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Trimethoprim-Sulfamethoxazole (TMP-SMZ) Dose Escalation versus Direct Rechallenge for Pneumocystis Carinii Pneumonia Prophylaxis in Human Immunodeficiency Virus—Infected Patients with Previous Adverse Reaction to TMP-SMZ

  1. Gifford S. Leoung1,
  2. James F. Stanford2,
  3. Michael F. Giordano5,
  4. Allan Stein3,
  5. Ramon A. Torres6,
  6. Carol A. Giffen4,
  7. Margaret Wesley4,
  8. Tricia Sarracco5,
  9. Ellen C. Cooper7,
  10. Valerie Dratter2,7,
  11. Jeffery J. Smith7,
  12. Kevin R. Frost7 and
  13. American Foundation for AIDS Research (amfAR) Community-Based Clinical Trials Networka
  1. 1HIVCare, San Francisco, California
  2. 2Kansas City AIDS Research Consortium, Kansas City, Missouri
  3. 3Community Research Initiative of South Florida, Coral Gables
  4. 4Information Management Services, Silver Spring, Maryland
  5. 5Cornell Clinical Trials Unit, New York Hospital / Cornell University Medical Center
  6. 6Clinical Directors Network
  7. 7American Foundation for AIDS Research, New York, New York
  1. Reprints or correspondence: Kevin Robert Frost, American Foundation for AIDS Research, 120 Wall St., 13th Fl., New York, NY 10005-3902 (kevin.frost{at}amfar.org)

  1. Presented in part: 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997 (abstract LB-10)

  • ↵a Members of the amfAR Data and Safety Monitoring Board and amfAR Community-Based Clinical Trials Network are listed after the text

 
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Abstract

Trimethoprim-sulfamethoxazole (TMP-SMZ) is the most effective Pneumocystis carinii pneumonia (PCP) prophylactic agent, but adverse reactions are common among human immunodeficiency virus (HIV)—infected patients and limit its use. This randomized, double-blind controlled trial compared 2 methods of TMP-SMZ reintroduction, 6-day dose escalation and direct rechallenge, for PCP prophylaxis in HIV-infected patients who had experienced previous treatment-limiting reactions. The primary end point was the ability to take single-strength TMP-SMZ daily for 6 months. Seventy-five percent of the dose-escalation group and 57% of the direct-rechallenge group continued to receive daily single-strength TMP-SMZ for 6 months (P=.014). Among premature discontinuations, 58% of the dose-escalation group and 70% of the direct-rechallenge group were due to adverse reactions. None of these reactions was serious. This study provides evidence that it is possible to successfully reintroduce TMP-SMZ to a significant proportion of HIV-infected patients who have experienced mild-to-moderate treatment-limiting adverse reactions

Despite recent advances in the management of human immunodeficiency virus (HIV) disease with the advent of highly active antiretroviral therapy and a decline in the incidence of opportunistic infections, Pneumocystis carinii pneumonia (PCP) continues to be a common life-threatening opportunistic infection among HIV-infected patients, and its prevention remains an important clinical management goal [1]

Although there are a variety of prophylaxis regimens, the drug most widely recommended is trimethoprim-sulfamethoxazole (TMP-SMZ) at a dosage of a single double-strength tablet (160-mg TMP and 800-mg SMZ) daily [2–6]. In addition to providing effective prophylaxis for PCP, there is evidence that TMP-SMZ is effective as prophylaxis for toxoplasmosis and also may be useful in preventing infections caused by a variety of other organisms [7–12]

One drawback in the use of TMP-SMZ is the high rate of adverse reactions in HIV-infected patients. In published studies, the rate of adverse reactions requiring discontinuation of TMP-SMZ varied from 9.4% to 54% [2, 8–10, 13–22]. Although the rate of drug discontinuation is lower for patients receiving PCP prophylaxis than treatment, patients receiving secondary prophylaxis have developed reactions, despite previously successful acute treatment with TMP-SMZ. For reasons that remain unclear, the rate of adverse reactions in HIV-infected patients is reported to be 5.4 times higher than the rate reported for HIV-negative patients [23]

Reported adverse event rates after rechallenge for persons with a history of reactions ranged from 13% to 47%, which are similar to the rates reported for patients with primary adverse events [7, 8, 24]. Although severe reactions have been described, the types of adverse events are similar, regardless of previous reaction history, and most commonly include skin rash, fever, flulike symptoms, and gastrointestinal disturbances. Two trials have reported that reactions to high-dose TMP-SMZ used for PCP treatment resolved in ∼80% of patients, despite continuation of therapy [7, 25]

Given the efficacy of TMP-SMZ for PCP prophylaxis and the low risk of severe reactions, even in persons with previous adverse reactions, many advocate attempted reintroduction of TMP-SMZ in persons with previous adverse events. The optimal reintroduction method is controversial; approaches have included direct rechallenge at full dosage and gradual dose escalation. We conducted this randomized, controlled trial to compare the success rates of dose-escalation and direct-rechallenge regimens [26–34]. Specifically, this trial compared a 6-day dose-escalation regimen to a direct-rechallenge regimen in HIV-infected patients with a history of mild-to-moderate fever and/or rash to TMP-SMZ. The dose-escalation regimen was modified to achieve a targeted maximum dose of 1 single-strength TMP-SMZ tablet daily rather than 1 double-strength TMP-SMZ tablet daily. Antihistamine use was required in both treatment groups during the TMP-SMZ reintroduction period [15, 35]. Daily single-strength TMP-SMZ was selected, rather than double-strength TMP-SMZ, on the basis of results of trials demonstrating equivalent effectiveness in preventing PCP [16, 36]. We felt that daily single-strength TMP-SMZ might be particularly appropriate in this patient population

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Methods

Study designThis was a randomized, double-blind, controlled study comparing the success of 2 approaches of TMP-SMZ reintroduction for PCP prophylaxis in HIV-infected patients with previous non—life threatening, but treatment-limiting, reactions of rash and/or fever to TMP-SMZ. Patients were randomized either to direct rechallenge with 1 single-strength TMP-SMZ tablet daily or to a 6-day incremental dose-escalation to 1 single-strength TMP-SMZ tablet daily (table 1). TMP-SMZ study drugs (Septra [placebo single-strength tablets] and Septra [placebo suspension]) were provided by Glaxo Wellcome. Patients were enrolled at 12 American Foundation for AIDS Research (amfAR) Community-Based Clinical Trials (CBCT) Network units

Table 1
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Table 1

Trimethoprim-sulfamethoxazole (TMP-SMZ) dose-escalation regimen in human immunodeficiency virus—infected patients with previous mild-to-moderate treatment-limiting rash and/or fever

The study was divided into a double-blind reintroduction phase and an open-label maintenance phase. All patients were instructed to begin antihistamine therapy 1 day before the first dose of study drug and to take it throughout the reintroduction period. The specific antihistamine regimen was determined by the patient and the patient's physician. During the reintroduction phase, patients in the dose-escalation group self-administered TMP-SMZ pediatric suspension in 5 incrementally increasing amounts, along with 1 TMP-SMZ placebo tablet daily (table 1). Direct-rechallenge group patients self-administered placebo suspension in increasing amounts, along with 1 single-strength TMP-SMZ tablet daily. Patients were allowed to repeat a scheduled daily dose once at each dose level and to withhold study drug for a maximum total of 2 days during reintroduction. Thus, the minimum time to achieve the full single-strength dose level was by day 6, whereas the maximum time was 13 days. Patients missing >2 doses during the reintroduction phase were declared to have treatment failure. After reintroduction, all patients were administered 1 open-label, single-strength TMP-SMZ tablet daily for 6 months (maintenance phase). Patients missing >1 week of consecutive doses or >30 doses during the maintenance phase were declared to have treatment failure. The use of antihistamines, nonsteroidal agents, or corticosteroids was encouraged during both the reintroduction and the maintenance phases, as needed for any adverse reactions

The primary end point was the ability of patients to take 1 single-strength TMP-SMZ tablet daily for 6 months. The sample size was calculated by using the primary end point with the objective of demonstrating equivalent treatment success. A difference of 20% in success rates between reintroduction methods was defined as clinically important. As a result, the sample size estimation was 200 patients

Eligibility criteriaPersons were eligible for this trial if they were HIV infected, required primary or secondary PCP prophylaxis, and had a history of mild or moderate rash or fever resulting in discontinuation of TMP-SMZ, as documented in their medical charts. Persons were excluded if they had received any TMP-SMZ since their qualifying adverse reactions, if they had taken any TMP-SMZ within 8 weeks before study randomization, or if they had a history of a severe reaction (i.e., anaphylaxis or Stevens-Johnson syndrome)

Clinical assessmentPatients were evaluated at a screening visit and on day 1 of the reintroduction phase when they were observed taking the first dose of study medication. Patients were evaluated at days 2, 7, and 14 and at months 1, 2, 4, and 6 for adverse events, use of adjunctive therapies, PCP diagnoses, and continued use of TMP-SMZ study drug

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Results

The study opened to enrollment in October 1995. Study data were reviewed on a regular basis by the amfFaR Data and Safety Monitoring Board (DSMB). At a regular meeting on 2 June 1997, the DSMB reviewed data on 190 patients, including end-point (month 6) data on 135 patients. Because the data showed that 80% of the patients in the dose-escalation group had successfully completed the protocol, compared with only 55% of the patients in the direct-rechallenge group (P=.0038, Fisher's exact test), the DSMB recommended that further accrual be halted. Study enrollment was closed on 6 June 1997, with 191 patients enrolled. The results reported here represent data from all 191 patients

Characteristics of the study populationOf the 191 patients enrolled in the study, 97 were randomized to the dose-escalation group and 94 to the direct-rechallenge group. The median age was 37 years (range, 20–61 years), and 84% were male. Mean CD4 cell count and CD4 percentage were 128 cells/mm3 and 9.5%, respectively. Time from last CD4 cell count to randomization ranged from 5 to 394 days. There were no statistically significant differences in the baseline demographics between treatment groups, except for a greater proportion of women in the direct-rechallenge group (table 2)

Table 2
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Table 2

Baseline characteristics of patients enrolled in a study of trimethoprim-sulfamethoxazole reintroduction in human immunodeficiency virus—infected patients with previous mild-to-moderate treatment-limiting rash and/or fever

EfficacySuccess was defined as the ability to continue receiving single-strength TMP-SMZ for 6 months. Overall, 127 (66.5%) of the 191 patients successfully completed the study (table 3). In the dose-escalation group, 73 (75%) of the 97 patients successfully completed the study, compared with 54 (57%) of 94 patients in the direct-rechallenge group (P=.01, Fisher's exact test)

Table 3
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Table 3

Results of a study of trimethoprim-sulfamethoxazole reintroduction in human immunodeficiency virus—infected patients with previous mild-to-moderate treatment-limiting rash and/or fever

Ninety-one (93.8%) of 97 and 86 (91.5%) of 94 patients in the dose-escalation and direct-rechallenge groups, respectively, successfully completed the blinded phase to reach the open-label, single-strength TMP-SMZ dose. Overall, 92% of patients were able to achieve open label single-strength TMP-SMZ dosing within the optimal 6-day reintroduction period. One patient in each group required the maximum 13 days to achieve open-label drug dosing

For those patients who were able to continue treatment into the open-label phase, the likelihood of success was even higher than the overall success rate for the study: open-label successes included 73 (80%) of 91 patients in the dose-escalation group and 54 (62.8%) of 86 in the direct-rechallenge group

The proportion of treatment failures in females was significantly higher than that in men in both groups. In the dose-escalation group, treatment failure was observed in 4 (40%) of 10 women versus 20 (23%) of 87 men, and, in the direct-rechallenge group, treatment failure was observed in 16 (76%) of 21 women versus 24 (33%) of 73 men

Adverse events and drug reactionsOverall, 43 (23%) of 191 patients discontinued study medication because of adverse events: 14 (14%) in the dose-escalation group and 29 (31%) in the direct-rechallenge group, including 1 death not related to study medication (P=.01)

No patient experienced a serious adverse drug reaction or required hospitalization because of the study medication. Of the 97 patients in the dose-escalation group, 14 patients discontinued because of adverse events; all were drug reactions (table 4). One patient in this group was unable to complete the reintroduction phase and reported fever and chills after a single dose. In each of the remaining 13 patients, treatment-limiting rash occurred during the open-label portion of the study. Eight of these patients experienced additional symptoms of pruritus or fever. Of these 13 patients, 10 experienced treatment failure within 3 weeks of study drug initiation

Table 4
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Table 4

Adverse events in a study of trimethoprim-sulfamethoxazole reintroduction in human immunodeficiency virus—infected patients with previous mild-to-moderate treatment-limiting rash and/or fever

Of the 94 patients randomized to the direct-rechallenge group, 29 discontinued prematurely because of adverse events. Eight of these 29 patients did not complete reintroduction phase. These patients discontinued on or before the third day of dosing for reactions including rash (1), fever (4), rash and fever (2), and other reactions (1). The remaining 21 discontinued patients experienced their adverse events during the maintenance phase. These events included rash (10), fever (5), rash and fever (1), other reactions than rash or fever (4), and death unrelated to study drug (1). Of the 21 patients discontinuing during the open-label phase, 11 discontinued within 3 weeks of beginning open-label TMP-SMZ

Rash and fever were the most common adverse events reported. There were no differences in the rates of rash reported in the 2 groups, whether including all patients enrolled or only those discontinuing early. However, patients in the direct-rechallenge group, including those who discontinued therapy early, had significantly higher rates of reported fever and headache

Use of adjunctive therapiesPatients were encouraged to use adjunctive therapies, including antihistamines, nonsteroidal agents, and corticosteroids, as necessary. Among those patients who successfully completed 6 months on study drug, the median length of antihistamine use was 9 days in each group. For nonsteroidal agents, the median length of use was 1 day in the dose-escalation group and 2 days in the direct-rechallenge group

Thirty patients used corticosteroids at some time during the study period (14 in the dose-escalation group and 16 in the direct-rechallenge group). However, for those patients who successfully completed the study, the median length of corticosteroid use was 0 days in both group. Of the 14 patients in the dose-escalation group, 6 patients used corticosteroids in conjunction with an adverse reaction. All 6 patients initiated corticosteroids within 14 days of starting TMP-SMZ therapy. Four of these patients ultimately failed to complete the 6-month study period. In the direct-rechallenge group, 13 of 16 patients used corticosteroids in conjunction with an adverse event. Eleven of the 13 initiated corticosteroid therapy within 14 days of starting study drug. Eight of the 13 ultimately failed to complete the study period

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Discussion

Overall, 127 (66%) of 191 patients were able to complete 6 months on single-strength TMP-SMZ. Although proportionally more patients in the dose-escalation group were able to remain on TMP-SMZ, compared with those in the direct-rechallenge group (75% vs. 57%, respectively), it should be noted that direct-rechallenge successes represented a majority of the patients in that treatment group. In some circumstances, the relatively lower success rate of direct rechallenge may be offset by its comparative simplicity

Since the mechanism of the adverse reaction to TMP-SMZ is unclear, predictors for its successful reintroduction remain unknown. However, since all patients enrolled had not been exposed to either TMP or SMZ within 8 weeks before randomization, limiting recent exposure may be important to reestablishing TMP-SMZ prophylaxis. None of the following was predictive of treatment failure: time from previous reaction requiring original discontinuation of TMP-SMZ; number of days required to achieve open-label dosing; time to or type of adverse reaction while continuing TMP-SMZ; use of supportive therapy (either antihistamines or steroids); or occurrence of opportunistic infections while enrolled in the study

Of the 43 patients who discontinued for adverse reactions, 30 (∼75%) had experienced their treatment-limiting reaction by day 21. This suggests that, regardless of the method used to reestablish TMP-SMZ prophylaxis, the probability of success is largely determined in the first 3 weeks of readministration

The choice and regimen of medications used to ameliorate adverse reactions attributed to the study drug were deliberately left to the patient and physician, to simulate the real life experience outside the usual controls associated with clinical studies

There were proportionally more women randomized to the direct-rechallenge group. However, women in both groups experienced treatment failure at a higher rate, compared with that for men. Specific reasons for this finding remains unclear; however, one hypothesis is that, since all patients received a single-strength dose, women may have received a greater dosage by weight, compared with that for men. The study was neither designed nor powered to explain this difference

During the study, there was 1 confirmed case of PCP in the dose-escalation group and 2 probable cases of PCP (one in each group). Although single-strength TMP-SMZ has been reported to be sufficient for PCP prophylaxis, this study was not powered to evaluate this and could not confirm its efficacy

In summary, we find that successful return to TMP-SMZ therapy can be achieved in patients who have had previous rash or fever while taking TMP-SMZ. Although dose escalation may significantly improve the likelihood of success, at least half of patients may be able to reestablish TMP-SMZ therapy by simple direct rechallenge, as long as they have not been exposed to the drug for at least 8 weeks. The majority of patients who will require drug discontinuation because of an adverse drug reaction will do so within 3 weeks of reinitiating TMP-SMZ. None of the TMP-SMZ—related reactions experienced were considered to be serious or life threatening or required hospitalization. Although more adverse event—related discontinuations were seen with direct rechallenge, there was no significant increase in rash, compared with that observed in the dose-escalation group. Use of adjunctive therapy may be helpful in maintaining patients on TMP-SMZ and does not place patients in jeopardy of a potentially worse adverse event

Despite the use of highly active antiretroviral therapy, there will remain a number of patients who require PCP prophylaxis and will experience adverse reactions to TMP-SMZ. We conclude that implementation of simple regimens for reintroduction of TMP-SMZ to patients who have experienced rash or fever may result in a significant proportion of patients able to reestablish PCP prophylaxis with the optimal agent, TMP-SMZ. However, TMP-SMZ reintroduction may not be prudent in persons with previous Stevens Johnson syndrome or other severe drug reactions resulting from TMP-SMZ or its components

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American Foundation for AIDS Research (amfAR)

Data and Safety Monitoring BoardHenry Masur (National Institutes of Health); Henry Chang (AIDS Healthcare Foundation); Deborah J. Cotton (Harvard Medical School); Mark A. Espeland (Bowman Grey School of Medicine); Charles F. Farthing (AIDS Healthcare Foundation); Michael D. Hughes (Harvard School of Public Health and London School of Hygiene and Tropical Medicine); and Robert J. Levine (Yale University School of Medicine)

Community-Based Clinical Trials NetworkMelanie Thompson and Rusty Moore (AIDS Research Consortium of Atlanta); Alvan Fisher and Gail Skowron (Brown University AIDS Program); Lisa Ferrigno and Oscar Klein (Clinical Directors Network of Region II); Samuel Merrick and Tricia Sarracco (Cornell Clinical Trials Unit); Joan Canniff and Calvin Cohen (Community Research Initiative of New England); John Cochrane and Carol Puckett (Community Research Initiative of South Florida); Gifford Leoung and Stacy Kobayashi (HIVCare); Shannon Schrader and Laurie Moonan (Houston Clinical Research Network); Janiece Larkin and Marilyn DePlato (Kansas City AIDS Research Consortium); Ronald Nahass and Nina Regevik (North Jersey Community Research Initiative); Jay Kostman and Carol Graeber (Philadelphia FIGHT); Thomas Ward and Linda Budan (Research and Education Group); and Lauren Rich and Elizabeth Yakim (Information Management Services)

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Footnotes

  • Informed consent was obtained from all patients, and human experimentation guidelines of the US Department of Health and Human Services were followed

  • Financial support: American Foundation for AIDS Research (amfAR)

  • Received February 5, 2001.
  • Revision received June 18, 2001.
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  1. J Infect Dis. (2001) 184 (8): 992-997. doi: 10.1086/323353
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  1. March 1, 2012 205 (5)
  1. Journal of Infectious Diseases
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