Henry Masur from the NIH [Abstract 586] reviewed selected topics in the category of opportunistic infections (OIs). He noted that the incidence of all OIs has decreased substantially. The incidence began to fall in the late 1980’s with the advent of nucleoside analog therapy and prophylaxis of opportunistic infections, and dropped more dramatically with the introduction of HAART in the mid to late 90’s. The most dramatic changes were in PCP, MAC, CMV, and toxoplasmosis. However, the frequency of these OIs has remained relatively stable since 1997, suggesting that "we’ve gone about as far as we can go." With regard to the frequency of OIs, more recent data indicate the following:

1. The current CD4 cell count rather than the CD4 nadir predicts the likelihood of developing OIs.
2. The viral load also correlates with OI risk.
3. Only about 50% of patients in clinical trials achieve the HIV viral load goal of <50 c/mL, which portends more therapeutic failures and an increase in the incidence of OIs.

With regard to cost effectiveness, the cost/quality-adjusted life year (QALY) for MAC prophylaxis with azithromycin is $31,000-$35,000 and $2,300 for PCP prophylaxis with TMP-SMX. Both are cost effective compared with other commonly accepted medical interventions such as mammogram, dialysis, or coronary bypass.

Why does PCP, a preventable disease, still occur in the era of HAART and PCP prophylaxis? An analysis of 2,365 cases from 1996-1999 showed that 45% of patients with PCP had not been receiving HIV care; 14% were receiving care but not receiving prophylaxis; 34% were receiving prophylaxis; 6.5% were not receiving prophylaxis because criteria for prophylaxis had not been met. Dr. Masur also discussed the implications of P. carinii resistance due to mutations in dihydropteroate synthase (DHPS). DHPS is essential for folate metabolism and is the target for sulfonamides and dapsone. There are substantial geographic variations in the distribution of resistance mutations, and there is a correlation with prior exposure to sulfonamides. Nevertheless, the data demonstrating reduced response is considered inconclusive, so these drugs are still considered to be the preferred agents for both prophylaxis and treatment. However, Masur warns that this could be problematic in the future and needs to be carefully followed. He also pointed out that the trimethoprim component in TMP-SMX is superfluous, since trimethoprim has no activity against P. carinii. Leucovorin should not be given when treating PCP with TMP-SMX because it reverses the anti-folate effect.

Dr. Masur finished by summarizing data on IL-2 therapy and suggested that it is time to give this approach a hard look. IL-2 is now administered by subcutaneous injection rather than by IV, making outpatient treatment feasible. There have been successful trials in other countries (Thailand and Argentina), demonstrating feasibility even in resource limited settings. The flu-like side effects are self-limited. Masur also noted that prior studies have shown that once a CD4 cell count increase has been achieved, the effect may be prolonged so that repeated treatment is not required. Large trials in patients with baseline CD4 cell counts >350cell/mm³ have shown substantial increases in the CD4 count, averaging 232 cells/mm³, with no important changes in viral load compared with controls. Two major trials are ongoing: 1) ESPRIT, for patients with a baseline CD4 count >300/mm³, and 2) SILCAAT, for patients with a CD4 count of 50-299/mm³. These large, multicenter clinical endpoint trials will assess whether the CD4 count increases associated with IL-2 therapy result in a reduction in HIV-related complications and an improved prognosis. Masur concluded that future strategies may include HAART followed by IL-2.

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