Treatment Action GroupTHE OI REPORT:
A Critical Review of the Treatment & Prophylaxis of
AIDS-Related Opportunistic Infections (OIs)

OIs IN THE ERA OF POTENT PROTEASE INHIBITOR CONTAINING REGIMENS
by Michael Marco

INTRODUCTION
Two years ago marked the dawn of the protease inhibitor era, one of dramatic breakthrough in our ability to treat HIV infection. Two years ago, on February 1, 1996, during the "late breakers" session at the Third Conference on Retroviruses and Opportunistic Infections in Washington DC. In front of a standing-room-only crowd of over a thousand, Bill Cameron presented preliminary results of Abbott's pivotal study 247, demonstrating that the protease inhibitor ritonavir, when added to an underlying regimen of reverse transcriptase inhibitors in severely immune-compromised patients (CD4 below 100) significantly decreased the occurrence of AIDS-related opportunistic infections (OIs) and death (Cameron 1996). The emotional impact of these data, indicating that, "For outcomes after one month on study, AIDS-or-death occurred in 69 [patients](12.7%) versus 149 [patients] (27.3%, p < 0.001, HR 0.44, 95% CI 0.33 - 0.58)" is still difficult to put into words. It was the first antiretroviral licensing study to show a survival benefit since BW-02 did so with AZT in 1987.

OI Endpoints in Abbott Study 247
Endpoint (OIRitonavir (N=543)Placebo (N=547)p-value
Cytomegalovirus (CMV), all sites1630<.05
Retinitis1317 
Other313 
Esophageal Candidiasis1638<.05
Mycobacterium Avium complex (MAC)69 
Pneumocystis carinii pneumonia (PCP)616<.05
Wasting28<.05
Kaposi"s Sarcoma822<.05
Non-Hodgkin"s Lymphoma37 
Others1026<.05

(Cameron 1996)

Later in 1996, at the Eleventh International AIDS Conference in Vancouver, British Columbia, additional data indicated the possibility of attaining profound, and hopefully prolonged antiretroviral suppression by simultaneously initiating therapy with one potent protease inhibitor and one or two new nucleoside reverse transcriptase inhibitors (RTIs). Before Vancouver, many simply added protease inhibitors to an underlying RTI regimen, as in Abbott 247. After Vancouver, and particularly after the release of the HHS Guidelines one year later, the standard of care evolved to improve the chances for maximal suppression with the simultaneous initiation of at least two new antiretrovirals at a time. Thus, the two-nucleoside era was succeeded by the era of HAART and, after Vancouver, by that of potent protease inhibitor combination therapy (PPICT).

Because all these changes occurred so rapidly, the full impact of PPICT on the incidence and prevalence of AIDS-related OIs did not begin to become clear until early 1997 at the Fourth Retrovirus Conference, later that spring with the release of the results of ACTG 320, and then more fully in fall 1997 at the 35th annual meeting of the Infectious Diseases Society of America (IDSA) and the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Three substantive themes in OI research and treatment emerged in 1997:

Incidence Rates of OIs in PWAs on HAART or PPICT
Michaels and colleagues, in conjunction with the Adult Spectrum of Disease Cohort (ASDC), conducted a retrospective cohort study of HIV-positive individuals (CD4s <200) attending an HIV outpatient clinic in New Orleans from 1 December 1994 to 1 January 1998 (Michaels 1998). Baseline characteristics grouped 1,181 patients before 1996 and 1,248 patients after 1996. The most common OIs, including PCP, CMV, MAC, KS, and wasting, were markedly lower in 1996 and 1997.

OI Incidence Rates from the Tulane/Adult Spectrum of Disease Cohort, 1994-1998
 Jan 94 to Dec 96 (N=1,181) Jan 96 to Jan 98 (N=1,284)p-value
PCP18.0%11.7%<0.01
Wasting 9.5%4.8%<0.01
MAC8.5%6.1%<0.05
CMV 4.6%3.0%<0.05
Kaposi's sarcoma4.3%2.5%<0.05
Toxoplasmosis2.9%1.9%<0.15
Dementia3.8%2.8%<0.20
Esophageal candidiasis9.5%8.0%<0.20
Cryptococcal meningitis3.3%2.7%<0.35
Cryptosporidiosis3.8%3.2%<0.45

(Michaels 1998)

The decreases are at least in part a testament to HAART/PPICT's direct antiretroviral effect and ensuing improvements in cell-mediated immunity, yet the decrease is also likely to be in part due the use of a macrolide (azithromycin, clarithromycin) for MAC prophylaxis, and behavioral modifications such as better dietary habits to prevent wasting, or a change in gay male sexual practices to avoid human herpes virus-8 (HHV-8).

At ICAAC 1997, Palella and colleagues presented data from the HIV Outpatient Study (HOPS) Group, a three-year study of PWAs with CD4 counts below 100. These data convincingly document the recent decline in OIs and death in patients on PPICT.

Decline in Deaths and OIs in 2,957 PWAs from the HOPS Group, 1994-1996
 DiedOI RateRx Included PI
19946.1%18.5%20% (4th quarter)
19956.9%18.0% 
1996 overall3.9%10.5% 
1996 3rd quarter2.8% 8.3% 
1996 4th quarter2.0% 3.2%75%

PI=protease inhibitor (Palella 1997)

The clearest demonstration of the PPICT on PWAs is documented in the preliminary data analysis of OI events in ACTG 320, the indinavir clinical endpoint study that randomized 1,156 patients with CD4 counts below 200 and at least three six months of prior AZT therapy to either AZT/3TC/indinavir (n=577) or AZT/3TC (n=579). The study was stopped early because of statistically significant differences in deaths and AIDS events favoring the triple therapy group (Hammer 1997).

At the 23rd ACTG Meeting in Washington, DC, Judith Currier presented Paige Williams' preliminary data analysis of the OI events in ACTG 320. Ninety-one OI events occurred in ACTG 320: 60 in the AZT/3TC arm and 31 in the AZT/3TC/indinavir arm. Below is a breakdown of the eight most common OIs:

OIs in ACTG 320: Preliminary Analysis
OI eventN casesAZT/3TC (N=575)AZT/3TC/indinavir (N=579)p-value
PCP23176<0.05
CMV18 (16 firstevent)1150.55
MAC15 (12 first event)57NS
Wasting431NS
Esophageal candidiasis431NS
Cryptosporidiosis431NS
NHL220NS
Kaposi's sarcoma321NS

(Currier 1997)

OIs in ACTG 320 Patients with <50 CD4 cells at Baseline (Preliminary Analysis)
OI/EventN casesAZT/3TCAZT/3TC/indinavir
PCP1082
CMV1495
MAC1037

(Currier 1997)

Incidence Rate (IR) of OIs in ACTG 320 per 100 Patient Years of Follow-up: Preliminary Analysis
OIIncidence rateAZT/3TCAZT/3TC/indinavir
PCP3.04.51.5
CMV2.33.51.3
MAC2.01.82.1

(Currier 1997)

More detailed analyses of ACTG 320 are underway but the incidence of OIs in the triple therapy arm of ACTG 320 may be among the lowest ever documented in a study this size with this patient population. It will be interesting to see if any of these OIs developed in individuals on prophylaxis, and at what CD4 count. For example, did patients with CD4 counts above 100 develop CMV or MAC?

This significant decrease in OIs, especially MAC and CMV, was also documented outside the United States. Two oral abstracts at the 37th ICAAC from the Hôpital de la Pitié-Salpêtrière in Paris reported a dramatic decrease in the rates of MAC and CMV after the initiation of PPICT.

Hôpital de la Pitié-Salpêtrière Cohort's Incidence Rates of MAC & CMV before and after PPICT/MAC
OI/MAC1/95 - 9/96 MACAfter 9/96 MACp-value MACref.MAC
MAC/MAC~14%MAC1.8%MAC<0.001 MAC(Jouen 1997) MAC
CMV/MAC18.7% MAC5.0% MAC<0.01 MAC 

(Baril 1997)

The Changing Natural History of OIs in the PPICT Era
While the incidence rate of OIs is decreasing since the advent of PPICT, the natural history of many OIs is changing as well. CMV for example, may now occur at higher CD4 counts, if those counts have recently risen. Some OIs, such as microsporidiosis, cryptosporidiosis, and progressive multifocal leukoencephalopathy (PML) are being successfully treated with PPICT alone. While most of the reports that follow are small case series from various institutions around world, their findings are being consecutively confirmed by other institutions.

Cryptosporidiosis, Microsporidiosis & PML
At the Fourth Retrovirus Conference, two posters reported on case series of patients with microsporidiosis and cryptosporidiosis who started PPICT. In the first case series, all five patients with cryptosporidiosis and seven patients with microsporidiosis had a remission of diarrhea within 12 weeks of starting PPICT. Only in one patient were parasites still observed in the stools, and only one patient relapsed (Carr 1997). In the second, 27 patients with chronic cryptosporidiosis and microsporidiosis began PPICT. After treatment, all but two patients with microsporidiosis cleared parasites from the stools (Benhamou 1997). Yet another group reported on the disappearance of microsporidiosis and absence of E. bienusi organisms in the stools of 15 patients who initiated PPICT in ARNS trials 034 and 054 (Goguel 1997). Since no curative therapy exists for cryptosporidiosis and microsporidiosis, these data are inspiring, yet in one sense they are not new. In 1992, Flanigan and colleague documented that patients whose CD4 counts rose above 180 cells while receiving AZT monotherapy (the old days) overcame cryptosporidiosis within a month (Flanigan 1992). This proves that the improved immune function that a decrease in viral load and an increase in CD4 cells reflect can overcome and kill these parasites.

A handful of abstracts have also documented the resolution of PML after the initiation of PPICT.

The most dramatic effect of HAART on PML is reported in (Albrecht 1997; Hoffmann 1997). A retrospective natural history study of 29 patients (median CD4 count of 40) with polymerase chain reaction (PCR) or histologically confirmed PML analyzed patient survival according to antiviral usage. In group "A", 14 patients never received or stopped antiviral therapy; 10 patients in group "B" were treated with nucleoside analogues alone; and five patients in group "C" were administered HAART.

Median Survival After PML Diagnosis According to Antiviral Usage
Antiviral UsageNSurvival (days)
Group A: never started, or stopped14123
Group B: nucleoside analogue(s)10127
Group C: HAART 5>500

(Albrecht 1997; Hoffman 1997)

At the time of presentation, four of five PPICT patients were still alive. They were progressing more slowly or had experienced resolution of their PML symptoms. Of interest, median CD4 count, prior AIDS diagnosis, or treatments, including Ara-C, foscarnet, or alpha interferon did not affect the survival of these patients.

CMV
PPICT might not benefit certain PWAs in preventing CMV retinitis. Jacobson and colleagues have reported on 5 patients with CD4 counts over 195 who developed CMV retinitis just 4 to 7 weeks after initiating PPICT (Jacobson 1997). Five to 24 weeks before initiating HAART, all five had CD4 counts below 85.

To demonstrate how the common CD4 threshold has changed after PPICT, Jacobson conducted a retrospective analysis of 76 patients from an ACTG study 266 who developed CMV retinitis between 7/95 and 8/96. The data below document the change:

CD4 Counts of Newly Diagnosed CMV Retinitis Cases Before and After PPIC
 Cases with CD4 >50Cases with CD4 >100
7/95 - 2/961/27 (4%)0
3/96 - 8/9614/49 (29%)7/49 (14%)

(Jacobson 1997)

Similar results from a prospective cohort study were recently reported by a group from Spain. Mallolas and colleagues documented 21 cases of CMV end-organ disease (nine initial episodes and 12 relapses) in patients on PPICT (Mallolas 1997). Nineteen (90%) of 21 cases occurred within two months of initiating PPICT, and none occurred during the three month median follow-up period (range: 0 - 8 months). The median CD4 count of the 21 cases was 30 (range: 2 to 225), however, 25% of the patients had more than 50 CD4 cells at diagnosis.

Thus, CMV retinitis will develop or progress in some patients despite a rise in CD4 count, from PPICT, to levels previously perceived as safe. It is possible that these patients had asymptomatic CMV retinitis or were CMV DNA PCR positive (viremic) and that the CMV virus had already seeded the eye before they started PPICT. Once the CMV is in the sanctuary of the eye, PPICT might not effectively halt the clinical progression to retinitis.

MAC
The incidence of disseminated MAC disease (dMAC) has decreased since the advent of PPICT, but the decrease may not be as large as for CMV and PCP. At the Fourth Retrovirus Conference, two teams reported on eight persons who developed MAC disease shortly after starting PPICT (Race 1997; Phillips 1997). All cases noted focal, inflammatory lymphadenitis (FIL) and fever. In fact, the three patients from Race and colleagues had CD4 counts below 50, FIL and developed MAC six to 21 days after initiating PPICT. According to Race, "The development of fever, leukocytosis, and FIL in patients with unrecognized MAC infection following initiation of PRI [PPICT] may be stimulating antigen-specific T-cell mediated inflammatory reactions."

These same findings were documented in Abbott's 247 ritonavir study. Ten of the 15 cases of MAC disease that occurred in the ritonavir arm were reported in the first 28 days of therapy, and several cases of lymphadenitis were identified (Judith Currier's personal communication with M. Heath-Chiozzi, ACTG 362 protocol).

THE EFFECT OF HIV ON THE NATURAL HISTORY OF OIs AND VICE VERSA
For many years we have known that a patient's CD4 count is a predictor of the development of certain OIs (e.g., before PPICT almost all CMV cases occurred in patients with CD4 counts below 50). Now, however, HIV load -- and its changes after initiating antiretroviral therapy -- might further help us in identify those at risk for some OIs.

Swindells, Currier and Williams conducted a retrospective data analysis (DACS 071) on 813 patients from four pre-PPICT ACTG antiviral studies which documented the predictive value of plasma HIV RNA and CD4 cells on the development of CMV, PCP and MAC (Swindells 1997). DACS 071 documented that both baseline and post-treatment HIV RNA levels -- as well as CD4 cell count -- were strong predictors of these three OIs. Patients with baseline HIV RNA over 100,000 copies/mL had twice the risk of PCP and five to six times the risk of CMV and MAC as those with less than 100,000 copies/mL. The relative risk (RR) for PCP, CMV and MAC was, 2.29, 5.64, and 4.74, respectively. Likewise, patients with CD4 counts below 75 had four to six times the risk of PCP, CMV and MAC. Alarmingly, patients with over 100,000 copies/mL of virus and CD4 counts below 75 had approximately 28 times the risk of MAC.

After the initiation of antiretroviral treatment, a one-log rise in HIV RNA doubled the risk of PCP and tripled the risk of CMV and MAC. An increase in CD4 count of just 50 reduced the risk of developing each OI by 30-35%. At eight weeks, a 0.5 log decrease in HIV RNA significantly reduced the risks of CMV and PCP, by approximately 70%. Any decrease in HIV RNA was shown to reduce the risk of MAC significantly. After 24 weeks on antiretroviral therapy, a sustained 0.5 log decrease in HIV RNA further reduced the risks -- for CMV and MAC by approximately 85%, and for PCP by 57%. After controlling for HIV RNA level, CD4 increases at week eight or 24 provided no extra benefit.

These viral load data -- albeit from older, pre-protease inhibitor studies -- will help identify specific "thresholds" or cutoff values for targeting prophylaxis regimens in patients at highest risk for OIs. For these three OIs, which cause significant morbidity and mortality, this study proves that lowering the HIV RNA level with potent antiretroviral therapy is necessary for proper prevention. Approved OI prophylaxis medications [e.g., TMP/SMX (Bactrim) for PCP and a macrolide for MAC] might not be effective prevention if a patient's HIV viral load is skyrocketing.

OIs Increase Risk of Death
Chaisson and colleagues presented data from a retrospective analysis of 2,081 HIV-positive patients from Johns Hopkins (mean follow-up period of 30 months). The development of PCP, CMV, MAC, esophageal candidiasis, Kaposi's sarcoma, non-Hodgkin's lymphoma, PML, dementia, wasting syndrome, toxoplasmosis and cryptosporidiosis was found to be independently associated with death while cryptococcal meningitis and herpes zoster were not. Moreover, the development of PCP, CMV, MAC and toxoplasmosis was associated with an increased risk of death and shorter survival regardless of CD4 count (Chaisson 1997).

Increased Risk of Death After Developing an OI
OIRelative Hazard95% Confidence Interval p value
MAC2.562.1 - 3.10.0001
Toxoplasmosis1.851.3 - 2.60.0003
CMV1.631.3 - 2.10.0001
PCP1.291.1 - 1.50.005

(Chaisson 1997)

The fact that these OIs increase the risk of death independently of CD4 count tells us that the development of an OI probably increases HIV expression and immune damage by causing immune activation. Thus, an OI is not just an annoying infection that warrants treatment, it is affecting the natural history of HIV with significant shorter survival. This alone warrants initiating effective OI prophylaxis regimens in patients at risk.

OIs Increase HIV Load
Bush and colleagues conducted a retrospective analysis of ten patients whose viral load was monitored before, at time of diagnosis, and after the resolution of PCP. Seven of the patients were antiretroviral naive and three continued antiretroviral monotherapy during their course of PCP. The medium serum HIV RNA prior to diagnosis of PCP (median time before onset = 81 days) was 113,850 copies per mL, as compared with 231,450 copies per mL at the time of PCP diagnosis (p=0.03). Nine of these ten patients had marked elevations of their HIV RNA upon developing PCP -- five of whom had three-times baseline or more. Seven of ten patients showed a decrease of their HIV RNA upon resolution of PCP (median HIV RNA = 198,500 copies/mL) (Bush 1997).

Similar results have been reported by Cooper and colleagues on a group of five children with dMAC who had elevated HIV RNA at the time of diagnosis. Four of the five children had an approximate one log drop in their HIV RNA within two months of initiating three or four-drug anti-MAC therapy (Cooper 1997).

The most convincing evidence that OIs increase HIV replication ("with a burst of virus") was recently published in Science (Orenstein 1997). Orenstein biopsied lymph nodes of patients to look for co-expression of HIV and OIs. Using in situ hybridization, he found that "unprecedented levels of HIV production were evident in the tissues of patients with OIs." Moreover, Orenstein found that the pathogens -- namely PCP and MAC -- were localized in macrophages and not lymphocytes.

HIV-Expression of Mononuclear Cells in Biopsied Lymph Nodes of PWAs with and without OIs
AIDS OINHIV+ cells/10mm3
PCP 1118.8
MAC 6 58.9
MTB 1 54.6
Histoplasmosis 1 26.3
M. kansasii 2 14.9
HIV+ - no OI  
Follicular hyperplasia24 2.8
Hyperplasia/Involution21 1.4
Involution18 2.0
Lymphoid depletion 4 0.5

(Orenstein 1997)

The elevation in HIV RNA seen with the development of PCP and MAC (and possibly other OIs) seriously calls into question the routine discontinuation or interruption of antiretroviral therapy when a patient develops an OI. This has been done to simplify the management of the toxicities that can occur from the combination of many medications. These data, however, suggest that effective antiretroviral therapy during the life-span of the OI may be necessary to prevent or control a burst of HIV expression.

Discontinuing OI Prophylaxis and Maintenance Therapy After PPICT
PPICT has been documented to decrease patients' viral RNA to undetectable levels and to raise CD4 counts. This remarkable antiviral activity is not matched by an equally strong cell-mediated immune recovery (i.e., an increase in broad and diverse CD4 number and function). Nonetheless, many patients with CD4 counts between 50 and 100 are seeing an increase of 100-200 cells. Researchers, clinicians and primary care physicians have been asking three primary questions about this rise in CD4 cells, such as: 1) What is the true significance of this increase? 2) Are these new CD4 cells as functional and competent as ones lost in the course of HIV-associated CD4 depletion? 3) Can OI prophylaxis be stopped in patients whose CD4 counts increase above the threshold of risk after starting PPICT?

Recent data suggest that the new CD4 cells acquired by PPICT might be able to function as well as old naive CD4 cells in some patients, but only after a certain period of time on PPICT. In May 1997, Connors and colleagues reported that HIV progression is associated with a preferential decline in naive CD4 T cells and that the disruption in one's complete CD4 T cell repertoire was most prevalent in PWAs with very low CD4 counts. After the initiation of PPICT, naive CD4 T cells only increased in number if they were present before initiation of therapy (Connors 1997) Thus, PPICT does not appear to completely restore depleted pathogen-specific immunity, regardless of initial increases in total CD4 lymphocyte count.

In July 1997, Autran and colleagues reported that there were three phases of CD4 T cell reconstitution after PPICT: 1) an early rise of memory CD4 cells; 2) a reduction in T cell activation with improved CD4 T cell reactivity to recall antigen; and 3) a late rise in "naive" CD4+ lymphocytes while CD8+ T cells declined, yet without complete normalization (Autran 1997). According to Bill Powderly at the 35th IDSA Meeting, an absolute recovery of one's complete immunologic functions after PPICT may not be possible and may depend on the degree of damage. But the recovery provided by PPICT may still be sufficient to protect against most OIs (Powderly 1997). A critical question still unanswered is, "How much immunologic recovery (and of what) is necessary for complete protection from OIs?" And will this answer pertain to all OIs or is it pathogen specific? With a complete understanding of the pathogenesis for PCP, MAC and CMV still unclear, Powderly contends:

We still do not know what the critical effector arms of the immune system are that provide protection against invasive disease...and, in most cases, we don't even know what (or how) to measure to determine if patients lack specific immunity." (Powderly 1997)

Discontinuing OI Prophylaxis
In late 1996, many months before these questions were actually addressed and before these data became available, primary care physicians, prison doctors and HMO clinicians were taking patients on PPICT off their MAC and PCP prophylaxis if their CD4 counts increased to above the threshold of risk (50 for MAC and 200 for PCP). This is still continuing even though the USPHS/IDSA OI prophylaxis guidelines panel recommends "continuing prophylaxis based on the nadir [the lowest level ever attained] of a patient's CD4 count." (USPHS 1997).

In order to test whether stopping OI prophylaxis is sound or harmful in patients whose CD4 counts have risen above a certain threshold, Currier and colleagues developed ACTG 362, the first "stop MAC prophylaxis trial." ACTG 362 is a randomized, double-blind, placebo-controlled trial available for enrollment to any PWA who is receiving antiretroviral therapy and has had a documented increase in CD4 cell count from below 50 on one occasion to above 100 on two separate occasions, sequentially, at least four weeks apart. There will be 636 patients enrolled. Participants will be randomized to receive azithromycin 1200 mg once weekly or matching placebo (a look-alike sugar pill) and will be followed closely every eight weeks until study closure or for 72 weeks. Patients whose CD4 count drops below 50 on two occasions at least four weeks apart will be offered open-label azithromycin. Patients will be stratified at baseline for prior use of MAC prophylaxis (ACTG 362).

ACTG 362 also has three important substudies, one looking at stopping PCP prophylaxis in 50 patients and two looking at specific immunologic parameters in patients on PPICT.

  1. ACTG 888: Impact of discontinuing primary PCP prophylaxis in patients receiving antiretroviral therapies who have had increases in CD4 counts to above 200 cells. Patients whose CD4 cell count has fallen below 200 on two separate occasions and those with symptoms of oral thrush or unexplained fever for over two weeks will restart conventional PCP prophylaxis and be discontinued from the PCP substudy.
  2. ACTG 889: In vitro or ex vivo correlates of risk for opportunistic infections: recall or naive antibody responses and recall DTH.
  3. ACTG 899: M. avium skin test reactivity and development of MAC disease.

Preliminary results from a study on discontinuing PCP prophylaxis were presented at the 37th ICAAC. Schneider and colleagues from the Netherlands presented data on 45 patients who discontinued their primary PCP prophylaxis and five who stopped their secondary prophylaxis. At the time of discontinuation, the mean CD4 cell count was 370 and HIV-RNA was undetectable in 40 patients. The remaining ten patients' HIV RNA levels did not exceed 15,000 copies/mL. The mean CD4 cell count nadir of the patients was 77. Eleven of the 50 patients were antiretroviral naive when they started PPICT. After a median follow-up of 3.9 months (range 0.4-30.5 months; median follow-up for the five secondary prophylaxis patients, 1.3 months), no episodes of PCP occurred (Schneider 1997). It is hard to make much of these results with such short follow-up. Likewise, only having data on five secondary prophylaxis patients tells us nothing about the wisdom of discontinuing maintenance therapy. Some are hopeful that ACTG 362 and 888 will help us answer questions about discontinuing primary OI prophylaxis. Both studies are well thought out, with proper patient management and specific safeguards.

Taking a patient off prophylaxis just because of cost (Bactrim is less than 25 cents a day) or convenience is presently neither recommended nor acceptable patient management. Until we have more answers, all physicians treating PWAs should follow the USPHS/IDSA OI prophylaxis guidelines.

Discontinuing Suppressive/Maintenance OI Therapy
Two small retrospective studies in which patients discontinued CMV maintenance treatment were presented at the 37th ICAAC. Torriani and colleagues from UCSD presented data on 8 patients who had "voluntarily" discontinued CMV maintenance therapy after long periods of non-progressive disease; five were on IV or oral ganciclovir and three were receiving intraocular cidofovir. At time of discontinuation, the median CD4 count of the patients was 172 (range: 63 - 404) and the median HIV RNA was 68,000 copies/mL (range: <200 - 508,000 copies/mL). None of the eight patients progressed after a median follow-up of 146 days (range: 72-205). Nevertheless, during this follow-up, six of eight patients had detectable [HIV] viral loads (Torriani 1997).

This study created some well-deserved controversy. NIAID's Michael Polis was the first up to the microphone asking Torriani how in the world could she discontinue CMV maintenance therapy on a patient with an HIV RNA of 508,000 copies/mL. Another question which occurred to an intelligent observer was, "Why didn't you take that patient over to the virology team of Richman and Havlir to get new antiretroviral therapy instead of monkeying with his/her CMV therapy?" Lastly, some wonder if those three patients on cidofovir intraocular therapy voluntarily went into the study with open arms, or were they just fed up or frightened by that needle poking them in the eye?

The Spanish team of Tural and colleagues conducted a similar, but less risky study. Seven newly diagnosed CMV retinitis patients on ganciclovir or foscarnet induction therapy were followed for observation. All were on antiretroviral therapy without protease inhibitors, were CMV DNA PCR positive, and had a median CD4 count of 56. Within 6.3 months, 5 patients experienced at least one relapse (8 relapses total). When protease inhibitors became available in Spain, all seven patients initiated PPICT. After 3.5 months on PPICT, all patients had at least 150 CD4 cells and undetectable HIV RNA and CMV DNA. Soon after, patients voluntarily discontinued maintenance therapy and had opthalmologic evaluations weekly for three months and subsequently every two weeks. Thus far, no CMV relapses have been documented (Tural 1997).

To confirm the relevance of their findings, Tural and colleagues are planing a prospective study which will use four specific criteria for entry: quiescent CMV, CD4 count over 150, undetectable HIV RNA, and undetectable CMV DNA. Torriani and colleagues from the ACTG and SOCA have also developed a sound, soon to open, 125 patient study, ACTG 379, "The Effects of Stopping CMV Maintenance Therapy."

No data have been generated on stopping patient's suppressive MAC therapy. To address this question, Judith Aberg and Judith Currier have developed a protocol concept sheet for the ACTG, CS 719: "Eradication of Disseminated Mycobacterium avium Complex (dMAC) After Twelve Months [of] Anti-Mycobacterial Therapy and Immune Reconstitution with Highly Active Antiretroviral Therapy (HAART)."

CONCLUSION
For PWAs who have access, 1997 was the year of PPICT. Two years ago, it was almost unthinkable that combination antiviral therapy could suppress HIV below the levels of detection. The results from ACTG 320 have proven that PPICT, compared with combination nucleoside analogue therapy, can increase survival and decrease OIs. The marked decrease in OIs is undoubtedly welcome news for PWAs. Nonetheless, many clinicians and researchers express caution and fear that we are in a "honeymoon phase" over our recent success. Some say that in six to 18 months we may well see a substantial number of patients fail PPICT, either due to antiretroviral drug resistance or patient non-adherence, and then see a substantial increase in OIs. The future is uncertain, especially for those heavily pretreated patients whose viral loads rebound and whose CD4 counts decrease significantly.

Only effective OI prophylactic regimens, such as Bactrim for PCP and a macrolide for MAC, can ensure patients who have failed PPICT proper protection from a cascade of OIs. We still do not have a thoroughly effective, inexpensive and convenient drug to prevent CMV. Luckily, Hoffmann-LaRoche has finally consented to provide its ganciclovir prodrug (valganciclovir) to the ACTG and SOCA for a study of preemptive therapy/targeted prophylaxis among PWAs whose CMV DNA is positive.

Given the uncertainties, answering the many questions about opportunistic infections and developing new drugs with increased activity will have to be a joint effort on the part of clinicians, researchers, primary care physicians, industry, government and people with HIV and treatment advocates.

*

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Currier JS, Williams, and the ACTG 320 Team: Preliminary ACTG 320 OI data analysis [presentation]. 23rd AIDS Clinical Trials Group Meeting, Washington, D.C., July 19-23, 1997
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Schneider, MME, Borleffs JCC, Jaspers CAJJ, Hoepelman IM: Discontinuation of Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients with an increase of their CD4 cell counts (>200/mm3), due to aggressive antiretroviral therapy [abstract: LB69]. 37th ICAAC, Toronto, 1997.
Swindells S, Currier JS, Williams P: DACS 071: Correlation of viral load and risk of opportunistic infections [abstract: 359]. 4th Conference on Retroviruses and Opportunistic Infections, Washington, D.C., 1997.
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