Mark R. Wallace

Comparisons of causes of death and mortality rates among HIV-infected persons : Analysis of the pre-, early, and late HAART (Highly active antiretroviral therapy) eras

Methods:Comparisons of death-related variables during the 3 eras were performed. Results:The number of deaths declined over the study period, with 987 deaths in the pre-HAART era, 159 deaths in the early HAART era (1997-1999), and 78 deaths in the late HAART era (2000-2003) (P < 0.01). The annual death rate peaked in 1995 (10.3 per 100 patients) and then declined to <2 deaths per 100 persons in the late HAART era (P < 0.01). The proportion of deaths attributable to infection decreased, but infection remained the leading cause of death in our cohort, followed by cancer. Of those who died, there was an increasing proportion of non-HIV-related deaths (32% vs. 9%; P < 0.01), including cardiac disease (22% vs. 8%; P < 0.01) and trauma (8% vs. 2%; P = 0.01) in the post-HAART versus pre-HAART era. Despite the absence of intravenous drug use and the low prevalence of hepatitis C coinfection in our cohort, an increasing proportion of deaths in the HAART era were attributable to liver disease, although the numbers are small. Conclusions:Despite increasing concerns regarding antiretroviral resistance, the death rate among HIV-infected persons in our cohort continues to decline. Our data show a lower death rate than that reported among many other US HIV-infected populations; this may be the result of open access to health care. A shift in the causes of death toward non-HIV-related causes suggests that a more comprehensive health care approach may be needed for optimal life expectancy; this may include enhanced screening for malignancy and heart disease as well as preventive measures for liver disease and accidents.

Infections associated with tumor necrosis factor-α antagonists

Abstract: Tumor necrosis factor (TNF)-α antagonists are promising therapeutic agents for patients with severe autoimmune and rheumatologic conditions. Unfortunately, their use has been associated with an increased rate of tuberculosis, endemic mycoses, and intracellular bacterial infections. Infliximab, 1 of 3 available drugs in this novel class, appears to be associated with the greatest risk of infection, likely because of its long half-life and induction of monocyte apoptosis. Prospective trials are necessary to determine the exact risk associated with these agents, particularly the newer TNF-α antagonists. More specific TNF-α blockers, which reduce inflammation while maintaining adequate immunity, are needed. In the meantime, a thorough work-up is mandatory for all febrile illness occurring in TNF-α blocker recipients. We present 4 patients who developed severe infections during TNF-α antagonist therapy, review the literature, and discuss current guidelines for surveillance and prophylaxis. Abbreviations: AIDS = acquired immunodeficiency syndrome, FDA = United States Food and Drug Administration, HIV = human immunodeficiency virus, PPD = purified protein derivative, RA = rheumatoid arthritis, TB = tuberculosis, TH1 = T-helper type 1, TNF = tumor necrosis factor, WBC = white blood cell count.

Incidence and risk factors for the occurrence of non‐AIDS‐defining cancers among human immunodeficiency virus‐infected individuals

The objective of this study was to determine the rates and predictors of non‐AIDS‐defining cancers (NADCs) among a cohort of human immunodeficiency virus (HIV)‐infected individuals.

Coccidioidomycosis: a descriptive survey of a reemerging disease. Clinical characteristics and current controversies.

Abstract: Coccidioidomycosis is a fungal disease with protean manifestations endemic to the Lower Sonoran Life Zone, which includes the hot deserts of the southwestern United States and areas of Mexico. Two hundred and twenty-three patients were found to have coccidioidomycosis at our institution from 1994-2002, the largest reported cohort of coccidioidomycosis patients since the 1950s. Of these patients, 58% presented with isolated pulmonary disease, 14% had high (>1:16) complement fixation titers without clear evidence of dissemination, 22% had definite disseminated disease, and 5% had unclassified disease. Enzyme immunoassay was a reliable diagnostic tool in those with symptomatic disease, but had a low specificity in those who were asymptomatic. Complement fixation titers of ≥1:16 were associated with dissemination to bone or skin but were not helpful in evaluating central nervous system disease. Thirteen percent of patients with high complement fixation titers (>1:16) without clear evidence of dissemination on presentation and 7% of those with isolated pulmonary disease eventually progressed to disseminated disease; 30% of Filipino patients with pulmonary disease progressed to disseminated disease. Nonwhite race was a predictor for dissemination; African American patients more often developed disseminated bony disease while Filipinos were more likely to develop cutaneous or central nervous system disease. Relapse of disseminated coccidioidomycosis occurred in 24% of patients; the risk was highest (71%) among those with central nervous system disease. Azole therapy was generally inferior to amphotericin B in disseminated disease. Predictors of permanent disability included African American or Filipino race, central nervous system disease, and bony disease. Abbreviations:, CF = complement fixation, CNS = central nervous system, CSF = cerebrospinal fluid, CT = computed tomography, EIA = enzyme immunoassay, LDH = lactate dehydrogenase, MRI = magnetic resonance imaging, OR = odds ratio, VP = ventriculo-peritoneal.

Treatment of Adult Varicella with Oral Acyclovir: A Randomized, Placebo-controlled Trial

OBJECTIVE To assess the efficacy of oral acyclovir in treating adults with varicella and to describe the natural history of adult varicella. DESIGN Double-blind, placebo-controlled randomized trial. SETTING A naval hospital. PATIENTS One hundred forty-eight of 206 consecutive adult active duty Navy and Marine Corps personnel who were hospitalized for isolation and inpatient therapy of varicella and who could be treated within 72 hours of rash onset completed the study. The diagnosis of varicella was confirmed by acute and convalescent serology in 143 of 144 patients with available paired sera. INTERVENTION Patients were randomly assigned to receive either acyclovir, 800 mg orally five times per day for 7 days, or an identical placebo. Separate randomization codes were used for patients presenting within 24 hours of rash onset and for those presenting 25 to 72 hours after rash onset. MEASUREMENTS Daily lesion counts, symptom scores, temperature measurements, and laboratory tests were used to monitor the course of the illness. RESULTS Early treatment (initiated within 24 hours of rash onset) reduced the total time to (100%) crusting from 7.4 to 5.6 days (P = 0.001) and reduced the maximum number of lesions by 46% (P = 0.04). Duration of fever and severity of symptoms were also reduced by early therapy. Late therapy (25 to 72 hours after rash onset) had no effect on the course of illness. Only four patients had pneumonia, and no encephalitis or mortality was noted. CONCLUSIONS Early therapy with oral acyclovir decreases the time to cutaneous healing of adult varicella, decreases the duration of fever, and lessens symptoms. Initiation of therapy after the first day of illness is of no value in uncomplicated cases of adult varicella. The low frequency of serious complications of varicella (pneumonia, encephalitis, or death) precluded any evaluation of the possible effect of acyclovir on these outcomes.

Malaria among United States troops in Somalia

PURPOSE United States military personnel deployed to Somalia were at risk for malaria, including chloroquine-resistant Plasmodium falciparum malaria. This report details laboratory, clinical, preventive, and therapeutic aspects of malaria in this cohort. PATIENTS AND METHODS The study took place in US military field hospitals in Somalia, with US troops deployed to Somalia between December 1992 and May 1993. Centralized clinical care and country-wide disease surveillance facilitated standardized laboratory diagnosis, clinical records, epidemiologic studies, and assessment of chemoprophylactic efficacy. RESULTS Forty-eight cases of malaria occurred among US troops while in Somalia; 41 of these cases were P falciparum. Risk factors associated with malaria included: noncompliance with recommended chemoprophylaxis (odds ratio [OR] 2.4); failure to use bed nets (OR 2.6); and failure to keep sleeves rolled down (OR 2.2). Some patients developed malaria in spite of mefloquine (n = 8) or doxycycline (n = 5) levels of compatible with chemoprophylactic compliance. Five mefloquine failures had both serum levels > or = 650 ng/mL and metabolite:mefloquine ratios over 2, indicating chemoprophylactic failure. All cases were successfully treated, including 1 patient who developed cerebral malaria. CONCLUSIONS P falciparum malaria attack rates were substantial in the first several weeks of Operation Restore Hope. While most cases occurred because of noncompliance with personal protective measures or chemoprophylaxis, both mefloquine and doxycycline chemoprophylactic failures occurred. Military or civilian travelers to East Africa must be scrupulous in their attention to both chemoprophylaxis and personal protection measures.

Syphilis and neurosyphilis in a human immunodeficiency virus type-1 seropositive population: Evidence for frequent serologic relapse after therapy

OBJECTIVE To describe clinical and treatment aspects of syphilis infection among patients seropositive for the human immunodeficiency virus (HIV). PATIENTS AND METHODS Results of serologic tests for syphilis, CD4+ T-lymphocyte counts, and clinical response to therapy were retrospectively monitored in 100 HIV-infected adults with syphilis from a tertiary-care military HIV program. RESULTS Of the 1,206 HIV-infected patients, 100 (8.3%) in the cohort had syphilis; 61 patients were treated for active syphilis. Serologic or clinical relapse eventually occurred in 10 of the 56 treated patients (17.9%) with follow-up available; 7 of the 10 who relapsed had previously received high-dose intravenous or procaine penicillin therapy. Relapse occurred more than 12 months after initial therapy in 6 of 10 patients (60%) who experienced relapse; 5 patients experienced multiple relapses. The mean CD4+ T-lymphocyte count was not predictive of relapse. Patients with reactive cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test titers (4 of 7 patients [57%]) or the rash of secondary syphilis (4 of 14 patients [29%]) were at highest risk of subsequent relapse or treatment failure when monitored for an average of 2 years. CONCLUSION Standard penicillin regimens, including high-dose intravenous penicillin, transiently lowered serum VDRL titers in nearly all cases, but were sometimes inadequate in preventing serologic and clinical relapse in patients infected with HIV type-1, especially among those with secondary syphilis and reactive CSF VDRL titers. Careful long-term follow-up is essential, and repeated courses of therapy may be needed for patients infected with HIV type-1 who have syphilis.

Effects of influenza vaccination in HIV-infected adults: a double-blind, placebo-controlled trial.

Annual influenza vaccine is recommended for persons with HIV infection. Recent reports indicate that immunizations may increase HIV replication in infected individuals. Forty-seven HIV-infected patients were randomized to influenza vaccine or saline placebo using a double blind study design. One month after vaccination, plasma HIV-1 RNA increased in the vaccinated but not placebo group (p = 0.029). At 3 months, CD4% dropped an average of 1.6 points in the vaccinated group compared to an increase of 0.1 points in the placebo group (p = 0.039). Patients on stable antiretroviral regimens had CD4% drop an average of 2.3 points in the vaccinated group at 3 months versus 0.1 points in the placebo group (p = 0.015). It is concluded that HIV-infected patients are at risk for increased HIV replication and decreases in CD4% following influenza vaccination. Since influenza has not been associated with significant morbidity in this population, further study of routine influenza vaccination for HIV-infected patients is warranted.

Safety and Immunogenicity of an Inactivated Hepatitis A Vaccine among HIV-Infected Subjects

BACKGROUND Hepatitis A is a major health risk for many human immunodeficiency virus (HIV)-infected individuals. Vaccination is a potentially attractive measure to reduce the incidence of hepatitis A among this population, but data on its safety and immunogenicity are incomplete. METHODS Ninety HIV-uninfected adults received an inactivated hepatitis A vaccine (VAQTA; Merck), and 90 HIV-infected subjects were randomized, in double-blind fashion, to receive either the vaccine or placebo. The HIV-infected subjects were stratified by CD4 cell count, with 45 subjects having CD4 cell counts of > or =300 cells/mm3 and 45 subjects having CD4 cell counts of <300 cells/mm3. Vaccine was given at weeks 0 and 24 of the study.Results. Seroconversion rates at week 28 of the study were 94% among the HIV-infected subjects and 100% among the HIV-uninfected control subjects. HIV-infected subjects with CD4 cell counts of <300 cells/mm3 had a seroconversion rate of 87%, and HIV-infected subjects with CD4 cell counts of > or =300 cells/mm3 had a seroconversion rate of 100%. The vaccine was generally well tolerated, and no adverse effect on either HIV load or CD4 cell count was found. CONCLUSION Hepatitis A vaccine was both immunogenic and safe among HIV-infected subjects.

Once Weekly Azithromycin Therapy for Prevention of Mycobacterium avium Complex Infection in Patients with AIDS: A Randomized, Double-Blind, Placebo-Controlled Multicenter Trial

We conducted a randomized, double-blind, placebo-controlled multicenter trial of azithromycin (1,200 mg once weekly) for the prevention of Mycobacterium avium complex (MAC) infection in patients with AIDS and a CD4 cell count of < 100/mm3. In an intent-to-treat analysis through the end of therapy plus 30 days, nine (10.6%) of 85 azithromycin recipients and 22 (24.7%) of 89 placebo recipients developed MAC infection (hazard ratio, 0.34; P = .004). There was no difference in the ranges of minimal inhibitory concentrations of either clarithromycin or azithromycin for the five breakthrough (first) MAC isolates from the azithromycin group and the 18 breakthrough MAC isolates from the placebo group. Of the 76 patients who died during the study, four (10.5%) of 38 azithromycin recipients and 12 (31.6%) of 38 placebo recipients had a MAC infection followed by death (P = .025). For deaths due to all causes, there was no difference in time to death or number of deaths between the two groups. Episodes of non-MAC bacterial infection per 100 patient years occurred in 43 azithromycin recipients and 88 placebo recipients (relative risk, 0.49; 95% confidence interval, 0.33-0.73). The most common toxic effect noted during the study was gastrointestinal, reported by 78.9% of azithromycin recipients and 27.5% of placebo recipients. Azithromycin given once weekly is safe and effective in preventing disseminated MAC infection, death due to MAC infection, and respiratory tract infections in patients with AIDS and CD4 cell counts of < 100/mm3.