David W. Barry

Spectrum of sensitivity to acyclovir of herpes simplex virus clinical isolates

HSV-1 and HSV-2 clinical isolates were tested for their in vitro sensitivity to acyclovir. The median ID50 for 32 genital HSV-2 isolates was 0.215 micrograms/ml and this was not significantly higher than a median value of 0.125 micrograms/ml for 28 oral HSV-1 isolates (p = 0.08). A wider range of ID50s was observed with the HSV-2 isolates compared with the HSV-1 isolates. The concentration of drug required to inhibit virus replication by 90 and 99 percent was approximately 10- and 100-fold greater than that producing 50 percent inhibition.

Rapid screening of antiretroviral combinations

Increasing evidence supports the view that therapy with combinations of antiretroviral drugs provides greater and more sustained benefits in the treatment of HIV infection than either monotherapy or sequential therapy. As the number of licensed and developmental antiretroviral agents grows, in vitro analysis is increasingly being used to aid in the selection of effective combinations. An assay has been designed to ascertain the inhibitory action of drug combinations on HIV-infected MT4 cells, allowing rapid evaluation of those that may be of use in the clinic. Manipulation of this system also provides data on the efficacy of drugs under conditions of high viral load and against resistant strains, providing valuable information for the treatment of antiretroviral-experienced patients with advanced disease.

1072 ALTERED PATHOGENICITY OF ACYCLOVIR (ACV) RESISTANT HSV FROM AN IMMUNODEFICIENT CHILD

The frequency and clinical significance of drug-resistant herpes viruses occurring in clinical settings requires thorough investigation. We have studied over 100 HSV isolates from a variety of sources and have found one group, from a 15 month boy with adenosine deaminase deficient type of severe combined immunodeficiency, which was resistant to both ACV and IUDR. During a 6 week hospitalization he received topical ophthalmic, parenteral and oral ACV for treatment of herpetic keratitis and cutaneous lesions involving face, hands and perirectal areas. Early treatment courses resulted in dramatic clinical improvement but later recurrences were characterized by chronic lesions unresponsive to ACV despite serum levels up to 6 mcg/ml. After death from Pseudomonas sepsis and pneumonia, postmortem tissues, although HSV-positive, showed no evidence of viral cytopathic effect. A 100-fold decrease in sensitivity to ACV was noted between early and late isolates. Thymidine kinase activity was normal in sensitive but absent in resistant isolates. Reduced apparent pathogenicity in man was paralleled by a 100-1000-fold decrease of these isolates in their virulence (as determined by PFU/LD50 and PFU/MID50 ratios) in normal, hairless and nude mice by intracerebral and cutaneous innoculation. Cutaneous infection caused by the resistant virus was less severe or produced low-grade, chronic, lesions rather than acutely fatal infections. Antiviral resistance can occur in selected clinical situations but diminished sensitivity may be associated with diminished virulence.

Disease and latency characteristics of clinical herpes simplex virus isolates after acyclovir therapy

Abstract Herpes simplex virus (HSV) type 1 from a bone marrow transplant recipient and HSV type 2 from a patient with genital herpes infection were examined for sensitivity to acyclovir after both patients received therapy with the drug. A 38- and 83-fold shift in sensitivity was detected in association with a marked decrease in viral thymidine kinase activity in isolates from both patients. The resistant HSV-1 isolate was approximately 900 times less neurovirulent for Balb/C mice but had similar cutaneous virulence in hairless mice compared with the patients sensitive strain. In contrast, there was no difference in pathogenicity between the sensitive and resistant HSV-2 isolates. Latency was detected in the trigeminal ganglia of mice after snout inoculation with both the sensitive and resistant HSV-1 isolates. The ganglion isolate from the resistant HSV-inoculated mouse was found to be sensitive to acyclovir, implying a selection for or reversion to the sensitive phenotype. No trigeminal ganglion latency was detected after inoculation with either HSV-2 isolate. Resistance to acyclovir can arise during therapy as a result of diminished viral thymidine kinase activity but does not appear to be associated with increased virulence.

New Initiatives in Combination Antiretroviral Chemotherapy

Although monotherapy with available antiretroviral agents has proved useful in terms of delaying disease progression and improving the survival of persons with AIDS, the utility of these compounds as single agents is limited by several factors, including incomplete suppression of viral replication, the emergence of resistant virus, and a gradual increase in viral burden over time.1,2 As the benefit of antiretroviral monotherapy wanes, immune function decreases, leading to disease progression and ultimately death.