Snapshots of the Literature

The Hopkins HIV Report:
A bimonthly newsletter for healthcare providers
Volume 9, Number 1, January 1997


Causes of Fever in Patients with HIV Infection [Barat LM, et al. Clin Infect Dis 23:320,1996)]: The authors prospectively evaluated the cause of fever in patients with HIV infection who were hospitalized at Boston City Hospital. Criteria for evaluation were temperature exceeding 100.4xF for two consecutive days or a single measurement of 101xF during the first 48 hours of hospitalization. A cause of fever was identified in 191 (87%) of 220 episodes. The largest single diagnostic category was community-acquired bacterial pneumonia, which accounted for 73 (33%). Other commonly encountered conditions are summarized in the table below.

Fever in HIV-Infected Patients
Hospitalized at Boston City Hospital

No. of Patients168
No. Episodes of Fever220
No. With Cause Identified191 (87%)

Major Causes:
  • Bacterial Infection
    Pneumonia -- 73
    Skin/Soft Tissue -- 18
    Endocarditis -- 10
    UTI -- 9
    Catheter sepsis -- 6
127 (60%)
  • Mycobacterial Infection
    M. avium complex -- 12
    M. tuberculosis -- 1
15 (7%)
  • P. carinii pneumonia
31 (14%)
  • Fungal (other)
    Cryptococcal meningitis -- 6
9 (4%)
  • Viral
8 (4%)
  • Tumor
    Lymphoma -- 5
7 (3%)
  • Other
    Pancreatitis -- 5
    Biliary tract -- 3
    Drug fever -- 2
13 (6%)


The most common category of microbial pathogens were bacteria, which accounted for 127 episodes (60%). The group with bacterial infections had a significant increase in injection drug use, elevated leukocyte counts, and higher CD4 cell counts (mean of 137 vs. 64/mm3). It should be emphasized that this was not a study of fever of unknown origin, but a prospective study of hospitalized patients with fever. This experience simulates our own at Hopkins in showing that the most common identifiable pathogens in patients requiring hospitalization are bacterial infections, despite the fact that they do not necessarily represent AIDS-defining complications. It should also be noted that pneumonia, presumably due to bacterial pathogens, is by far the most common cause of death currently reported for patients with HIV infection, and this category was the largest single category in this series. By John G. Bartlett, M.D.


Prospective Evaluation of Fever of Unknown Origin in Patients Infected with HIV [Lozano F, et al. Eur J Clin Microbiol Infect Dis 15:705,1996]: This is a prospective study of HIV-infected patients over 14 years of age who were hospitalized in 14 hospitals in Spain with fever of unknown origin (FUO), as defined by the classic (Petersdorf) criteria: fever >38.3xC for at least three weeks and the lack of an etiologic diagnosis with a one week evaluation. During the 15-month study period (1992-93) there were 3,603 admissions of HIV-infected persons, and 128 (3.5%) satisfied the criteria for FUO. The most common diagnoses, in rank order, were tuberculosis in 69 (54%), visceral leishmaniasis in 23 (18%), disseminated MAC in 10 (8%), lymphoma in 8 (6%), sinusitis in 7 (5%), PCP in 7 (5%), disseminated CMV disease in 5 (4%), and a variety of other conditions. No diagnosis was established in 7 cases (5%). The utility of this review in the U.S. is somewhat limited by the high rates of tuberculosis and leishmaniasis, which reflect the idiosyncracies of HIV infection of Spain. Nevertheless, this report clearly supports recommendations made by some groups that FUO in HIV-infected patients be considered as an independent category, separate from classic FUO. Major differences are the facts that HIV-infected patients usually have an etiologic diagnosis established, and infectious diseases are by far the dominant causes. By John G. Bartlett, M.D.


Prophylaxis Against Disseminated MAC with Weekly Azithromycin, Daily Rifabutin or Both [Havlir DV, et al. N Engl J Med 335:392,1996]: This is a multicenter, double-blind randomized trial of 693 HIV-infected patients with CD4 cell counts <100/mm3 randomized to receive rifabutin (300 mg/day), azithromycin (1200 mg/week) or both drugs. Results are summarized in the table below.

The major end point of the study was M. avium complex (MAC) bacteremia within one year. MAC bacteremia occurred in 15.3% treated with rifabutin, 7.6% given azithromycin, and 2.8% given both drugs. These differences are statistically significant. There was also a statistically significant difference in rates of pneumonia or sinusitis: 20.5% among recipients of rifabutin, 10.0% in those taking azithromycin, and 4.9% in those who received the combination. Side effects were sufficient to require discontinuation of the study medicine in 21% of those treated with the combination, which was significantly greater than with either drug alone. Of the 18 patients who developed MAC bacteremia despite azithromycin prophylaxis, 2 (11%) had azithromycin-resistant strains. These two patients account for less than 1% of those initially assigned to the azithromycin treatment arm. None of the 21 isolates of MAC bacteremia in the rifabutin group was resistant to rifabutin.

MAC Prophylaxis:
Comparison of Azithromycin, Rifabutin, or Both


Rifabutin
n=223
Azithromycin
n=223
Both
n=218
Incidence of MAC
(Intent-to-treat)
52 (23%) 31 (14%) 18 (8%)
Cumulative
Incidence at 1 yr.
15.3% 7.6% 2.8%
Sinusitis
or pneumonia
21% 10% 5%
Dose-limiting
Toxicity
6.7% 5.6% 10.3%

This study demonstrates the superiority of azithromycin prophylaxis for MAC compared to rifabutin. The rates of MAC were approximately the same as those noted in a study using clarithromycin prophylaxis (see below). Besides superior efficacy, azithromycin has a number of additional advantages over rifabutin: 1) the convenience of once weekly dosing is certainly an advantage among patients who have an extraordinary "pill burden" in late stage disease; 2) rifabutin is an increasingly difficult drug to give due to the extensive interactions with protease inhibitors as well as other agents commonly used in HIV infection; 3) cost analysis per case prevented shows a substantial ad- vantage for azithromycin compared to rifabutin, and 4) the reduction in rates of pneumonia and sinusitis is a notable additional benefit of azithromycin prophylaxis. By John G. Bartlett, M.D.


A Randomized Trial of Clarithromycin as Prophylaxis Against Disseminated MAC Infection in Patients with Advanced AIDS [Pierce M, et al. N Engl J Med 335:384,1996]: This study compared clarithromycin (500 mg twice daily) vs. placebo in 667 patients with a CD4 cell count <100/mm3. The study was stopped at the first interim analysis after MAC bacteremia was noted in 19 of 333 patients (6%) assigned to clarithromycin compared to 53 of 334 (16%) in the placebo group. These differences were statistically significant. There was also a survival advantage with clarithromycin prophylaxis: ten month mortality was 32% in clarithromycin recipients compared to 41% in the placebo group. Among the 19 patients who developed MAC bacteremia despite clarithromycin prophylaxis, 11 had a MIC of 512 fg/ml or more. Compared to the study summarized above, this analysis showed: 1) a survival advantage for clarithromycin vs. placebo; 2) a comparable rate of decrease in MAC bacteremia; 3) a higher rate of clarithromycin-resistant MAC in those with "breakthrough bacteremia" (11% vs. 60%); 4) a larger pill burden (14 vs. 2/week), and 5) a reduction in the cost/case presented (based on the lower purchase price for azithromycin for this indication). In an as yet unpublished ACTG trial comparing clarithromycin to rifabutin to the combination, clarithromycin was superior to rifabutin for the prevention of MAC. Clarithromycin resistance occurred in patients who failed prophylaxis, but at a lower rate than was seen in this placebo-controlled trial. By John G. Bartlett, M.D.


A Trial Comparing Nucleoside Monotherapy with Combination Therapy in HIV-Infected Adults with CD4 Cell Counts from 200 to 500/mm3 [Hammer SM, et al. N Engl J Med 335:1081,1996]: This is the well known ACTG 175 study involving 2,467 patients randomized to receive AZT alone, AZT/ddI, AZT/ddC or ddI alone. Primary end points included a decline in CD4 cell count of 50% or greater, an AIDS-defining diagnosis, or death. Results of the study for those with prior antiviral therapy and those with no prior treatment are summarized in the table.

Rates of Disease Progression

AZTAZT/ddIAZT/ddCddI
Prior Therapyn = 350n = 350n = 348n = 352
Progression
133 (38%)76 (22%)93 (27%)90 (2%)
Death
36 (10%)20 (6%)31 (9%)18 (5%)
No Prior Therapyn = 269n = 263n = 267n = 268
Progression
63 (23%)37 (14%)27 (10%)46 (17%)
Death
18 (7%)11 (4%)9 (3%)11 (4%)
Total619613615620
Progression
196 (32%)113 (18%)120 (20%)136 (22%)
Death
54 (8.7%)31 (5.1%)40 (6.5%)29 (8.2%)



The results indicated that AZT monotherapy was inferior to the other three regimens. This study is comparable to the European-Australian Delta Trial in demonstrating that monotherapy with AZT is now antiquated, except for use in pregnancy to prevent vertical transmission. In contrast to the Delta Trial, this study included a ddI monotherapy arm, and this group appeared to do well, leading some authorities to conclude that ddI is acceptable monotherapy in selected circumstances. By John G. Bartlett, M.D.


The Relation of Virologic and Immunologic Markers to Clinical Outcomes After Nucleoside Therapy in HIV-Infected Adults with 200 to 500 CD4 Cells/mm3 [Katzenstein DA, et al. N Engl J Med 335:1091,1996]: This is a substudy of ACTG 175 with an analysis of viral burden and analysis of HIV phenotype after eight weeks of treatment. There were 391 participants in this substudy. The decrease in HIV RNA was 0.26 logs in AZT recipients, 0.65 logs for ddI alone, 0.93 logs for AZT/ddI, and 0.89 logs for AZT/ddC. Increased rates of progression were associated with higher baseline concentrations of plasma HIV RNA, reduced suppression of HIV RNA with treatment and the presence of syncytium-inducing strains. Also noteworthy is the observation that the reduction in viral burden was less profound with ddI monotherapy compared to combination treatment. By John G. Bartlett, M.D.


Effects of Lamivudine on Replication of Hepatitis B Virus in HIV-Infected Men [Benhamou Y, et al. Ann Intern Med 125:705,1996]: Lamivudine (3TC) is a potent inhibitor of hepatitis B viral replication. A prior clinical trial in patients without HIV infection showed promising results [N Engl J Med 333:1657,1995]. The present study, which was conducted in Paris, addresses the same issue, but in patients infected with HIV as well as hepatitis B (HBV). Forty consecutive coinfected patients were treated with lamivudine, 600 mg/day, or the same dose followed by 300 mg/day as treat-ment for HIV. Serum concentrations of HBV DNA were measured at two month intervals, using PCR for HBV DNA performed at baseline and repeated at months 2, 6 and 12. After 12 months, 26 of 27 patients who had high baseline HBV replication rates had a reduction in HBV DNA concentrations to <5 pg/ml. Five of these patients had HBV DNA detectable only by PCR. Two patients who stopped lamivudine had a rebound with high levels of HBV DNA. This study shows the potential benefit of 3TC for hepatitis B and the potential advantage of this drug in treating patients with co-infections involving HIV and HBV. By John G. Bartlett, M.D.


Economic Impact of Treatment of HIV-Positive Pregnant Women and Their Newborns with Zidovudine [Mauskopf JA, et al. JAMA 276:132,1996]: The authors estimated the economic impact of treating pregnant women with HIV infection using the standard regimen of AZT as recommended by the U.S. Public Health Service. The costs of health care were for AZT and its administration. Estimates of the reduction in vertical transmission rates were based on results of ACTG 076. Assuming a reduction in vertical transmission rates from 25.5% to 8.3%, the cost of treatment for 100 HIV-infected pregnant women was $104,502. The reduction in costs for pediatric HIV infection was $1,701,333. The resulting net savings was $1,596,831 per 100 patients or approximately $16,000 in savings per patient. The importance of implementing the U.S. Public Health Guidelines for prevention of vertical transmission of HIV using appropriate screening and treatment with AZT is a no-brainer, but those who need an economic incentive to bolster this position now have it. By John G. Bartlett, M.D.


Prospective Trial of Paromomycin for Cryptosporidiosis in AIDS [Flanigan TP, et al: Am J Med 1996;100:370]: This prospective, single-arm trial involved 44 patients from ten centers and assessed the clinical response and oocyst excretion over 4 weeks while patients were receiving paromomycin at a dose of 500 mg QID. All enrollees had CD4 cell counts <200/mm3 and at least 5 days of diarrhea due to cryptosporidia in exclusion of other evaluable causes. Eleven did not complete four weeks of therapy due to intercurrent illness; 48% responded clinically with resolution or improvement of diarrhea; complete resolution occurred in only 9%. There was no significant difference in CD4 cell count between responders and non- responders. Oocysts were cleared from stool at 4 weeks in 27%, but only single samples were examined. As most other studies have shown, paromomycin often results in symptomatic improvement but rarely "cures" infection. Long-term effectiveness was not studied and has been lacking in other published reports. Yet another lukewarm appraisal of this drug for cryptosporidiosis underscores the need for more effective therapy. By Peter C. Belitsos, M.D.


Intestinal Inflammation, Ileal Structure and Function in HIV [Bjarnason I, et al: AIDS 1996;10:1385]: In this well-designed, controlled trial an elaborate array of intestinal absorption and permeability testing was performed to assess ileal function in HIV infection. Normal controls and patients with Crohn disease were compared with 30 HIV-infected patients at various stages of disease with and without diarrhea. AIDS patients with diarrhea had normal bile acid but reduced vitamin B-12 absorption compared to non- infected controls. Patients with AIDS diarrhea, however, had significant malabsorption of both (P<0.001), and the malabsorption was more severe than was seen in Crohn ileitis. Despite this, ileal biopsies in these patients showed nonsignificant abnormality in morphometric analyses. This study not only provides further support to the literature on the prevalence of vitamin B-12 deficiency in AIDS, but also lends credence to recent observations of the potential value of cholestyramine in the treatment of chronic diarrhea of unknown cause in AIDS [AM J Gastro 1995;90:2051, 1994;89:379]. By Peter C. Belitsos, M.D.


This article is from The Johns Hopkins University AIDS Service,
The Hopkins HIV Report: A bimonthly newsletter for healthcare providers.