Biomedical subjects

S M Lemon

Publications and source records attributed to S M Lemon.

At least 55 records · Page 3Linked to original sources

PubMed1997

Immunoprecipitation and virus neutralization assays demonstrate qualitative differences between protective antibody responses to inactivated hepatitis A vaccine and passive immunization with immune globulin.

Antibodies to hepatitis A virus (anti-HAV) were measured in children from two separate vaccine trials (n = 70) 4 weeks after a dose of inactivated hepatitis A vaccine (VAQTA). The geometric mean titers (GMTs) of anti-HAV were 49.3 and 45.2 mIU/mL by immunoassay, while reciprocal GMTs of neutralizing anti-HAV were 6.5 and 15.0 by an 80% radioimmunofocus inhibition test (RIFIT) and 55.6 and 92.0 by antigen reduction assay (HAVARNA). The GMT of antibody detected by radioimmunoprecipitation (RIPA) was > or =401. These data establish serologic correlates of protection against disease and show that RIPA is most sensitive for detection of early vaccine-induced antibody. Sera collected from adults (n = 20) 7 days after administration of immune globulin contained similar antibody levels by immunoassay (45.1 mIU/mL) and slightly higher GMTs of neutralizing antibody (27.5 by RIFIT and 146 by HAVARNA) but negligible precipitating antibody (GMT, 5.6). These results are best explained by differences in the affinity of antibodies for virus following active versus passive immunization.

Adult↗

PubMed1997

Development of a more thermostable poliovirus vaccine.

In 1991, a goal of improved thermostability of oral poliovirus vaccine (OPV) was set, and the Product Development Group was established under the Children's Vaccine Initiative to achieve this goal. Several initial research strategies were unsuccessful. The substitution of deuterium oxide for water in the final blending stage of vaccine production resulted in a significantly more stable product at temperatures of > or = 37 degrees C. A large body of clinical data shows the safety of deuterium at the dosage that would be given with this vaccine. However, reservations about the public acceptability of the vaccine, combined with the progress achieved in polio eradication with the current vaccine and the availability of vaccine vial monitors to indicate time and temperature exposure of every vial of OPV, have resulted in a recommendation that vaccine development cease. This product development activity has been instructive for the process of introduction of new vaccines.

Deuterium Oxide↗

PubMed1997

Type A viral hepatitis: epidemiology, diagnosis, and prevention.

Hepatitis A virus (HAV) infection occurs worldwide and is an important cause of acute viral hepatitis in the US. In this review, I cover the epidemiology, course of infection, clinical manifestations, serological responses, and prevention of this infection. Although most patients completely recover from this disease, elderly patients have a substantial mortality risk. Recently licensed vaccines are highly efficacious.

Adolescent↗

PubMed1996

Structural requirements for initiation of translation by internal ribosome entry within genome-length hepatitis C virus RNA.

Cap-independent translation of hepatitis C virus (HCV) RNA is mediated by an internal ribosomal entry segment (IRES) located within the 5' nontranslated RNA (5'NTR), but previous studies provide conflicting views of the viral sequences which are required for translation initiation. These discrepancies could have resulted from the inclusion of less than full-length 5'NTR in constructs studied for translation or destabilization of RNA secondary structure due to fusion of the 5'NTR to heterologous reporter sequences. In an effort to resolve this confusion, we constructed a series of mutations within the 5'NTR of a nearly full-length 9.5-kb HCV cDNA clone and examined the impact of these mutations on HCV translation in vitro in rabbit reticulocyte lysates and in transfected Huh-T7 cells. The inclusion of the entire open reading frame in HCV transcripts did not lead to an increase in IRES-directed translation of the capsid and E1 proteins, suggesting that the nonstructural proteins of HCV do not include a translational transactivator. However, in reticulocyte lysates programmed with full-length transcripts, there were multiple aberrent translation initiation sites resembling those identified in some picornaviruses. The deletion of nucleotides (nt) 28-69 of the 5'NTR (stem-loop IIa) sharply reduced capsid translation both in vitro and in vivo. A small deletion mutation involving nt 328-334, immediately upstream of the initiator AUG at nt 342, also resulted in a nearly complete inhibition of translation, as did the deletion of multiple intervening structural elements. An in-frame 12-nt insertion placed within the capsid-coding region 9 nt downstream of the initiator AUG strongly inhibited translation both in vitro and in vivo, while multiple silent mutations within the first 42 nt of the open reading frame also reduced translation in reticulocyte lysates. Thus, domains II and III of the 5'NTR are both essential to activity of the IRES, while conservation of sequence downstream of the initiator AUG is required for optimal IRES-directed translation.

Amino Acid Sequence↗

PubMed1996

Specific interaction of glyceraldehyde 3-phosphate dehydrogenase with the 5'-nontranslated RNA of hepatitis A virus.

Initiation of translation of hepatitis A virus (HAV) RNA occurs by internal entry and is likely to involve the interaction of trans-acting cellular protein factors with cis-acting structural elements of an internal ribosomal entry segment (IRES) within the 5'-nontranslated RNA. To characterize interactions between African green monkey kidney (BS-C-1) cell proteins and the predicted stem-loop IIIa (nucleotides 155-235) located at the 5' border of the HAV IRES, we utilized an electrophoresis mobility shift assay (EMSA) to identify a 39-kDa RNA-binding protein (p39). Amino-terminal amino acid sequencing of highly purified p39 revealed absolute identity with human glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The identity of p39 as simian GAPDH was further confirmed by antigenic and biochemical similarities between p39 and human GAPDH. Analysis of the RNA binding properties of simian GAPDH revealed that this cellular protein interacts with two additional sites in the HAV 5'-nontranslated RNA, one located between nucleotides 1-148 and the other between nucleotides 597-746. Competitive EMSAs also demonstrated that GAPDH and human polypyrimidine tract-binding protein, a putative picornavirus translation initiation factor, compete with each other for binding to stem-loop IIIa, suggesting that the relative cytoplasmic abundance of GAPDH and polypyrimidine tract-binding protein in individual cell-types may be an important determinant of viral translation activity. Human GAPDH was found to destabilize the folded structure of the stem-loop IIIa RNA based upon observed decreases in the circular dichroism spectra of this RNA following binding of the protein. This RNA helix-destabilizing activity of GAPDH could directly influence IRES-dependent translation and/or replication of picornavirus RNA.

Amino Acid Sequence↗

PubMed1996

A replication-deficient adenovirus enhances liposome-mediated nucleic acid transfer into a stable cell line expressing T7 RNA polymerase.

Liposome-mediated transfer of nucleic acids into a cell line expressing bacteriophage T7 RNA polymerase was enhanced by addition of a replication-deficient adenovirus (Ad5-259A) to transfection mixtures. Increasing quantities of Ad5-259A resulted in a dose-related (up to 30-fold) enhancement of reporter gene activity expressed in BT7-H cells transfected with plasmid DNA containing the reporter sequence fused to the internal ribosome entry site of encephalomyocarditis virus. Similarly, Ad5-259A enhanced reporter gene expression 7-fold following transfection of DNA containing the reporter sequence under transcriptional control of the Rous sarcoma virus long terminal repeat. Addition of Ad5-295A to transfection mixtures increased the proportion of cells staining positively for reporter gene activity, from 2 to 25% when the reporter was expressed via the T7 polymerase and from 20 to 50% when the reporter was under the control of a eucaryotic promoter. Thus, Ad5-259A enhanced reporter protein activities expressed by cytoplasmic T7-directed transcription and cap-independent initiation of translation, or nuclear transcription and cap-dependent translation. Transfection enhancement was blocked by neutralizing antibody to Ad5, and is most likely related to the endosome-disrupting activities of the virus. Adenovirus enhancement of liposome-mediated transfection provides a useful method for efficient nucleic acid transfer into eucaryotic cells.

Adenoviruses, Human↗

PubMed1996

Seroepidemiological survey of hepatitis B and C virus infections in Ghanaian children.

The seroprevalences of hepatitis B virus (HBV) and hepatitis C virus (HCV) markers were evaluated in a random sample of 803 children attending school in Ashanti-Akim North district in Ghana in order to gain a better understanding of transmission patterns of these viruses, particularly horizontal transmission of HBV. This rural district is typical of 70% of the Ghanaian population. The overall seroprevalence of at least one marker of HBV infection was 61.2%, with rates increasing from 48% to 80% between the ages of 6-18 years (P < 0.001). The overall HBsAg seroprevalence was 15.8%, with the proportion of HBsAg positives amongst those with anti-HBc increasing from 39.3% in 6-7-year-olds to 51.8% in 12-13-year-olds. It appears that horizontal transmission during this age period was accompanied by a high rate of HBsAg carriage. Among those infected but not carriers, i.e., those HBsAg negative and anti-HBc positive, > 50% lacked detectable levels of anti-HBs, an unusual pattern of convalescent immune response to HBV. The overall seroprevalence of anti-HCV was 5.4% and did not differ significantly by age or gender. Anti-HCV seroprevalence was not associated with the presence of any HBV marker. A better understanding of the unusually high prevalences of HBV and HCV infections demonstrated in this population is likely to influence vaccination and blood transfusion policies and to stimulate further evaluations of these infections and their vehicles of spread in highly endemic regions such as sub-Saharan Africa.

Adolescent↗

PubMed1996

Mutations within the 5' nontranslated RNA of cell culture-adapted hepatitis A virus which enhance cap-independent translation in cultured African green monkey kidney cells.

Mutations in the 5' nontranslated RNA (5'NTR) of an attenuated, cell culture-adapted hepatitis A virus (HAV), HM175/P16, enhance growth in cultured African green monkey kidney (BS-C-1) cells but not in fetal rhesus monkey kidney (FRhK-4) cells (S. P. Day, P. Murphy, E. A. Brown, and S. M. Lemon, J. Virol. 66: 6533-6540, 1992). To determine whether these mutations enhance cap-independent translation directed by the HAV internal ribosomal entry site (IRES), we compared the translational activities of the 5'NTRs of wild-type and HM175/P16 viruses in two stably transformed cell lines (BT7-H and FRhK-T7) which constitutively express cytoplasmic bacteriophage T7 RNA polymerase and which are derived from BS-C-1 and FRhK-4 cells, respectively. Translational activity was assessed by monitoring expression of a reporter protein, chloramphenicol acetyltransferase (CAT), following transfection with plasmid DNAs containing bicistronic T7 transcriptional units of the form luciferase-5'NTR-CAT. In both cell types, transcripts containing the 5'NTR of HM175/P16 expressed CAT at levels that were 50- to 100-fold lower than transcripts containing the IRES elements of Sabin type 1 poliovirus or encephalomyocarditis virus, confirming the low activity of the HAV IRES. However, in BT7-H cells, transcripts containing the 5'NTR of wild-type virus. This translational enhancement was due to additive effects of a UU deletion at nucleotides 203 and 204 and a U-to-G substitution at nucleotide 687 of HM175/P16. These mutations did not enhance translation in FRhK-T7 or Huh-T7 cells (a T7 polymerase-expressing cell line derived from human hepatoblastoma cells) or in vitro in rabbit reticulocyte lysates. These results demonstrate that mutations in the 5'NTR of a cell culture-adapted HAV enhance viral replication by facilitating cap-independent translation in a cell-type-specific fashion and support the concept that picornaviral host range is determined in part by differences in cellular translation initiation factors.

Animals↗

PubMed1996

Capsid coding sequence is required for efficient replication of human rhinovirus 14 RNA.

Mechanisms by which the plus-sense RNA genomes of picornaviruses are replicated remain poorly defined, but existing models do not suggest a role for sequences encoding the capsid proteins. However, candidate RNA replicons (delta P1 beta gal and delta P1Luc), representing the sequence of human rhinovirus 14 virus (HRV-14) with reporter protein sequences (beta-galactosidase or luciferase, respectively) replacing most of the P1 capsid-coding region, failed to replicate in transfected H1-HeLa cells despite efficient primary cleavage of the polyprotein. To determine which P1 sequences might be required for RNA replication, HRV-14 mutants in which segments of the P1 region were removed to frame from the genome were constructed. Mutants with deletions involving the 5'proximal 1,489 nucleotides of the P1 region replicated efficiently, while those with deletions involving the 3' 1,079 nucleotides did not. Reintroduction of the 3' P1 sequence into the nonreplicating delta P1Luc construct resulted in a new candidate replicon, delta P1Luc/VP3, which replicated well and expressed luciferase efficiently. Capsid proteins provided in trans by helper virus failed to rescue the nonreplicating delta P1Luc genome but were able to package the larger-than-genome-length delta P1Luc/VP3 replicon. Thus, a 3'-distal P1 capsid-coding sequence has a previously unrecognized cis-active function related to replication of HRV-14 RNA.

Amino Acid Sequence↗

PubMed1996

Epitopes exposed on hepatitis delta virus ribonucleoproteins.

A total of 17 antibodies, raised in several nonhuman species and specific for different regions on the delta antigen (delta Ag), were used to map, via immunoprecipitation, those domains exposed on the surface of the viral ribonucleoprotein (RNP). These studies showed that the domains for the nuclear localization signal and the C-terminal extension, unique to the large form of delta Ag, are exposed. Also exposed is the C-terminal region of the small form of delta Ag. In contrast, reactivity was not found with the coiled-coil domain needed for protein dimerization. When the hepatitis delta virus (HDV) RNA was released by treatment of viral RNP with vanadyl ribonucleoside complexes, no change in the pattern of delta Ag epitope presentation was detected, consistent with the interpretation that a multimeric protein structure persists in the absence of RNA. These RNP studies have implications not only for understanding of the process of HDV assembly but also for evaluation of the immune responses of an infected host to HDV replication.

Animals↗

PubMed1996

Translation initiation in GB viruses A and C: evidence for internal ribosome entry and implications for genome organization.

GB viruses A and C (GBV-A and GBV-C) are two recently described RNA viruses which appear to be members of the Flaviviridae. Although both viruses appear to contain long 5' nontranslated regions, the sites of polyprotein initiation and the presence of core-like proteins remain to be determined. Translation studies were undertaken to determine the mechanism and sites of polyprotein initiation in GBV-A and GBV-C. Rabbit reticulocyte lysates programmed with monocistronic RNAs containing 5' ends of GBV-A or GBV-C fused in-frame with the chloramphenicol acetyltransferase (CAT) open reading frame generated GBV-CAT fusion proteins in vitro. Site-specific mutagenesis and N-terminal sequencing located the sites of translation initiation immediately upstream of the putative signal sequence for the GBV E1 envelope glycoproteins. Efficient translation of the monocistronic GBV-CAT RNAs required the inclusion of GBV coding sequences. This, coupled with the presence of at least 523 nucleotides of 5' nontranslated RNA containing multiple AUG codons, suggests that translation initiation of these RNAs did not utilize a ribosome scanning mechanism. Translation of bicistronic RNAs containing 5' nontranslated sequences within the intercistronic space was consistent with the presence of a weakly active internal ribosome entry site in both GBV-A and GBV-C. Secondary structure predictions indicate that the 5' ends of these viruses assume similar complex structures distinct from those identified in the internal ribosome entry site-containing picornaviruses, pestiviruses, and hepatitis C viruses. The data indicate that GBV-A and GBV-C are unique members of the Flaviviridae that do not contain core-like proteins at the N termini of their putative polyproteins.

Amino Acid Sequence↗

PubMed1996

Stability of a stem-loop involving the initiator AUG controls the efficiency of internal initiation of translation on hepatitis C virus RNA.

The initiation of translation on the positive-sense RNA genome of hepatitis C virus (HCV) is directed by an internal ribosomal entry site (IRES) that occupies most of the 341-nt 5' nontranslated RNA (5'NTR). Previous studies indicate that this IRES differs from picornaviral IRESs in that its activity is dependent upon RNA sequence downstream of the initiator AUG. Here, we demonstrate that the initiator AUG of HCV is located within a stem-loop (stem-loop IV) involving nt -12 to +12 (with reference to the AUG). This structure is conserved among HCV strains, and is present in the 5'NTR of the phylogenetically distant GB virus B. Mutant, nearly genome-length RNAs containing nucleotide substitutions predicted to enhance the stability of stem-loop IV were generally deficient in cap-independent translation both in vitro and in vivo. Additional mutations that destabilize the stem-loop restored translation to normal. Thus, the stability of the stem-loop is strongly but inversely correlated with the efficiency of internal initiation of translation. In contrast, mutations that stabilize this stem-loop had comparatively little effect on translation of 5' truncated RNAs by scanning ribosomes, suggesting that internal initiation of translation follows binding of the 40S ribosome directly at the site of stem-loop IV. Because stem-loop IV is not required for internal entry of ribosomes but is able to regulate this process, we speculate that it may be stabilized by interactions with a viral protein, providing a mechanism for feedback regulation of translation, which may be important for viral persistence.

Antigens, Viral↗

PubMed1995

Identification and site-directed mutagenesis of the primary (2A/2B) cleavage site of the hepatitis A virus polyprotein: functional impact on the infectivity of HAV RNA transcripts.

The junction between 2A and 2B proteins of the hepatitis A virus (HAV) polyprotein is processed by the virus-encoded 3C protease to liberate the precursor for capsid proteins, but details of this cleavage remain poorly defined. We identified the location of this primary cleavage by a novel approach involving expression of HAV polypeptides in eukaryotic cells via recombinant vaccinia viruses. A substrate polyprotein spanning the putative HAV 2A/2B site was fused at its C-terminus to a poliovirus VP1 reporter sequence. This substrate was cleaved efficiently in trans by protease 3C derived from another recombinant vaccinia virus expressing a 3C precursor protein. N-terminal sequencing of the 2B-poliovirus VP1 fusion product identified the site of cleavage as the Gln836/Ala837 dipeptide, 144 residues upstream of the originally predicted site. Two mutations were introduced at the P1 position of the 2A/2B site. Gln836-->Asn, and Gln836-->Arg. Asn substitution at the P1 residue reduced the efficiency of cleavage in the vaccinia expression system and resulted in a small replication focus phenotype of virus rescued from infectious HAV RNA transcripts. Arg substitution abolished cleavage and was lethal to HAV replication. In addition to identifying the site of the primary HAV polyprotein cleavage, these results shed light on the in vivo specificities of the HAV 3C protease.

3C Viral Proteases↗

PubMed1995

An infectious cDNA clone of a cytopathic hepatitis A virus: genomic regions associated with rapid replication and cytopathic effect.

Rapidly replicating, cytopathic (rr/cpe+) variants of hepatitis A virus (HAV) isolated from persistently infected BS-C-1 cells have numerous mutations from cell culture-adapted rr/cpe- HAV. To determine which mutations in one rr/cpe+ virus, HM175/18f, determine enhanced replication in BS-C-1 cells, a series of chimeric viruses was rescued from infectious cDNAs in which HM175/18f genomic segments were placed within the background of a related rr/cpe- virus, HAV/7. Chimeric viruses containing the P2 region of HM175/18f produced replication foci in BS-C-1 cells that were larger than HAV/7, but not as large as HM175/18f virus. Enhanced viral replication required mutations in both 2B and 2C proteins, suggesting that these proteins remain closely associated during replication. Mutations in 5' nontranslated RNA (5'NTR) or P3 proteins had no independent effect, but acted cooperatively with mutations in P2 proteins to enhance replication and render the virus capable of conventional plaque formation. Cytopathic effects correlated with viral replication capacity and were not the result of any single mutation. Full expression of the rr/cpe+ phenotype required mutations within the 5'NTR, P2, and P3 segments. These results suggest novel interactions between the 5'NTR and P2 proteins during HAV replication and provide useful new infectious cDNA clones.

Animals↗

PubMed1995

Self-association of a synthetic peptide from the N terminus of the hepatitis delta virus protein into an immunoreactive alpha-helical multimer.

The formation of hepatitis delta antigen (HDAg) multimers is required for full biologic activity of this protein and for replication of the hepatitis delta virus. To determine the residues responsible for multimerization, three peptides [ delta 12-49, delta 25-60(Y), delta 12-60(Y)] from the putative coiled-coil multimer-forming domain of HDAg were chemically synthesized and biophysically characterized by circular dichroic spectroscopy, deuterium-exchange mass spectrometry, gel filtration, chemical crosslinking, and ultracentrifugation. By circular dichroism the 50-residue peptide delta 12-60(Y) was half-denatured above 80 degrees C and was 97% alpha-helical at 5 degrees C and 84% alpha-helical at 37 degrees C. By deuterium exchange, peptide delta 12-60(Y) was 93% alpha-helical at 25 degrees C. Its high alpha-helicity and melting temperature are due to the formation of an alpha-helical multimer consisting of four or more chains. All three synthetic peptides reacted with human anti-HDAg antibodies in an enzyme-linked immunosorbent assay, but only peptide delta 12-60(Y) was detected in a sandwich radioimmunoassay in which successful antigens must display at least two antibody-binding sites, which correlates with the ability of this peptide to form multimers. Peptide delta 12-60(Y) also interfered with the self-association of natural HDAg into multimers. These results have significant practical implications for development of improved diagnostic tests, antiviral agents, and possibly even vaccines for prevention of hepatitis delta virus disease.

Amino Acid Sequence↗

PubMed1995

Subcellular distribution of large and small hepatitis delta antigen in hepatocytes of hepatitis delta virus superinfected woodchucks.

Hepatitis delta virus (HDV) encodes only a single protein, the hepatitis delta antigen (HDAg), which is expressed as two molecular forms (large and small) with different functions in viral replication. Compared with small antigen, large antigen has a 19 residue carboxyl terminal extension. Antibodies that recognize a large antigen-specific epitope within this carboxyl extension, or an epitope shared by both large and small antigens (total antigen), were used in immunohistochemical studies of liver sections from superinfected woodchuck carriers of woodchuck hepatitis virus. There were no differences in the subcellular distributions of large and total antigens, with both generally present only in nuclei of hepatocytes. Rare cells demonstrated cytoplasmic staining. Complete or partial granular nucleoplasmic staining with stained nucleoli was the most common pattern observed. Within 31 days of infection, 0.1% to 19% (mean = 7.4%) of all hepatocytes contained antigen. The proportion of these nuclei containing large antigen ranged from 0 to 100% (mean, 39%), and increased during the first month of infection. The number of antigen-positive nuclei and the proportion staining for large antigen were reduced with progression to chronicity, correlating with reductions in the level of viremia. Thus, the large hepatitis delta antigen shares a common subcellular distribution with small antigen and is found in an increasing proportion of the nuclei of infected cells during the course of acute infection.

Animals↗

PubMed1995

Hepatitis A virus and blood products: virus validation studies.

As there have been reports of the transmission of hepatitis A virus by single units of blood, virus validation studies were carried out to determine the fate of the virus at four major steps (cryoprecipitation, solvent/detergent inactivation, DEAE chromatography and lyophilization) involved in the production of solvent-detergent inactivated factor VIII products. If the reduction in infectivity is additive over the four steps, the total reduction would be between 8.6 and 9.3 log10. It is unlikely that such a reduction would provide a sufficient safety margin, particularly if the original plasma pool from which the FVIII was prepared, was obtained from a population in which hepatitis A virus was not rare. In such a situation, an additional method of effectively reducing hepatitis A virus infectivity should preferably be included in the production process.

Blood Banks↗

PubMed1995

Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062).

The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over a 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 +/- 192 ng.h/ml), maximum concentration of drug in serum (1,751 +/- 180 ng/ml), and half-life (2.04 +/- 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 +/- 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 +/- 1,222 ng.h/ml) and maximum concentration of drug in serum (5,220 +/- 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2.79 +/- 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 +/- 0.15 in HIV-infected patients with hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy-proven cirrhosis, our results suggest that ZDV, could accumulate in HIV-infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.

Administration, Oral↗