) within the context of monotherapy and to assess the presence of the M184V substitution in the case of 3TC-resistant viruses. Whether the success of 3TC in clinical trials could be due, in part, to an increase in the fidelity of HIV reverse transcriptase conferred by the M184V substitution was also considered. METHODS: Two separate monotherapy studies were evaluated, one involving adults with CD4 counts > or = 300 x 10(6)/l, and the second involving children, some of whom had received antiretroviral treatment previously, while others were drug naive. Peripheral blood and plasma samples were collected regularly, and HIV isolation and determinations of drug median inhibitory concentration values were performed using umbilical cord mononuclear cells as targets. Amplification of the 184 mutation was performed by the polymerase chain reaction, using specific primer pairs. Fidelity determinations using purified, recombinant HIV reverse transcriptase derived from either wild-type virus or viruses that contained the 184V substitution were performed. RESULTS: Phenotypic resistance was detected in almost all subjects at times ranging from 8-20 weeks after initiation of therapy. The 184V substitution was usually detected prior to the occurrence of phenotypic resistance to 3TC. Fidelity determinations revealed that the 184V substitution conferred an approximately 5- to 10-fold increase in HIV reverse transcriptase fidelity. In addition, titres of patient sera tested for their ability to neutralize autologous sequential viral isolates were stabilized in patients receiving 3TC therapy as opposed to other drugs. CONCLUSIONS: Resistance to 3TC developed in virtually all subjects treated with this drug, and was associated with the appearance of an M184V mutation in HIV reverse transcriptase. The clinical benefit of 3TC therapy may be attributable in part to selection of viruses that are less able to replicate and mutate than the wild types.

Adult↗
PubMed2001

Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012).

OBJECTIVE: To examine the emergence and fading of NVP resistance (NVP(R)) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DESIGN: We examined NVP(R) in women and infants who received NVP in the HIVNET 012 clinical trial, including 41 out of 48 women with infected infants, 70 randomly-selected women with uninfected infants, and 33 out of 49 infected infants. METHODS: Plasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. RESULTS: NVP(R) mutations were detected in 21 out of 111 (19%) women tested 6-8 weeks after delivery. The rate of NVP(R) was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVP(R) mutations faded from detection within 12-24 months in all 11 evaluable women. High baseline viral load and low baseline CD4 cell count were associated with development of NVP(R). NVP(R) mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6-8 weeks of age. The most common NVP(R) mutation detected in infants was Y181C. Those mutations faded from detection by 12 months of age in all seven evaluable infants. Of nine evaluable infants with late HIV-1 infection, only one had evidence of NVP(R). CONCLUSIONS: NVP(R) was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVP(R) mutations were detected in women versus infants. NVP(R) was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time.

Anti-HIV Agents↗
PubMed2000

Mutation takes no vacation: can structured treatment interruptions increase the risk of drug-resistant HIV-1?

We use a mathematical model to study the dynamics of HIV-1 replication during structured treatment interruptions (STIs) in infected patients. The model predicts rapid viral rebound, restoration of a latently infected cell pool, and critically, partially resistant mutant rebound that may be missed because of high levels of wild type virus. Because partially resistant viruses are capable of mutating to full resistance, a substantial increase in their numbers represents a threat to therapeutic response durability. Compared with continued treatment, STIs may increase the chance of mutation to full resistance by several thousandfold.

Anti-HIV Agents↗
PubMed2005

Determinants of HIV drug resistance mutations in plasma virus after treatment interruption.

This study examines the utility of resistance testing during treatment interruption, making comparisons with the current IAS guidelines. A total of 188/1279 tests (14%) were performed during treatment interruption; 69/188 tests (36.7%) demonstrated key mutations. Time off therapy and the total number of previous drugs were both significantly associated with the presence of mutations. We conclude that resistance testing is of value up to 3 months after treatment interruption, and may convey some benefit up to 12 months.

Drug Resistance, Multiple, Viral↗
PubMed2000

Genes that modify the hemochromatosis phenotype in mice.

Hereditary hemochromatosis (HH) is a prevalent human disease caused by a mutation in HFE, which encodes an atypical HLA class I protein involved in regulation of intestinal iron absorption. To gain insight into the pathogenesis of hemochromatosis, we have bred Hfe knockout mice to strains carrying other mutations that impair normal iron metabolism. Compound mutant mice lacking both Hfe and its interacting protein, beta-2 microglobulin (B2m), deposit more tissue iron than mice lacking Hfe only, suggesting that another B2m-interacting protein may be involved in iron regulation. Hfe knockout mice carrying mutations in the iron transporter DMT1 fail to load iron, indicating that hemochromatosis involves iron flux through DMT1. Similarly, compound mutants deficient in both Hfe and hephaestin (Heph) show less iron loading than do Hfe knockout mice, indicating that iron absorption in hemochromatosis involves the function of Heph as well. Finally, compound mutants lacking Hfe and the transferrin receptor accumulate more tissue iron than do mice lacking Hfe alone, consistent with the idea that interaction between these two proteins contributes to the control of normal iron absorption. In addition to providing insight into the pathogenesis of HH, our results suggest that each of these genes might be a candidate modifier of the human hemochromatosis phenotype.

Animals↗
PubMed2005

Dynamic force spectroscopy of glycoprotein Ib-IX and von Willebrand factor.

The first stage in hemostasis is the binding of the platelet membrane receptor glycoprotein (GP) Ib-IX complex to the A1 domain of von Willebrand factor in the subendothelium. A bleeding disorder associated with this interaction is platelet-type von Willebrand disease, which results from gain-of-function (GOF) mutations in amino acid residues 233 or 239 of the GP Ibalpha subunit of GP Ib-IX. Using optical tweezers and a quadrant photodetector, we investigated the binding of A1 to GOF and loss-of-function mutants of GP Ibalpha with mutations in the region containing the two known naturally occurring mutations. By dynamically measuring unbinding force profiles at loading rates ranging from 200-20,000 pN/s, we found that the bond strengths between A1 and GP Ibalpha GOF mutants (233, 235, 237, and 239) were significantly greater than the A1/wild-type GP Ib-IX bond at all loading rates examined (p < 0.05). In addition, mutants 231 and 232 exhibited significantly lower bond strengths with A1 than the wild-type receptors (p < 0.05). We computed unloaded dissociation rate constant (k(off)(0)) values for interactions involving mutant and wild-type GP Ib-IX receptors with A1 and found the A1/wild-type GP Ib-IX k(off)(0) value of 5.47 +/- 0.25 s(-1) to be significantly greater than the GOF k(off)(0) values and significantly less than the loss-of-function k(off)(0) values. Our data illustrate the importance of the bond kinetics associated with the VWF/GP Ib-IX interaction in hemostasis and also demonstrate the drastic changes in binding that can occur when only a single amino acid of GP Ibalpha is altered.

Amino Acid Sequence↗