Plasma leptin concentration increases early during highly active antiretroviral therapy for acquired immunodeficiency syndrome, independent of body weight.

Leptin, the protein product of the obese gene (ob), is secreted by adipocytes. Circulating leptin levels correlate with fat mass in humans, including individuals infected with HIV. Leptin serves as an adipostatic hormone, a permissive factor for reproduction and a modulator of immune function. Leptin is a cytokine, and has been demonstrated to enhance CD4 cell proliferation and IL-2 secretion from CD4 cells in vitro. The role of leptin in HIV-positive patients treated with highly active antiretroviral therapy (HAART) has not been well defined. We haveevaluated leptin levels in HIV-infected individualsduringthe early phase of HAART. We measured plasma leptin levels in 15 antiretroviral-naive HIV positive patients at baseline and after 1 and 4 weeks of HAART. After the first week of therapy, mean leptin level and CD4 count were increased compared to baseline, 6.0 vs 7.2 ng/ml (p = 0.004) and 377 vs 432 cells/ul (p = 0.014), respectively. In contrast, mean body mass index (BMI) remained unchanged 27.0 vs 26.8 kg/m2 (p < 0.08). After four weeks of therapy, leptin and BMI values were unchanged compared to baseline, 6.0 vs 5.9 (p < 0.4) and 27.0 vs 26.9 (p < 0.5), respectively, whereas CD4 count continued to increase to 491 cells/ul (p < 0.012 compared to baseline). These data demonstrate an early transient increase in plasma leptin levels in HIV positive patients initiated on HAART, despite a lack of change in BMI. It is unclear if the transient increase in leptin is related to its role as a cytokine, a metabolic regulator, or reproductive factor.

Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature.

BACKGROUND: A recent resurgence of primary and secondary syphilis has been observed in certain population groups, particularly among persons infected with human immunodeficiency virus (HIV). Liver involvement is an infrequently recognized complication of early syphilis, with no previous reports among HIV-infected patients. METHODS: We describe 7 cases of syphilitic hepatitis in HIV-positive individuals and review the literature. RESULTS: At our institutions, all patients presented with a rash consistent with secondary syphilis. Each case was characterized by a conspicuous increase in serum alkaline phosphatase level (mean level +/- standard deviation, 905 +/- 523.6 IU/L) and milder elevations in serum transaminase levels. The mean CD4+ absolute T cell count was 317 cells/mm3, and the median rapid plasma reagin (RPR) titer was 1 : 128. There was a significant correlation between higher CD4+ cell counts and the RPR titers (R=0.93; P=.002). Symptomatic resolution and biochemical improvement, particularly a significant decrease in serum alkaline phosphatase levels (P=.02), occurred following antibiotic therapy. CONCLUSIONS: Hepatic dysfunction is not uncommon in HIV-infected persons and is attributable to multiple causes. In the appropriate clinical setting, syphilitic hepatitis is an easily diagnosed and reversible etiology of liver dysfunction. The recognition of this entity will prevent unnecessary evaluation of abnormal liver enzyme levels in HIV-positive patients.

Care of HIV-infected pregnant women in maternal-fetal medicine programs.

OBJECTIVE: To survey the evolution over the past decade of attitudes and practices of obstetricians in maternal-fetal medicine fellowship programs regarding the management of human immunodeficiency virus (HIV)-infected pregnant women. METHODS: Directors of all 65 approved maternal-fetal medicine training programs were sent questionnaires, responses to which were to reflect the consensus among members of their faculties. Programs were stratified based upon the number of HIV-infected pregnant patients cared for in the previous year. RESULTS: Responses reflect experience with over 1000 infected pregnant women per year, nearly one-quarter with advanced disease. Combination antiretroviral therapy was prescribed by all respondents, universally in the 2nd and 3rd trimesters. A three-drug regimen (often containing a protease inhibitor) was used more often by those who treated at least 20 HIV-infected pregnant patients per year than by those programs seeing a lower number of patients (80 vs 59%). Despite the known and unknown risks of the use of antiretrovirals during pregnancy, only half of all responding programs report adverse events to the Antiretroviral Pregnancy Registry; reporting was more common among the institutions seeing a higher number of patients (61 vs 45%). Seventy-eight percent of higher volume programs enroll their patients in clinical studies, usually multicenter, versus 35% of lower volume programs. CONCLUSIONS: Care for HIV+ pregnant women has dramatically changed over the past decade. Antiretroviral therapy is now universally prescribed by physicians involved in maternal-fetal medicine training programs. Given limited experience with these agents in the setting of pregnancy, it is essential for maternal-fetal medicine practitioners to actively report on adverse events and participate in clinical trials.

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II).

OBJECTIVE: Comparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DESIGN: Randomized, open-label. SETTING: Fourteen HIV Clinical Research Centers. PATIENTS: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts > or = 200 x 10(6)/l and plasma HIV-1 RNA levels > or = 10,000 copies/ml. INTERVENTIONS: Stavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. MAIN OUTCOME MEASURES: The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and < or = 50 copies/ml and changes in CD4 cell counts were compared. RESULTS: In an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were < or = 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P= 0.001). The occurrence of serious adverse events was not significantly different between arms. CONCLUSION: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.

Alterations in serum levels of lipids and lipoproteins with indinavir therapy for human immunodeficiency virus-infected patients.

Alterations in lipid metabolism have been associated with the use of protease inhibitors. Sequential lipid analyses were performed on serum samples from human immunodeficiency virus-infected antiretroviral-naive patients who received indinavir in combination with two nucleoside reverse transcriptase inhibitors. Serum levels of cholesterol, triglycerides, high-density lipoproteins (HDLs), and low-density lipoproteins (LDLs) were measured at baseline and at periodic intervals. After 48 weeks of indinavir therapy, mean serum levels +/- SD rose as follows: cholesterol, from 167.2 +/- 36.0 to 206.3 +/- 32.4 mg/dL (P < .0005); triglycerides, from 110.4 +/- 47.5 to 158.4 +/- 72.5 mg/dL (P < .0101); and LDLs, from 106.6 +/- 35.1 to 136.1 +/- 31.6 mg/dL (P = .0029). There was no significant change in the serum HDL fraction. Mean serum lipoprotein (a) levels +/- SD rose from 6.5 +/- 1.4 to 9.6 +/- 2.0 mg/dL after 30 weeks (P = .0695). Potential mechanisms for the noted increases include alterations in serum lipoprotein lipase activity or changes in hepatic lipid metabolism. The clinical significance of these changes remains to be determined.

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

A dose response study of hepatitis A vaccine in healthy adults who are > or = 30 years old and weigh > or = 77 kg.

The dose response relationship of 25-, 50-, and 100-U doses of an inactivated hepatitis A vaccine was examined in 358-seronegative volunteers in a 2-dose schedule. The 50-U and 100-U groups had statistically significantly higher seroconversion rates than the 25-U group at weeks 2, 4, 8, and 24. Seroconversion was statistically significantly greater for the 100-U compared with the 25- and 50-U doses 2 weeks after the first injection but was not significantly different by 4 weeks after the first injection in the 50- and 100-U dose groups. After 2 injections, all subjects in all groups seroconverted. The vaccine was well tolerated at all dosage levels.

Mutation in region III of the DNA polymerase gene conferring foscarnet resistance in cytomegalovirus isolates from 3 subjects receiving prolonged antiviral therapy.

Three human immunodeficiency virus-infected subjects with progressive cytomegalovirus (CMV) retinitis despite prolonged antiviral therapy had buffy coat CMV isolates that were resistant to both ganciclovir and foscarnet. Genetic analysis of the resistant isolates showed that each contained a well-known ganciclovir resistance mutation in the viral UL97 phosphotransferase sequence, as well as a mutation (Ala to Val at codon 809, V809) in conserved region III of the DNA polymerase (Pol) sequence. A segment of the Pol sequence from one of the clinical isolates was transferred to CMV laboratory strain AD169 by homologous recombination. The recombinant virus containing V809 showed 6.3-fold increased foscarnet resistance and 2.6-fold increased ganciclovir resistance. Occurrence of the V809 mutation in 3 unrelated cases suggests that it is a clinically significant viral genetic marker for foscarnet resistance and decreased susceptibility to ganciclovir.

A phase II/III trial of antimicrobial therapy with or without amikacin in the treatment of disseminated Mycobacterium avium infection in HIV-infected individuals. AIDS Clinical Trials Group Protocol 135 Study Team.

OBJECTIVE: To determine the clinical and microbiologic benefit of adding amikacin to a four-drug oral regimen for treatment of disseminated Mycobacterium avium infection in HIV-infected patients. DESIGN: A randomized, open-labeled, comparative trial. SETTING: Outpatient clinics. PATIENTS: Seventy-four patients with HIV and symptomatic bacteremic M. avium infection. INTERVENTIONS: Rifampin 10 mg/kg daily, ciprofloxacin 500 mg twice daily, clofazimine 100 mg every day, and ethambutol 15 mg/kg orally daily for 24 weeks, with or without amikacin 10 mg/kg intravenously or intramuscularly 5 days weekly for the first 4 weeks. MAIN OUTCOME MEASURE: Clinical and microbiologic response at 4 weeks; quantitative level of bacteremia with M. avium. RESULTS: No difference in clinical response was noted with the addition of amikacin to the four-drug oral regimen, and only 25% in either group had a complete or partial response at 4 weeks. A comparable quantitative decrease in bacteremia was noted in both treatment groups, with 16% of patients being culture-negative at 4 weeks and 38% at 12 weeks. Toxicities were mainly gastrointestinal. Amikacin was well tolerated. Median survival was 30 weeks in both groups. CONCLUSIONS: The addition of amikacin to a four-drug oral regimen of rifampin, ciprofloxacin, clofazimine, and ethambutol did not provide clinical or microbiologic benefit.

Infectious causes of acute pancreatitis.

A wide variety of infectious agents has been associated with acute pancreatitis. Strict diagnostic criteria were developed to assess with relationship between individual microorganisms and acute pancreatitis. Pathologic or radiologic evidence of pancreatitis associated with well-documented infection was noted with viruses (mumps, coxsackie, hepatitis B, cytomegalovirus, varicella-zoster virus, herpes simplex virus), bacteria (Mycoplasma, Legionella, Leptospira, Salmonella), fungi (Aspergillus), and parasites (Toxoplasma, Cryptosporidium, Ascaris). Clues to the infectious nature of pancreatitis lay in the characteristic signs and symptoms associated with the particular infectious agent. How often these agents are responsible for idiopathic pancreatitis is unclear.

Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group.

BACKGROUND: Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS: We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS: In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS: For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.

Mycobacterium kansasii bacteremia in patients infected with human immunodeficiency virus.

In a retrospective review of microbiology records at the George Washington University Hospital from 1980 through 1990, Mycobacterium kansasii bacteremia was identified in 10 patients; this finding represented 4.5% of nontuberculous mycobacterial blood cultures. M. kansasii was isolated from respiratory specimens from all 10 patients, and pulmonary parenchymal changes were noted in five patients. The median survival time was 14 weeks; however, only five patients received therapy with two or more drugs active against M. kansasii.

Wasting syndrome in AIDS: pathophysiologic mechanisms and therapeutic approaches.

Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever and diarrhea. The pathophysiologic mechanisms responsible for this syndrome are not well defined, but it is clear that this is a multifactorial process in which the relative contribution of individual etiologic factors vary among patients. Considerations include inadequate diet, malabsorptive phenomena, metabolic derangements, and cytokine activity. The onset of opportunistic infections is often accompanied by a hypermetabolic state characterized by progressive weight loss. Potential cytokines that may promote weight loss in AIDS patients include tumor necrosis factor, interleukin-1, interleukin-6, and alpha-interferon. At present there is no effective treatment. Multiple therapeutic methods, including enteral and parenteral alimentation, appetite stimulants, recombinant growth hormone, and cytokine modulators, are currently being explored.

Anterior segment findings in AIDS patients with cytomegalovirus retinitis.

BACKGROUND: Anterior segment findings in AIDS patients presenting with cytomegalovirus (CMV) retinitis have not been specifically addressed in the American literature. METHODS: Our study evaluated 21 AIDS patients with CMV retinitis. RESULTS: Nineteen (90%) of these patients exhibited corneal endothelial deposits concurrent with CMV retinitis. The endothelial deposits were microscopic, opaque, linear flecks arranged in a reticular-like fashion. Of 42 eyes evaluated, 32 (76%) demonstrated active CMV retinitis. Corneal endothelial deposits were noted in 26 (81%) of the 32 eyes with retinitis. These corneal endothelial deposits were absent in the eyes which did not have CMV retinitis. CONCLUSION: Meticulous examination of the retina of an HIV-positive or AIDS patient who presents with reticularly arranged, linear, flecked corneal endothelial deposits should be performed to ensure that the diagnosis of CMV retinitis can be ruled out.

Randomized study of didanosine monotherapy and combination therapy with zidovudine in hemophilic and nonhemophilic subjects with asymptomatic human immunodeficiency virus-1 infection. AIDS Clinical Trial Groups.

To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients.

Cerebral schistosomiasis caused by Schistosoma haematobium: case report.

The CNS is an unusual site of ectopic infection in schistosomiasis. Cerebral lesions are caused primarily by Schistosoma japonicum, and spinal cord lesions are due primarily to Schistosoma mansoni and Schistosoma haematobium. S. haematobium is an unusual cause of cerebral mass lesions although schistosomal eggs can be frequently found in the brains of individuals in countries where S. haematobium is endemic. We describe a patient with a space-occupying cerebral lesion and schistosomal granulomas on pathological examination. S. haematobium was identified in urine and serologically. The cerebral lesion responded to therapy with praziquantel and corticosteroids. It has been postulated that granulomatous lesions develop following egg laying by errant worms migrating in the vicinity of the cerebral circulation or in response to eggs deposited from more distant sites by embolization. A species-specific serological diagnosis can be made by FAST (Falcon assay screening test)-ELISA with western blot confirmation.

Disseminated pneumocystosis presenting as a pleural effusion.

Extrapulmonary pneumocystosis recently has been reported in a number of tissues. Most cases occurred in patients receiving aerosolized pentamidine prophylaxis. We report a case of disseminated pneumocystosis presenting as a large pleural effusion without apparent lung involvement where Pneumocystis carinii was the only pathogen identified. The absence of parenchymal lesions on chest x-ray film, the lack of hypoxemia and the minimal uptake of gallium all argue against significant lung involvement. The patient was successfully treated with chest tube drainage, intravenous and inhaled pentamidine and orally administered dapsone and trimethoprim. The addition of inhaled pentamidine to intravenously administered pentamidine may have increased pleural fluid levels substantially and its use coincided with the patient's improvement.

Management and therapy of human immunodeficiency virus-infected pregnancies in maternal-fetal medicine fellowship training programs.

OBJECTIVE: To determine attitudes and practices of obstetricians in maternal-fetal medicine fellowship programs regarding the management of human immunodeficiency virus (HIV) infection and the use of zidovudine during pregnancy. METHODS: We sent a questionnaire to the directors of all 78 approved maternal-fetal medicine fellowship programs. The responses, reflecting the consensus of the staffs of each program, were obtained and tabulated. RESULTS: Although their programs annually provide care for more than 2100 pregnant women infected with HIV, less than 25% of all maternal-fetal medicine fellowship directors reported that their patients participate in multicenter studies of HIV infection complicating pregnancy. Nearly two-thirds of the infected women are excluded from such multicenter studies. More than 70% of all program directors believe that zidovudine should be offered to symptomatic pregnant women infected with HIV; one-half question whether zidovudine poses short-term fetal risks. Nevertheless, nearly half of all HIV-infected pregnant women they manage are excluded from trials of zidovudine therapy during pregnancy. CONCLUSIONS: Many HIV-infected pregnant women who receive care in clinics of maternal-fetal medicine fellowship programs are excluded from multicenter studies. Consideration should be given to creating a national registry for this important, currently unreported, clinical resource.

Sexually transmitted diseases and travelers.

Sexually active travelers are at risk for a variety of STDs, including traditional venereal infections such as gonorrhea, chlamydial urethritis, syphilis, chancroid, and herpes simplex infection. More recently, hepatitis B, hepatitis C, and HIV-1 have also been described. Risk varies depending on the geographic area of travel and the type of sexual contact. Physicians should be aware of the prevalence of antimicrobial resistance of N. gonorrhoeae and H. ducreyi because this will affect empiric antibiotic therapy. Prevention should focus on proper and consistent usage of barrier contraceptives.