selection of optimal anti-pneumocystis treatment, the role of steroids and options ..... Black, J. R., Feinberg, J., Murphy, R. L., Fass, R. J., Carey, J. & Sattler, F. R. ...
JAC
Journal of Antimicrobial Chemotherapy (1997) 40, 315–318
Current issues in the treatment and prophylaxis of Pneumocystis carinii pneumonia in HIV infection Stephen D. Morris-Jones and Philippa J. Easterbrook* Department of HIV and Genitourinary Medicine, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
Pneumocystis carinii pneumonia (PCP) remains the most common serious opportunistic infection affecting HIVinfected adults and children, despite a decline in its incidence since the widespread introduction of prophylaxis. 1–3 Both in the USA and Europe, more than a quarter of cases of first-time PCP still occur in persons unaware of their HIV status,4,5 highlighting the importance of early identification of HIV infection by encouraging those at high risk of becoming HIV-infected to undergo testing. Once found to be HIV seropositive, all patients should have regular medical follow-up to ensure that primary PCP prophylaxis is initiated at the appropriate time. The clinical presentation, diagnosis and management of PCP have been comprehensively reviewed recently.6 We address here several management issues, including the selection of optimal anti-pneumocystis treatment, the role of steroids and options for salvage therapy, the current status of prophylactic regimens for adults and children, and the management of intolerance to prophylaxis. Whatever the severity of disease, the cornerstone of PCP treatment remains co-trimoxazole, given at a total daily dose of 20 mg/kg of trimethoprim and 100 mg/kg of sulphamethoxazole in two to four divided doses, either intravenously or orally. Treatment is for 21 days, and should be followed by continuous prophylaxis. Side-effects, which usually become apparent after 1–2 weeks of therapy, are common, and include fever, rash (40%), bone marrow suppression (40%), nausea and vomiting (25%), and liver function abnormalities (20%);7 these are sufficiently severe to require discontinuation of co-trimoxazole therapy in about a third of cases. 8 The second-line therapy for severe PCP, if co-trimoxazole cannot be tolerated, is intravenous pentamidine, at a daily dose of 4 mg/kg for 21 days. Again, adverse effects are frequent and include nephrotoxicity (60%), leucopenia (45%), hypotension (25%), nausea and vomiting (25%), hypoglycaemia and/or hypocalcaemia (20%).7 Close monitoring of serum electrolytes, glucose, calcium and blood pressure during therapy is required. A further regimen for patients with mild or moderately severe PCP who cannot tolerate co-trimoxazole, is dapsone
with trimethoprim for 21 days. A recent trial showed comparable rates of efficacy and dose-limiting toxicity with dapsone as with co-trimoxazole or clindamycin with primaquine.8 Methaemoglobinaemia due to dapsone occurs in most patients but only rarely is symptomatic or necessitates cessation of therapy. Although unlicensed in the UK for PCP treatment, combination clindamycin/primaquine is being widely used as an alternative to iv pentamidine. Clindamycin is usually given orally at a dose of 600 mg three times daily together with a daily 30 mg oral dose of primaquine.8–10 Important haematological toxicity occurs in over 25% of patients, and a rash in 20%, but in general this combination is very well tolerated.8 Clostridium difficile infection should be remembered as a possible cause of diarrhoea in these patients. Atovaquone, a hydroxynaphthoquinone originally developed as an antimalarial agent but with powerful cidal activity against pneumocystis in the animal model,11 has now been approved in the UK for the treatment of mild or moderately severe PCP, at a dose of 750 mg three times daily.12 Its high failure rate12 and apparently low toxicity profile13 reflect the poor absorption and bioavailability of the current formulation. For this reason, it is usually reserved for patients with mild PCP who are intolerant of both co-trimoxazole and the second-line regimens. It should not be considered a therapeutic option in patients with severe PCP or those who have diarrhoea or malabsorption. Other unlicensed drugs with a role limited to ‘salvage’ therapy include trimetrexate/folinic acid, and eflornithine. Experimental drugs under study are albendazole, terbinafine, and 1-671,329, a 1,3- -glucan synthesis inhibitor. The use of adjuvant corticosteroid therapy in adult patients with moderate to severe PCP is well established. In severe disease, when arterial oxygen saturation is below 91% and the partial pressure below 8.0 kPa, adjuvant highdose corticosteroids reduce both the risk of respiratory failure and death,14–16 as well as the rate of intolerance to co-trimoxazole.17 Results from a small paediatric study suggest that its use in children is also associated with
*Corresponding author.
315 © 1997 The British Society for Antimicrobial Chemotherapy
Leading article improved survival.18 However, some reports suggest that adjuvant corticosteroids may exacerbate co-existing CMV disease in those with advanced immunosuppression.19,20 Several reports of outbreak clusters of PCP infection, together with the frequent failure of even the most sensitive methods to detect P. carinii in immunocompetent individuals, suggest that PCP may be due to re-infection rather than reactivation.6 As a result, some authorities have recommended the re-evaluation of infection control guidelines with regard to limiting direct exposure of those at risk to known cases of PCP.21 However, data are insufficient to support this recommendation as standard practice, and more research is needed to identify routes of transmission for PCP. Several studies have observed the profound effect of the introduction of widespread PCP prophylaxis on overall survival, quality of life and resource utilization in HIV infection.22 But questions remain as to who should receive prophylaxis. Evidence from numerous well-designed, randomized, controlled trials have confirmed the benefits of prophylaxis in: (i) patients with absolute CD4 lymphocyte counts below 200 106/L (or a CD4 percentage below 14–16%) and those with higher counts who have oropharyngeal thrush or unexplained fever for more than 2 weeks; and (ii) all patients with a previous episode of PCP.23 No data support the initiation of prophylaxis in patients who do not meet these standards, and the premature use of prophylaxis carries a risk of sensitization. At least until more data are available, the substantial increases in circulating CD4 lymphocyte numbers seen with the advent of powerful anti-retroviral drug combinations cannot be assumed to reflect complete restoration of the immune repertoire. The risk, therefore, of PCP (as with other opportunistic infections) is determined by the lifetime CD4 lymphocyte nadir, and prophylaxis should be continued (Masur, H., data presented at Fourth Conference on Retroviruses and Opportunistic Infections, Washington DC, USA, 1997). For the moment, resistance of P. carinii to co-trimoxazole is not a clinical problem. However, the finding of isolates with recently acquired point mutations in the gene which codes for the enzyme dihydropteroate synthetase, a key enzyme target of cotrimoxazole, may indicate that susceptibility to this drug will not continue indefinitely.24 Effective prevention of PCP in the HIV-infected paediatric population requires that children born to HIVinfected women are identified as early in life as possible, since more than half of the cases of PCP in those with perinatally acquired HIV infection occur in children aged between 3 and 6 months.25 It is now recommended that PCP prophylaxis is initiated for all HIV-exposed children at 4–6 weeks of age, while they are still undergoing evaluation for HIV infection, regardless of their CD4 lymphocyte count.26 Prophylaxis should be discontinued in children who are subsequently found not to be HIVinfected, but should be continued through the first year of life in those whose infection status remains unknown.
The choice of which of the three standard prophylaxis regimens (co-trimoxazole, dapsone and aerosolized pentamidine) to use in clinical practice is often problematic, since regimens of varying dose and frequency are available. Oral regimens are effective and inexpensive but have a high incidence of side-effects. Aerosolized pentamidine is better tolerated but is more expensive and lacks the antitoxoplasma activity of either co-trimoxazole or dapsone with pyrimethamine, and the antibacterial effect of co-trimoxazole (protective against, for example, sinusitis, bronchitis, pneumonia and bacteraemia). A large clinical trial of these primary prophylaxis regimens confirmed that use of co-trimoxazole 960 mg was the regimen of choice.27 Alternatives include the use of 480 mg daily (or 960 mg three times per week), dapsone (50 mg bd or 100 mg daily), dapsone/pyrimethamine (50 mg daily/ 50 mg weekly or 200 mg weekly/75 mg weekly), and aerosolized pentamidine (300 mg fortnightly via a Microcirrus nebulizer, Intersurgical, Wokingham, UK). A recent meta-analysis of 35 randomized trials involving 6538 patients confirmed the superior efficacy of cotrimoxazole in preventing both PCP and toxoplasmosis, but also that the rate of adverse events was reduced by 43%, without loss of efficacy, if 480 mg was given daily or 960 mg was given three times a week, instead of daily.28 Dose reduction diminished the toxicity of dapsone, but at the expense of efficacy. The analysis also showed that for those patients who were intolerant of the oral regimens, a dose increase in aerosolized pentamidine from 300 mg per month to 300 mg twice monthly halved the prophylaxis failure rate. A major predictor of prophylaxis failure is a fall in the CD4 lymphocyte count to below 75 106/L.29 Further PCP prophylactic activity may be achieved in such severely immunosuppressed patients by the addition of weekly azithromycin, similar to the prophylactic regimen for atypical mycobacterial disease.30 Despite numerous descriptive studies of the adverse events associated with co-trimoxazole, there are relatively few data on the optimal management of toxicity.31 With a non-life-threatening adverse reaction, such as a mild rash or abnormalities in liver function, there is little guidance on whether it is preferable to continue therapy, re-introduce the drug at a lower and gradually increasing dose or use a desensitization regimen. However, desensitization to co-trimoxazole should only be attempted if rash or fever occurs without evidence of associated mucositis or exfoliation. In a recent study, rapid desensitization to co-trimoxazole was achieved in 71% of patients longterm.32 However, the reported success rate varies considerably according to the protocol adopted.33–35 In co-trimoxazole-intolerant patients, the use of dapsone may also be problematic, because of the similarity between dapsone and co-trimoxazole. In a retrospective review, 40% of co-trimoxazole-intolerant patients were also subsequently intolerant of dapsone.36 Interestingly, it has been recently reported that gradual initiation of co-trimoxazole
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Leading article as primary PCP prophylaxis reduces the incidence of treatment-limiting adverse effects within the first 12 weeks, compared with commencing immediately with the full dose (960 mg).37 PCP prophylaxis should be administered to pregnant women, and co-trimoxazole is the preferred oral agent,38 although owing to concerns about teratogenicity some physicians may choose to initiate therapy after the first trimester, or minimize systemic drug absorption by using inhaled pentamidine. However, a retrospective review of pregnant HIV-infected women indicated no increased risk of congenital malformations with the use of co-trimoxazole.39 Less clinical experience has been accumulated for other agents, but pyrimethamine should be used with great caution because of its reported teratogenicity even at low doses.
References 1. Hoover, D. R., Saah, A. J., Bacellar, H., Phair, J., Detels, R., Anderson, R. et al. (1993). Clinical manifestations of AIDS in the era of Pneumocystis prophylaxis. New England Journal of Medicine 329, 1922–6. 2. Pitkin, A. D., Grant, A. D., Foley, N. M. & MIller, R. F. (1993). Changing patterns of respiratory disease inHIV positive patients in a referral centre in the United Kingdom between 1986–7 and 1990–1. Thorax 48, 204–7. 3. Katz, M. H., Hessol, N. A., Buchbinder, S. P., Hirozawa, A., O’Malley, P. & Holmberg, S. D. (1994). Temporal trends of opportunistic infections and malignancies in homosexual men with AIDS. Journal of Infectious Diseases 170, 198–202. 4. Duchin, J. S., Sohlberg, B., Buskin, S., Hopkins, S., Simon, P. (1996). Risk factors for Pneumocystis carinii pneumonia: delayed diagnosis of HIV-infection and failure to receive prophylactic therapy. In Proceedings of the Eleventh International Conference on AIDS, Vancouver, Canada, 1996. Abstract TuB114. 5. Flepp, M., Ledergerber, B., Schenker, C., Egger, M., Gebhardt, M. & Luthy, R. (1996). Pneumocystis carinii pneumonia as first AIDS indicator disease in the era of primary prophylaxis—why does it still occur? In Proceedings of the Eleventh International Conference on AIDS, Vancouver, Canada, 1996. Abstract TuB113. 6. Miller, R. F., Le Noury, J., Corbett, E. L., Felton, J. M. & De Cock, K. M. (1996). Pneumocystis carinii infection: current treatment and prevention. Journal of Antimicrobial Chemotherapy 37, Suppl. B, 33–53. 7. Sattler, F. R., Cowan, R., Nielsen, D. M. & Ruskin, J. (1988). Trimethoprim–sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Annals of Internal Medicine 109, 280–7. 8. Safrin, S., Finkelstein, D. M., Feinberg, J., Frame, P., Simpson, G., Wu, A. et al. (1996). Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. Annals of Internal Medicine 124, 792–802. 9. Black, J. R., Feinberg, J., Murphy, R. L., Fass, R. J., Carey, J. & Sattler, F. R. (1991). Clindamycin and primaquine as primary treatment for mild and moderately severe Pneumocystis carinii
pneumonia in patients with AIDS. European Journal of Clinical Microbiology and Infectious Diseases 10, 204–7. 10. Black, J. R., Feinberg, J., Murphy, R. L., Fass, R. J., Finkelstein, D., Akil, B. et al. (1994). Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS clinical trials group 044. Clinical Infectious Diseases 18, 905–13. 11. Hughes, W. T., Gray, V. L., Gutteridge, W. E., Latter, V. S. & Pudney, M. (1990). Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrobial Agents and Chemotherapy 34, 225–8. 12. Hughes, W., Leoung, G., Kramer, F., Bozzette, S. A., Safrin, S., Frame, P. et al. (1993). Comparison of atovaquone (566C80) with trimethoprim–sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. New England Journal of Medicine 328, 1521–7. 13. Dohn, M. N., Weinberg, W. G., Torres, R. A., Follansbee, S. E., Caldwell, P. T., Scott, J. D. et al. (1994). Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Annals of Internal Medicine 121, 174–80. 14. Bozzette, S. A., Sattler, F. R., Chiu, J., Wu, A. W., Gluckstein, D., Kemper, C. et al. (1990). A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. New England Journal of Medicine 323, 1451–7. 15. Gagnon, S., Boota, A. M., Fischl, M. A., Baier, H., Kirksey, O. W. & La Voie, L. (1990). Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. New England Journal of Medicine 323, 1444–50. 16. Bozzette, S. A. & Morton, S. C. (1995). Reconsidering the use of adjunctive corticosteroids in Pneumocystis pneumonia? Journal of Acquired Immune Deficiency Syndromes and Human Retro virology 8, 345–7. 17. Caumes, E., Roudier, C., Rogeaux, O., Bricaire, F. & Gentilini, M. (1994). Effect of corticosteroids on the incidence of adverse cutaneous reactions to trimethoprim–sulfamethoxazole during treatment of AIDS-associated Pneumocystis carinii pneumonia. Clinical Infectious Diseases B18, 319–23. 18. Sleasman, J. W., Hemenway, C., Klein, A. S. & Barrett, D. J. (1993). Corticosteroids improve survival of children with AIDS and Pneumocystis carinii pneumonia. American Journal of Diseases of Children 147, 30–4. 19. Nelson, M. R., Erskine, D., Hawkins, D. A. & Gazzard, B. G. (1993). Treatment with corticosteroids—a risk factor for the development of clinical cytomegalovirus disease in AIDS. AIDS 7, 375–8. 20. Jensen, A.-M. B., Lundgren, J. D., Benfield, T., Nielsen, T. L. & Vestbo, J. (1995). Does cytomegalovirus predict a poor prognosis in Pneumocystis carinii pneumonia treated with corticosteroids? Chest 108, 411–4. 21. Walzer, P. D. (1991). Pneumocystis carinii—new clinical spectrum? New England Journal of Medicine 324, 263–5. 22. Gallant, J. E., McAvinue, S. M., Moore, R. D., Bartlett, J. G., Stanton, D. L. & Chaisson, R. E. (1995). The impact of prophylaxis on outcome and resource utilization in Pneumocystis carinii pneumonia. Chest 107, 1018–23.
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Leading article 23. Kaplan, J. E., Masur, H., Holmes, K. K., Wilfert, C. M., Sperling, R., Baker, S. A. et al. (1995). USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: an overview. Clinical Infectious Diseases 21, Suppl. 1, S12–31. 24. Locke, A., Meshnick, S., Lane, B., Cannon, M., Kileen, A., Beals, T. et al. (1997). Mutations in Pneumocystis carinii associated with prophylaxis breakthroughs in AIDS patients. In Proceed ings of the Fourth Conference on Retroviruses and Opportunistic Infections, Washington, DC, 1997. Abstract No. 3. 25. Simonds, R. J., Oxotby, M. J., Caldwell, M. B., Gwinn, M. L. & Rogers, M. F. (1993). Pneumocystis carinii pneumonia among US children with perinatally acquired immunodeficiency virus infection. Journal of the American Medical Association 270, 470–3. 26. Wilfert, C. M., Masur, H., Gross, P. A., Kaplan, J. E., Holmes, K. K., Phair, J. P. et al. (1995). Quality standard for the prophylaxis of Pneumocystis carinii pneumonia in infants and children born to women infected with human immunodeficiency virus. Clinical Infectious Diseases 21 Suppl. 1, S132–3. 27. Bozzette, S. A., Finkelstein, D. M., Spector, S. A., Frame, P., Powderly, W. G., He, W. et al. (1995). A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. New England Journal of Medicine 332, 693–9. 28. Ioannidis, J. P. A., Cappelleri, J. C., Skolnik, P. R., Lau, J. & Sacks, H. S. (1996). A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Archives of Internal Medicine 156, 177–88. 29. Saah, A. J., Hoover, D. R., Peng, Y., Phair, J. P., Visscher, B., Kingsley, L. A. et al. (1995). Predictors for failure of Pneumocystis carinii pneumonia prophylaxis. Journal of the American Medical Association 273, 1197–202. 30. Dunne, M. W., Havlir, D., Dube, M., Sattler, F., Forthal, D., Kemper, C. et al. (1996). Prevention of Pneumocystis carinii pneumonia with azithromycin. In Proceedings of the Eleventh International Conference on AIDS, Vancouver, 1996. Abstract TuB410.
31. Jung, A. C., Douglas, S. & Paauw, D. S. (1994). Management of adverse reactions to trimethoprim–sulfamethoxazole in human immunodeficiency virus-infected patients. Archives of Internal Medicine 154, 2402–6. 32. Gluckstein, D. & Ruskin, J. (1995). Rapid oral desensitization to trimethoprim–sulfamethoxazole (TMP-SMZ): use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP-SMZ. Clinical Infectious Diseases 20, 849–53. 33. Bachmeyer, C., Salmon, D., Guerin, C., Barre, C., Hazebroucq, G., Sicard, D. et al. (1995). Trimethoprim– sulphamethoxazole desensitization in HIV-infected patients: an open study. AIDS 9, 299–300. 34. Piketty, C., Gilquin, J. & Kazatchkine, M. D. (1995). Efficacy and safety of desensitization to trimethoprim–sulfamethoxazole in human immunodeficiency virus-infected patients. Journal of Infectious Diseases 172, 611. 35. Beardsall, A. D., Coker, K., Woodfall, B. & Conway, B. (1996). Cotrimoxazole (TMP-SMX) desensitization using adjunctive steroid therapy in HIV/AIDS patients. In Proceedings of the Eleventh Inter national Conference on AIDS, Vancouver, 1966. Abstract TuB414. 36. Jorde, U. P., Horowitz, H. W. & Wormser, G. P. (1993). Utility of dapsone for prophylaxis of Pneumocystis carinii pneumonia in trimethoprim–sulfamethoxazole-intolerant, HIV-infected individuals. AIDS 7, 355–9. 37. Para, M. F., Dohn, M., Frame, P., Becker, S., Finkelstein, D. & Walawander, A. for the ACTG study team (1997). ACTG 268 trial–gradual initiation of trimethoprim/sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia. In Proceedings of the Fourth Conference on Retroviruses and Opportunistic Infec tions, Washington, DC, 1997. Abstract No. 2. 38. Sperling, R. S. & Stratton, P. (1992). Treatment options for human immunodeficiency virus-infected pregnant women. Obstet rics and Gynecology 79, 433–8. 39. Briggs, G. G., Freeman, R. K. & Yaffe, S. J. (1990). Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neo natal Risk, 3rd edn. Williams & Wilkins, Baltimore, MD.
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