Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease.

In a human immunodeficiency virus-infected subject, cytomegalovirus (CMV) isolated 9 months after the patient began oral ganciclovir prophylaxis was resistant to ganciclovir and cidofovir and contained mutations in both UL97 and Pol coding regions. At 1 year, retinitis developed, which progressed despite intravenous ganciclovir followed by foscarnet and then cidofovir. A subsequent buffy coat virus isolate was resistant to all three drugs and contained new mutations in UL97 and Pol. By individually transferring the observed mutations to laboratory strain AD169, it was shown that a mutation at codon 603 of UL97 conferred resistance to ganciclovir, a mutation at codon 412 of Pol conferred resistance to both ganciclovir and cidofovir, and a mutation at codon 802 of Pol conferred resistance to ganciclovir and foscarnet. This case illustrates the development of multidrug resistance during prolonged exposure to antiviral therapy for CMV and cross-resistance arising from point mutations in the CMV Pol gene.

Diagnosis of cytomegalovirus (CMV) polyradiculopathy and documentation of in vivo anti-CMV activity in cerebrospinal fluid by using branched DNA signal amplification and antigen assays.

Branched chain DNA assay (bDNA), cytomegalovirus (CMV) antigen assay, and cerebrospinal fluid (CSF) viral culture were studied for their utility in the diagnosis of CMV polyradiculopathy and for documenting in vivo antiviral effects. CMV was demonstrated in 15 of 16 patients by bDNA assay, 15 of 16 by CMV antigen assay, and 11 of 15 by CSF culture. When clinical criteria and results of the other two assays were used as reference standards, the sensitivity of bDNA was 94% and 100% and the specificity 95.2% and 100%; the CMV antigen assay sensitivity was 94% and 100% and specificity was 85.7% and 100%. Nine (90%) of 10 patients with polyradiculopathy and follow-up CSF culture showed a drop in CMV DNA after treatment; however, only 2 (20%) improved clinically. These results suggest that bDNA and antigen assays may be useful methods for the diagnosis of CMV polyradiculopathy, but treatment failures may not be due to inadequate antiviral activity.

HIV viral load markers in clinical practice.

Plasma HIV RNA determinations are an important prognostic marker of disease progression and, when used appropriately, provide a valuable tool for the management of individual patients. But what constitutes appropriate use?

Combination treatment and single drugs: interview with Margaret Poscher, M.D. Interview by John S. James.

AIDS: Margaret Poscher, M.D., Assistant Clinical Professor at the University of California Medical Center, and Director of HIV Clinical Services at the University of California Mt. Zion, speaks favorably about combination antiretroviral therapy for HIV disease. She foresees AZT plus 3TC as being used as initial therapy, when 3TC is approved, for patients who have CD4 counts below 500, or have a certain threshold level of HIV RNA. Individuals with high levels of HIV RNA are more likely candidates for triple combination therapy. Viral load can be used as an indicator to determine which patients are the best candidates for which treatments. Dr. Poscher has seen many changes in CD4 count and viral load when different combination therapies are used. For example, with the combination of d4T and 3TC, Dr. Poscher has seen at least one long, ten-fold, viral load reduction--and when the RNA goes down, the CD4 count goes up. Dr. Poscher suggests using low doses of the antiretrovirals to minimize side effects.^ieng

Combination treatment and single drugs: interview with Margaret Poscher, M.D. Interview by John S. James.

AIDS: In a two-part interview with AIDS Treatment News (ATN), Margaret Poscher, M.D., discusses treatment strategies, including her use of combination antiretrovirals and managed care. When asked what to do for individuals who have never been on treatment but have had a sudden dramatic drop in CD4, Dr. Poscher suggests trying the triple combination AZT plus 3TC plus ddI, as long as the viral load is very high. Unfortunately, 3TC is difficult to obtain for individuals with a CD4 count that is not below 100. Dr. Poscher shares the concerns of many others that patients under managed care are less likely to receive the care they need. If insurance does not cover certain tests or therapies, the patient is forced to pay out-of-pocket, which is often not possible. Dr. Poscher is also concerned that many patients are not receiving the aggressive combination treatments now available. Many patients are either on AZT monotherapy or ddc monotherapy, which she considers useless. She sites paperwork and time as major obstacles for physicians who are not getting involved in the 3TC expanded-access program and combination therapies. Dr. Poscher foresees an increase in treatment options, which will hopefully increase survival.^ieng

Successful treatment of varicella zoster virus meningoencephalitis in patients with AIDS: report of four cases and review.

OBJECTIVE: Neurologic complications are common in patients with AIDS. Herpes zoster is a common early manifestation of HIV infection, but there have been few reports of encephalitic complications and nearly all have been postmortem. We report four cases of varicella zoster virus (VZV) meningoencephalitis diagnosed and treated antemortem, and briefly review the relevant literature. SETTING: Mount Zion Medical Center, San Francisco, California, USA. PATIENTS: Four HIV-positive male patients with antibodies to VZV in their cerebrospinal fluid. INTERVENTION: Treatment with intravenous acyclovir (three cases) and intravenous ganciclovir (one case), which resulted in resolution of all symptoms except blindness in one patient. CONCLUSION: Antibodies to VZV in the cerebrospinal fluid of HIV-positive individuals may allow early diagnosis and lifesaving treatment of VZV meningoencephalitis.

Severe opportunistic infections in AIDS patients with late-stage disease.

BACKGROUND: Clinicians caring for patients who have acquired immunodeficiency syndrome (AIDS) need to be aware of the wide variety of infectious diseases that can occur. Although Pneumocystis carinii pneumonia (PCP) is the most common AIDS-defining infection, other opportunistic infections associated with advanced immunodeficiency can develop after an initial diagnosis. METHODS: To ascertain AIDS-defining opportunistic infections that developed at the time of or after an AIDS diagnosis, and intensive chart review was conducted for 45 homosexual men with AIDS who died from 1990 through 1992. Time to death after first occurrence of these infections was also determined. RESULTS: The most common opportunistic infection occurring as the initial AIDS-defining illness was PCP (31 percent). The most common opportunistic infection occurring as a secondary disease was cytomegalovirus (CMV) disease (40 percent), followed by disseminated Mycobacterium avium complex (33 percent) and invasive candidiasis (31 percent). Each of these latter infections was associated with a poor prognosis (median time to death < or = 8 months). CONCLUSIONS: Diseases caused by CMV, disseminated M. avium complex, and invasive candidiasis were uncommon presenting manifestations of AIDS but were common secondary diseases that tended to be associated with limited survival. With increasing survival and a declining incidence of PCP as a result of medical therapy, other severe opportunistic infections might become increasingly recognized.

5-HIAA in cerebrospinal fluid and deficit schizophrenic characteristics.

Higher CSF 5-HIAA concentrations and lower CSF HVA concentrations have been associated with various measures of slowed motor behaviour and communication in schizophrenic patients. To derive a single, reliable measure of deficit characteristics in schizophrenic patients, we entered four items of the BPRS reflecting negative symptoms, a work history measure derived from the Strauss-Carpenter scale, and three subscale scores of the WAIS-R into a principal-components analysis to derive a single factor score. The CSF 5-HIAA concentrations were within the normal range of values, and correlated directly with this factor score, but CSF HVA concentrations were not associated with the deficit factor score. These findings add support to the hypothesis that brain serotonin function is associated with deficit schizophrenic characteristics.

Effects of thioglucoses on sensitivity to insulin hypoglycemic convulsions.

Based on the effects of gold thioglucose (GTG), we have previously proposed a regulatory center in brain which adjusts the convulsive response to insulin hypoglycemia. The sensitivity to insulin hypoglycemic convulsions is decreased 24 hr and increased 1 week after a single i.p. injection of GTG. The differences are in the brain's convulsive response to equal hypoglycemia, as the blood glucose response to insulin is unchanged. The generalized convulsive threshold, reflected in the sensitivity to nonmetabolic pentylenetetrazol (Metrazol) convulsions, is not altered. Despite its systemic administration, GTG causes lesions focused in the ventromedial hypothalamus. In the present study, this regulatory center was explored further by the ability of two thioglucoses to substitute for GTG. beta-D-Thioglucose had no effect. 5-Thioglucose simulated the early (24 hr) action of GTG but had no effect at 1 week. However, unlike GTG, 5-thioglucose did not cause the ventromedial hypothalamus lesion. The early (24 hr) and late (1 week) components are thus dissociated. The early effect on insulin hypoglycemic convulsions does not require a ventromedial hypothalamus lesion. Structure-activity relationships and relationships to glucoregulatory systems are discussed.