W. David Hardy

A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021.

BACKGROUND Pneumocystis carinii pneumonia (PCP) continues to be the most common index diagnosis in the acquired immunodeficiency syndrome (AIDS), but it is not clear which of several available agents is the most effective in preventing a recurrence of PCP. METHODS We conducted a comparative, open-label trial in 310 adults with AIDS who had recently recovered from an initial episode of PCP and had no treatment-limiting toxic effects of trimethoprim-sulfamethoxazole or pentamidine. All the patients were treated with zidovudine and were randomly assigned to receive either 800 mg of sulfamethoxazole and 160 mg of trimethoprim once daily or 300 mg of aerosolized pentamidine administered every four weeks by jet nebulizer. The participants were followed for a median of 17.4 months. RESULTS In the trimethoprim-sulfamethoxazole group (n = 154) there were 14 recurrences of PCP, as compared with 36 recurrences (including 1 extrapulmonary recurrence) in the aerosolized-pentamidine group (n = 156). The estimated recurrence rates at 18 months were 11.4 percent with trimethoprim-sulfamethoxazole and 27.6 percent with pentamidine (P < 0.001). The risk of a recurrence (adjusted for initial CD4 cell count) was 3.25 times higher in the pentamidine group (P < 0.001, 95 percent confidence interval, 1.72 to 6.16). There were no significant differences between the groups in survival or in hematologic or hepatic toxicity. Crossovers from trimethoprim-sulfamethoxazole to aerosolized pentamidine were more common than the reverse (27 vs. 4 percent), partly because of the study protocols for the management of leukopenia. There were 19 serious bacterial infections in the trimethoprim-sulfamethoxazole group and 38 in the pentamidine group. The time to a first bacterial infection was significantly greater for those assigned to trimethoprim-sulfamethoxazole (P = 0.017). CONCLUSIONS In patients with AIDS who are receiving zidovudine, trimethoprim-sulfamethoxazole is more effective than aerosolized pentamidine in conventional doses for the prevention of recurrent pneumocystis infection.

A Comparison of Immediate with Deferred Zidovudine Therapy for Asymptomatic HIV-Infected Adults with CD4 Cell Counts of 500 or More per Cubic Millimeter

BACKGROUND The clinical benefits of zidovudine remain unproved in patients with asymptomatic human immunodeficiency virus (HIV) infection when CD4 cell counts exceed 500 per cubic millimeter. We compared zidovudine therapy given immediately with deferred therapy in such subjects. METHODS Beginning in 1987, subjects with asymptomatic HIV infection and 500 or more CD4 cells per cubic millimeter were randomly assigned to receive placebo or zidovudine (either 500 or 1500 mg per day, starting immediately). In 1989, the study was modified so that open-label treatment with 500 mg of zidovudine per day (deferred therapy) was offered when CD4 cell counts fell below 500 per cubic millimeter. The study end points included overall survival, survival free of the acquired immunodeficiency syndrome (AIDS), toxic effects, and changes in CD4 cell counts. RESULTS There were 1637 subjects who could be evaluated: 547 in the deferred-therapy group, 549 in the group receiving 500 mg of zidovudine immediately, and 541 in the 1500-mg group. The subjects were followed for up to 6.5 years (group medians, 4.8, 4.8, and 4.9, respectively). There was no significant difference in AIDS-free survival in the deferred-therapy group as compared with the low-dose or high-dose groups (81 cases of progression to AIDS or death vs. 81 and 74, respectively; P = 0.95 and P = 0.13) or in overall survival (51 deaths vs. 47 and 46; P = 0.25 and P = 0.16). The decline in CD4 cells was slower in both immediate-therapy groups than in the deferred-therapy group (P < 0.001 for both). Adverse effects were uncommon, and before the study modification their incidence was similar among the treatment groups, but severe anemia and granulocytopenia were more frequent in the 1500-mg group than in the deferred-therapy group (P < 0.001). CONCLUSIONS In asymptomatic, HIV-infected adults with 500 or more CD4 cells per cubic millimeter, treatment with zidovudine slows the decline in the CD4 cell count but does not significantly prolong either AIDS-free or overall survival. These results do not encourage the routine use of zidovudine monotherapy in this population.

Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.

Two-Year Safety and Virologic Efficacy of Maraviroc in Treatment-Experienced Patients With CCR5-Tropic HIV-1 Infection: 96-Week Combined Analysis of MOTIVATE 1 and 2

Background:Maraviroc, the first approved CCR5 antagonist, demonstrated 48-week safety and virologic efficacy in CCR5-tropic HIV-infected, treatment-experienced patients; however, critical longer-term safety and durability of responses are unknown. Methods:Two-year follow-up of 2 prospective, randomized, blinded studies of maraviroc once daily or twice daily, or placebo in treatment-experienced patients with R5-tropic HIV-1 receiving an optimized background regimen. Unblinding occurred after the week-48 visit of the last enrolled patient. Safety and virologic parameters were assessed through week 96. Results:One thousand forty-nine patients were randomized and received study drugs. HIV-1 RNA was <50 copies per milliliter at week 96 in 39% and 41% of patients receiving maraviroc every day or twice a day, respectively. Among patients with HIV-1 RNA <50 copies per milliliter at week 48, 81% and 87% of patients receiving maraviroc every day or twice a day, respectively, maintained this response at week 96. At week 96, median CD4+ T-cell counts increased from baseline by 89 and 113 cells per cubic millimeter with maraviroc every day and twice a day, respectively. Exposure-adjusted rates of adverse events were similar with maraviroc or placebo. No new or unexpected events were observed after week 48. Conclusions:Maraviroc-containing antiretroviral regimens maintained durable responses in treatment-experienced patients with R5 HIV-1 through 96 weeks of treatment with a safety profile similar to placebo.

Immune changes in HIV-1 infection: Significant correlations and differences in serum markers and lymphoid phenotypic antigens☆

Human immunodeficiency virus type 1(HIV-1) induces extensive immune cell alterations which can be detected by changes both in serum levels of soluble immune activation products and in several lymphoid phenotypic markers. The current studies were conducted in 70 HIV-1 seropositive subjects to determine whether changes among four important serum immune activation markers (neopterin, beta-2 microglobulin, soluble CD8, and soluble IL-2 receptor) and seven lymphoid phenotypic markers (CD38, HLA-DR, CD57, CD11b, CD45RA, leu8, and CD71) reflect similar or disparate aspects of immune pathology. On the basis of correlation coefficient calculation, four groups of related markers (Fig. 1) were identified: Group A, sIL-2R was related to group B where serum neopterin, beta 2M, sCD8 levels, and lymphocyte CD38 antigen expression correlated closely. Loss of CD45RA or Leu 8 antigens in group C correlated with group B and D markers increase. HLA-D in group D was a more distantly related immune activation marker. Phenotypic markers CD57, CD11b, and CD71 did not correlate with the immune activation processes reflected by the serum and phenotypic marker groups A-D. Correlations between serum and certain lymphoid phenotypic markers were generally stronger later in HIV-1 infection when CD4 levels were less than 500/mm3. This study provides information for selecting markers for investigating immune changes in HIV-1 infection and immune-related diseases. Many serum and lymphoid phenotypic markers reflect related aspects of immune dysregulation. However, some markers can indicate different aspects of disease.

Foscarnet treatment of acyclovir-resistant herpes simplex virus infection in patients with acquired immunodeficiency syndrome: Preliminary results of a controlled, randomized, regimen-comparative trial

Herpes simplex virus (HSV) resistant to acyclovir can produce persistent mucocutaneous ulcerative disease in patients with the acquired immunodeficiency syndrome (AIDS). The incidence of clinically significant acyclovir-resistant HSV disease has dramatically increased since the advent of the AIDS epidemic. The primary mechanism of acyclovir resistance is induction of viral mutants defective or deficient in thymidine kinase, the viral-encoded enzyme, which catalyzes the rate-limiting step in the triphosphorylation of acyclovir to its active form (acyclovir triphosphate). Foscarnet, a potent inhibitor of HSV DNA polymerase, does not require phosphorylation for its antiviral activity. This compound has been found to be effective in the treatment of acyclovir-resistant HSV infection by several investigators. A recently completed dose-comparative trial of foscarnet in AIDS patients with acyclovir-resistant HSV has confirmed the safety and efficacy of two doses of foscarnet (40 mg/kg every 8 or 12 hours) in the treatment of this disease, as well as providing preliminary evidence supporting the utility of foscarnet maintenance therapy in delaying recurrence of HSV lesions. Analysis of data from this trial has been complicated by the tremendous variability in lesion size at initiation of therapy, making any statistically valid comparison of treatment regimens almost impossible. A further trial in AIDS patients with acyclovir-resistant HSV infection has been designed to define better the role of foscarnet maintenance and, in light of evidence that a significant proportion of initial recurrences are due to acyclovir-sensitive HSV, to examine the potential utility of acyclovir maintenance following foscarnet induction therapy.

Fatal, disseminated pneumocystosis in a patient with acquired immunodeficiency syndrome receiving prophylactic aerosolized pentamidine

On rapporte un cas de pneumocystose disseminee mortelle chez un homme atteint de SIDA, sans signes cliniques de pneumonie qui avait recu un traitement prolonge par la pentamidine en aerosol a titre preventif

High dose oral ganciclovir treatment for cytomegalovirus retinitis.

BACKGROUND The oral formulation of ganciclovir is approved at a dose of 3.0 g/day for maintenance treatment of cytomegalovirus (CMV) retinitis following an initial induction course of intravenous (IV) anti-CMV therapy. Median time to progression of CMV retinitis is 12-20 days shorter with oral compared to IV ganciclovir maintenance, likely due to the limited oral bioavailability of ganciclovir. OBJECTIVES We hypothesized that higher systemic drug exposures associated with increased doses of oral ganciclovir would be associated with increased efficacy. STUDY DESIGN Maintenance treatment of CMV retinitis with higher than standard doses of oral ganciclovir (>3.0 g/day) was studied in 281 AIDS patients with previously treated, stable retinitis randomized to 3.0, 4.5 or 6.0 g/day oral, or 5 m/kg/day IV ganciclovir. Graders unaware of treatment assignments determined retinitis progression using fundus photographs. Vision, other ophthalmic measures and safety were assessed open-label. RESULTS Median days to photographic progression were 41, 50, 57 and 70, respectively (P=0.052; 3.0 g vs. IV). Hazard ratios for progression relative to IV were 1.66, 1.28 and 1.19 (P=0.016 for 3.0 g). NONMEM-modeled estimates of average serum ganciclovir concentration area under the curve (AUC(0-24)) correlated best with time to progression (P=0.0019). Six grams per day oral ganciclovir was most similar in efficacy to IV, although broad confidence intervals prevented a conclusive comparison. Patients receiving oral ganciclovir had a lower frequency of sepsis and IV catheter events. CONCLUSIONS This study suggests that the efficacy of ganciclovir for the maintenance treatment of CMV retinitis improves with increasing total drug exposure (measured as average serum concentration AUC(0-24)). All four regimens of ganciclovir were reasonably well tolerated, with safety profiles similar to what has been reported in prior work.

Treatment of refractory oral candidiasis with fluconazole. A case report.

Abstract We describe a patient with the acquired immunodeficiency syndrome who had persistent oral esophageal pseudomembranous candidiasis clinically refractory to nystatin, clotrimazole, and ketaconazole. In vitro resistance to clotrimazole was demonstrated as well. The patient received temporary relief with intravenous amphotericin B therapy, but this was associated with serious adverse effects, including transfusion-requiring anemia, azotemia, and severe thrombophlebitis. Despite two courses of intravenous amphotericin B therapy, the patients highly symptomatic, recurrent oral and esophageal candidiasis continued. The patient was then treated with fluconazole and obtained immediate relief without associated adverse effects.

Screening of herbal extracts against multi-drug resistant Acinetobacter baumannii.

Antibiotic resistance is increasing resulting in a decreasing number of fully active antimicrobial agents available to treat infections with multi‐drug resistant (MDR) bacteria. Herbal medicines may offer alternative treatment options. A direct inoculation method simulating the standard disc diffusion assay was developed to determine in vitro antimicrobial activity of sixty herbal extracts against MDR‐Acinetobacter baumannii (A. baumannii). Eighteen herbal extracts inhibited MDR‐A. baumannii on agar plates, although the magnitude and quality of bacterial inhibition differed considerably among the antibacterial herbal extracts. Next, minimal inhibitory concentration (MIC) of these antibacterial herbal extracts was calculated using a broth microdilution assay. For most herbal extracts, the larger the zone of inhibition on agar plates, the lower the MIC. In general, hetero‐resistance on agar plates correlated with higher MIC. The skip well phenomenon was seen with two herbal extracts. In conclusion, 30% of the screened herbal extracts demonstrated in vitro antibacterial activity against MDR‐A. baumannii using similar rigorous testing methods as those commonly employed for assessing antimicrobial activity of synthetic antibacterial agents. Characterization of a specific compound conferring this antibacterial activity of the herbal extracts may help to identify novel antimicrobial agents active against highly resistant bacteria. Copyright