Opportunistic infections in the HAART era
Brian A. Boyle, MD, for HIV&Hepatitis.com
As we are all well aware the incidence of opportunistic infections (OIs) has fallen dramatically since HAART became available in 1996, despite some evidence of declining use of OI prophylaxis .
While the data indicates that the decline has levelled off somewhat this should not have been unexpected and probably is due to a combination of factors, including HAART failures and refusal of or non adherence to HAART and prophylactic medications. Several studies, including some presented at this conference, indicate that the patient is at minimal risk for contracting certain opportunistic infections if he or she achieves and maintains significant immunologic reconstitution with HAART. This data has existed for some time and several reviews containing recommendations regarding prophylaxis discontinuation have been published  and the DHHS prophylaxis for OI guidelines has been revised to recommend prophylaxis discontinuation in certain OIs when HAART reconstitution occurs.
During a plenary session on OIs, Dr. HansJakob Furrer from Switzerland discussed “Opportunistic infections: what’s new?” . He began by recognizing the remarkable decline in OI incidence and by making the point that achieving a CD4+ cell count greater than 200 cells/mm3 and maintaining that level for 6 months is a valuable marker for a significant decrease, and perhaps elimination, of the risk of almost all OIs. This level is likely to be sufficient to prevent Pneumocystis carinii pneumonia (PCP) and Toxoplasmosis, [4, 5], but even lower levels of reconstitution may be equally protective against other OIs and some cancers. Patients with CD4 cell counts greater than 100 cells/mm3 appear to be at minimal risk for cytomegalovirus (CMV), Mycobacterium avium Complex (MAC) and Cryptococcosis and CNS lymphoma, major causes of morbidity and mortality in the AIDS population [6, 7].
Taking this concept one step further, Dr. Furrer discussed prophylaxis discontinuation. As cited above, there are now several studies that strongly indicate that prophylactic medications for both primary and secondary infections can be stopped when patients regain and hold for 3-6 months sufficient CD4+ cells to be above the threshold for starting prophylaxis. This is very encouraging data, especially since the pill burden and side effects of some prophylactic medications may compromise the patients ability to be strictly adherent to their HAART regimen. Despite this data, some of which Dr. Furrer has published, he remains somewhat cautious regarding discontinuing prophylaxis for certain conditions, stating that the discontinuation of prophylaxis against PCP, CMV and MAC may be safe in some patients but that it needs further evaluation.
While further data would be nice, in view of the studies cited above, I am not sure I fully agree with Dr. Furrer’s hesitation, especially in patients with a CD4+ cell count well above the threshold for prophylaxis for more than 6 months and with a viral load less than 50 copies/mL. Of course, there still remains some risk. Careful monitoring is required and patients who are barely above a cut-off ought to be continued on prophylaxis until there is more data regarding safety. But, weighing the risk and benefit of continuing sometimes poorly-tolerated and burdensome prophylactic or treatment regimens, most patients and physicians are now generally siding with discontinuation where the studies indicate that it is generally safe.
Dr. Chris Boshoff from London discussed the aetiology of Kaposi’s sarcoma (KS) and it’s association with Kaposi’s sarcoma-associated herpesvirus (“KSHV” or “HHV-8) . This association has become so strong that there is now little doubt that KSHV is involved in inducing the proliferation of the tumour cells that cause KS in HIV-infected patients. Further, there is some demographic data that strongly indicates that KSHV may also be significantly involved in classic KS. Several latent proteins produced by KSHV seem to be the critical causative agents and research is underway to determine how to decrease or modify these proteins to interfere with their role in cell proliferation and transformation. Further, many of us have had patients with advanced KS that have improved with HAART and data supports this clinical finding. So, as with many opportunistic diseases, KS can resolve with partial immune system restoration, although the exact level of restoration required is unclear and may vary from patient to patient.
Several presenters during this plenary session discussed CMV disease. Dr. Jane Deayton from London reported on a prospective study that evaluated the efficacy of HAART in clearing CMV viraemia . The median CMV viral load in patients prior to HAART was 4.90 log10 copies/mL. After 6 months of HAART therapy, this viral load had declined 2.6 log10 copies/mL, which equated to a mean antiviral efficacy of the regenerating immune system of 61.5%, which can be compared to that of gangciclovir’s mean efficacy of 91.5% against wild type CMV. Dr. Deayton believes that this finding of efficient viral clearance by a regenerating immune system lends support to the concept that the reconstituted immune system is capable of CMV control without CMV antiviral therapy. She noted, however, that the extent and time course of this clearance may be highly variable and dependent on a number of factors, including the number of CMV-specific precursor cells which remain prior to HAART and the rapidity of their differentiation.
The findings of Dr. Deayton explain the findings of several clinical studies, including one presented by her at this conference , indicating that primary and secondary CMV therapy can be safely discontinued in patients with a CD4+ cell count greater than 100 cells/mm3 on HAART; however, it also should encourage continuation of that therapy until the patient is clearly in the safety zone of CD4+ cell count for a significant period of time. Further, as the study by Dr. Deayton shows, patients who have CMV therapy discontinued need to be monitored carefully for evidence of a recurrence of their retinitis or viraemia. Three patients in Dr. Deayton’s study had recurrence of their CMV viraemia, one because of neutropenia associated with hydroxyurea and 2 who had a virologic failure of their HAART regimen, and this was associated in one patient with CMV resistance. Therefore, Dr. Deayton recommends genotyping of CMV for resistance mutations if treatment of CMV disease becomes necessary following HAART failure.
Finally, to end on a note of caution, we have all seen or heard of a patient that had an OI such as CMV retinitis despite having recovered a CD4+ cell count that should have taken them out of risk for that disease. Most of us are also familiar with the data that indicates that certain holes in the patient’s immunologic repertoire may persist, despite significant immune reconstitution. Dr. Sung-Chin Pan from Taiwan presented data indicating that some patients that have a marked rise in their CD4+ cell count may still lack the CMV-specific CD4+ cell reactivity necessary to prevent or control CMV disease .
He proposed that post-HAART CMV retinitis may be due to a poorly reconstituted immune system response to CMV and proposed the testing of CMV-specific immune reactivity in high-risk patients who may benefit from continued CMV prophylaxis or treatment.
This is certainly a good suggestion and may have application to all prophylaxis discontinuation; however, most clinicians will not have this testing available on a routine basis and cost-effectiveness will certainly be at issue given that most patients appear to reconstitute adequately against the common OIs. An alternative, but not as elegant proposal, is to continue a high degree of vigilance for OIs in all patients who reconstitute with HAART and take prompt action if OI symptoms or signs appear.
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