Opportunistic Infections (OIs)

-Christian Hoffmann –

In Western industrialized countries, many opportunistic infections (OIs) that in previous years were considered prevalent, are now quite rare. This is particularly true for infections associated with severe immunodeficiency, such as CMV and MAC disease. The incidence of these OIs has been reduced to less than one-tenth of their frequency in the pre-HAART era (Brooks 2009, Buchacz 2010). ART has not only decreased the incidence of the OIs, but it has also changed the course of OIs considerably. In early years of the AIDS epidemic, the life expectancy of individuals diagnosed with their first AIDS defining illness was two to three years, at most. Today, however, many patients now live with AIDS for 15 years or longer. In our own clinical study of 144 patients with cerebral toxoplasmosis, data from 1990-1993 indicated a 5-year survival rate of 8%; it climbed to 30% by 1994-1996, and then to 80% since 1997 (Hoffmann 2007).

Up to 90% of patients who develop AIDS or severe opportunistic infections are unaware of their HIV infection status. Typically, these patients seek medical attention late and when their overall health condition is serious. Since AIDS remains life-threatening, every HIV clinician should be familiar with the diagnosis OIs and their respective therapy. Even with recent improvements, over the years, many challenges still exist. First, there is still no adequate treatment available for diseases such as PML or cryptosporidiosis. Second, resistance to treatment has become an increasing problem in other OIs such as PCP. Even today OIs like PML have a mortality rate comparable to that of a non-Hodgkin-lymphoma (ART-CC 2009). Third, ART does not always lead to immediate improvement. ART may even complicate things, given the atypical course of a variety diseases under ART (see below a separate sub-chapter on the so-called “immune reconstitution inflammatory syndrome” IRIS). Moreover, there are no documented guidelines for OI prophylaxis outside of the US, and the US recommendations last updated in 2008 (www.aids.info), cannot always be adopted elsewhere, since the seroprevalence rates of many infectious agents often differ.

Moreover, in small HIV centers or regions with low HIV prevalence, diagnostic problems for many OIs may occur, due to a lack of familiarity with and inability to recognize these rare pathogens. Therefore, it is highly recommended that specimens be sent to specialized reference laboratories. If needed, then further advice can also be sought from a specialized clinician or a clinical HIV center.

The predominant rule for nearly all OIs is that the poorer the immune status of the patient, the earlier the invasive diagnostic procedures should begin. The primary aim should not be to spare patients of the unpleasant procedures associated with extensive diagnostic test.  Moreover, diagnostic tests must be repeated, if the results are inconclusive and nothing can be identified the first time. Also, treatment should be initiated almost immediately.

The second rule is that many OIs can be excluded if the immune status is known. Table 1 indicates the CD4 cut-off values and the expectancy of certain OIs.

Table 1: Important cut-offs for CD4 T cells, above which particular AIDS illnesses are improbable. However, exceptions are always possible.

No cut-off

Kaposi’s sarcoma, pulmonary tuberculosis, HZV, bacterial pneumonia, NHL

< 250/ml

PCP, esophageal candidiasis, PML, HSV

< 100/ml

Cerebral toxoplasmosis, cryptococcosis, miliary tuberculosis

< 50/ml

CMV retinitis, atypical mycobacteriosis

The third OI rule is that if ART is not already in place, then it should be started as quickly as possible. Immune reconstitution is the best protection against relapses or other OIs. For patients with some OIs, such as PML or cryptosporidiosis, which have no specific therapy, starting ART is essentially the only hope. Especially in these cases there is no time to waste. ART should also be started rapidly in cases of PCP or toxoplasmosis. Although OI therapy is not without toxicity and problems regarding interactions the choice of antiretroviral drugs has increased making it easier to react to side effects. In ACTG 5164, a total of 282 subjects with an acute OI (63% PCP) were randomized to initiate ART immediately or after OI treatment (Zolopa 2009). At 48 weeks significantly less mortalities and AIDS-infections occurred in the group starting ART immediately. CD4 T cell counts also increased more rapidly. The risk of changing ART was slightly higher in immediate group, however, not the number of adverse events, hospitalization or cases of IRIS. With such results ACTG A5164 provides clear arguments for an immediate initiation of ART in the face of an existing PCP. However, this does not necessarly apply to all OIs (Lawn 2011): Two randomized studies in patients with cryptococcal meningitis (Makadzange 2010) and tuberculous meningitis (Torok 2009) showed unfavorable effects when starting ART too early (see also chapter on late presenters).

The following chapter is intended to be a relevant practical overview and does not include clinical rarities. The literature cited refers to interesting reviews and, almost exclusively, to controlled studies and when applicable, randomized studies.

References, OI reviews

Antiretroviral Therapy Cohort Collaboration (ART-CC). Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Clin Infect Dis 2009, 48:1138-51

Brodt HR, Kamps BS, Gute P, Knupp B, Staszewski S, Helm EB. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997, 11:1731-8.

Brooks JT, Kaplan JE, Holmes KK, et al. HIV-associated opportunistic infections—going, going, but not gone: the continued need for prevention and treatment guidelines. Clin Inf Dis 2009, 48:609–611

Buchacz K, Baker RK, Palella FJ Jr, et al. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study. AIDS 2010, 24:1549-59.

Hoffmann C, Ernst E, Meyer P, et al. Evolving characteristics of toxoplasmosis in patients infected with human immunodeficiency virus-1: clinical course and Toxoplasma gondii-specific immune responses. Clin Microbiol Infect 2007, 13:510-5.

Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunis-tic pathogens during potent antiretroviral therapy. Ann Intern Med 2002, 137:239-50.

Lawn SD, Török ME, Wood R. Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections. Curr Opin Infect Dis 2011, 24:34-42.

Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA 1999, 282: 2220-6.

Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis 2010, 50:1532-8.

McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW. Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. AIDS 1999, 13:1687-95.

Sepkowitz KA. Effect of HAART on natural history of AIDS-related opportunistic disorders. Lancet 1998, 351: 228-230.

Torok ME. Randomized controlled trial of immediate versus deferred antiretroviral therapy in HIV-associated tuberculous meningitis. Abstract H-1224, 49th ICAAC 2009, San Francisco.

Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS 2009, 4:e5575.


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