Discontinuing Prophylaxis for Opportunistic Infection: Guiding Principles

Home , Chemoprophylaxis, Opportunistic infection

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Judith S. Currier From the Department of Medicine, University of California, Los Angeles, California

Several large observational studies have documented the reduced risk of opportunistic infections among recipients of potent combination antiretroviral therapy. These data raise the

question of whether subjects who respond to antiretroviral therapy need to continue pro- Downloaded from https://academic.oup.com/cid/article/30/Supplement_1/S66/393981 by guest on 24 September 2021 phylaxis for opportunistic infection. Factors to consider when deciding whether it is safe to discontinue prophylaxis include the following: (1) the risk of developing the specific opportunistic infection; (2) the consequences of the infection (morbidity and availability of effective therapy); (3) both the short-term and long-term toxicity of the agent used for prophylaxis; (4) the potential for drug interactions between the agent used for prophylaxis and other therapies for human immunodeficiency virus infection; (5) the psychological benefit of discontinuing a treatment during the course of a chronic disease; (6) the risk of development of drug resistance during prophylaxis; and (7) costs. This article reviews current data on predicting risk of opportunistic infection, the most critical of these factors.

The development of safe and effective chemoprophylaxis risk of developing the specific OI; (2) the consequences of the against opportunistic infections (OIs), specifically Pneumocystis infection (morbidity and availability of effective therapy); (3) carinii and Mycobacterium avium infections, was a significant the short-term and long-term toxicity of the agent used for clinical development during the first decade of the AIDS epi- prophylaxis; (4) the potential for drug interactions between the demic. Data collected since the advent of potent combination agent used for prophylaxis and other HIV-infection therapies; antiretroviral therapy (and the widespread use of prophylaxis) (5) the psychological benefit of discontinuing a treatment dur- have documented dramatic declines in rates of OIs [1–4]. ing the course of a chronic disease; (6) the risk of development These recent trends have raised important questions regard- of drug resistance during prophylaxis; and (7) costs. These gen- ing the optimal use of prophylaxis for OIs among patients eral risks and benefits are summarized in table 1. receiving antiretroviral therapy in this new era. Ideally, ran- Examples of disease-specific risks and benefits of discontin- domized, controlled clinical trials would provide us with un- uing primary and secondary prophylaxis for PCP and MAC biased answers on the safety of discontinuing prophylaxis for infection and secondary prophylaxis for CMV retinitis are sum- specific diseases. It is unlikely that specific trials will be con- marized in table 2. Of these factors, perhaps the most difficult ducted for each indication for prophylaxis; hence, it is useful to determine and the most important is the risk of developing to identify the factors that need to be considered in deciding an OI. This topic will be the focus of the remainder of this whether to discontinue prophylaxis. article. This paper will outline the general principles that help frame the question of whether to stop OI prophylaxis for patients who have sustained increases in CD4ϩ cell numbers. In addi- Defining the Threshold of Risk of the Disease at Which tion, data that pertain to OI risk will be reviewed. Although It is Safe to Discontinue Prophylaxis the principles for stopping primary and secondary prophylaxis Identifying a threshold of risk at which it is safe to discon- are similar, clearly the specific risks and consequences vary by tinue prophylaxis may be useful for interpreting data from ob- the disease (P. carinii pneumonia [PCP] vs. cytomegalovirus servational studies. There are at least 4 options for determining [CMV] and M. avium complex [MAC] infections) and the drugs the threshold at which it is safe to discontinue prophylaxis. One involved. approach is to set the threshold of safety at the risk of disease A set of guiding principles that can be applied to each sit- that was observed for subjects receiving prophylaxis in the orig- uation can be used as a framework for clinical decision-making. inal placebo-controlled trials in which the efficacy of prophy- These principles include consideration of several factors: (1) the laxis was established. If the rate of disease is below this level in contemporary observational studies of subjects whose CD4ϩ Reprints or correspondence: Dr. Judith S. Currier, University of Califor- cell counts increase (and who are not receiving prophylaxis), nia, Los Angeles, Center for AIDS Research & Education, 10833 LeConte then it could be considered safe to discontinue prophylaxis. Ave., Room #BH-412-CHS, Los Angeles, CA 90095 (jscurrier@mednet .ucla.edu). An example is provided by data from the MAC prophylaxis trials conducted by the California Collaborative Treatment Clinical Infectious Diseases 2000;30:S66±71 ᭧ 2000 by the Infectious Diseases Society of America. All rights reserved. Group (CCTG) and the AIDS Clinical Trials Group (ACTG) 1058-4838/2000/3004S-0005$03.00 that established the superiority of azithromycin and clarith- CID 2000;30 (Suppl 1) Guiding Principles for Discontinuing OI Prophylaxis S67

Table 1. Factors to consider in developing recommendations for stopping prophylaxis for opportunistic infection (OI). Consideration Factors Risks Risk of developing OIa; morbidity/mortality due to the OI; uncertainties regarding restarting prophylaxis in the future (i.e., drug rash due to TMP-SMZ) Benefits Psychological benefit; decreased pill burden; reduced toxicity; decreased potential for drug interactions and for development of drug resistance; decreased cost NOTE. TMP-SMZ, trimethoprim-sulfamethoxazole. a Factors that increase risk include a lower CD4 cell count nadir, higher viral load, history of an AIDS- Downloaded from https://academic.oup.com/cid/article/30/Supplement_1/S66/393981 by guest on 24 September 2021 defining opportunistic infection, and shorter duration of CD4 cell count increase. romycin over rifabutin [5, 6]. In the intent-to-treat analysis of disease at which discontinuing prophylaxis represents a rea- the CCTG trial (which compared azithromycin with rifabutin sonable strategy, when setting priorities for the use of limited and with the combination), the 1-year cumulative incidence of resources. disseminated MAC infection was 15.3% in the rifabutin group, Finally, a fourth option is to set the threshold at the rate of 7.6% in the azithromycin group, and 2.8% in the combination- the OI among subjects whose CD4ϩ cell count increases are therapy group. In the ACTG trial, which compared clarith- sustained during potent combination antiretroviral therapy and romycin with rifabutin and with the combination, the 1-year continuing prophylaxis. This rate could be obtained either from incidence rates of MAC infection were in the same range: 5% prospective randomized trials or from observational data. in the clarithromycin group, 10% in the rifabutin group, and Observational and nonrandomized intervention studies (in 5% in the combination group. which prophylaxis is discontinued for an entire group) can pro- Thus, if the risk of MAC infection in any specific subset of vide preliminary estimates of the rates of specific OIs among patients after discontinuing prophylaxis is below the 5%–7% 1- subjects who have discontinued prophylaxis; however, the “gold year cumulative incidence rate, then it could be concluded that standard” should remain the randomized clinical trial. Obser- the use of prophylaxis may not be warranted. This is not to vational studies may underestimate the risk of OI if the subjects say that the use of prophylaxis offers no benefit, since it is who chose to begin or discontinue prophylaxis are healthier in possible that the risk could be further reduced with the use of ways that are not easily measured or if the use of prophylaxis prophylaxis. This option may represent an unacceptably high is not adequately captured (as with chart review of medication risk since it relies on historical data that include people with use). In addition, unusual presentations of the OI might not low CD4ϩ cell counts. be captured. A second option is to set the acceptable threshold of risk for Ideally, randomized clinical trials to evaluate the efficacy of discontinuing prophylaxis at the risk of the disease among peo- prophylaxis for patients whose increases in CD4ϩ cell counts ple who have CD4ϩ cell counts above the previous thresholds have been sustained can provide estimates of the disease risk for initiating prophylaxis (i.e., 200/mm3 for PCP and 50/mm3 prospectively and confirm the results of observational studies. for MAC infection). Before the advent of more potent antir- If these investigations are designed as equivalence studies, the etroviral therapy, these were the rates of disease considered low sample size may be prohibitive. For example, if a study was enough to warrant the noninitiation of prophylaxis. This ap- designed to exclude a difference of 12% between the rates of proach was taken in an observational study of the risk of MAC MAC infection among subjects who continued prophylaxis ver- infection and PCP in which the Adult Spectrum of Disease sus those receiving placebo, and the expected rate of MAC clinical database was used [7]. In this study, the risks of PCP infection was 3%, the study would need to enroll 11000 subjects. and MAC infection were assessed for subjects whose CD4ϩ cell An alternative approach is to design these studies to be large values had previously been below established guidelines for enough to detect a meaningful rate of disease in the placebo institution of prophylaxis (50 cells/mm3 for MAC infection and arm. Such studies are currently being conducted by the ACTG 200 cells/mm3 for PCP) but had since increased above that of the Community Program for Clinical Research in AIDS threshold and who were no longer receiving prophylaxis. These (CPCRA), comparing the risk of MAC infection among pa- rates were compared with rates for subjects whose values had tients whose CD4ϩ cell counts increased from !50/mm3 to 1100/ never declined below the thresholds. The authors found com- mm3 and were sustained [8, 9]. Preliminary results of a ran- parably low rates of both of these OIs between the 2 groups domized trial of discontinuing PCP prophylaxis have already of subjects. been reported [10]. It is critical that these studies have sufficient A third alternative would be to define the rate of OI at which follow-up time and that they include patients representative of prophylaxis is no longer cost-effective by use of a formal cost- those currently receiving antiretroviral therapy (e.g., including benefit analysis. Although this quantitatively more rigorous ap- patients with incompletely suppressed HIV replication). These proach is frequently less appealing to clinicians, it may be rea- types of studies may also help to identify factors associated sonable to use cost-benefit analysis to determine the rate of with higher risk of developing future OIs. S68 Currier CID 2000;30 (Suppl 1)

Table 2. Examples of the risks and benefits of discontinuing primary and secondary prophylaxis: disease- specific issues to consider. Prophylaxis (agent) Risks Benefits Primary and secondary, Recurrent PCP (can be life-threatening); 1 less pill/day (or thrice weekly dosing); for PCP (TMP-SMZ) loss of protection against bacterial reduced risk of bacterial resistance (?) infections Primary and secondary, Recurrent MAC infection (not immediately Fewer GI side effects; psychological for MAC infection so, but life-threatening); may upregulate benefit of stopping therapy, owing to (azithromycin) HIV replication; loss of protection against CD4 cell increase; reduced risk of Downloaded from https://academic.oup.com/cid/article/30/Supplement_1/S66/393981 by guest on 24 September 2021 bacterial infections bacterial resistance (?) Secondary, for CMV Relapse of CMV infection with loss of vi- Elimination of daily infusions, toxicity retinitis (iv ganciclovir) sion; unknown risk of recurrent CMV vi- of the drug (anemia, neutropenia); remia; potential risk of immune-mediated reduced costs; reduced risk of cathe- vitritis ter-related infection; psychological benefit of stopping therapy, owing to CD4 cell increase NOTE. CMV, cytomegalovirus; GI, gastrointestinal; MAC, Mycobacterium avium complex; PCP, Pneumocystiscarinii pneumonia; TMP-SMZ, trimethoprim-sulfamethoxazole.

Although large randomized trials may confirm the results of pretherapy plasma HIV RNA levels and therapy-induced observational data for discontinuation of primary prophylaxis, changes in HIV RNA levels with use of data from the nucle- these types of studies may be less feasible for evaluating dis- oside antiretroviral therapy era (ACTG 175) [20]. Each 1-log continuation of secondary prophylaxis for MAC infection and decrement in baseline viral load (i.e., baseline viral load of 1000 CMV infection because of the heterogeneity of these oppor- in 1 patient vs. 10,000 in another) was associated with an 83% tunistic diseases. In this setting, patients with established MAC reduction in the risk of developing AIDS-defining illness or or CMV infection who have responded to antiretroviral therapy death. In addition, patients who experienced a 1-log10 reduction can be followed in observational studies to determine risk fac- in plasma HIV RNA levels during therapy were 65% less likely tors for relapse of MAC or CMV infection after discontinuing to develop AIDS or death during the study, a finding that maintenance therapy (secondary prophylaxis) against these suggests that both baseline levels and therapy-induced changes pathogens. To date, several studies of CMV infection [11–16] are important to consider. and 1 study of MAC infection [17] have found that discontin- Marschner et al. combined data from 1330 patients in 7 stud- uation of maintenance therapy has not been followed by re- ies conducted during the nucleoside era to further assess the crudescence of disease. The data from these studies can be used joint effects of plasma viral load and CD4ϩ cell count on the collectively to identify the risk of reactivation and the char- risk of disease progression or death [21]. These investigators acteristics of patients who remain disease-free over long found that the risk of disease progression decreases propor- intervals. tional to the decrease in HIV RNA. In addition, they deter- Although setting threshold levels can be helpful in designing mined that the prognostic implications of any given HIV RNA intervention trials and interpreting observational studies, pre- reduction depended on the response of the CD4ϩ cell count to dicting an individual patient’s risk of developing an OI is also treatment. The lack of decline in the plasma HIV RNA level ϩ important. Plasma viral (HIV) load, duration of CD4 cell during therapy more strongly indicated a higher risk for disease ϩ count increase, CD4 cell count nadir, lack of pathogen-specific progression if it occurred in conjunction with no increase in immunity, and history of OI have all been identified as markers CD4ϩ cell count. In this analysis, the risk of disease progression for increased OI risk. was reduced by 51% for every 10-fold decrease in HIV RNA over 6 months of therapy, and each CD4ϩ cell count increase of 100/mm3 was associated with a 24% reduction in the risk of The Role of CD4+ Cell Counts and Plasma Viral Load progression. in Predicting OI Risk Williams et al. specifically focused on the relationship be- Several studies have described the relationship of plasma tween baseline levels and treatment-induced changes in HIV HIV load to the risk of progression to AIDS or death [18–24]. RNA and the risk of 3 OIs [25]. Data on 842 patients enrolled This work has clearly demonstrated the prognostic value that in antiretroviral therapy trials from the nucleoside antiretroviral ϩ viral load adds to that of the CD4ϩ cell count data in predicting era were used to evaluate the relationship between CD4 cell the risk of disease progression and death. Less is known about count and plasma viral load changes and the risk of developing how antiviral therapy–induced changes in viral load and CD4ϩ PCP, MAC infection, or CMV disease. It should also be noted cell counts might be used to help inform clinical decisions about that these analyses were adjusted for the use of prophylaxis. the use of prophylaxis. As expected, baseline CD4ϩ cell and plasma HIV RNA mea- Katzenstein et al. examined the prognostic value of both surements were independent predictors of these OIs. For every CID 2000;30 (Suppl 1) Guiding Principles for Discontinuing OI Prophylaxis S69 decrement of 50 CD4ϩ cells at baseline, the risk of developing most useful in predicting the short-term risk of developing an any 1 of the OIs increased by 40%–60%. The relative risk of OI. an increase in OI risk associated with each 1-log increase in Early reports [30–32] suggested that patients receiving ther- baseline HIV RNA (log10 copies/mL) varied across the OIs, apy with protease inhibitors might develop OIs at higher-than- ranging from 1.74 for PCP to 2.57 for CMV infection and 3.13 expected CD4ϩ cell values; however, subsequent experience has for MAC infection. Early (week 8) reductions in plasma viral shown that this appears to be a relatively rare event. Michelet load after the initiation of therapy were associated with sig- et al. reported on 46 patients in whom clinical events occurred nificant reductions in the risks of PCP, MAC infection, and after initiation of therapy with protease inhibitors, during the Downloaded from https://academic.oup.com/cid/article/30/Supplement_1/S66/393981 by guest on 24 September 2021 CMV infection. It is noteworthy that these early decreases in first year of protease inhibitor availability in France [33]. For ϩ plasma HIV RNA better predicted risk than did increases in the group who developed OIs, the mean CD4 cell count before CD4ϩ cell count. This may be explained in part by the fact that protease inhibitor therapy was 22/mm3, and the mean time to these studies found only very modest increases in CD4ϩ cell the onset of the event was 62 days, with 68% of the events count. Collectively, these studies indicate that decreases in viral occurring within the first 2 months of such therapy. The mean ϩ 3 load, even modest ones, reduce the OI risk. CD4 cell count at the time of the event was 74/mm , and the Data from the protease era on the prognostic role of the mean reduction in plasma viral load was 1.6 log10 copies/mL. CD4ϩ cell count and plasma viral load have yielded findings These results suggest that patients who begin therapy with ϩ similar to those described with regard to nucleoside-treated pa- very low CD4 cell counts remain at high risk of developing tients. The early clinical end-point trials using protease inhib- an OI during the first several months of therapy, even as their ϩ itors provide additional insight into the use of CD4ϩ cell count CD4 cell counts increase and their viral loads decrease. These and plasma viral load in predicting OI risk. It is important to data support the idea that discontinuing prophylaxis should be ϩ note that these studies were conducted primarily with subjects delayed at least until the CD4 cell increase has been sustained who were receiving OI prophylaxis, which may limit the con- for 6 months. Although it is clear that the critical determinant of OI risk clusions that can be drawn. Nessly examined the utility of ϩ ϩ remains the current CD4 cell number, data are emerging to plasma HIV RNA and CD4 cell changes for predicting clinical suggest that the nadir CD4ϩ cell count may provide additional events with use of data from a clinical trial of indinavir [26]. information. The influence of this nadir on the subsequent risk Independent predictors of clinical end points included baseline ϩ of developing an OI was examined in the EuroSIDA Study CD4 cell count, baseline plasma HIV RNA level, last available cohort [34]. Rates of disease progression were compared be- HIV RNA level and CD4ϩ cell count, and average changes in tween 2 groups of patients: (1) subjects whose CD4ϩ cell counts these parameters over time. A threshold value of 350 CD4ϩ had never dropped below 150/mm3 (n=4230 ) and (2) subjects cells/mm3 was observed, above which no clinical events oc- who previously had lower CD4ϩ cell counts that increased to curred. It is interesting that no such threshold was identified and were sustained at 1200/mm3 during therapy (n=1122 ). for plasma HIV RNA level; however, the risk of developing a ϩ Subjects in group 2 were further stratified by nadir CD4 cell clinical event was reduced by 89% among subjects who had at count (!50, 50–99, and 100–150). The rate for development of least 1 HIV RNA level measurement !500 copies/mL. an AIDS-defining illness or death was statistically significantly Data from ACTG 320, a study that compared a combination ϩ lower for those whose CD4 cell count had never dropped of indinavir, zidovudine, and lamivudine with a combination below 150/mm3 (3.7 events per 100 patient-years) than the rate of ziduvudine and lamivudine, provide additional insight into in each of the subgroups with lower nadir CD4ϩ cell counts. OI risk in the setting of potent antiretroviral therapy [27, 28]. Events occurred at the rates of 5.9, 8.1, and 6 events per 100 The majority of the clinical end points in the three-drug arm patient-years for subjects with nadir CD4ϩ cell counts !50, ϩ occurred early in the study in patients with CD4 cell counts 50–99, and 100–149/mm3, respectively, which suggests that the below the established thresholds for each OI. In addition, those nadir value may be an important factor in the decision to dis- whose plasma HIV RNA levels were suppressed to !500 copies/ continue OI prophylaxis. The CD4ϩ cell count nadir was also mL were much less likely to develop an AIDS-defining event found to be a risk factor for PCP in the Adult Spectrum of during follow-up than were those who had HIV RNA levels Disease Study database among patients whose CD4ϩ cell counts of 1500 copies/mL [29]. increased during antiretroviral therapy [7]. Collectively, these data indicate that plasma viral load may Other markers of pathogen-specific immunity are now being be important to consider when making decisions about whether scrutinized to determine their utility in predicting the risk of to stop prophylaxis, or whether to restart prophylaxis for pa- specific OIs. Preliminary reports concerning assays evaluating ϩ tients who are approaching a CD4 cell count threshold. in vitro lymphocyte function (lymphoproliferative assays) While it is clear that having a higher plasma viral load in- against specific pathogens (MAC and CMV) have suggested creases the risk of disease progression over time at any CD4ϩ that these tests may help identify patients who could possibly cell value, it appears that absolute CD4ϩ cell values may be safely discontinue maintenance therapy (secondary prophy- S70 Currier CID 2000;30 (Suppl 1) laxis) after a sustained increase in CD4ϩ cell count during ther- the prevention of Mycobacterium avium complex (MAC) disease in HIVϩ ϩ р apy [35–37]. These assays are not yet standardized or available patients with CD4 counts 100 cells/mL [abstract 205]. In: Program and abstracts of the 3d Conference on Retroviruses and Opportunistic Infec- outside of research settings, but if preliminary reports are con- tions (Washington, DC). Alexandria, VA: Foundation for Retrovirology firmed, they hold promise for the future. and Human Health, 1996. In summary, data available from both epidemiological stud- 7. Dworkin MS, Hanson DL, Jones JL, Kaplan J, the Adult/Adolescent Spec- ies and clinical trials suggest that the increases in CD4ϩ count trum of HIV Disease Project (ASD). Risk for primary Pneumocystis carinii pneumonia (PCP) and disseminated nontuberculous mycobacteriosis induced by antiretroviral therapy offer protection against OIs. ϩ ϩ (dMb) after antiretroviral therapy (ART) associated increase in the CD4 Plasma viral load and both current and nadir CD4 cell count Downloaded from https://academic.oup.com/cid/article/30/Supplement_1/S66/393981 by guest on 24 September 2021 T-lymphocyte count [abstract 692]. In: Program and abstracts of the 6th add further prognostic information, and markers of pathogen- Conference on Retroviruses and Opportunistic Infections (Chicago). Al- specific immunity may eventually help guide discontinuation of exandria, VA: Foundation for Retrovirology and Human Health, 1999. secondary prophylaxis. In the short term, the CD4ϩ cell count 8. Currier JS, Williams PL, Koletar S, et al. Randomized placebo-controlled is the most important factor to consider when making decisions trial of azithromycin prophylaxis for the prevention of Mycobacterium avium complex in subjects with increases in CD4 cells on antiretroviral about starting or stopping prophylaxis. therapy [abstract LB-23]. In: Program and abstracts of the 39th Inter- ϩ 3 It is true that if 2 people have CD4 cell counts of 350/mm , science Conference on Antimicrobial Agents and Chemotherapy (San and if the plasma viral load is 100,000 copies/mL in one and Francisco). Washington, DC: American Society for Microbiology, 1999. 10,000 copies/mL in the other, the person with the higher viral 9. El-Sadr WM, Burman W, Grant L, et al. Prophylaxis for Mycobacterium load is at greater risk of progressing to a clinical event over avium complex can be deferred among patients with a past CD4 count !50 cells/mm3 who responded to antiretroviral therapy: results of a pla- time. However, as long as the CD4ϩ cell count can be moni- cebo-controlled trial (CPCRA 038) [abstract 247]. In: Program and ab- tored, there are no compelling data to suggest that the high stracts of the 7th Conference on Retroviruses and Oportunistic Infections. viral load alone is reason to start PCP prophylaxis when the Alexandria, VA: Foundation for Retrovirology and Human Health, 2000. CD4ϩ cell count is 1200/mm3. The higher viral load might 10. Lopez JC, Pena JM, Miro JM, et al. 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