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Preaching What We Practice: New Guidelines for OI Prophylaxis

In the most recent revision of the U.S. Public Health Service/Infectious Diseases Society (USPHS/IDSA) guidelines for opportunistic infection (OI) prophylaxis released in late August, the pronouncements of medical officialdom have largely caught up with the practices of experienced providers and patients.¹ Population-based data from New York and across the country have shown a sharp decline in AIDS-related OIs and mortality that began in late 1995 and has continued, albeit at a somewhat slower pace, through the first half of 1999.^2,3 The astonishing improvement in the lives of our patients has become so ubiquitous that by 1998 medical residents in one New York City hospital were unfamiliar with the evaluation and treatment of Pneumocystis carinii pneumonia (PCP) (personal communication, Abigail Zuger, MD), a situation that would have been inconceivable only a year or two earlier. These dramatic changes were tied to the widespread use of OI prophylaxis and to the introduction of potent combination antiretroviral therapy and were accelerated by the availability of PIs. Prospective, randomized, controlled trials also demonstrated significant protection from OIs as well as striking improvements in CD4-cell counts and HIV viral loads.^4,5

The upshot has been nothing short of a revolution in AIDS care. As CD4-cell counts soared, viral loads plummeted, beds on inpatient HIV wards emptied, and patients with advanced HIV disease gained weight and went back to work as a result of potent combination therapy, some patients and providers took the initiative and simply stopped OI prophylaxis -- and nothing much happened. Indeed, data from a number of recent studies indicate at least partial recovery of immune function in patients receiving PI-based combination antiretroviral therapy.^6,7 The most recent revision of the guidelines largely acknowledges what has already become widely accepted practice by experienced clinicians.

Observational Data on Withdrawal of PCP Prophylaxis

Guidelines promulgated by the PHS have to be data-driven, and thus far the majority of the data have concerned withdrawal of PCP prophylaxis among patients who have had a good response to potent combination antiretroviral therapy. Most of the available data refers to discontinuation of primary prophylaxis and derives from two large observational studies from Europe. These studies demonstrated substantial protection for patients who respond to antiretroviral therapy and then discontinue primary prophylaxis for PCP. By and large, these patients have had a sustained increase in CD4 counts to greater than 200 cells/mm³, with an approximate median CD4 count of 350 cells/mm³ at discontinuation of prophylaxis. In this context "sustained" means that the median follow-up ranged from 6 to 12 months after prophylaxis was stopped. The overwhelming majority had achieved an optimal viral load response, and most of those who still had measurable virus tended to have values less than 10,000 copies/ml. The Swiss HIV Cohort Study is an observational effort at seven sites where HIV-infected individuals who are at least 16 years old are followed every six months. STOPCOX (COX is the acronym for co-trimoxazole, the European name for TMP-SMX) was a prospective substudy of patients receiving potent, combination antiretroviral therapy and primary PCP prophylaxis who achieved both a total CD4 count above 200 cells/mm³ and a CD4 percent of at least 14 for three months or more.⁸ CD4-cell counts were repeated every three months, and participants were followed for the development of PCP and toxoplasmosis as well as survival. Of 262 patients, 88.5% were prescribed a PI-containing regimen, and 46.2% were seropositive for Toxoplasma gondii. The median CD4 count at nadir was 110 cells/mm³. At time of entry into STOPCOX, the median CD4 count was 325 cells/mm³ and median viral load was 2.0 log₁₀. Participants were followed for a median of 11.3 months (range, 3 to 18.8), and by the study's end the me-dian CD4 count had increased to 422 cells/mm³ and the viral load had decreased to 1.9 log₁₀. Not a single case of PCP or toxoplasmosis was diagnosed.

The EuroSIDA cohort has a similar structure except that all participants had CD4 counts less than 500 cells/mm³ at enrollment. Study subjects are followed every six months at 52 sites in Europe and Israel. Among patients receiving "highly active antiretroviral therapy" ("HAART" -- defined here as at least one PI and at least two NRTIs prescribed after July 1996), 378 subsequently discontinued PCP prophylaxis and were followed for up to two years.⁹ Most (319) had never had PCP, although 59 had been receiving secondary PCP prophylaxis. The median CD4 counts at nadir were 123 cells/mm³ and 60 cells/mm³, respectively, for the primary and secondary prophylaxis groups; similar increases in CD4 counts (164 cells/mm³ and 174 cells/mm³, respectively) were seen after initiating HAART. At the time prophylaxis was stopped, the median CD4 counts for the two groups were almost identical (274 cells/mm³ and 270 cells/mm³, respectively), and the median viral load was 500 copies/ml in both groups. Forty-eight percent in each group had viral loads less than 500 copies/ml and only a small proportion (12% in the primary and 7% in the secondary prophylaxis group) had viral loads above 50,000 copies/ml. Although 9.7% in the primary prophylaxis group and 17% in the secondary group still had total CD4 counts under 100 cells/mm³ when prophylaxis was stopped, overall, the majority of the patients discontinued prophylaxis when their CD4 counts had exceeded 200 cells/mm³ for at least six months and their viral loads were suppressed to less than 10,000 copies/ml. Not a single case of PCP or toxoplasmosis was observed with 247 person-years of follow-up.

Data from Randomized and Retrospective Studies

Although these large studies were observational, data from an ongoing randomized study¹⁰ and retrospective data from the CDC¹¹ support these results. No cases of PCP had yet occurred when an interim analysis of a multicenter, open-label trial in Spain was presented in February.¹⁰ At that time the median follow-up was 6.7 months. Participants had either a prior history of PCP or a CD4 count less than 200 cells/mm³ and were receiving a PI-based regimen of at least three drugs and PCP prophylaxis. Prior to enrollment, all participants had achieved both a total CD4 count greater than 200 cells/mm³ and a viral load less than 5,000 copies/ml for at least three months. About half of the participants had a history of injection drug use. Subjects were randomized to continue or to stop their prescribed PCP prophylaxis. Overall the study population was significantly immunosuppressed, with a history of total CD4 counts below 200 cells/mm³ for more than 41 months. Most -- 77% in the stop-prophylaxis arm and 85% in the continue-prophylaxis arm -- had viral loads below 500 copies/ml at study entry.

The New Guidelines

Primary PCP Prophylaxis

Despite these encouraging data, the optimal criteria for discontinuing prophylaxis are still unknown. Should a sustained reduction in viral load -- and to what level -- trigger withdrawal of prophylaxis, or is a sustained CD4 count response above 200 cells/mm³ sufficient? Under what circumstances should prophylaxis be reinstituted? For now, the guidelines suggest that CD4 count increases be sustained above 200 cells/mm³ for at least three to six months before primary PCP prophylaxis is withdrawn. Vague wording for the correlative viral-load response suggests a "sustained reduction" for at least three to six months as well, but "reduction" is not further defined. It is important to remember that the first PHS guidelines for PCP prophylaxis used a small prospective cohort followed at the NIH Clinical Center and a much larger observational database from the Multicenter AIDS Cohort Study to define patients at highest risk, so reliance on observational data to revise the guidelines now should not be disquieting.¹²

Secondary PCP Prophylaxis

Because of the small number of patients studied thus far who have discontinued secondary prophylaxis, the guidelines refrain from making a clear recommendation. At least one ongoing study (ACTG 888) in which a significant proportion of patients stopping prophylaxis have had a prior episode of PCP should provide additional information in the near future.

Other OIs

For patients on primary or secondary prophylaxis for other OIs, the data are also scant. The conclusion that one should withdraw primary prophylaxis for OIs other than PCP or discontinue chronic maintenance therapy (secondary prophylaxis) has been inferred from a number of sources, including the accumulating evidence of minimal risk for PCP after discontinuing primary prophylaxis, CDC retrospective data, and the overall decrease in OIs in population-based data. Primary prophylaxis for Mycobacterium avium complex (MAC), still recommended for adults and adolescents with CD4 counts less than 50 cells/mm³, may be stopped when the CD4 count is sustained above 100 cells/mm³ "for a reasonable period (e.g., more than three to six months)" and viral loads have been "suppressed" for a similar period. However, a randomized double-blind study of weekly azithromycin prophylaxis in 643 patients who have responded to PI-based combination therapy (ACTG 362) has had only two MAC endpoints after a median follow-up of 56 weeks. This finding suggests that the risk of stopping primary MAC prophylaxis is no greater than that of stopping primary PCP prophylaxis in antiretroviral responders.

The PHS recommendation regarding primary prophylaxis against cytomegalovirus (CMV) has always been guarded. Without specific data, the new version of the guidelines has not addressed its withdrawal in antiretroviral-therapy responders. Discontinuation of secondary prophylaxis (chronic maintenance therapy) for CMV and MAC is also handled differently. Based on a number of prospective observational studies,^13,14 the guidelines now recommend that chronic maintenance therapy for CMV retinitis may be discontinued in antiretroviral-therapy responders who experience a substantial rise in total CD4 counts to above 100 to 150 cells/mm³ for at least three to six months, and whose viral loads have been adequately suppressed. Considerably less information -- a single paper describing a handful of patients -- is available on the risks of discontinuing chronic maintenance therapy for disseminated MAC infection.¹⁵ Very stringent criteria were utilized before discontinuation of maintenance therapy in these patients, including an adequate CD4-cell count response to PI-based potent combination therapy, receipt of at least a year of combination maintenance therapy for disseminated MAC, and two negative blood cultures plus a negative bone marrow culture for MAC. The revised guidelines acknowledge that patients with disseminated MAC and an increase in CD4 counts above 100 cells/mm³ after 6 to 12 months of HAART may be at low risk for recurrence, but discontinuation of maintenance therapy is not recommended because of the paucity of available data.

"HAART" Regimens

It is important to understand that the data that underlie the revised guidelines were generated almost exclusively from patients receiving PI-based combination antiretroviral therapy. Recently, non-PI-containing combination therapies that have demonstrated a significant impact on CD4-cell counts and viral load have also been termed "HAART." In fact, the same clinical benefits may accrue to potent triple reverse transcriptase inhibitor regimens -- whether based on an NNRTI, such as efavirenz, or an NRTI, such as abacavir -- but evidence is not yet available.

Other Changes in OI Prophylaxis

There are a number of other important changes in the revised guidelines. The criteria for initiating PCP prophylaxis have been broadened to include a prior AIDS-defining illness other than PCP for patients who would not otherwise qualify for prophylaxis according to the existing criteria (CD4 count <200 cells/mm³, thrush, and unexplained fever >100°F for more than two weeks). This recommendation is based on data from the Adult and Adolescent Spectrum of Disease project, which is a CDC-sponsored retrospective chart abstraction study in a large number of hospitals and clinics.¹¹ Atovaquone has been added as an alternative for patients intolerant of TMP-SMX, based on the results of a study that showed equivalent protection from PCP for atovaquone or dapsone in sulfa-intolerant individuals.¹⁶

An enormous joint effort by the ACTG, Community Program for Clinical Research on AIDS, the CDC, and the Pan-American Health Organization resulted in the completion of a study comparing a two-month course of rifampin and pyrazinamide with a standard course of INH for preventing tuberculosis in PPD-positive patients.¹⁷ Short-course prophylaxis provided equivalent protection and is a reasonable alternative approach to daily (or twice-weekly) INH for nine months, although the use of rifampin (or its substitution by rifabutin) in patients receiving PIs or NNRTIs must be carefully considered because of potential drug interactions.

For the first time the guidelines address human herpesvirus 8 (HHV-8), the putative cause of Kaposi's sarcoma, and hepatitis C virus (HCV) as OIs. Although the new section on HHV-8 acknowledges that both potent combination antiretroviral therapy and antiherpes agents such as ganciclovir and foscarnet have resulted in lower rates of KS, neither routine serologic testing to identify patients at risk nor prophylactic use of anti-CMV agents has been established. On the other hand, because injection drug use is the primary route of HCV transmission in the U.S., the guidelines advise routine testing of patients for HCV coinfection and offer numerous recommendations for changing drug-use behaviors. These include substance-abuse treatment, safe injection practices, and avoidance of excessive alcohol by coinfected patients to limit hepatic damage. Recommended safe injection practices include obtaining sterile syringes from pharmacies or needle exchange programs (where available). These are bold recommendations for a federal agency, and should be applauded.

Conclusion

In the rapidly changing world of HIV disease management, the uses of OI prophylaxis continue to evolve. In the era when antiretroviral therapy offered only a brief reprise from progressive immunodeficiency, fine-tuning prophylaxis and extending its reach were noble and appropriate goals. Now, the successes of combination antiretroviral therapy have dramatically altered the natural history of treated HIV disease and are driving the withdrawal of prophylaxis against PCP -- an OI that at one time had affected 78% of all AIDS patients. Although there are far fewer data, the trend for managing other common end-stage complications, such as MAC and CMV, is following suit. The range of available agents for PCP and TB prophylaxis continues to expand, as does the definition of AIDS-related OIs, which now includes other chronic viral coinfections and their sequelae (e.g., hepatitis, HPV, HHV-8), even though there is not much that can be done about them at this time in terms of chemoprophylaxis.

Response to antiretroviral therapy -- as measured by increased CD4 cell counts and control of viral load -- is not in itself a guarantee that all patients will reclaim the full repertoire of protective immune responses. There have been anecdotal reports of patients who have relapsed with a specific OI despite high CD4 cell counts and undetectable viral loads. For such people, and for the much larger number of patients who do not thrive on the new treatment regimens for HIV, continued prevention of OIs will remain an important aspect of disease management, and this latest iteration of the PHS guidelines will be welcome news.

— Judith Feinberg, MD

Dr. Feinberg is an Associate Editor of ACC.

Published in AIDS Clinical Care November 1, 1999

Citation(s):

1. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1999 August 20 48 RR-10 1-66.

2. Update: Trends in AIDS incidence -- United States, 1996. MMWR Morb Mortal Wkly Rep 1997 Sep 19 46 861-867.

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3. Palella FJ et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998 Mar 26 338 853-860.

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4. Hammer SM et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997 Sep 11 337 725-733.

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5. Gulick, RM et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997 Sep 11 337 734-739.

6. Lederman MM et al. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: Results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 1998 Jul 178 70-79.

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7. Autran B et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997 Jul 277 112-116.

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8. Furrer H et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. N Engl J Med 1999 Apr 29 340 1301-1306.

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9. Weverling GJ et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis in HIV-1-infected patients treated with highly active antiretroviral therapy. Lancet 1999 April 17 353 1293-1298.

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10. Lopez JC, Pena JM, Miro JM, Podzamczer D. Discontinuation of PCP prophylaxis is safe in HIV-infected patients with immunological recovery with HAART. Preliminary results of an open, randomized and multicenter clinical trial. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 abstr. LB7. .

11. Dworkin M et al. The risk of Pneumocystis carinii pneumonia (PCP) and disseminated nontuberculous mycobacteriosis (dMb) after an antiretroviral therapy (ART) associated increase in the CD4+ lymphocyte count. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 abstr. 692. .

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13. MacDonald JC et al. Lack of reactivation of cytomegalovirus retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy. J Infect Dis 1998 May 177 1182-1187.

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14. Tural C et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis 1998 April 177 1080-1083.

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15. Aberg JA et al. Eradication of disseminated Mycobacterium avium complex in four patients after 12 months antimycobac-terial therapy combined with highly active antiretroviral therapy. J Infect Dis. 1998 November 178 1446-1449.

16. El-Sadr et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med 1998 December 24 339 1889-1895.

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17. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR. 1998 October 30 47 201-251.