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Being Alive
Chris Griffin
March 5, 1998
Being Alive 1998 Mar 5: 5

Many reports at the Conference concerned the significantly lower incidence of various opportunist infections (OIs) following the triple-drug combinations used in Highly Active Antiretroviral Therapy (HAART). These decreases were across the board, including every major AIDS complication we have grown familiar with: PCP, CMV, MAC, KS, toxoplasmosis, dementia, candida, PML, cryptosporidiosis, microsporidiosis, cryptococcal meningitis (Crypto), herpes, and moluscum. The good news is not limited to the lower incidence rates of OIs. Many studies showed that people with the historically untreatable infections-Kaposi's sarcoma, PML, and severe moluscum-improved significantly following the initiation of HAART (see below).

These reports, of course, lead to the speculation that HAART and the subsequent increase of CD4s increases effective immunity to these infections, and that these new CD4 cells may indeed be functional. More investigative work needs to be done before we can determine if this is so.

It is important to stress that all this good news does not not extend to everyone. People are still getting OIs despite the availability of HAART, and people are still dying from the more serious ones. We have a lot to be grateful for in this new era, but we have only turned a corner. We have certainly not shut a door; we have no idea what lies before us. Complacency about OIs in this protease age would be an enormous mistake. Drug companies and researchers must continue to seek new drugs to combat these infections; to stop doing so could prove fatally short-sighted.

Below is a summary of Conference reports which provide new information about specific opportunistic infections.

CMV The most dramatic decreases in the incidence of specific OIs were in CMV and PCP. The drop in cases of PCP is probably due as much to increased effective prophylaxis as it is to HAART. But with CMV the situation is different, since prophylaxis for this OI has been less than optimal. Because of its low bio-availability, oral ganciclovir has not proven to be an especially effective prophylaxis against CMV (although it has been used for this purpose). Even so, without effective means of prophylaxis, multiple studies show that improved immunity brought on by HAART has produced dramatic reductions in the cases of CMV, as much as an 85% drop. A CD4 count below 50 is still considered a major risk factor for CMV; it's just that with HAART fewer people are finding their CD4 counts going that low.

People who have already experienced CMV infections have cause to celebrate. Not long ago, a person diagnosed with CMV could pretty much count on being dependent for the rest of his/her life upon IV drugs to keep the infection at bay and keep him/her sighted and alive. A permanent catheter was a given. The invention of the retinal implant then allowed some people to live without the IV drugs, but the life of an implant was only 8-12 months and multiple surgeries were expected. Even then, the prognosis was not good: eventually, the CMV could be expected to break through. Now, however, people with improved CD4 counts (above 85, one study suggests) are going off of IV drugs, delaying or foregoing altogether additional implant surgeries, and stopping oral ganciclovir prophylaxis, with no ill effects so far. This is indeed good news.

Some cases of retinal inflammation were reported in people with prior CMV infections after beginning HAART. These patients were taken off anti-CMV therapy after their CD4 counts rose above 200. There were no cases of CMV progression, but inflammation did occur in four out of eight patients 2-16 weeks after their CD4 increase.

At last year's Conference (as reported in these pages), there were two reports of CMV breaking through despite HAART and improved CD4s. Studies this year seem to conclude that if a breakthrough is to occur, it will happen in the first 2-3 months of HAART, and will be the result of an already-active infection that shows up before the full benefits of HAART are realized. After three months of HAART, clinicians recorded a major (if not total) decrease in the incidence of CMV in people with initial CD4 counts below 50, but whose T-cell count went above 85 following HAART.

Last year, we reported on the development of a ganciclovir pro-drug, which promised to deliver as much drug to the system orally as intravenous treatments. This drug would in one fell swoop provide both an effective prophylactic drug against CMV and make permanent catheters and IV infusions obsolete as first-line defenses against CMV. The AIDS community was outraged when it learned that Hoffman-La Roche had closed down the development of this drug-clearly in response to the reduced incidence of CMV. To their credit, the company has responded to community pressure and has reopened this development program, and we can expect to see this pro-drug produced and available before too long. MAC One study reported on the "eradication" or "cure" of MAC after 12 months of antibacterial therapy combined with HAART. "This is the first report to our knowledge," write the authors, "in which antibacterial therapy for MAC has been successfully discontinued in patients with AIDS after presumed immune reconstitution following HAART." In the pre-HAART era, there were no reports of any cure of MAC: chronic suppressive anti-MAC therapy was lifelong, and relapse was associated with discontinuation of antibacterials. Prior to HAART, the mean survival time with MAC was less than one year, but this study reported on four patients who were still asymptomatic a year after diagnosis. The researchers could find no clinical evidence of MAC 10 months after stopping anti-MAC therapy.

KS Many clinicians reported on a regression of KS lesions: in some patients the lesions grew smaller, less dark; in others there was full resolution. There were reports, however, that HAART in some cases tended to exacerbate the KS lesions shortly after beginning therapy, causing increased pain, irritation and edema (swelling). This reaction resolved when drug therapy was stopped. People with pulmonary KS (lesions in their lungs) especially benefited from triple-therapy.

Just as last year, a lot of attention was given to the role of the herpes virus (KSHV: Kaposi's Sarcoma Associated Herpesvirus) in inducing or contributing to or actually causing the development of KS. The jury is still out, but it seems clear that KSHV is at best simply a co-factor in producing KS, along with the HIV itself and one's suppressed immune system.

PML We can certainly be heartened by the reports that show significant improvement in some people with PML following HAART. Prior to the arrival of protease inhibitors, a diagnosis of PML was untreatable and essentially an irreversible death sentence. In light of this, these limited reports of brain lesions shrinking and of improved cognitive function are to be celebrated. Two studies concluded that HAART is the most significant factor influencing survival time following a PML diagnosis, and that the treatment was of substantial benefit to a number of patients. This was not universally true, however. Despite HAART, PML continued to prove fatal to some.

The anti-CMV drug Cidofovir (Gilead Sciences) was investigated for anti-PML activity. Results were inconclusive; some patients improved, others worsened. It is significant as well that all patients were receiving a protease inhibitor-containing drug regimen, which in itself could account for improvements. Nonetheless, the reporters stated, "The partial clinical improvement observed, together with the lack of known treatment and the in vitro activity of Cidofovir (against toxo) indicate that further evaluation of Cidofovir in PML is warranted." Toxoplasmosis One physician reported a 73% decline in cases of toxo since the advent of HAART. Improved prophylaxis is certainly responsible as well.

One study concluded that as prophylaxis against toxo, a thrice-weekly dose of sulfadiazine-pyrimethamine (an antibiotic known as Eon) is as effective as the usually-prescribed daily dose.

Cryptosporidiosis, Microsporidiosis Studies reported on resolution of symptoms and clearance of these organisms in many people after starting HAART.

Moluscum This non-life-threatening but highly annoying and often disfiguring fungal infection has long been the bane of people with AIDS. One particularly riveting poster showed photographs of a man with severe refractory moluscum on his face, with giant cutaneous lesions, who started HAART and experienced a profound resolution of the infection as his viral load dropped and his CD4 count rose. Another poster reported that IV Cidofovir for four weeks produced good results in diminishing the scope and severity of moluscum in patients whose moluscum had not responded to HAART. Some improvement was also seen using a topical cream containing 3% Cidofovir.