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The C terminus of the human immunodeficiency virus type 1 (HIV-1) accessory protein vpr acts in viral cell cycle arrest, nuclear localization, and apoptosis. Polymorphisms in this region are described in series of long-term nonprogression cases. We determined vpr sequences of archived baseline specimens from 96 participants in a historical trial of single- versus double-nucleoside reverse-transcriptase inhibitors. These sequences were then analyzed by study-entry and -outcome characteristics such as baseline absolute CD4(+) T cell count, prior treatment, CD4(+) T cell response, and clinical endpoints. Frequency of C-terminal mutations did not correlate to any measures of disease intensity. Changes in that portion of vpr did not attenuate disease.

A semiquantitative PCR assay for the detection of BK virus in urine was developed using primers for BK virus that specifically amplified BK but not JC virus. DNA was extracted from urine through treatment with proteinase K followed by DNA precipitation with sodium acetate. Semiquantitation was achieved by amplifying serial dilutions (1:1, 1:10, 1:100, and 1:1,000) of the urine specimens. Each assay included both positive (stock BK virus and previously positive patient urine) and negative (no template) controls. A urine sample was interpreted as positive if any of the serial dilutions showed amplification of the DNA fragment of the expected size. For some patient-derived samples, amplification of the expected-size fragment was achieved with a dilute template whereas no amplification was achieved with a concentrated template. This was attributed to interfering substances in the urine. PCR results were compared with urine cytology and shown to be more sensitive. Validation studies were performed at the University of Nebraska Medical Center, utilizing a separate qualitative PCR assay that detects both BK and JC virus and distinguishes between them by restriction enzyme digestion patterns. Of 46 urine samples analyzed using both methods, 22 were positive by both assays, 18 were negative by both assays, 5 were positive only by the Nebraska method, and 1 was positive only by our method. In comparison with the Nebraska PCR, our PCR assay had a sensitivity of 81% and specificity of 95%. For twenty-one (43%) of 49 immunocompromised patients, tests were postive when specimens were submitted because of clinical suspicion of BK virus infection.

Mitochondrial toxicity was evaluated in peripheral lymphocytes obtained from a cohort of 10 subjects with extensive exposure to nucleoside reverse transcriptase inhibitors (NRTI) and matched controls. Mitochondrial copy number was expressed as the ratio of mitochondrial (cytochrome b)-to-nuclear (pyruvate kinase) genes as measured by real-time polymerase chain reaction. There was no significant difference between the mtDNA : nuclear DNA ratios for the NRTI-treated subjects (mean ratio 187.2) versus the matched controls (mean ratio 199).

Strains of human immunodeficiency virus type 1 (HIV-1) with reduced sensitivity to zidovudine have been isolated from patients treated with this drug for six months or more1. Resistance to zidovudine is associated with late-stage disease, low CD4 lymphocyte counts, longer antiretroviral therapy, and specific mutations in the reverse transcriptase gene of HIV-12,3. The clinical importance of infections with resistant HIV-1 isolates is not well understood. We describe a patient with symptomatic HIV-1 infection who had primary infection with a virus resistant to zidovudine, according to both phenotypic and genotypic analyses. Case Report The patient was a 20-year-old . . .

Epstein-Barr Virus (EBV) causes infectious mononucleosis and establishes lifelong infection associated with cancer and autoimmune disease. To better understand immunity to EBV, we performed a prospective study of natural infection in healthy humans. Transcriptome analysis defined a striking and reproducible expression profile during acute infection but no lasting gene changes were apparent during latent infection. Comparing the EBV response profile to multiple other acute viral infections, including influenza A (influenza), respiratory syncytial virus (RSV), human rhinovirus (HRV), attenuated yellow fever virus (YFV), and Dengue fever virus (DENV), revealed similarity only to DENV. The signature shared by EBV and DENV was also present in patients with hemophagocytic syndromes, suggesting these two viruses cause uncontrolled inflammatory responses. Interestingly, while EBV induced a strong type I interferon response, a subset of interferon induced genes, including MX1, HERC5, and OAS1, were not upregulated, suggesting a mechanism by which viral antagonism of immunity results in a profound inflammatory response. These data provide an important first description of the response to a natural herpesvirus infection in humans.

To optimize nucleoside reverse transcriptase inhibitor (nRTI) antiretroviral therapy, 137 subjects who had been treated with didanosine monotherapy for more than 3 years in the AIDS Clinical Trials Group (ACTG) 175 study were randomized to zidovudine and didanosine (dual therapy) or zidovudine, didanosine, and lamivudine (triple therapy). Evaluation of early (8 week) change in HIV plasma RNA demonstrated that addition of lamivudine and zidovudine provided significantly greater virologic suppression compared to the addition of zidovudine alone (mean decrease of 1.27 vs. 0.74 log(10) copies/ml, n = 108, p = 0.007). Both dual and triple therapy provided significant long-term decreases (from study entry to mean at Weeks 40 and 48) in HIV plasma RNA: 0.62 and 0.86 log(10) copies/ml, respectively (n = 110). However, the difference between treatments was not significant (p = 0.16). At 48 weeks, 26% of subjects starting study treatment had500 copies/ml of plasma HIV RNA. The CD4 count response was greater at 4 weeks for triple versus dual therapy: a mean increase of 51 vs. 12 CD4 cells/ml(3) (n = 126, p = 0.039). The difference at Weeks 40 and 48 was not significant (a 22 cell increase vs. a 1 cell decrease, n = 129, p = 0.41). Zidovudine and didanosine treatment, with or without lamivudine, was well tolerated and only 2 of 137 (1.5%) of study participants developed an AIDS-defining event over 48 weeks.

Nucleoside analog-based regimens remain an integral component of combination therapy for use in both antiretroviral treatment-naive and experienced HIV-infected patients. To further define treatment responses to new antiretroviral therapy in patients with long-term experience to dual nucleoside analog therapy (zidovudine [ZDV] plus didanosine [ddI] or ZDV plus zalcitabine [ddC]), 325 subjects derived from the AIDS Clinical Trials Group (ACTG) 175 trial were randomized to three different combination regimens: (1) continuation of ZDV + ddI or ZDV + ddC (continuation arm), (2) addition of 3TC to ZDV + ddI or ZDV + ddC (addition arm), or (3) a switch to ZDV + 3TC therapy (switch arm). Both the addition and switch arms sustained significantly greater short-term (baseline to week 4) mean CD4+ cell count increases compared with the continuation arm (+36, +28 versus -4 cells/mm3; p = 0.012) and long-term CD4+ cell count responses (baseline to weeks 40/48: +32, +19 versus -9 cells/mm3; p = 0.003). Superior short-term (baseline to week 8) mean decreases in plasma HIV RNA (p0.001) were achieved by both the addition and switch arms (0.53 log10 and 0.54 log10 copies/ml, respectively) compared with the continuation arm (0.13 copies/ml) whereas no differences in long-term virologic suppression were observed (p = 0.30). At week 48, no differences were observed in the proportions of subjects who had HIV RNA levels below 500 copies/mL: 18% of subjects in each treatment arm (3-way p = 1.0). Overall, the treatments were well tolerated and only nine subjects (3%) died or developed one or more AIDS-defining events. While this study confirms the intrinsic antiretroviral activity of 3TC, only modest marker changes and limited short-term viral suppression are seen with incremental addition of the drug. The current approach of using 3TC in maximally suppressive regimens is preferred.

Study Objective. To characterize the concentration-time profiles of zidovudine and zidovudine-glucuronide in semen and serum of men infected with the human immunodeficiency-1 virus (HIV-1). Design. Open-label observational study. Setting. University-affiliated teaching hospital and research center. Patients. Four asymptomatic HIV-1-infected men. Interventions. Zidovudine administration was followed by an 8-hour intensive pharmacokinetic study on day 1. Over the next 8 days, a dose administration and timed single-sample strategy was employed to determine serum and semen concentration time profiles simultaneously. Measurements and Main Results. Zidovudine and zidovudine-glucuronide concentrations were uniformly higher in semen than in serum except at 1 hour after the dose. The median area under the curve ratio (semen AUC0–48:serum AUC0–∞) was 3.31 for zidovudine and 15.04 for zidovudine-glucuronide. Conclusion. Zidovudine and zidovudine-glucuronide reach high levels in seminal plasma relative to serum. The virologic, pharmacodynamic, and public health implications of distribution to this compartment require further study.

Antiviral susceptibilities to ganciclovir, foscarnet, and cidofovir and sequencing of UL97 and DNA polymerase were done on 23 cytomegalovirus (CMV) isolates from 10 immunocompromised persons with end-organ CMV disease who were treated with ganciclovir alone or ganciclovir followed by foscarnet. Screening of UL97 for ganciclovir resistance mutations was done by restriction digest analysis. Of 14 isolates resistant to ganciclovir, 11 (79%) contained one or more UL97 mutations at codons known to confer resistance to this compound, and 10 (91%) had a concordant mutant pattern by restriction digest analysis. Of 9 isolates containing mutations in conserved regions of the DNA polymerase, 8 were resistant to ganciclovir, and 4 were cross-resistant to cidofovir. All isolates were susceptible to foscarnet. It is concluded that ganciclovir-resistant clinical CMV isolates may contain UL97 mutations, DNA polymerase mutations, or mutations in both genes. Ganciclovir therapy may select for CMV isolates that are cross-resistant to cidofovir.

Because few data exist on the effect of recombinant human erythropoietin (EPO) for anemia not induced by zidovudine (ZDV) in persons with AIDS, we analyzed a subset of 523 subjects not taking ZDV (‘non-ZDV’) who participated in an open-label EPO treatment program involving 1943 subjects. Non-ZDV subjects had a mean hematocrit of 27.3% on entry and their mean weekly EPO dose was 354–464 U/kg that was given for a mean of 17 weeks. EPO was well tolerated with an adverse event discontinuation rate of 2.3%. The mean hematocrit increased to 30.8% at week 6 and remained between 32 and 34% for the next 18 weeks. Subjects requiring one or more transfusion per 6-week period decreased from 43% before study entry to 14% for weeks 13–18 and 18% for weeks 19–24. These changes were comparable to those observed in the entire group of 1943 patients. We concluded that EPO was safe and as effective for anemia in persons with AIDS not taking ZDV as for those receiving it.

Cytomegalovirus (CMV) is the most important of the 8 presently-recognized human herpes viruses in terms of its pathogenic potential in immunocompromised hosts. CMV is responsible for substantial morbidity after solid organ and bone marrow transplantation [1,2] and is the most common cause of ‘opportunistic’ viral disease in HIV/AIDS [3]. Prevention and treatment of CMV disease is clearly a high priority.

Four intravenous dosages of foscarnet given for 10 days were compared with no therapy in persons with AIDS who had asymptomatic cytomegalovirus (CMV) viremia. CMV viremia was quantitated by endpoint cell dilution microcultures, pp65 antigenemia assay, and measurement of CMV DNA in peripheral blood leukocytes by a quantitative-competitive PCR. Human immunodeficiency virus type 1 (HIV-1) viremia was quantitated by endpoint cell dilution microculture, serum p24 antigen assay, and PCR for HIV-1 RNA in plasma. Twenty-seven subjects who had received a median of 22 months of nucleoside antiretroviral therapy were enrolled. Twenty-two subjects received foscarnet, which was well tolerated and decreased the CMV burden, as reflected by all three indicator assays. During the 10 days of dosing, the level of CMV viremia, as measured by 50 percent tissue culture infective doses, decreased from 117.5 to 12.7 (P = 0.001), the amount of CMV DNA decreased from 20,328 copies to 622 copies per 150,000 leukocytes (P = 0.02), and the level of CMV pp65 antigenemia decreased from 14.9 to 1.6 positive peripheral blood mononuclear cells per 50,000 leukocytes (P = 0.008). A significant pharmacodynamic relationship was found between the peak foscarnet concentration and a decrease in the level of CMV antigenemia (P < 0.05). Foscarnet had no effect on quantitative HIV-1 microcultures during the 10 days of treatment, but the HIV-1 p24 antigen level in serum decreased significantly, from 454 to 305 pg/ml (P = 0.01). Also, a significant pharmacodynamic relationship was seen between plasma HIV-1 RNA concentrations and both peak foscarnet concentration (P < 0.01) and the area under the foscarnet time-concentration curve (P < 0.05). Reductions in the levels of CMV and HIV-1 viremia correlated quantitatively with systemic exposure to foscarnet, whereas control subjects actually experienced an increase in CMV and HIV-1 burdens. The dual antiviral activity of foscarnet shown in this trial encourages investigation of its use in combination with other antiretroviral therapies for persons with AIDS.

Cytomegalovirus (CMV) is the most important pathogen in the human herpes family for immunocompromised hosts. Recognition and monitoring of CMV disease has been improved due to development of four quantitative laboratory assays for CMV: antigenemia, polymerase chain reaction for CMV DNA, branched DNA assay, and the hybrid capture assay. Prevention of posttransplant CMV disease is possible with acyclovir or ganciclovir. Preemptive therapy, which is treatment begun when a laboratory marker signifies impending tissue-invasive CMV disease, offers a cost-effective alternative to prophylaxis, but could be initiated too late in cases of fulminant CMV. Future strategies for control of CMV disease include determining the threshold quantity of CMV (‘viral load’) capable of producing tissue damage, developing drugs with a better therapeutic index than the presently available compounds, and insights into CMV pathogenesis especially regarding tissue tropism of the virus, which varies according to the underlying basic disease of the host.

BackgroundAntiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and findings1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; pConclusionEFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial registrationwww.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.

In recent years, drug abuse has been identified as the most important factor in the spread of the AIDS epidemic (1). In the injection drug use (IDU) population, the sharing of contaminated injection equipment is a major means of transmitting HIV-1 (2, 3), the primary etiologic agent of AIDS. Several reports suggest that the course of HIV-1 infection is accelerated and that the mortality is increased in IDU patients (4–7), although results of some studies are contradictory (8, 9). As in other AIDS risk groups, multiple co-factors have been considered as possible contributors to the development of AIDS in HIV-1-infected drug abusers (10). A special cofactor postulated to be important in this patient group has been drug-induced immunologic disturbances (11, 12). This “co-factor hypothesis” is supported by a large body of evidence from clinical studies, animal models, and in vitro investigations (reviewed in 13–19).

A series of randomized, placebo-controlled, double-blind clinical trials conducted from 1980 to the present provide the basis for appropriate management of varicella-zoster virus (VZV) infections. Placebo recipients in these studies have also provided valuable natural history data on the clinical course of VZV infections. The protocols in toto have shown acyclovir (ACV) to be safe and effective for treatment of nearly all forms of acute VZV infection. A number of issues still need to be addressed, including appropriate dosage, importance of early initiation of therapy, cost-benefit ratio, and viral resistance. Considering the data in aggregate, the author recommends ACV treatment for all acute VZV infections in immunocompromised hosts; for acute herpes zoster infections in all adults; and for varicella in otherwise healthy adults and adolescents, and children who contract it from a sibling.

The most frequent complication of herpes zoster is postherpetic neuralgia, usually defined as chronic pain in the area of the exanthem that persists for at least a month after the skin lesions have healed. Several clinical studies of acyclovir showed a reduction in severity and duration of acute pain, but provided no definitive data for chronic pain. In order to determine if acyclovir therapy could reduce chronic pain, we reanalyzed data from the largest U.S. placebo-controlled treatment trial of 187 immunocompetent persons with herpes zoster. By considering pain as a continuum, we found that the median duration of pain in acyclovir recipients was 20 days vs. 62 days for their placebo counterparts (P = 0.02). Thus, acyclovir has been shown to reduce chronic zoster-associated pain. We also noted that the absence of pain at the onset of cutaneous herpes zoster did not preclude its later development.

Culture supernatants from lipopolysaccharide (LPS)-treated murine microglial cells were found to markedly induce the expression of human immunodeficiency virus (HIV)-1 in the chronically infected human promonocytic cell line U1 as detected by measurements of HIV-1 p24 antigen release into U1 culture supernatants. Antibody to tumor necrosis factor (TNF)-alpha had an inhibitory effect on the induction of virus by microglial cell supernatants. Also, treatment of microglia with pentoxifylline, an inhibitor of TNF-alpha production, resulted in suppressed amounts of TNF in the supernatants of LPS-treated microglia and in a reduced stimulatory capacity of these supernatants on HIV-1 expression in U1 cells. These findings support the concept that TNF-alpha production by glial cells plays a pathogenetic role in HIV-1-associated brain disease by promoting the expression of the virus in infected cells.

We compared the cytomegalovirus (CMV) antigenemia assay with shell vial cultures of polymorphonuclear leukocyte (PMNL)-enriched blood fractions for rapid diagnosis of CMV viremia. PMNL fractions of 280 blood specimens from 171 patients (170 solid-organ transplant recipients and 1 patient undergoing pretransplant evaluation) were inoculated in shell vial and conventional CMV cultures. A commercially available kit (CMV-vue kit; INCSTAR Corp.) was used for the CMV antigenemia assay, in which PMNL preparations were stained with monoclonal antibodies directed against the CMV protein pp65. Mixed-leukocyte blood fractions from the same blood specimens were inoculated in parallel shell vial and conventional cultures. CMV viremia (defined by the isolation of CMV in conventional cultures) was detected in 32 (13%) of 245 PMNL fractions included in the final analysis. Twenty-eight (87.5%) were also positive in the CMV antigenemia assay, whereas 22 (69%) were positive in shell vial cultures. Ten (4%) additional PMNL fractions positive only in the CMV antigenemia assay were from eight patients with active CMV infections (six patients), who had previous or subsequent episodes of CMV viremia (seven patients), or in whom CMV was isolated in cultures of simultaneously obtained mixed-leukocyte fractions (three patients). Overall, the CMV antigenemia assay was significantly more sensitive than shell vial cultures for detection of CMV in the PMNL fraction of blood leukocytes (P < 0.01, McNemar's test), and we recommend it as the method of choice for rapid diagnosis of CMV viremia.

A quantitative coculture assay is described for determining susceptibility of HIV-1 isolates to zidovudine and sCD4 (178)-PE40 (a 60 kDa hybrid protein consisting of the gp120 binding region of CD4 linked to the translocation and ADP-ribosylation regions of Pseudomonas aeruginosa exotoxin). The assay was relatively simple to perform and gave highly reproducible results often within three to five days. IC50 values of zidovudine for HIV-1 strains isolated from two AIDS patients and an asymptomatic seropositive individual were in the range 0.001-0.002 mumol. Isolates obtained after six months of zidovudine treatment had zidovudine IC50 values of 0.01-0.5 mumol. All isolates were equally sensitive to sCD4 (178)-PE40 (IC50 1-5 micrograms/ml). HIV-1 activation in the chronically infected cell line U-1 was inhibited by sCD4 (178)-PE40 but not by zidovudine.

A study was conducted to compare our standard culture with a new microculture procedure for isolation of human immunodeficiency virus type 1 (HIV-1) from blood leukocytes. A total of 137 blood specimens from 102 HIV-1 antibody-positive individuals (52 were asymptomatic, 31 were symptomatic, and 19 had AIDS) were cultured in a microculture system in which 10(6) of the patients' peripheral blood mononuclear cells (PBMC) were cocultured with 10(6) phytohemagglutinin (PHA)-stimulated PBMC from an HIV-1 antibody-negative blood donor in 1.2 ml of culture medium. Results were compared with those of a historical control group of 139 standard HIV-1 cultures from 108 HIV-1 antibody-positive subjects (58 were asymptomatic, 36 were symptomatic, and 14 had AIDS). For standard cultures, 10 x 10(6) of the patients' PBMC were cocultured with 5 x 10(6) PHA-stimulated PBMC from an HIV-1 antibody-negative blood donor in 15 ml of culture medium. HIV-1 was isolated in 128 (93%) microcultures and 133 (96%) standard cultures. Both methods identified more than 75% of the positive cultures within 7 days and 100% of the positive cultures within 14 days. The isolation rates for HIV-1 in microcultures compared with standard cultures were 91 versus 93% (specimens from asymptomatic individuals), 93 versus 96% (specimens from symptomatic individuals), and 97 versus 100% (specimens from patients with AIDS). The median time to positivity for both culture methods was 7 days, and this correlated significantly with symptoms and CD4+ cell counts. The microculture method is a sensitive and less expensive system for isolation of HIV-1 from PBMC of HIV-1 antibody-positive individuals, and we recommend it as the culture method of choice, especially for children and patients with AIDS and severe anemia or leukopenia whose blood volume is an important consideration.

Five recipients of solid-organ transplants who were infected with human immunodeficiency virus (HIV) were studied at the University of Minnesota, and our data were compared with data from 83 reported cases of HIV-infected recipients of solid organs from other centers. Sixty-six of the 88 patients were seronegative for HIV before transplantation and received organs or transfusions of blood from individuals who were seropositive for HIV. Seven patients (four recipients of kidney transplants and three recipients of liver transplants) received transplants after routine screening for HIV. Twenty-five (28%) of the 88 patients developed AIDS, and 20 (80%) of these 25 patients died of AIDS-related complications a mean of 37 months after transplantation. Another nine patients (10%) had other HIV-related diseases. The mean time of progression to AIDS was 27.5 months among all patients with AIDS. For patients who were seronegative for HIV at the time of transplantation, the mean time of progression to AIDS was 32 months, whereas patients seropositive before transplantation developed AIDS within 17 months. Shortly after transplantation, eleven (17%) of the patients who were initially seronegative experienced a febrile syndrome attributed to HIV. Ten patients, including eight recipients of kidney transplants and two recipients of liver transplants, maintained normal allograft function despite low-dose immunosuppressive therapy.

To determine the pharmacokinetic parameters of acyclovir disposition in neonates with renal dysfunction.Prospective sequential open enrollment of neonates with presumed herpes group virus infections.Neonatal intensive care units in the greater Minneapolis-St. Paul metropolitan area.Sixteen neonates with gestational ages between 27 and 40 weeks (median 38 weeks) were given acyclovir between days 1 and 56 of life to treat presumed herpes virus infections. Six infants were critically ill with multisystem disease, five infants had hepatic failure and underwent blood exchange transfusion, and five infants had renal failure. A mean of four (range 1 to 19) serum acyclovir concentrations per patient were measured by radioimmunoassay. Pharmacokinetic parameters were calculated from acyclovir concentrations in 46 samples from 16 patients.The pharmacokinetic disposition of acyclovir was described as a two-compartment model. Although the ranges for acyclovir clearance and terminal elimination (t 1/2 beta) were wide, a statistically significant relationship was demonstrated between clearance and beta versus serum creatinine concentration. The average t 1/2 beta for infants with serum creatinine level less than 1 mg/dl (88 mumol/L) was 5.0 hours, and 15.6 hours for those with serum creatinine level greater than 1 mg/dl.Neonates with hepatic or renal dysfunction or young premature infants accumulate acyclovir when dosed without adjustment for organ dysfunction. Measurement of serum creatinine or creatinine clearance can be useful in the dosing of acyclovir in neonates.

Remarkably, interest in the pathogenetic effect of opiates on the course of bacterial infection can be traced to the late 19th century (1). Although the infectious disease complications of intravenous (IV) drug use were clearly recognized by the mid-20th century (2,3), serious attention to the mechanisms whereby opiates might participate in the pathogenesis of infectious disease did not surface until the past decade. Contemporary interest in this area of research has been rekindled, in no small way, by the epidemic of acquired immunodeficiency syndrome (AIDS) and realization that IV drug users are a critically important high risk group in the spread of this devastating infection (4).

Because morphine has been shown to alter the function of human T lymphocytes and monocytes, we postulated that morphine would promote the growth of HIV-1 in these cells. To test this hypothesis, a coculture assay was used consisting of phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMC) from normal donors and PBMC which had been infected with a viral isolate from an asymptomatic patient, HIV-1AT. The growth of HIV-1AT, as reflected by the concentration of p24 antigen in coculture supernatants, was markedly increased in cocultures that contained morphine. A bell-shaped dose-response curve was observed with three- to fourfold increased growth at a morphine concentration of 10(-12) M. Augmentation of HIV-1AT growth by morphine required an interaction with the PHA-activated donor PBMC. Furthermore, potentiation of HIV-1AT growth by morphine was stereospecific and was antagonized by naloxone and beta-funaltrexamine indicating involvement of an opiate receptor mechanism. These findings provide an additional explanation of how opiates could act as a cofactor in the pathogenesis of HIV-1 in intravenous drug users.

Study objective: To determine whether acyclovir administered orally affects the duration and severity of varicella in otherwise normal children. Design: Randomized, placebo-controlled, double-blind trial. Setting: Patients' residence and university hospital clinic. Patients: One hundred five children between 5 and 16 years of age with laboratory-confirmed varicella entered the study. Of the 102 who were included in the final analysis, 50 received acyclovir and 52 received placebo. Interventions: Placebo or acyclovir was given orally four times daily, for 5 to 7 days. The acyclovir dose was adjusted as follows: 5 to 7 years of age, 20 mg/kg; 7 to 12 years, 15 mg/kg; and 12 to 16 years, 10 mg/kg. Measurements and main results: Acyclovir recipients, compared with the placebo group, defervesced sooner (median, 1 day vs 2 days; p =0.001), experienced onset of cutaneous healing sooner, as reflected by a decrease in number of lesions (median, 3 days vs 2 days; p =0.002), and had fewer skin lesions (median, 500 vs 336; p =0.02). Acyclovir did not significantly change the rate of complications of varicella (10% in the acyclovir group vs 13.5% among placebo subjects). Adverse drug effects were not observed. Acyclovir recipients had lower geometric mean serum antibody titers to varicella-zoster virus than their placebo counterparts 4 weeks after the onset of illness, but antibody titers in both groups were similar 1 year later. Conclusions: These results provide evidence that acyclovir is useful and well tolerated for treatment of varicella in otherwise healthy children.

Study objective To determine the sensitivity of herpes simplex virus isolates to acyclovir and the importance of resistant isolates in hospitalized patients. Design Retrospective incidence cohort study. Setting All herpes simplex virus isolates cultured over 1 year from patients followed at a tertiary care center. Patients Consecutive herpes simplex virus isolates were collected from 207 patients, including immunocompetent patients, patients with malignancy, neonates, bone marrow and organ transplant recipients, and patients seropositive for human immunodeficiency virus. Measurements and main results A rapid nucleic acid hybridization method was used to assess susceptibility to acyclovir. Acyclovir-resistant herpes simplex viruses were recovered from 7 of 148 immunocompromised patients (4.7%) but from none of 59 immunocompetent hosts. Clinical disease was found in all 7 patients with resistant herpes simplex virus and was more severe in pediatric patients. All resistant isolates were from acyclovir-treated patients and had absent or altered thymidine kinase activity by plaque autoradiography. Conclusion Herpes simplex virus resistant to acyclovir arises relatively frequently in immunocompromised patients and may cause serious disease. Rapid detection of resistance permits antiviral therapy to be individualized. Antiviral susceptibility testing to monitor viral resistance should be encouraged, especially in tertiary care settings.

To determine whether apparently healthy persons who have had repeatedly reactive enzyme immunoassays and an indeterminate Western blot assay for antibody to the human immunodeficiency virus type 1 (HIV-1) are infected with HIV-1 or HIV-2, we studied 99 such volunteer blood donors in a low-risk area of the country. The subjects were interviewed about HIV risk factors. Coded blood specimens were tested again for HIV-1 antibody (by two different enzyme immunoassays, a Western blot assay and a radioimmunoprecipitation assay) and for HIV-2 antibody by enzyme immunoassay, for HIV-1 by the serum antigen test, for HIV-1 by culture, for human T-cell leukemia virus Type I or II antibody by enzyme immunoassay, and for sequences of HIV DNA by the polymerase chain reaction. Of the 99 blood donors, 98 reported no risk factors for HIV-1 infection; 1 donor had used intravenous drugs. After a median of 14 months (range, 1 to 30) from the time of the initial test, 65 subjects (66 percent) were still repeatedly reactive for HIV-1 antibody on at least one immunoassay. In 91 subjects (92 percent) the Western blot results were still indeterminate, whereas in 8 they were negative. No donor met the criteria for a positive Western blot assay for HIV-1, and none had evidence of HIV-1 or HIV-2 infection on culture or by any other test. We conclude that persons at low risk for HIV infection who have persistent indeterminate HIV-1 Western blots are rarely if ever infected with HIV-1 or HIV-2.

The CMV-vue antigenemia assay was evaluated by using mixed-leukocyte (ML) blood fractions. Of 234 ML fractions studied, 32 (14%), 23 (10%), and 20 (8.5%) were positive in the CMV-vue assay and conventional and shell vial cultures, respectively. The CMV-vue assay was more sensitive than shell vial cultures for rapid detection of cytomegalovirus. ML fractions are appropriate specimens for the cytomegalovirus antigenemia assay.

Acyclovir has been shown to shorten the course of chickenpox in otherwise healthy children by 25–33% according to three placebo controlled trials in the United States.1 2 3 All clinical events monitored were favourably affected by acyclovir, with the most important differences being reductions in degree and duration of fever, constitutional illness score, and number of residual lesions present at the 28 day follow up examination. No appreciable adverse events were reported. These studies also identified two subsets of patients particularly suitable for acyclovir therapy: adolescents and children who acquired chickenpox from a family member. The main controversy regarding use of acyclovir is not its clinical usefulness, which is scientifically incontestable, but whether treatment is needed for a relatively benign disease. To fully appreciate the impact of acyclovir on chickenpox you need to make daily visits to treated subjects and controls, as our research nurse clinicians …

Objective. —To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry CD4+cell count. Design and Interventions. —Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo. Setting. —University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019. Patients. —A total of 1565 asymptomatic HIV-infected subjects with entry CD4+cell counts less than 0.50×109/L (500/μL). Main Outcome Measure. —Time to progression to AIDS or death. Results. —During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (P=.008,.004,.007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (P=.002,.08,.04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4+cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo. Conclusions. —Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4+cell counts less than 0.30×109/L (300/μL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored. (JAMA. 1994;272:437-442)

Cytomegalovirus is the major cause of infection after solid organ or bone marrow transplantation (1, 2). Cytomegalovirus is also a problem for other groups of patients, especially neonates and pers...

To the Editor.— Recently, the issue of risk for human immunodeficiency virus (HIV) infection among health care workers has received heightened attention in both the lay and medical press, with an underlying theme of this renewed concern being a distrust of the current data ( Newsweek . November 20, 1989:82-83). 1 Current Centers for Disease Control guidelines are predicated on the observed HIV seroconversion rate of 0.42% seen in studies of health care workers who suffer documented work-site exposure to HIV. 2,3 Health care workers with exposure to body fluids of HIV-infected persons are frequently traumatized emotionally and may be advised to begin prophylaxis with zidovudine. 4 Data such as those reported by Imagawa et al 5 and Haseltine 6 raise the possibility that the false-negative rate of HIV serological testing might be significant in certain populations. Since the Centers for Disease Control recommendations regarding HIV exposure of health care workers were

One-hundred thirty-two renal transplant recipients were systematically screened for viral infections and the findings correlated with the clinical course. One-hundred ten patients showed evidence of infection with herpesviruses and 89 patients showed laboratory evidence of infection with cytomegalovirus (CMV) uncomplicated by bacterial infections or technical complications. Patients without viral infections were usually asymptomatic. After recovery and development of anti-viral antibodies, most patients were asymptomatic despite the persistence of viral excretion in the urine. In contrast, the onset of viral infections were almost always accompanied by a significant clinical illness characterized by fever, leukopenia, and renal malfunction. Of 89 patients with cytomegalovirus infections, 83 survived at least three months. In these patients, the fever appeared to be self-limited and resolution of the fever was accompanied by increases in anti-CMV antibody. Renal biopsies demonstrated typical rejection reactions in all the biopsied patients and renal malfunction usually responded to anti-rejection treatment. Six of the 89 patients with CMV infections died within a month of viral isolation. These patients could be distinguished from those who recovered by a decreased or absent antibody response to the virus, suppressed lymphocyte responses to mitogen in autochthonous blood, and absent histologic evidence of rejection in the renal allografts. Thus, two paradoxical responses to CMV infections are seen in transplant patients: In the relatively immunocompetent patient, the infection is associated with renal allograft rejection, a prompt antibody response to the virus, and recovery. The severely immunosuppressed patient cannot make an antibody response, does not exhibit allograft rejection as a cause of renal malfunction, he may be further immunosuppressed by the viral infection, and is susceptible to sequential opportunistic infections leading to death.

4 young children with active cytomegalovirus (C.M.V.) infection were found, by an in-vitro lymphocyte-proliferation assay, to have a C.M.V.-specific cell-mediated immune defect. These children had antibodies to C.M.V. and were actively shedding C.M.V. in the urine when studied. Their general cellular immune responses were intact, with normal numbers of T lymphocytes and normal in-vitro responses to mitogens and at least one antigen. 3 of the 4 mothers studied shortly after delivery had decreased cell-mediated immunity to C.M.V. These findings suggest that an antigen-specific immune defect facilitates transmission of virus from mother to infant and permits persistence of viral replication in the offspring.

31 adults took part in a randomised, placebo-controlled, double-blind trial of intravenous acyclovir therapy (500 mg/m 2 intravenously 3 times daily for 5 days) for acute herpes zoster. Acyclovir reduced pain, decreased erythema, prevented the formation of new lesions, and healed skin faster than did placebo. The duration of viral shedding was also significantly shorter in acyclovir recipients (2 days versus 5 days). However, 6 (35%) of 17 acyclovir recipients had recurrence of pain after the drug was discontinued, and acyclovir did not appear to affect post-herpetic neuralgia. Acyclovir therapy was associated with a transient rise in serum creatinine levels, and may have been related to nausea and vomiting. Intravenous acyclovir was effective therapy for acute herpes zoster but the ideal treatment regimen might be a lower daily dose given for a longer period.

Among 181 patients undergoing allogeneic bone marrow transplantation over a five-year period (1978 through 1982), cytomegalovirus (CMV) infection was a frequent and often lethal complication. Recipient pretransplant serology was the most important predictor of posttransplant CMV infection. CMV infection occurred in 26/137 seronegative recipients and in 28/44 seropositive recipients (P less than .001). Among patients who developed CMV infection, the time to infection was identical in seronegative and seropositive patients (median, 71 days post transplant). Bone marrow donor CMV serology did not significantly influence CMV infection rate. CMV infection was strongly associated with acute graft-v-host disease (AGVHD), occurring in 34/81 patients with AGVHD and 20/100 without GVHD (P less than .001). AGVHD preceded CMV infection by 33.7 days (mean) in patients developing both complications. Patients who developed CMV infections had also received more cellular blood products post transplant. These data suggest that CMV infection may occur through reactivation of latent virus (in seropositive recipients) or through exogenous exposure, possibly through transfused blood products, but that duration of immunoincompetence may be more critical than route of exposure in timing of clinically evident CMV infection. Prophylaxis tailored to the likely infectious source and more effective GVHD prevention both may be critical in preventing CMV infection after bone marrow transplantation.