There has been a dramatic decline in the developed world in the number of HIV-associated opportunistic infections and, with that, of AIDS-related mortality, over the last 3 years[1,2]. In many series, the incidence of new opportunistic infections has declined by 75-80%[2,3]. This has occurred as a consequence of improved antiretroviral therapy, which leads to the suppression of viral replication and an at least partial recovery of immune function. Although, in general, both decreased viral replication and immune reconstitution go hand in hand, it is not completely clear which of the two consequences of improved therapy is most critical in the prevention of opportunistic infections. To further explore this question, it is worth reviewing the association between viral replication and the risk of opportunistic infection.
It has long been recognized that there is a strong association between declining CD4 lymphocyte counts and the risk of specific opportunistic infections[4-6]. Indeed, different degrees of risk could be established at varying CD4 cell counts for most of the common opportunistic infections. It was also realized that CD4 cell counts alone could not account entirety for the risk at an individual level; not all patients with CD4 counts <50× 106 cells/l would develop Pneumocystis carinii pneumonia, disseminated Mycobacterium avium complex or cytomegalovirus retinitis in the ensuing years. Many of the early epidemiologic studies identified risk factors (usually clinical) that were independent of the CD4 cell count, such as oral candidiasis or unexplained fever, as being associated with increased risk of P. carinii pneumonia or prior opportunistic infections increasing the risk of M. avium complex or cytomegalovirus[7,8]. Although these additional risk factors were often included in guidelines for prevention of opportunistic infection, it seemed unlikely that they represented a causal association but instead were markers for something else that was more closely related to the pathogenesis of opportunistic infections.
When measurement of plasma viral HIV RNA became available, its utility as a marker for HIV disease progression was rapidly assessed. As the seminal studies from the Multicenter AIDS Cohort Study (MACS) demonstrated [10,11] plasma HIV RNA offered a powerful predictor of the risk of developing AIDS or dying from AIDS that was independent of the CD4 lymphocyte count. Patients with higher viral loads had a much greater risk of developing an AIDS-related illness (which by definition was, in most cases, an opportunistic infection); this was true even for patients with very low CD4 lymphocyte counts. More recent analyses have examined the relationship between plasma HIV RNA and the risk of specific opportunistic infections and have found consistent results. The MACS investigators re-analyzed their data to evaluate baseline viral load as a predictor of opportunistic infections in a multivariate model. Once again they confirmed that CD4 count was associated with an increased risk of P. carinii pneumonia. The relative risk was 3.7 times greater in patients whose CD4 count was below 200×106 cells/l compared to those above. The HIV plasma RNA at baseline also was a strong influence on the risk of P. carinii pneumonia. In patients with a baseline viral load greater than 90 000 copies/ml, the risk of P. carinii pneumonia was 11 times greater than that of patients whose viral load was less than 30 000 copies/ml. Interestingly, in this model, clinical symptoms such as candidiasis or fever were no longer significant, thus suggesting that the risks seen in previous analyses for these clinical symptoms was in fact explained by the degree of HIV viral progression measured by viral load. AIDS Clinical Trials Group (ACTG) investigators analyzed the relationship between HIV viral load and the risk of opportunistic infections in several clinical trials and found it to be independent of CD4 lymphocyte count. For example, in their analysis a 100-cell decrease in CD4 count increased the risk of P. carinii pneumonia by 30%. Each log increase in an HIV viral load increased the risk of P. carinii pneumonia twofold. For cytomegalovirus infections, a 100 cell decrease in baseline CD4 count increased the risk of infection by 40%, and each log increase in baseline HIV viral load increased the risk of cytomegalovirus disease almost fourfold.
All of these analyses reflect data generated prior to the introduction of more potent antiretroviral therapy. Analysis of trials of less potent therapy, such as dual nucleoside combination therapy, did suggest that reductions in plasma HIV RNA with therapy reduced the risk of AIDS and opportunistic infections. This became more obvious with the introduction of more potent therapy such as the protease inhibitors and several groups have reported that lowering the viral load was associated with lower risks of progression[15,16]. In a retrospective analysis of predictors of opportunistic infections in advanced HIV disease at the Johns Hopkins HIV Clinic, the use of protease inhibitors was associated with a decreased risk of opportunistic infections. A CD4 count less than 50 × 106 cells/l was associated with an increased risk of opportunistic infections. Neither of these observations is novel. However, this analysis also showed that achieving an undetectable HIV RNA was associated with a dramatic decrease in risk of opportunistic infections in a multivariate model. Currier and colleagues  analyzed opportunistic infections occurring in the recently published ACTG 320 trial  that compared a zidovudine-lamivudine- indinavir regimen with zidovudine-lamivudine in patients with advanced HIV disease. As previously reported, opportunistic events and death were significantly reduced in the three-drug group, with reductions in P. carinii pneumonia and cytomegalovirus being the most notable. Interestingly, the median time to an event was considerably shorter in the three-drug arm (7 weeks compared with 13 weeks) which raises the possibility that events in this arm were clustered early before any reversal of immunodeficiency. Although baseline viral load was predictive of opportunistic infections, so was the inability to achieve virological control; the relative risk of opportunistic infection in patients whose HIV plasma RNA did not drop by at least 0.5 logs at 4 or 8 weeks was 5.9 times that of those who had a virological response. Thus the data suggests that both viral RNA and CD4 count give valuable information in assessing the risk of opportunistic infections. Changes in either of these in response to therapy changes the risk of opportunistic infections.
Several important concepts in the management of opportunistic infection in patients with AIDS arise from these observations. Active antiviral management of HIV infection should be part of the management of acute opportunistic infection. Opportunistic infections developing in the context of potent antiretroviral therapy may not represent failure of such therapy. Prophylaxis of opportunistic infections may best achieved by the use of potent antiviral therapy directed against HIV.
Acute opportunistic infections increase the plasma HIV RNA and, as noted, have been associated with an increased risk of further opportunistic infections and death. The increased risk of dying is in part due to the morbidity of these infections. However, macrophages, infected with M. avium complex and P. carinii can be highly productive sources of HIV in lymph nodes. Thus opportunistic infection may cause more rapid progression of HIV disease by increasing HIV production as reflected by HIV viremia. Treatment of the primary opportunistic infection may not restore the viral burden to original levels and so effective antiviral therapy should be introduced as early as practicable into the management of the acute opportunistic infection. This may have other benefits; it may be possible, in some cases, ultimately to discontinue treatment for opportunistic infections in patients in whom HIV replication is successfully controlled[20-23].
As noted earlier, opportunistic infection may occur in the context of potent antiretroviral therapy with good virologic response. Typically, these occur early after initiation of therapy (within 2-3 months) probably when there is only partial immune recovery. That partial immunity may be sufficient to alter the clinical presentation; infections may be localized (such as lymphadenitis with M. avium complex) or have different manifestations (such as vitritis with cytomegalovirus retinitis). From the clinician‚s perspective it is important to recognize that these do not represent failure of antiviral therapy which should, if possible, be continued unchanged while there is a response in HIV plasma viremia.
The recognition that viral load also affects risk of opportunistic infections has the greatest impact for prophylaxis of such infections. At the very least, the guidelines for prophylaxis that are currently used  should be re-addressed to account for viral load as well as CD4 count. More fundamentally, consideration should be given to the necessity for prophylaxis in patients whose CD4 count rises with antiretroviral therapy. Current published recommendations  suggest continuing prophylaxis for opportunistic infections based on the lowest CD4 count seen in a particular patient. This was largely generated by a small study that looked at patients after 3 months of highly active antiretroviral therapy and suggested that although the CD4 cell count increased, there was not an increase in naive cells unless those cells were present prior to infection and that disruptions in the T-cell repertoire were not corrected. With more extensive evaluation and greater experience with potent antiretroviral therapy, it is now clear that in fact there is some degree of immunological restoration. It appears that the CD4 response to highly active antiretroviral therapy is in fact biphasic; i.e. there appear to be two distinct of periods or phases in response. The second phase, starting after about 2-3 months, is characterized by a slow increase in naive CD4 cells and gradual recovery of the T-cell repertoire.
Is this degree of immune restoration from potent antiretroviral therapy alone sufficient to prevent opportunistic infections in patients previously at risk? In other words, can prophylaxis be discontinued when CD4 cell count rises above threshold levels? Three recent observational studies [26-28] have analyzed the withdrawal of P. carinii prophylaxis in individuals who have CD4 cell counts > 200×106 cells/l after the initiation of potent antiretroviral therapy was analyzed. No P. carinii events were observed with a median follow up of 10-13 months. The median CD4 cell counts at the time of discontinuation was over 300×106 cells/l. These studies are reinforced by the preliminary results of a randomized controlled trial which found no cases of P. carinii pneumonia at a median of 7 months of follow-up in patients whose prophylaxis was withdrawn. Thus, given the immunological data and clinical experience, one might safely conclude that primary prophylaxis for P. carinii is no longer needed in patients whose CD4 cell count has risen above 200×106 cells/l with antiretroviral therapy. This is not to say that P. carinii pneumonia will not occur in some patients, because subtle selective defects in host immunity may persist in some patients.
Questions do remain. Is there a minimal duration of immune recovery before one would stop prophylaxis? Do patients need to have complete suppression of viral replication before stopping prophylaxis and, if not (as some evidence indicates), is there a maximal “safe“ level of viral replication where prophylaxis is unnecessary? Could prophylaxis be stopped at lower CD4 cell counts in patients whose viral replication is suppressed? Can we extrapolate from these data to prophylaxis for other infections such as M. avium complex or cytomegalovirus? What about secondary prophylaxis (i.e. patients who had prior P. carinii pneumonia)? Obviously most of these questions require more studies for complete answers and additional trials are in progress. However, one can reasonably conclude that primary prophylaxis for any pathogen will be unnecessary in any patient who responds to antiretroviral therapy with suppression of viral replication and a rise in CD4 cell count. For patients with incomplete viral suppression, more caution is advisable and at least close monitoring with frequent CD4 cell count measurements should be performed. However, we can clearly conclude that the cornerstone of treatment and prevention of opportunistic infections will be effective antiretroviral therapy.
At this point, the decreased rates of opportunistic infection are associated with parallel decreases in plasma viral load and increased CD4 lymphocyte count. The relative importance of these markers of risk may well be distinguishable in the future, as patients are seen in whom plasma HIV RNA levels rise but where the CD4 lymphocyte remains stable. Careful analysis of such patients may help identify further the correlates of protection against opportunistic infection as well as helping to define failure of antiretroviral therapy.
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