Where did you get the idea that I have said AZT causes AIDS, Mr. Carter?
People already came down with PCP and Kaposi sarcoma when AZT was still
mouldering on the shelf, waiting for Burroughs-Wellcome to buy it up.
What I am saying is that these young, very sick men were not helped in any
proper medical way.  They were finished off with AZT.  Some of them may
even have been friends of yours.

I'm in a rotten mood tonight, so don't YOU give me any trouble!  I see
Chris Noble has a lot to say at the end of this thread (can't be anything
good), so I'd better go after him...

I find utterly incomprehensible, have made yet another erroneous
claim."

Please take center stage, Mr. Carter, and explain to the class, in your
usual bumbling fashion, where I have made an erroneous claim.

I've read enough studies on the subject.  They're covering up the grade 4
events, while they are as important as the AIDS events.

"wilyretrovirus" <purfling@nospam.yahoo.com> wrote in message

Liver Adverse Events are Most Common in HIV

 Grade 4 Events Are as Important as AIDS Events in the Era of HAART

AIDS Journal of Acquired Immune Deficiency Syndromes 2003; 34(4):379-386

Ronald B. Reisler, MD, MPH; Cong Han, PhD; William J. Burman, MD; Ellen M. Tedaldi, MD; James
D. Neaton, PhD

From the Institute of Human Virology, University of Maryland, Baltimore, MD (Dr Reisler);
University of Washington, Seattle, WA (Dr Han); Denver Public Health Department, University of
Colorado, Denver, CO (Dr Burman); Temple University Hospital, Philadelphia, PA (Dr Tedaldi);
and University of Minnesota, School of Public Health, Minneapolis, MN (Dr Neaton).

ABSTRACT

Objective: To estimate incidence and predictors of serious or life-threatening events that are
not AIDS defining, AIDS events, and death among patients treated with highly active
antiretroviral therapy (HAART) in the setting of 5 large multicenter randomized treatment
trials conducted in the United States.

Methods: Data were analyzed from 2947 patients enrolled from December 1996 through December
2001. All patients were to receive antiretrovirals throughout follow-up. Data collection was
uniform for all main outcome measures: serious or life-threatening (grade 4) events, AIDS, and
death.

Results: During follow-up, 675 patients experienced a grade 4 event (11.4 per 100
person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272 died (4.6 per
100 person-years). The most common grade 4 events were liver related (148 patients, 2.6 per 100
person-years). Cardiovascular events were associated with the greatest risk of death (hazard
ratio = 8.64; 95% CI: 5.1 to 14.5). The first grade 4 event and the first AIDS event were
associated with similar risks of death, 5.68 and 6.95, respectively.

The most common grade 4 events were: liver related (148 patients; rate = 2.6 per 100 person
years); neutropenia (89; 1.5/100 person-year); anemia (64; 1.1/100 person-year); cardiovascular
(51; 0.89/100 person-year); pancreatitis (50; 0.85/100 person-year); psychiatric (44; 0.75/100
person-year); kidney-related (34; 0.58/100 person-year); thrombocytopenia (32; 0.54/100
person-year); and hemorrhage (25; 0.42/100 person-year).

The findings for patients coinfected with hepatitis B and/or C emphasize the importance of
evaluating comorbidities. Patients coinfected with hepatitis B and/or C have higher incidence
rates of grade 4 liver events. In multivariate analyses for these patients who were all
prescribed HAART, hepatitis B and/or C coinfection was the only significant predictor of grade
4 liver events, the most common grade 4 event seen in this cohort. It is possible that the
risks and benefits of HAART therapy on morbidity and mortality are different among patients
with these coinfections.

There is a need to carefully assess comorbid conditions, socioeconomic status, recreational
drug and alcohol use, and concomitant medications at baseline and throughout follow-up. If
therapy could be optimized to reduce the incidence of these serious or life-threatening events
by even a modest amount, the impact on morbidity and mortality would be great. For example,
patients at increased risk for cardiovascular events might benefit from being placed on a
protease inhibitor-sparing HAART regimen. Similarly, patients with a history of severe
depression may be better off with an efavirenz-sparing HAART regimen.

Our finding that African American race was associated with an increased risk of renal events
illustrates the difficulty in attribution of adverse events to HAART outside of the context of
a randomized trial. It is well established that blacks have a higher risk of renal failure than
whites in the US population.81 Whether HAART exacerbates this risk is uncertain. If it does,
and we know that some specific drugs have been associated with acute renal changes (e.g.,
adefovir),82 then this would be an important consideration for risk stratification for starting
or maintaining ART.

Conclusions:

Grade 4 events are as important as AIDS events in the era of HAART. To adequately evaluate the
impact of HAART on morbidity, comorbidities and other key factors must be carefully assessed.

BACKGROUND

The introduction of highly active antiretroviral therapy (HAART) and an improved understanding
of HIV-1 viral dynamics led to a dramatic decline in US AIDS-related morbidity and mortality
beginning in 1996. This dramatic decline, together with the hope that HIV could be eradicated,
led clinicians and HIV treatment guideline committees to adopt an aggressive strategy in
treating HIV,6 focusing primarily on the benefits of HAART: "hit early, hit hard." However, as
current antiretroviral therapy is unable to eradicate HIV,8 and is associated with increased
toxicities, HIV treatment guideline committees have recently adopted a less aggressive set of
guidelines for treating HIV.

All 4 classes of antiretrovirals (ARVs) and all 19 Food and Drug Administration-approved ARVs
have been directly or indirectly associated with life-threatening events and death. However,
the cause of many serious or life-threatening events is multifactorial and clear attribution to
the use of HAART, specific ARV drugs, HIV infection, or other factors is frequently not
possible. Potential risk factors for the development of life-threatening clinical events among
HIV-infected individuals on HAART include HIV virus-host interactions, stage of HIV disease,
ARV drugs, genetic predisposition, age, comorbid conditions, coinfections (e.g., hepatitis B or
hepatitis C), concomitant medications, nutritional status, recreational drugs and alcohol,
other social behaviors and practices, and physician experience.

The short-term toxicities and benefits of HAART have been well described in the setting of
clinical trials; however, data quantifying morbidity in the era of HAART are limited. We
therefore estimated the incidence and determinants of serious or life-threatening events that
are not AIDS defining, AIDS events, and death among patients treated with HAART in the setting
of 5 large multicenter randomized treatment trials conducted in the United States.

METHODS

Study Population

The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) is a National
Institutes of Health-funded clinical trials group that conducts research through a national
network of community-based clinical sites. The trials were conducted in 18 community-based
units located in 16 cities throughout the United States: Chicago, IL; San Francisco, CA;
Detroit, MI; New York, NY; Portland, OR; Houston, TX; Atlanta, GA; New Haven, CT; Newark, NJ;
Camden, NJ; Philadelphia, PA; Washington, DC; Albuquerque, NM; New Orleans, LA; Denver, CO; and
Richmond, VA. Each unit provides HIV primary care but differs in its configuration, varying
from geographically limited, hospital clinic-based units to geographically widespread units
with a variety of hospital-based, private practice, community health care, and health
maintenance organization providers.

Patients participating in 1 of 5 CPCRA clinical trials formed the cohort for this
investigation. These trials were chosen because they used a common system for collection of
adverse events and AIDS events, and in all studies patients were to receive antiretroviral
therapy (ART) throughout follow-up. Two studies were comparisons of initial HAART regimens
(NvR: CPCRA 042 and FIRST: CPCRA 058); one study evaluated the effect of stopping prophylaxis
for MAC (Mycobacterium Avium Complex) (CR-MAC-CPCRA 048); one study evaluated the effect of
interleukin-2 (IL-2) on viral load and CD4 cell count (IL-2: CPCRA 059)68; and another study
(MDR: CPCRA 064) is evaluating the effect of a 4-month interruption of ART on clinical
progression. For the latter 2 studies, only patients enrolled in the control groups (i.e., the
group without IL-2 in CPCRA 059 and the group assigned to receive continuous ART in CPCRA 064)
were used in these analyses.

For these analyses, grade 4 events are defined as non-AIDS-related events considered severe or
life threatening (i.e., meeting grade 4 severity status). Grade 4 events included laboratory
abnormalities, clinical signs and symptoms, diseases, and clinical syndromes. In the case of
grade 4 laboratory abnormalities, specific criteria for grade 4 severity is specified in a
toxicity manual devised by the Division of AIDS, National Institutes of Allergy and Infectious
Diseases, National Institutes of Health. For many clinical conditions, specific criteria for
defining grade 4 severity are stated in the manual. In some cases clinical judgment was used to
determine the severity grade. In such cases, the following guideline was given to characterize
a grade 4 event: "extreme limitation in activity-significant assistance required; significant
medical intervention/therapy required, hospitalization or hospice care possible." For the sake
of this analysis, we have presented the most common grade 4 events and have grouped them
accordingly: cardiovascular events were grouped to include cardiac or vascular events (i.e.,
cardiac arrest, myocardial infarction, cerebrovascular accident, deep vein thrombosis,
pulmonary embolism, unstable angina, congestive heart failure, and splenic infarct);
kidney-related events were grouped to include kidney failure, grade 4 elevation in serum
creatinine (>6 x upper level of normal [ULN]), and HIV-related nephropathy; hemorrhage events
were grouped to include gastrointestinal bleeding, bleeding (at an unspecified location), nose
bleeding, and hematuria (gross); liver-related events were grouped to include grade 4
transaminase elevations (>10? ULN), grade 4 elevations of bilirubin (>5 x ULN), clinical
hepatitis, fulminant hepatitis, liver failure, toxic hepatitis, cirrhosis, fatty liver, hepatic
encephalopathy, and liver disorder/disease; pancreatitis events were grouped by grade 4
elevation of amylase (>5 x ULN), grade 4 elevation of lipase (>5 x ULN), and clinical
pancreatitis; thrombocytopenia events included grade 4 diminution of platelets (<20,000/mm3)
and idiopathic thrombocytopenic purpura; psychiatric events included suicide attempt, suicidal
ideation, hallucinations, depression, anxiety/panic attack, delirium, psychosis, paranoia,
bipolar disorder, and manic hyperactivity/agitation; grade 4 anemia is defined as diminution of
hemoglobin < 6.5 g/dL ; and grade 4 neutropenia is defined as absolute neutrophil count <500
/mm3.

Importantly, according to protocol, any event considered to be grade 4 in severity was to be
reported irrespective of the relationship to the treatments under investigation and
irrespective of any other medications taken concomitantly. Grade 4 events were to be reported
even if study treatments had been temporarily discontinued. All grade 4 events were reported,
not just the first to occur. At minimum, patients were to be seen every 4 months during
follow-up. Grade 4 events were centrally reviewed by a nurse who coded the event according to a
coding system based on the 9th revision of the International Classification of Diseases.

We performed a subset analysis with regard to liver events, attempting to see whether chronic
viral hepatitis co-infection impacted on grade 4 liver events, grade 4 events overall, AIDS
events, and death. In the serology analysis, we limited our analysis to the 3 studies that
collected hepatitis serology at baseline: CPCRA 058, CPCRA 059, and CPCRA 064. In these 3
studies, serology for hepatitis B (hepatitis B surface antigen) and hepatitis C (hepatitis C
antibody) infection was performed at baseline. This analysis reflects 1628 patients from these
3 studies with baseline serologies that were treated with ART. The serology data were collected
uniformly in these 3 studies, although the assay methodology varied by site and over time. We
do not attempt to compare this subset to the overall group. To facilitate the analysis of the
impact of chronic viral hepatitis coinfection on the incidence of grade 4 events, mortality,
and AIDS, in the serology cohort, we considered hepatitis B and hepatitis C together.

RESULTS

Between December 1996 and December 2001, 2947 patients with a diagnosis of HIV infection were
enrolled into 1 of 5 CPCRA clinical trials defining the cohort for this analysis. Patient's
clinical status ranged from relatively early HIV disease to advanced HIV disease. Fifty-three
percent of patients were ARV naive, and 47% were treatment experienced at the time of
enrollment. Average age was 39.3 years; 83% were male and 17% were female; 41.5% were white,
44.8% were African American, and 13.7% were Latino. Approximately 16% of patients reported a
history of injection drug use, and 55% reported homosexual activity as an HIV risk factor. CD4+
cell count averaged 211 cells/mm3 (interquartile range: 38-322 cells/mm3), and 40.0% had a
prior clinical AIDS diagnosis.

All patients in this cohort were prescribed ART following enrollment. At 12 months of
follow-up, 1951/2120 (92%) were prescribed ART with 1475/2120 (70%) on protease inhibitor-based
regimens, 421/2120 (20%) on nonnucleoside reverse transcription inhibitor-based regimens (no
protease inhibitor), and 55/2120 (3%) solely on nucleoside reverse transcription inhibitors.
Thus, at 12 months, 169/2120 (8%) had either temporarily or permanently discontinued ART.

Median follow-up was 20.7 months (interquartile range: 13.3-32.3 months), a total of 5940
person-years. During follow-up, 675 patients experienced a grade 4 event (11.4 per 100
person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272