The introduction of effective chemoprophylaxis against opportunistic infections (OI) was a major advance in the management of HIV-infected patients when antiretroviral therapies were not potent enough, as the relapse of new OI episodes often lead to a fatal outcome . This was particularly true for Pneumocystis carinii pneumonia (PCP), cerebral toxoplasmosis (CT), cytomegalovirus (CMV) retinitis, and disseminated Mycobacterium avium complex (MAC) infection. Maintenance treatment for those OI was made with different drugs and regimens, but in the face of persistent immunosuppression the risk of relapses continued, and the effectiveness of secondary prophylaxis varied from excellent for PCP to low for CMV retinitis [2–8]. The preferred agent for the prevention of PCP relapses was cothrimoxazole. Pyrimethamine and sulfadiazine were used for preventing new CT episodes. Azithromycin and clarithromycin were used as secondary prophylaxis for disseminated MAC infection. Either ganciclovir or foscarnet were administered for preventing CMV retinitis relapses. The toxicity of these agents was not negligible, particularly for those used against CMV disease . Moreover, allergic reactions were often seen with drugs recommended for preventing PCP or CT [4,5,9].
With the use of combination antiretroviral therapy, and particularly after the introduction of protease inhibitors, a dramatic reduction in the number of OI and mortality associated with HIV infection has been observed [10–12]. This is related mainly to the improvements of immune function occurring in HIV-infected persons as a consequence of potent suppression of virus replication. Immune recovery in patients undergoing highly active antiretroviral therapy (HAART) seems to occur in two phases [13–15]. During the first phase (usually lasting 2–3 months after the initiation of HAART), a rapid increase in CD4 T cells, primarily of the memory phenotype, occurs mainly as a consequence of redistribution and peripheral expansion of pre-existing cells . Therefore, it does not represent true immune recovery. During the second phase (starting 2–3 months after HAART), a more gradual increase in CD4 T lymphocytes, mainly naive cells, occurs, and most probably represents gradual repair and recovery of the immune system, unmasking a still functional thymus in adults . It is now well established that primary prophylaxis against OI can be discontinued during this second phase in subjects having a good immunological and virological response to antiretroviral therapy [18–20]. Here we present evidence supporting that even discontinuation of secondary prophylaxis can be attempted without risk in HIV-infected persons being on maintenance treatment for OI and experiencing a good response to HAART.
Patients and methods
All HIV-infected individuals in the Centers for Disease Control and Prevention (CDC) C.3 category who were attending the out-patients clinic of one HIV/AIDS reference centre in Madrid and who were receiving secondary chemoprophylaxis for OI were recruited in a prospective fashion at the time they began HAART with two nucleosides and one protease inhibitor. The inclusion began in March 1997 and the last patient was recruited in March 1998. All individuals were seen regularly at the out-patient clinic every 2–4 months. Both CD4 cell counts and plasma viral load values were recorded at each visit. Measurement of CD4 T cells was performed using flow cytometry (Coulter, Barcelona, Spain), and plasma viraemia was quantified using the second generation branched-DNA assay (Quantiplex 2.0, Chiron, Madrid, Spain).
When CD4 cell counts were > 100 × 106 cells/l and plasma HIV-RNA was < 500 copies/ml at the month 3 after the introduction of HAART, all patients were recommended to stop their chemoprophylaxis against OI. Moreover, changes in therapy were allowed during the 18-month follow-up in order to maintain undetectable plasma viraemia.
Fifty-eight individuals were included in the study. Their mean age was 34 years (range, 24–63 years), and 44 were male. Twenty-nine had acquired HIV infection through needle sharing, 16 through homosexual contacts, one by transfusion of contaminated blood, and the remainder by heterosexual relationships. All had < 200 × 106 CD4 T cells/l and measurable plasma HIV-RNA at the time of recruitment. Their mean CD4 cell count was 114 × 106/l (range, 3–188 × 106/l), and their mean plasma viral load was 28 456 HIV-RNA copies/ml (range, 1834–345 879 copies/ml). Only eight patients were naive for antiretroviral therapy; the others had been exposed to nucleoside analogues either as monotherapy or dual combinations.
Only 53 patients could be analysed at 18 months. The remaining five individuals were lost to follow-up (two), did not stop the prophylactic medication (two), or committed suicide (one). After being on HAART for 18 months, their mean CD4 cell count was 289 × 106/l (range, 145–788 × 106/l), and their mean plasma viral load was 2202 HIV-RNA copies/ml (range, < 500–13 879 copies/ml).
Table 1 summarizes the chemoprophylaxis recommended to these individuals as protection against OI relapses. By far, PCP prophylaxis was the most frequent, although a further nine subjects were receiving maintenance therapy after suffering cerebral toxoplasmosis. One subject was receiving chemoprophylaxis against disseminated MAC infection, visceral leishmaniasis, and PCP. Similarly, another five individuals were receiving drugs for the prevention of more than one infectious condition.
Only two episodes of OI were recorded in the 53 individuals who completed 18 months of follow-up after the discontinuation of secondary chemoprophylaxis. One developed tuberculous lymphadenitis 5 months after stopping prophylaxis for MAC and PCP, despite having a good response to antiretroviral treatment (CD4 cell count of 253 × 106/l and undetectable viral load at the time of the diagnosis). Another subject suffered a new episode of PCP, although she admitted having interrupted antiretroviral treatment for 6 weeks because of gastrointestinal intolerance; this patient had 46 × 106 CD4 cells/l and plasma viraemia > 500 000 copies/ml at the time PCP was diagnosed once again. She began again a triple combination including nelfinavir instead of indinavir, and again reached undetectable plasma viraemia, and a CD4 cell count > 200 × 106/l. Cothrimoxazole was discontinued 6 months later, and no PCP relapses have occurred since.
Since the early 1990s, and before the impact of the current potent antiretroviral therapies, the widely use of primary prophylaxis as well as of life-long secondary prophylaxis (maintenance therapy) for the most common OI has been associated with an improvement in the life expectancy of HIV-infected patients . The enormous reduction in the rate of opportunistic events and in mortality [10–12] observed since the introduction of HAART has allowed consideration of discontinuation of such prophylactic regimens, as their toxicity, cost, and impact on patient's quality of life are not negligible [12,20].
Recently, several authors have demonstrated that primary prophylaxis can be stopped without risk in severely immunosuppressed patients who experience a significant reduction in plasma viraemia accompanied by an increase in the number of CD4 T cells [18,19]. Evidence supporting that such restoration of the immune function might allow discontinuation of secondary prophylaxis are scarce. Stopping maintenance treatment with ganciclovir in patients who suffer CMV retinitis has been associated with a long-lasting remission, as long as both the CD4 cell count and plasma HIV-RNA are under control [21,22]. Likewise, sporadic reports have indicated that immune restoration produced by HAART can permit stopping suppressive therapy for MAC and candidiasis [23,24]. However, it should be kept in mind that the immune recovery is not immediate , and latent pathogens can still become symptomatic during the first weeks on therapy [26,27]. The development of OI shortly after beginning HAART can also reflect a form of type IV hypersensitivity reaction, representing the fact that the relevant T-cell clones still were present but unable to exert adequate effector function or to expand to adequate numbers in the presence of high levels of HIV. In other words, this immune restoration syndrome mainly represents an acute inflammatory response to latent pathogens by a newly competent immune system [28–30].
In our study, discontinuation of secondary prophylaxis was considered 3 months after beginning HAART, and exclusively if HIV plasma viraemia was undetectable. Recent studies have pointed out the separate predictive value of plasma HIV-RNA on the further risk of opportunistic infections [31,32]. It appears that stressing the immune system with even low levels of virus replication can influence negatively the function of CD4 T-cells, despite their numbers being increased in response to treatment. Conversely, rapid complete control of HIV replication with combination antiretroviral therapy might allow the discontinuation of chemoprophylaxis even before the CD4 cell count has reached the widely used threshold of 200 × 106/l. In our study, patients who had reached undetectable viraemia and > 100 × 106 CD4 cells/l as early as 3 months after beginning HAART did not experience further OI relapses during 18 months of follow-up.
The only two persons in our study who developed a new OI during 18 months after discontinuing secondary chemoprophylaxis, did not reflect a failure of a HAART-driven immune recovered system to prevent the relapse of a previous illness. One developed tuberculosis, which is a relatively common condition in Spain , and which often appears in HIV-infected carriers without severe immunosuppression. Another developed PCP, but she admitted to have voluntarily discontinued antiviral treatment for a while, and in fact her CD4 cell counts had declined significantly during that interval. If these two subjects are excluded from the analysis, there were no OI during the follow-up period of 76.5 patient-years, resulting in an upper 95% confidence interval of incidence of less than 3% patient-years. As a reference, the average incidence of relapses in patients being on secondary prophylaxis for PCP, MAC, CT, and CMV were 10, 15, 20, and >50%, respectively, in the pre-HAART era [1–8].
In conclusion, this study demonstrated that secondary prophylaxis can be safety discontinued in HIV-infected patients who have experienced both virological and immunological response to HAART. The benefit of this intervention should reduce costs, drug side-effects, and pharmacologic interactions, and indirectly it will improve patients’ quality of life and adherence to antiretroviral treatment.
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