PCP. MAC. KS. CMV. These bite-sizeabbreviations of long, florid diagnoses and rare, grotesque diseaseswere once on the tip of every PWA's tongue. But enter protease-basedcombos in 1996, and within two years, the HIV death rate in the U.S.had plummeted by 70 percent. Thanks to HAART and the array ofantibiotics that KO opportunistic infections (OIs), these nastyacronyms are no longer among AIDS's top killers. Now meet the newlethal lingo: HCV. HPV. HIVAN. NHL. Not to mention such HAART spoilerssuch as drug resistance and side effects.

What a difference a decade makes: In 1992, the top causes of death among PWAs were unspecified pneumonia, pneumocystis cariniipneumonia (PCP), bacterial infections and Kaposi's sarcoma (KS).Unpublished data from the CDC shows that in 1998, unspecified pneumoniaand bacterial infections still headed the list -- an early sign of thenow-infamous difficulties of HAART regimens, which can bolster theimmune system to avoid such OIs. But next are liver complications,kidney damage and heart disease. Now where the hell did they come from?

Confirming this pattern is a recent studyconducted at Case Western Reserve University. Michael Lederman, MD, andcolleagues examined the causes of death among 260 PWAs treated at alocal hospital from January 1995 through December 1999. While thosewith a history on HAART avoided the big AIDS acronyms, they tended todie of "end-organ failure" -- surprise! -- damage to the liver, kidneyand heart. This trend is reported across the U.S. and Europe.

Why this shift in the deathscape? Inaddition to HAART's dramatic reduction in the old-guard OIs, afrustrating Catch-22 accounts for the rising incidence of organfailure: HAART can reboot the immune system, but it can also causecholesterol levels to skyrocket, putting HIVers at risk for heartdisease, and its often-high toxicity can take a vicious toll onessential organs. Also, HIVers have high rates of hepatitis B or C, andwhen these viruses join forces with HIV, they can increase each other'svirulence. Moreover, there's a definite but dimly understood linkbetween HIV, even when well controlled, and cancer.

POZ asked four top HIV docs thischeerless but pressing question: Why is the Grim Reaper blazing thesenew trails? Each physician singled out recent patient deaths andperformed a kind of diagnostic autopsy, removing the "Died of AIDS"label to examine which specific complications were responsible, what --if anything -- could have been done to prevent a fatality and what thetake-home message is for all of us HIVers who are dying to stay alive.

CASE NO. 1

Cause of Death
Non-Hodgkins' lymphoma, June 2000

Patient
Gay white man, mid-40s, Boston, tested positive in 1989

What Went Wrong
This man had a long history of serial monotherapy," says his doc,Calvin Cohen, MD, an HIV practitioner in Boston and medical director ofCommunity Research Initiative of New England. Cohen's patient went on aprotease combo in 1996 that cut his viral load from 80,000 to below10,000 and boosted his CD4 count from 310 to 400. "He was doing well --a little bit of a party boy, the occasional STD, but nothing that gotin the way of his regimen." In 1998 his viral load rebounded, his CD4sstarted dropping, and he complained of neuropathy. After a completecocktail switch, his viral load improved a bit, but then his CD4s fellbelow 200, and he went on Bactrim, an anti-PCP prophylactic. When hisCD4s continued to drop, he tried a Sustiva/ritonavir combo, but thefirst messed with his moods and the second caused lipoatrophy (the loss,rather than redistribution, of fat). At this point, off therapy with150 CD4s, he hunkered down, waiting for new meds from the pipelineinstead of recycling an old combo. "He had a sense we were losingground, but he didn't want to know every dip of the roller coaster,"Cohen recalls.

The PWA soon started having night sweats,occasional moments of disorientation (they laid it off to a recentEcstasy jaunt), nausea, vomiting, abdominal pain and fevers. A biopsyof a few enlarged lymph nodes in his belly confirmed non-Hodgkin'slymphoma (NHL) that had already spread, and that Cohen says doctors hadbeen unable to detect at an earlier, more easily treatable, stage. Hisdoctors thought he would tolerate chemo better with a lower viral loadand higher T-cell count, so Cohen put him on a combo with thethen-experimental PI Kaletra (lopinavir and ritonavir). But he vomitedup all his meds. "At this point, he lost ground very rapidly," Cohensays. "The cancer was running rampant, and nothing would keep him well."

Backstory
This man's misfortune had partly to do with the dimly understood linkbetween HIV-battered immune systems and cancer, particularly NHL andKaposi's Sarcoma (KS) -- both thought to be caused by viral infections(Epstein-Barr and human herpes virus 8, respectively). Most cliniciansagree that these were more common in HIVers prior to HAART, though somedata suggest that NHL has remained constant and may even be rising. Forhis part, Cohen has seen few patients with well-controlled HIV developNHL or KS. "It's not clear yet what it would take to make the rate ofthese cancers in HIVers closer to zero. But," he adds, "that's mostlybecause we don't understand cancer."

Cohen says that he thinks this man is one ofthose HIVers whose recent deaths are rooted in what he calls, with grimhumor, "old AIDS" -- a syndrome in which they have developed not onlyviral resistance to many HIV meds but also irreparable immune-systemdamage. As Cohen notes, doctors increasingly think this might happenwhen CD4 cells fall below 200, even if they rebound later witheffective therapy.

Take-home
"Minimizing the virus' resistance to therapies in any way we can iscrucial," Cohen says. "We have more meds than before, but we don't havean unlimited number. If you're having adherence troubles on a med, takeit seriously and talk to your doctor -- don't just take it half thetime and risk developing resistance."


CASE NO. 2

Cause of Death
Staphylococcus pneumonia, February 2001

Patient
African-American woman, 18, New York City, infected at birth

What Went Wrong
A bright,successful high school senior with a loving, supportive family, thisyoung woman came, at age 15, to Montefiore Hospital. She was doing wellon a four-drug combo, but soon her hoarse voice led to the discovery ofnodules on her vocal chords. "The first biopsy didn't answer what itwas, so we treated it symptomatically," says Adolescent AIDS Programhead Neal Hoffman, MD. It ended up being MAC (mycobacterium aviumcomplex), a common but dreaded OI, yet "no one had ever reported such asymptom for MAC before -- we called all around the country."

At this point, the young woman had a 50,000viral load and fewer than 50 CD4s. "You don't see MAC except inpatients with low T cells who were never on treatment or who arefailing it. It turned out she wasn't adherent on her regimen," Hoffmansays. "We worked with her on that and pushed her viral load down tobelow 10,000."

Still, her MAC was progressing, and her healthdeclining. New treatment included a mobile central IV that enabled herto go to her prom and graduation, and then take a summer vacation. "Wedecreased her hospitalizations, which had included several ER visitswhen her airway would close up," Hoffman says. "We put her on Kaletra,changed her NRTIs." Her CD4s rose above 50, but in fall 2000, she had ablood clot and was put on an anticoagulant. Then her IV line had to bepulled when she developed a staph infection in it, which led toanti-staph therapy. She nonetheless developed chronic pneumonia that,Hoffman says, was likely from the original staph infection. "With allher complications, she ended up stopping her antiretrovirals -- it wastoo much." She died last February from staph pneumonia with bleedingabnormalities. "Ultimately she made a decision to limit how muchintervention she was willing to accept," Hoffman says of her lastwishes to have no intubation or ventilation, and no resuscitation whenher heart and breathing stopped.

Backstory
Hoffman says that because neither his team nor any HIV specialistsaround the country recognized vocal-chord nodules as a MAC symptom, itstreatment was delayed. He is currently "writing the case up" because ithasn't been previously documented. "AIDS patients are not onlysusceptible to infections," he says, "but to unusual manifestations,and all treatments carry complications." What reallyhappened here, says Hoffman, is "we spent a year taking care ofproblems that are hard to treat without a stable immune system. The onequestion I'll always have is: Could this have been prevented if therewere more work done to help her to adhere to her regimen? We put her ontriple therapy, but I think she was missing a dose a day." Still thefact that this young woman -- born 15 years before effective HAART --lived 18 years is itself remarkable. Most mid-'80s HIV positivenewborns lived an average of five years.

Take-home
Hoffman says that, for HIV docs, "the lesson here is to be vigilantabout a change in symptoms. Look for a cause, and then alway pursue adiagnosis -- weighing that against the risks that might accompany anysubsequent procedure." But again, the backstory here is one of a hostof complications arising in the wake of a bottomed-out immune system,due in part to checkered adherence. That's why Hoffman stresses thecritical importance of counseling, mental health services and supportgroups in HIV-care settings, particularly for adolescents. "They don'twant to disappoint their parents or providers, so they often don'tdisclose their adherence problem," he says. "Fortunately simplerregimens are coming out, but still we find youth motivating one anotheris more effective than just us working with them one on one."


CASE NO. 3

Cause of Death
Cardio-respiratory failure due to liver failure, December 2000

Patient
African-American male, 53, Baltimore, tested positive in 1990

What Went Wrong
Triply infected with HIV and both hepatitis B and C (HCV), he was onseveral antiretroviral combos over the years, including proteaseinhibitors. "Eventually he became intolerant of retrovirals becausethey all gave him high liver enzymes," says his physician, DavidButcher, MD, an HIV practitioner in Baltimore. "He started showingrapidly worsening signs of chronic liver failure" -- including ascites,a massive accumulation of fluid in the abdomen that needs to beregularly drained with a long needle. Unfortunately, necessarynutrition and protein gets drained out with it. The man lived foranother year with these complications before dying of hep-relatedcardio-respiratory failure, caused by the stress that his liver diseaseput on the heart and lungs.

Backstory
Butcher says that this man is emblematic of his predominantlyAfrican-American AIDS patients and their high incidence of IV drug useand hepatitis C, which Butcher calls his practice's "biggest issue." Hesays the No. 1 cause of death among his HIV positive patients is liverfailure related to chronic viral hepatitis. With their livers shuttingdown, they often suffer from malnutrition and other life-threateningcrises, though their CD4s may be high and their HIV prognosis hopeful."Together, HIV and hep C are a double-whammy, "Butcher says. "Theyaccelerate each other's progression rate, so those who are co-infectedhave a worse prognosis overall."

Take-home
The importance of spotting and treating both hep B and C earliest istotal. "Advanced liver disease doesn't leave many options," Butcherwarns, before stressing that hep C treatment, still far from widelyeffective, "has improved a lot in a year." He cites the "newgold-standard" combo of interferon and ribaviran. "Interferon hasalways had heavy side effects like depression, but a far-easier-to-takeonce-weekly injection is coming out soon." Response rates for the newcombo are up to a dramatic 50 percent, so if caught early, hep C can beeradicated in six to 18 months. Researchers are increasinglyrecommending that doctors treat co-infected patients for hep B or Cwhile their immune systems are still hearty, to rein in the hep andkeep the liver in shape for a future onslaught of HIV meds.


CASE NO. 4

Cause of Death
Pneumonia, congestive heart failure, kidney failure, April 2001

Patient
African-American man, 48, Los Angeles, tested positive in 1985

What Went Wrong
This man was a long-term survivor with low T cells, says his doc, HIVspecialist Gary Cohan, MD, managing director of Pacific Oaks MedicalGroup, in LA. About 18 months before he died, he developed HIV-relatednethropathy (HIVAN), a form of kidney failure most commonly seen inAfrican-American HIVers with CD4s below 200. "Soon we had him ondialysis three times a week," Cohan recalls, "but because he developedintolerance to his HIV meds -- we're not exactly sure why -- he starteddialyzing them out, too -- and he was on his fifth combination already.So his HIV was definitely notwell controlled. We put him on OI prophylaxis, but he dialyzed these,too, and got pneumonia. His kidneys were now under full attack by theHIV, and that was the beginning of a long downward spiral." Ultimatelyhe suffered heart failure from end-stage kidney disease and fluidoverload in a patient with wasting syndrome and a very weakened heartmuscle, or cardiomyopathy."

Backstory
"We tried everything to save this man," Cohan says. "Dialysis,diuretics, antibiotics, heart medication -- but ultimately his entirebody was far too weak to fight anymore. We call this multi-organ systemfailure." Cohan attributes this man's kidney disease and death to --you guessed it -- the "old AIDS" dilemma of resistant virus. Suchpatients are left with a shrinking arsenal of med options to suppress avirus that has likely exacted an irreparable toll on their immunesystem. "We caught him very early, started him on a low-protein diet,stopped meds we thought might be contributing to [HIVAN] and put him ondialysis," Cohan says, but once the unchecked HIV unleashed its fullwrath on this man's kidneys, "there was nothing more we could do."

Take-home
There is much to learn about the relationship between HIV and HIVAN (aswell as other kinds of kidney failure in HIVers), although we do knowthat its disproportionate prevalence in blacks is thought to be ofgenetic origin. Most research suggests that HIV is active in thekidney, and that HAART lowers one's risk of HIVAN or slows itsprogression to end-stage liver disease. In recent years AIDS docs havepushed to conduct kidney biopsies on at-risk patients because signs ofkidney complications might be a cue to start combo therapy earlier thanusual -- say, when the CD4 count hits 350. Echoing many physicians,Cohan urges stepped-up research in this area: "When the kidneys go,everything goes."

CASE NO. 5

Cause of Death
Heart attack, February 2001

Patient
White male, early 50s, Los Angeles, tested positive in 1985

What Went Wrong
A medical professional retired because of AIDS, this patient had "hadhis ups and downs," according to Cohan, but "by the time the year 2000rolled around, he was doing better than ever." A protease combo hadsuppressed his viral load, and his hep C was under control. For 10years he had what Cohan calls "unrelated heart problems" -- a too-thickheart wall and arrhythmia -- "but he was on treatment to keep his heartpumping properly and doing fine." Until...

Backstory
"There was nothing here that made me think HIV was related to thisdeath," Cohan says, adding that the only HIV link may be that proteasetherapy further deprived oxygen to his clogged, weak-walled heart. "Asfor an interaction between his HIV meds and his heart meds, we werealways very careful about that." Cohan also says that this man's casewas likely an exception to the growing trend of protease-relatedelevated cholesterol, which can precipitate a heart attack. "We're veryworried about that -- how long would it take for us to gum up ourarteries for a heart attack if our cholesterol levels suddenly shootfrom normal to way high, and stay that way?" Of course, there are medslike Lipitor to treat high cholesterol, "but few interact OK with HIVmeds," Cohan says.

Take-home
Very often, meds that squash HIV can create other problems. "You can'tignore this incidence of high cholesterol, diabetes and hypertension inHIVers on combo therapy," Gary Cohan says. "You have to address themaggressively." Like other cutting-edge docs, Cohan makes a point ofputting eligible patients on protease-sparing combos that seem to be"as or more effective than the protease, and less toxic," he says. "Onecombo with Sustiva beats PI combos hands down."

But this patient's case may illustrate a moregeneral and important point: As HAART ushers more and more HIVers intoa once-unthinkable middle-age, they have no choice but to protectthemselves against the same old humdrum health problems that plague thegeneral population -- heart disease, high blood pressure, cancer. "Inthe early '90s I used to joke with my patients when they came in with apack of Marlboros in their pocket," Cohan recalls. "Now I'm their worstnightmare of a Jewish mother." Still, HAART complicates these humdrumcanards of aging so that it's often hard for HIVers to determine wheretheir "normal" problems end and their HIV- or HAART-related ones begin.

Are there common lessons to be learnedfrom these disparate profiles to keep us HIVers stayin' alive well intothe 21st century? You bet.

Ya gotta be irresistible. Most HIVersdie these days from complications (old OIs or new organ failure) thatoccur when their CD4 cells fall below 200 and their immune systemcollapses -- a result of viral resistance leading to HAART failure.Everyone has a responsibility here: Researchers must keep concoctingnew meds to take HIV by surprise, doctors must tune into the latesttreatment thinking, and HIVers must enlist all possible support toavoid the adherence flubs that enfeeble an effective cocktail. (Anddon't forget that bareback sex, needle sharing and other forms of"strain swapping" among HIVers are viewed by many as a surefire recipefor mass-scale viral resistance and treatment failure -- a spoiler ofall HAART's good work so far.)

Every new solution presents a new problem.While HAART has saved many a life, it can also trigger new,life-threatening health crises such as high cholesterol, high bloodpressure and diabetes. Even as you and your doctor work to minimizethese effects, pharma must not minimize the nasty side effects of theirdrugs: Once more, we need better research on the drugs we have as wellas better drugs.