We determined the susceptibility to antiviral drugs of clinical isolates of human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C, D, and E. Isolates from treated and untreated patients were tested for sensitivity to zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), nevirapine (NVP), foscarnet (PFA), and ritonavir (RNV). The susceptibility to these different drugs was broadly similar between the different subtypes of HIV-1. Isolates of subtype D showed a tendency toward slightly lower susceptibility to all the antiviral drugs, which could be related to the rapid growth characteristics of these isolates.

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The emergence of azidothymidine (AZT)-resistant human immunodeficiency virus (HIV) variants in clinical samples was studied by a direct genomic sequencing method. Sequential lymphocyte samples from four patients, who had been treated with AZT for up to 27 months, were shown to gradually accumulate multiple nucleotide changes, some of which are known to be associated with AZT resistance. Several samples were shown to contain mixtures of wild-type and mutated genomes, indicating gradual rather than sudden changes in the HIV-1 quasispecies. These results demonstrate for the first time that automated solid-phase DNA sequencing is a rapid and useful tool for investigation of antiviral drug resistance and suggest that DNA sequencing may be important in routine clinical diagnostics in the future.

One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.

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Background There is increasing interest in the use of purified cannabidiol (CBD) as a treatment for a wide range of conditions due to its reported anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties. Objective The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single ascending dose of a new lipid-based oral formulation of CBD in healthy volunteers after a high-fat meal. Methods A total of 24 eligible healthy volunteers (aged 18-48 years) were randomised to one of three sequential cohorts (each with six active and two placebo subjects). Cohort 1 received 5 mg/kg CBD or placebo, cohort 2 received 10 mg/kg CBD or placebo (cohort 2), and cohort 3 received 20 mg/kg CBD or placebo. Data relating to adverse events, vital signs, clinical laboratory assessments, 12-lead ECGs, physical examinations and concomitant medications were collected to assess safety and tolerability. Blood samples were collected up to 8 days postdose and plasma was analysed by liquid chromatography and mass spectrometry to assess the pharmacokinetics of the CBD formulation. Results CBD was well tolerated in the healthy volunteers (mean age: 24.0 years) treated with a single oral dose of CBD. There were no safety concerns with increasing the dose and the safety profiles of the CBD-treated and placebo-treated subjects were similar. The most frequently reported treatment emergent adverse events (TEAEs) were headache (17%) and diarrhoea (8%). There were no reported serious adverse events (SAEs) and no clinical laboratory findings, vital signs, ECGs or physical examination findings that were reported as TEAEs or were of clinical significance during the study. After a high-fat meal, CBD was detected in plasma samples at 15 min postdose; the median time to maximum plasma concentration (T max) was 4 h across all three CBD dose cohorts. The CBD plasma exposure [maximum observed plasma concentration (C max) and the area under the concentration-time curve (AUC)] increased in a dose-proportional manner and declined to levels approaching the lower level of quantification by day 8. The terminal elimination half-life was approximately 70 h, suggesting that 2-3 weeks are needed to fully eliminate CBD. Conclusions This new CBD formulation demonstrated a favourable safety and tolerability profile in healthy volunteers that was consistent with the profiles reported for other purified CBD products. No severe or serious AEs were observed in this study and there were no safety concerns. Trial Registration ACTRN12618001424291. Registered August 2018.

The separate (+) and (−) enantiomers of the acyclic guanosine analogue 9-[4-hydroxy-2-(hydroxymethyl)-butyl]guanine (2HM-HBG) were tested for inhibition of varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). In all cases the (−) enantiomer was the most active enantiomer. The (+) enantiomer was 10 times less active than the racemate against VZV and inactive against HSV-1 and -2. The parent compound, 9-(4-hydroxybutyl)guanine, containing an unbranched side chain, was inactive against VZV, whereas substitution with a hydroxymethyl group at the 2 or 3 position of the side chain conferred anti-VZV activity. The effect of hydroxymethyl substitution may increase the recognition of the compound by the VZV thymidine kinase by increasing its similarity to the natural substrate thymidine. Further substitution of the side chain of the parent compound with oxygen, fluorine or hydroxyl groups did not confer antiviral activity against VZV. Two VZV strains were isolated which could be grown in the presence of high concentrations of 2HM-HBG and which were also cross-resistant to other nucleoside analogues. These strains induced very little viral thymidine kinase activity in infected cells and thus were probably deficient for a functional thymidine kinase. 2HM-HBG exhibited a persistent antiviral effect even after the nucleoside was removed from the medium of VZV-infected cells, whereas acyclovir did not show this effect.