Opportunistic Infections in the Protease Era
February 21, 1998
This article is adapted from a presentation for the International AIDS Society - USA CME Program, Sheraton Grand Hotel, Los Angeles, California
Dramatic declines in the rates of opportunistic infections have been observed since the beginning of 1996. These declines are partially explained by improved use of prophylaxis and by the widespread use of potent combination antiretroviral therapy including protease inhibitors. This presentation will highlight recent data on trends in opportunistic infections and in particular how recent advances in therapy alter OI risk and inform our decision about the use of prophylaxis.
Trends in OI Risk -- Surveillance Data and Cohort Studies
Data from a number of sources indicate that the incidence and mortality from AIDS related complications have decreased in the past two years. In the U.S., surveillance data for the first six months of 1996 indicated a decrease in deaths among persons with AIDS which were attributed to antiretroviral therapy and prophylaxis (MMWR 1997; 46: 37: 861-7). Data from New York City demonstrated a 56% reduction in AIDS deaths per day during the first six months of 1996.
In Europe similar trends have been reported on the impact of improved therapy on risk of HIV disease progression. Egger et al reported on trends in disease progression among 5,000 participants in the Swiss Cohort Study. They compared the risk of developing an AIDS defining illness by year of enrollment in the cohort. Compared to those who enrolled in 1988-1990 the risk of progression to AIDS was reduced by 18% for those enrolled in 1991-2, 23% among those enrolled in 1993-4, and by 73% among those enrolled in 1995-96. The risk of developing an AIDS defining illness decreased by 42% for those who received three drug antiretroviral therapy compared to no therapy.
Investigators from the Hospital Pitie-Salpetriere in Paris reported rates of MAC and CMV since the introduction of protease inhibitors in France. Rates of MAC were unchanged between the first semester of 1995 (15 cases per 100 pt yrs) and the first semester of 1996 (13 cases per 100 pt yrs). However after the introduction of protease inhibitors in June of 1996 rates of MAC dropped dramatically to 1.8 per 100 pt yrs. Among nearly 700 patients followed while receiving protease inhibitors, only 7 cases (1%) were reported to have developed MAC. The median time from starting PI therapy to MAC diagnosis was 60 days and in all but one the CD4 was <50 and the HIV RNA >50,000 copies. A single patient developed MAC with an HIV RNA <200 and this was cultured from a lymph node. (Jouan, ICAAC 1997).
The same group reported experience with CMV since the time PI therapy became available in France. The incidence of CMV was followed in a cohort of 2014 patients with AIDS. The incidence of CMV fell from 18.7 cases per 100 pt years to 5.0 cases per 100 pt years from the 18 months prior to June 1996 to the 6 months following the introduction of PI therapy. The fourteen cases of CMV that developed after PI therapy had a median CD4 of 20 cells/mm and only 2 had a CD4 >100 cells. These data confirm the dramatic impact of combination therapy including protease inhibitors in patients with AIDS.
Moore and colleagues from the Johns Hopkins AIDS Program analyzed incidence rates of several OI's from 1991 through 1996 using data from their large clinical cohort (Moore, IDSA 1997). During 1996 they report significant reductions in the risk of CMV (81% decrease), and non statistically significant decreases in rates of MAC ( 45%) or toxoplasmosis (56%). Overall rates of hospitalization were down by 36%, but interestingly rates of PCP were no different in 1996 than in previous years. Factors associated with lower rates of CMV, MAC, and toxoplasmosis included the use of combination therapy, increases in CD4 >50 cells, and decreases in HIV RNA to below the limits of detection.
OI Rates from Clinical Trials
Marked and sustained elevations of CD4 counts and suppression of plasma HIV can be achieved by recently licensed HIV protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) in combination with nucleoside analogues. Although most of these studies have not included clinical endpoints, in three studies, a reduction in new or recurrent AIDS defining events and death has been demonstrated when protease inhibitors (ritonavir, saquinavir and indinavir) were used in patients with CD4 <200 (Cameron, Hammer).
In the Abbott 247 study which included 1090 patients with a mean CD4 count of 20, the overall rate of new AIDS defining conditions and death was reduced by 56% in the ritonavir arm compared to placebo. When the actual clinical events are examined more closely it is of interest that Mycobacterium Avium Complex was the first clinical event in 7 patients in the ritonavir arm compared to 11 events in the placebo group. When new and recurrent events were combined the number of MAC events was very similar in the two arms of the study, 15 in the ritonavir arm compared to 18 in the placebo arm suggesting that at least during the first six months after starting protease inhibitor therapy the risk of MAC was not significantly reduced by the addition of the protease inhibitor. On the other hand the addition of ritonavir was associated with a 50% reduction in the rate of PCP both as new and recurrent events during this same follow-up time (31 events in the placebo arm compared to 13 in the ritonavir arm).
AIDS Clinical Trials Group Study 320 demonstrated a reduction in clinical endpoints and improved survival for patients with CD4 <200 cells randomized to Indinavir + 3TC + AZT compared to the two drug combination of AZT + 3TC ( Hammer, NEJM 1997). Data from ACTG 320 provides additional insight into OI risk in the setting of potent therapy (Currier, 1998). Overall AIDS defining events were reported in 80 of the 1156 randomized patients (91 events) during a median follow-up of 38 weeks. Patients randomized to the three drug combination of IDV + AZT + 3TC had significantly fewer clinical events. PCP, CMV, and MAC were the most common events and the time to development of both PCP and CMV were longer in the two drug arm. The finding that MAC events were equally distributed between treatment arms (8 in the 2 drug arm; 9 in the three drug arm) raised concerns that MAC might still develop in the patients on a protease regimen. Closer look at the patients who developed MAC in the 3 drug arm shows that all but one had CD4 <50 at entry except(one had 55 CD4 cells). The majority of events (6/9) in the three drug arm occurred within 7 weeks of study entry and the 3 events that occurred later were in patients who failed to obtain an increase in CD4 >50. Interestingly one patient had achieved a decrease in HIV RNA by week 8 prior to developing MAC.
In addition to the data from the three clinical endpoint trials two groups of investigators have described 8 cases of MAC presenting after starting protease inhibitor therapy. All of these cases presented with focal inflammatory lymphadenitis and fever within one month after starting the protease inhibitor (Philips, Race). The cases were notable for the absence of MAC in the blood and for the fact that the patients were not receiving MAC prophylaxis. These cases suggest that the partial restoration in immune function after initiation of protease inhibitor therapy may have altered the presentation of MAC. Careful examination of the data from the Abbott 247 study supports this finding, 10 of the 15 cases of MAC that occurred in the ritonavir were reported in the first 28 days of therapy.
The currently available data on clinical events in patients receiving potent antiretroviral therapy suggests that we may expect to see an alteration in the presentation of MAC and that rates of MAC may be reduced when patients respond to antiretroviral therapy, however the extent of the protection and the timing of protection after initiation of therapy remains unknown.
Can We Better Target Prophylaxis ?
In a similar type of analysis Staszewski et compiled data from 1448 patients enrolled in six controlled clinical trials of AZT + 3TC vs control treatments and examined the relationship between degree of HIV RNA suppression and clinical outcome (Staszewski, ICAAC 1997 abstract I-129). During the median one year of follow-up 195 patients progressed to AIDS. Ninety six percent (188/195) of the patients who developed disease progression failed to supress HIV RNA to below 5,000 copies/ml (Roche Amplicor). Of the 323 patients who maintained HIV RNA to below 5,000 copies during the follow-up only 7 (2%) died or developed disease progression. The events that occurred in this group included 2 non HIV-related deaths, 2 lymphomas, 1 CMV retinitis and 2 had disease progression after HIV RNA rose above 5,000 copies/ml. These data suggest that the degree of suppression needed to prevent clinical events may be less than what is needed for a durable antiretroviral response (i.e., you do not need to be below the limit of detection to prevent clinical progression for at least the short term).
Determining which patients are at highest risk of MAC, PCP, and CMV remains difficult. In addition to CD4 number prior studies have suggested CD4 % may be useful. Preliminary results from an ACTG cross protocol analysis (DACS 071) suggest that baseline values of HIV RNA may be an independent predictor of the risk of developing disseminated MAC after control for absolute CD4 counts (Swindells, 1997). Using data from 842 patients enrolled in the virology substudies of ACTG 116A/116 B/ 117, 175 and 241 an association between baseline HIV RNA values (Roche Amplicor assay) and risk for MAC was identified. After adjusting for baseline CD4, every one log increment in the baseline values for HIV RNA was associated with a 3 fold increase in the risk of MAC and a 2 fold increase in the risk for PCP and CMV. Among those patients with a baseline CD4 of <50 ( the guideline for prophylaxis for MAC) the patients with a baseline HIV RNA >100,000 had a 1.4 fold increase in the risk of MAC compared to those with HIV RNA of <100,000 copies/ml and a 2 fold increase in the risk of CMV. In addition, modest decreases in viral load of 0.5 log after 8 weeks of antiretroviral therapy were associated with a 70% reduction in the risk of MAC at 24 mos. Early changes in HIV RNA appeared to be more predictive than changes in CD4 number in these studies of nucleoside analogues.
These preliminary data suggest that HIV RNA may be helpful in determining which patients are at highest risk for MAC, CMV and PCP. It is important to recognize that these data were derived from studies prior to the availability of protease inhibitors, but nonetheless suggest that viral laod may be useful in determining how to target OI prophylaxis. These data also suggest that lowering levels of HIV RNA in plasma even by a modest amount are associated with a reduction in the subsequent risk of MAC, CMV, and PCP.
Spector and colleagues performed analyses of the relationship of baseline HIV RNA, CD4, CMV PCR and risk of CMV retinitis from the Roche 1654 oral ganciclovir study (Spector, 1997). Patients who were CMV PCR positive had a 3.4 fold increase in the risk of CMV relative to those who were CMV negative. HIV RNA values at baseline added additional information to CMV PCR in predicting CMV risk; among those who were CMV PCR + for every one log increase in HIV RNA the risk of CMV increased 3 fold. When HIV RNA and CMV PCR load were included in the same models it appeared that CMV PCR was a stronger predictor of CMV risk. Additionally the risk of CMV was greatly reduced among those who were initially CMV PCR + and converted to negative on oral ganciclovir. These results suggest that CMV PCR will turn out to be a useful predictor of CMV risk, what we need to learn is whether potent HIV therapy might lower CMV PCR and hence reduce the risk without specific prophylaxis.
Current USPHS/IDSA guidelines recommend that decisions about the initiation of OI prophylaxis should be based on the lowest value the patient has experienced. These recommendations are based on data that was available in November of 1996. Clearly we now know that lowering viral load is associated with a reduction in OI risk, but what we are lacking data on is the durability of this protection. Data has emerged to suggest that there may be an increased risk possibly for both CMV and MAC in the first month after starting combination therapy including a protease inhibitor. If patients continue to respond with an increase in CD4 and viral load supression after four months then withdrawl of prophylaxis might be considered. Factors to consider in this decision are the baseline viral load, history of prior OI's and the toxicity/inconvenience of the prophylaxis. Controlled clinical trials are currently in progress to address this question.
Cameron B, Heath-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS in advanced HV immunodeficiency with ritonavir. (Abstract LB6a). 3rd Conference on Retroviruses and Opportunistic Infections, January 28-February 1, 1996, Washington, D.C.
Currier JS, Williams PL, Becker S, et al. Incidence rates on risk factors for opportunistic infections in a Phase II Trial Comparing Indinavir + ZDV + 3TC to ZDV + 3TC. 5th Conference on Retroviruses and Opportunistic Infections. February 1-5, 1998.
Egger M, Hirschel B, Franciolo P, Sudre P et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective study. British Medical Journal 1997; 315: 1194-1199.
Jouan M, Cambau E, Baril L, et al. Decreased incidence of Disseminatd MAC Infections in 689 AIDS patients receiving protease inhibitors. (Abstract I-30) 37th ICAAC, September 28-October 1, 1997.
Moore RD, Keruly JC, Chaisson E. The effectiveness of combination antiretroviral therapy in clinical practice. (Abstract 213) 35th Annual IDSA September 13-16, 1997.
Phillips P, Zala C, Rouleau D, et al. Mycobacterial lymphadenitis: Can highly active antiretroviral therapy (HAART) unmask subclinical infection? (Abstract 351) 4th Conference on Retroviruses and Opportunistic Infections, January 22-26, 1997.
Race E, Adelson-Mitty J, Barlam T, et al. Focal inflammatory lymphadenitis (FIL) and fever following initiation of protease inhibitor (PRI) in patients with advanced HIV-1 disease. ( Abstract 352) 4th Conference on Retroviruses and Opportunistic Infections, January 22-26, 1997.
Romeu J, Balague M, Ruiz L, et al. Effect of maintaining sequential HIV-1 viral load values below a certain threshold on progression and mortality. 37th ICAAC ( Abstract I-137) September 28-October 1, 1997 Toronto, Canada.
Staszewski S, Demasi R, Dawson D, et al. Progression to AIDS is very rare when Hiv RNA is below 5000 copies/ml. 37th ICAAC ( Abstract I-129), September 28-October 1, 1997 Toronto, Canada.
Swindells S, Currier JS, Williams P. DACS 071: Correlation of viral load and risk for opportunistic infection. ( Abstract 359) 4th Conference on Retroviruses and Opportunistic Infections, January 22-26, 1997.
Spector SA, Hsia K, Crager M, et al. Impact of oral ganciclovir (GCV) on plasma cytomegalovirus DNA and development of CMV disease in advanced AIDS. (Abstract I-232). 37th ICAAC September 28-October 1, 1997 Toronto, Canada.