[Electronic distribution for GENA/aegis by the Sisters of St. Elizabeth]

 Volume 8 no. 8

 Gay Men's Health Crisis: Treatment Issues 
 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
> Treatment Highlights from Yokohama Conference
  >> New Ways to Measure Viral Burden
  >> HIV in the Lymph System
  >> Protease Inhibitors
  >> Little Benefit to "Early" Use of AZT, again
  >> A More Promising NNRTI?
  >> Other New Anti-HIV Drugs
  >> Mono, Combo or Sequential Therapy
  >> Opportunisitic Infections 
  >> Long Term Survivors
  >> Reducing Maternal-Fetal HIV Transmission
 > HIV-Related Weight Loss and Wasting 
 > Nutritional and Wasting Reports at the 10th Int'l Conference
 > Donald Kotler on the Gut, Inflammation and HIV 

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Treatment Highlights from Yokohama Conference
 by David Gold

The Tenth International Conference on AIDS, held in Yokohama, Japan 
from August 7 to 12, included a total of 709 oral presentations and 
2,760 poster presentations. Numerous satellite conferences, 
community meetings and press conferences also took place. 
Treatment Issues this month presents an overview of the major 
treatment themes emerging at the conference. Next month's edition 
will provide in-depth coverage of the presentations on antivirals, 
immune therapies, opportunistic infections, HIV pathogenesis, 
diagnostics and alternative therapies.

New Ways to Measure Viral Burden

Diagnostic techniques that measure the amount of HIV in the blood 
were a major focus at this year's International Conference. The two 
products receiving the greatest attention were Hoffmann-LaRoche's 
HIV RNA polymerase chain reaction (PCR) and Chiron's "branched-
chain DNA" (bDNA). These two assays measure the same thing - the 
RNA that forms HIV genes in free virus particles.

Both methods may be useful in clinical trials, where they could 
provide a quick assessment of the effectiveness of anti-viral 
therapies without having to wait for clinical endpoints (the onset of 
opportunistic infections or death). For individual patients and their 
physicians, these tests ultimately may provide a way to track 
disease progression more clearly. An increase in someone's HIV 
population might indicate that their current treatment had lost its 
effectiveness and thus point to the need to alter antiviral therapy.
Both Roche's PCR and Chiron's bDNA are now available for use by 
physicians, but these assays are not approved by the FDA for 
diagnostic use in HIV disease, and "research or scientific use" must 
be claimed. The price of these tests is steep for now -- at least 
$200.

Analyzing Viral Load Decreases

Currently approved anti-HIV therapies (AZT, ddI, ddC, d4T) can 
decrease HIV levels in the blood, at least temporarily. It is hoped 
that these decreases will translate into slower disease progression 
and increased survival for patients. This relationship has yet to be 
demonstrated, though.

In Yokohama, several studies did suggest that a drop in viral load 
caused by anti-viral therapy predicts clinical improvement in human 
beings. The NIH-sponsored trial ACTG 116B/117 produced data 
indicating that individuals whose HIV levels go down by 50 percent 
or more during the first month of therapy also experience a 
reduction in new opportunistic infections. A 254-person Veterans 
Affairs (VA) study similarly found evidence that decreases in viral 
load after starting AZT correlate with improved health.

HIV in the Lymph System

The new viral burden tests so far have been used almost exclusively 
to measure HIV levels in the blood. Yet, researchers have come to 
realize over the past few years that much of the early HIV 
replication occurs not in the blood but in the lymph system. Dr. 
Ashley Hasse presented data suggesting that approximately 25 
percent of the CD4 cells in the lymph nodes are infected by HIV. This 
is a much larger portion than previously thought. Using a new type of 
molecular technology, Hasse detected a "staggeringly large" amount 
of HIV-infected CD4 lymphocytes and macrophages in the lymph 
system.

Yet, a small study by NIH researchers suggested that current 
antiretroviral therapies may have a very minimal impact on HIV 
levels in the lymph system. When asymptomatic, HIV-positive 
individuals were given AZT monotherapy, the amount of HIV found in 
lymphoid tissue remained largely unchanged. In more advanced 
patients who added ddI to AZT therapy, there was a "temporary 
reduction" in HIV replication in the lymph tissue in four of six 
patients. 

Protease Inhibitors

Much of the discussion about new antiviral therapies centered 
around HIV protease inhibitor compounds. Approximately twenty of 
these compounds are now under development, but most are not yet in 
human trials. Of those that are in human trials, virtually no new data 
were reported. Hoffmann-LaRoche presented previously released 
data on saquinavir from ACTG 229 (see Treatment Issues, June 
1994). Researchers from Merck discussed the company's overall 
development program in only general terms. Preclinical data 
measuring antiviral effect in test tubes and bioavailibility (how 
much of the drug gets into the bloodstream) in animals were 
presented by at least eight companies. 

Viral Resistance to Protease Inhibitors

The most important new information about protease inhibitors came 
from the Third International Workshop on Resistance, held in Kauai, 
Hawaii immediately preceding the International Conference.
There, researchers from Wellcome Research Labs presented viral 
resistance profiles based on test-tube studies of five protease 
inhibitor compounds under development. Of concern, similar 
resistance patterns were seen in many of the compounds. In fact, 
two key mutations were associated with resistance to four of the 
five compounds.

Interestingly, HIV resistant to Merck's compound, L-735,524, was 
still sensitive to Roche's saquinavir, though. Dr. Emillio Emini of 
Merck Research Laboratories reported that after six to eight months, 
the HIV in most patients on L-735,524 is resistant to the protease 
inhibitor compounds created by Abbot and DuPont-Merck, but not to 
saquinavir. However, one patient, among the first given L-735,524, 
eventually developed virus that was ten times more resistant than 
normal to all protease compounds tested, including the Roche, 
Vertex and Searle compounds.

Roche researchers reported that after one year of treatment with 
saquinavir at 600 mg three times per day, 50 percent of patients 
showed evidence of harboring resistant HIV with a mutation at one 
of two points in the virus's genes. Stefano Vella, M.D., summarized 
data indicating that the combination of saquinavir and AZT delayed 
the emergence of resistance to both drugs.

Little Benefit to "Early" Use of AZT, again

New data was released from ACTG 019, a long running, placebo-
controlled study of AZT in over 3,200 HIV-positive patients. Paul 
Volberding, M.D., of the University of California San Francisco 
presented data on 1,637 individuals who began the study with over 
500 CD4 cells and were randomized to either AZT or placebo. After a 
median follow-up of five years, patients randomized to AZT had 
higher median CD4 cells, but there was no significant difference in 
disease progression or death. The results of this study, which will 
be discussed in greater detail next month, appear to be consistent 
with results from the Concorde study announced last year. In that 
study, the use of "early" AZT in asymptomatic HIV-positive 
individuals provided measurable increases in levels of CD4 cells but 
no significant advantage in terms of disease progression or survival.

A More Promising NNRTI?

Some have already written off the class of drugs known as non-
nucleoside reverse transcriptase inhibitors (NNRTIs). Yet, a number 
of reports at Yokohama suggested that these compounds may still be 
promising, especially when used in combination with two nucleoside 
analogs. Although resistance seems to develop rapidly with both 
nevirapine and delavirdine, a European study reported that 
resistance may develop less quickly with loviride, an NNRTI 
manufactured by Janssen Pharmaceuticals.

Other New Anti-HIV Drugs

Aside from the reports about the protease inhibitor compounds, 
there was little data about new anti-HIV therapies. Dr. Robert Gallo 
reported that hydroxyurea, a drug already approved as a treatment 
for some forms of chronic leukemia, inhibits a cellular enzyme 
necessary for HIV to reproduce. Hydroxyurea seems synergistic with 
AZT. Burroughs Wellcome reported that it is developing three new 
nucleoside analogs, all now in clinical trials, and an 
immunomodulator compound known as "Tucaresol," which should 
begin phase I trials by the end of 1994. A small study of interleukin-
4 suggested that the compound, although unimpressive as a Kaposi's 
sarcoma therapy, increased CD4 levels and decreased HIV levels. 

Mono, Combo or Sequential Therapy

A number of small studies suggested that switching (sequential) 
therapy from AZT to ddI may be more beneficial than continued long-
term AZT monotherapy. An retrospective analysis conducted by the 
U.S. Multicenter AIDS Cohort Study (MACS) found that men with 
intermediate stage HIV infection and on long-term AZT had a one-
third better survival rate if they added ddI or ddC to the AZT. Men 
who exchanged monotherapies did no better than those who stayed on 
AZT. Yet, the issue of combining versus switching drugs remains 
unsettled and probably awaits the results of larger trials now 
underway (ACTG 175 and the Delta trial). For more advanced patients 
with very low CD4 counts, combination therapy still has not proven 
better than monotherapy and may be associated with more toxicity.

Opportunisitic Infections 

The leading story in terms of OI treatment was data about Serrano 
Labs' human growth hormone (see below). Unfortunately, no data was 
presented about the use of oral ganciclovir for CMV prophylaxis. 
Shortly before the conference, Treatment Issues reported that a 
placebo-controlled study of oral ganciclovir had been halted after 
initial results indicated a significantly lower level of CMV disease 
and a "trend toward increased survival" in patients given the drug. 
The drug's manufacturer, Syntex, was unable to put together the data 
quickly enough to be presented at the international conference as 
late-breaking news. The data are now scheduled for release at a U.S. 
conference in October.

Long Term Survivors

"Long-term nonprogressors" (individuals infected with HIV for at 
least seven to twelve years with no decline in CD4 counts) elicited a 
flurry of reports this year. David Ho, M.D., of the Aaron Diamond 
Research Center in New York, reported that the long term 
nonprogressors he is observing have extremely low levels of HIV in 
their blood and that their CD8 cells may be playing a critical role in 
suppressing HIV replication. Neutralizing antibodies to HIV also 
remained high, indicating some continued viral replication in 
nonprogressors. The viral strains from two of Dr. Ho's subjects grew 
poorly in cell cultures and seemed defective in some way.

Reducing Maternal-Fetal HIV Transmission

While the conference was in session, the Food and Drug 
Administration approved the use of AZT to reduce perinatal 
transmission. Guidelines were issued in the CDC's Morbidity and 
Mortality Weekly Report (August 5, 1994; vol. 43, no. RR-11).
A presentation by Yvonne Bryson, M.D., reported that HIV-positive 
mothers with higher viral burden, lower CD4 counts and more 
advanced disease were more likely to transmit HIV to their infants. 
Efforts are now underway to initiate trials using Merck's protease 
inhibitor to see whether this drug's comparatively large initial 
reduction in viral load further reduces mother-to-child 
transmission.

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HIV-Related Weight Loss and Wasting 
 by David Pieribone

HIV-associated weight loss, or wasting syndrome, is a major cause 
of illness and death in patients with late-stage HIV infection. It can 
be divided into two categories: acute weight loss, which often 
rebounds after an opportunistic infection is brought under control, 
and chronic weight loss, which is more difficult to reverse. Either 
decreased nutrient intake or alterations in metabolism can lead to 
weight loss. These factors can arise directly from HIV infection as 
well as from opportunistic infections, cancers or pre-existing 
gastrointestinal disease. 

It is important to differentiate between mere loss in weight and the 
loss of protein stores (in lean tissue) that occurs during HIV 
infection. When acute weight loss is halted by treating an 
opportunistic infection, an individual may regain lost weight by 
adding fat rather than rebuilding lean tissue. Simply taking in more 
nutrients does not automatically produce recovery from wasting. 
AIDS-related wasting differs qualitatively from starvation. In 
starvation, the body's protein stores and muscle mass is conserved 
while basic metabolic rates slow and fat deposits are broken down 
for energy. During AIDS, the reverse happens. Studies by Kotler and 
others meanwhile indicate that death from wasting is related to the 
loss of lean body mass rather than just the amount of weight loss.[1]

Alterations in Metabolism

Primary infection with HIV or secondary opportunistic infections 
changes the body's metabolic pathways. Abnormal patterns of 
protein and lipid metabolism result, with nutrients transferred from 
lean to adipose (fat) tissue. Some inflammatory cytokines 
(intercellular immune regulators), such as tumor necrosis factor 
(TNF) and interleukin-1, have been associated with metabolic 
dysregulation and wasting.[2] Their chronic release during HIV 
infection seems to play a major role in HIV-related wasting. 
Endocrine abnormalities, including changes in gonadal, adrenal and 
thyroid function, have been noted in HIV-infected individuals and are 
another possible cause of weight loss and wasting.[3,4] One recent 
paper reported that people with AIDS-related wasting syndrome had 
significantly less testosterone and more prolactin and cortisol than 
similar people without wasting.[5] Testosterone promotes the growth 
and maintenance of muscle tissue. The decrease in testosterone may 
be related to the increased prolactin. Cortisol is an adrenal hormone 
that modulates stress. One of its functions is to free existing 
protein stores to repair tissue damage elsewhere in the body.
Finally, progressive muscle weakness (myopathy), is an ill-defined 
condition that may be caused by HIV itself or extended use of AZT. It 
is reversible in the latter case.

Approved Treatments for Wasting

Two appetite stimulants are the only FDA-approved therapies 
specifically for AIDS-related wasting syndrome.

Dronabinol (Marinol) is the psychoactive component of marijuana. In 
trials, dronabinol improved appetite and weight gain (mostly body 
fat) in about half of the participants. Side effects associated with 
Dronabinol include dizziness, thinking abnormalities, asthenia 
(weakness or loss of strength) and euphoria.

Megestrol acetate (Megace) is a synthetic progesterone (steroid 
hormone) in oral suspension. A twelve-week, placebo-controlled 
study conducted in patients with AIDS-related wasting provided the 
basis for its approval. Weight gains of five to seven pounds were 
observed in the megestrol acetate group, and two-pound losses were 
observed in the placebo group.[6] Phase II studies are underway to 
evaluate the combination of Marinol and Megace.

Side effects of Megace include high blood pressure, leg swelling, 
diabetes and impotence. (In addition, there was a trend toward a 
higher death rate in one study's treatment arm.) Megace, like 
Marinol, is widely considered to increase weight without adding to 
lean body mass (see article on the Tenth International Conference on 
AIDS). Appetite stimulants alone may not be able to 
overcome the basic metabolic changes wrought by the chronic 
response to HIV and the concurrent opportunistic infections. 
Reversing wasting may require "anabolic" agents that, like 
testosterone, promote muscle formation and discourage fat buildup.

Human Growth Hormone

Recombinant human growth hormone (rHGH) and insulin-like growth 
factor (IGF-1) are two growth stimulators currently under study as 
therapies for wasting.

rHGH is a synthetic version of pituitary gland-derived human growth 
hormone. It is made by genetic engineering and used for the 
treatment of dwarfism. rHGH can induce positive nitrogen balance, 
promote protein sparing and increase weight gain and lean body mass 
in patients with AIDS-related wasting.[7] Side effects of rHGH 
include joint aches, fevers and high blood pressure.

Two preliminary studies published last year found that human 
growth hormone triggered significant weight gain in people with HIV 
wasting.[8,9] See the box on the International Conference on AIDS for 
the first analysis of a much larger, more extended trial of rHGH. The 
presentation on this trial was very encouraging.

IGF-1 is produced by the liver in response to human growth hormone. 
Many, but not all, of growth hormone's effects seem to really be the 
result of IGF-1. A trial comparing growth hormone and insulin-like 
growth factor is being conducted at the National Cancer Institute, 
but a trial examining the combination of the two yielded negative 
results (see below).

Anabolic Steroids

Testosterone and the chemically similar synthetic anabolic steroids 
have been used by athletes and body builders to increase their 
muscle mass and stamina. Anabolic steroids can be dangerous, 
though, and medical supervision is desirable.

Community doctors have found that testosterone replacement 
therapy can improve patients' mood, sexual function, appetite and 
energy, although the long-term effects on immune function are not 
known. Testosterone replacement is generally not sufficient to 
manage weight loss and increasing testosterone levels to above 
normal can have adverse effects, including liver damage.
A limited number of studies indicates that some of the newer 
synthetic oral testosterone derivatives have fewer side effects, and 
anecdotal reports claim that they increase immune cell populations 
(CD8 and CD4). Dr. Kotler, at St. Luke's/Roosevelt Hospital in New 
York, is conducting trials with oral oxandrolone, a synthetic 
anabolic. Early results indicate that patients taking oxandrolone 
experience weight gain. Upon termination of treatment, weight loss 
resumed, however. There was no evidence of CD8 or CD4 cell 
increases resulting from oxandrolone therapy. During short-term 
use, no overt side effects were noted but studies examining long-
term use have not been done. The effects of anabolic steroids on 
women in particular need further monitoring, although oxandrolone 
is reputed to have few masculinizing effects.

Anabolic steroids such as deca-durabolin have become popular as an 
underground therapy among people with AIDS. Many feel that these 
compounds work much better when accompanied by a rigorous 
exercise program. Future studies should be conducted to evaluate the 
combination of anabolic steroids with growth hormone and 
testosterone replacement. The ideal therapy may well be an 
individualized one that includes hormone- and cytokine-modulating 
agents as needed but starts with such simple supportive measures 
as exercise and food supplements.

Cytokine Modulators

Pentoxifylline is a medication for blood circulation disorders. It 
also inhibits the activity of TNF and might in this way help reverse 
wasting syndrome. An NIH-sponsored study has found that after 
eight weeks on pentoxifylline, triglycerides (lipids) in blood serum 
dropped significantly and TNF production went down.[10] Researchers 
at the Veterans Affairs Hospital in Brooklyn, New York studied the 
drug's effect on wasting syndrome in patients with AIDS but were 
not able to detect any weight gain or reversal of wasting.[11] Another 
recent study found that pentoxifylline at a dose of 800 mg three 
times daily did not affect the T-cell counts, viral load or TNF in 
eight patients treated for three weeks.[12]

Thalidomide is enjoying a revival as a TNF blocker. Recently, two 
separate studies, one in France and another at Rockefeller University 
in New York City, have shown significant weight gain in patients 
receiving thalidomide. Thalidomide's abilities in this area are now 
the subject of further study. For the latest results, see the article on 
the AIDS Conference.

OP-1, a mixture of polypeptides, glycopeptides and glycosides, is 
another reputed TNF inhibitor. Its developer, Omega 
Pharmaceuticals, is just now beginning clinical trials of OP-1 for 
AIDS-related wasting.

Malabsorption

Cells in the GI tract are particularly prone to damage during HIV 
infection, and this results in reduced absorption of nutrients. The 
HIV virus itself, intestinal parasites, and colitis induced by 
cytomegalovirus (CMV) are the main sources of tissue damage. The 
diarrhea connected with these conditions also may result in 
malabsorption. Fat, carbohydrate, protein and micronutrient (vitamin 
and mineral) malabsorption can occur. Malabsorption may also be a 
condition that pre-exists infection with HIV.

Infection by intestinal parasites triggers diarrhea and 
malabsorption in persons with AIDS by causing atrophy of the villi 
- the small threadlike projections on the interior of the small 
intestines which absorb nutrients when working properly. Given the 
variety of intestinal parasites, electron microscopic analysis of 
intestinal biopsy is required for a conclusive diagnosis. This 
procedure is both uncomfortable and expensive. It is also difficult to 
perform and may be unavailable in many places.

The protozoa Cryptosporidium parvum, the most commonly identified 
parasite in people with AIDS, causes massive secretory diarrhea. 
Paramomycin (Humatin) at 500 mg four times a day has 
demonstrated positive results in some patients although relapse is 
common after the drug is discontinued.[14] For persons with a more 
mild infection, a lactose-free, low-fat diet with a high calorie, 
protein-rich fluid supplementation is helpful. The large amounts of 
sugars or long-chain proteins found in some nutritional drinks tend 
to engender bloating and heightened diarrhea. Persons with severe 
untreatable diarrhea may also require parenteral (intravenous) fluid 
administration to maintain a normal state of hydration and 
electrolyte balance. 

Among the drugs under investigation for cryptosporidiosis is 
intravenous azithromycin. This formulation of the drug is available 
directly from the manufacturer, Pfizer, on a compassionate use 
basis (call 800/742-3029 for further information). Side effects of 
IV azithromycin include nausea and abdominal pain. Oral 
azithromycin failed to show an effect on the frequency of bowel 
movements, parasite shedding in the stool or overall clinical 
response in a placebo-controlled study of 90 patients with 
cryptosporidiosis conducted at Cornell Medical Center.[15]

Another anti-crypto agent in development consists of concentrated 
antibodies derived from cow's milk. Bioimmune Systems of Salt Lake 
City is just beginning preliminary human trials in HIV-negative 
individuals of its oral, milk-derived antibody product, known as 
Immuno-C. An efficacy trial for 40 people with AIDS-related 
cryptosporidiosis is expected later in the fall and will include six to 
eight sites around the country. More information may be obtained by 
calling Joy Erickson of Bioimmune Systems at 801/582-2345.

A second cow's milk preparation is called CryptoGAM. It is 
manufactured by Immucell and licensed by Univax. CryptoGAM failed 
as an oral agent in several early trials apparently because it was 
broken down in the stomach before it reached the intestines. A new 
open label trial is currently being conducted by Louis Fries, M.D., 
from Univax. Very high dose CryptoGAM (40 grams per day) is 
introduced directly into the duodenum via a nasogastric tube. 
Patients interested in the trial can contact Dr. Fries at 301/770-
3099.

Microsporidia (Enterocytozoon bieneusi or Septata intestinalis) is a 
second common GI parasite in people with AIDS. Infection can cause 
diarrhea and decreased intestinal absorption.[16] The drug albendazole 
has shown some promise and is currently the subject of an NIH-
sponsored trial. A preliminary report on eight patients from Dr. 
Dominique Anwar of Grady Memorial Hospital in Atlanta indicates 
that atovaquone (an approved treatment for pneumocystis 
pneumonia) may be effective in reducing diarrhea.[17]

As a preventive measure, HIV-infected people with low CD4 counts 
should be extremely careful about the water they consume. There are 
only three acceptable forms: distilled, deionized or boiled. Water 
filters, standing water (wells), spa waters and bottled spring water 
can be contaminated with intestinal parasites. Ice cubes and soda 
fountain-type drinks which mix tap water with syrup can also be 
contaminated. Use distilled, deionized or boiled water in all foods 
that will not be cooked and require water for their preparation. 
Because even the smallest amount of contaminated water can cause 
infection, fruits and vegetables rinsed with tap water could be a 
source of parasistes.

Nutritional Support

Nutritional support is very important for individuals with HIV 
infection. Anabolic drugs will have little effect without sufficient 
diet. Studies also indicate that diets high in protein and complex 
carbohydrates, moderate in fats and sugars are important for good 
immune function.

Use of nutritional drinks such as Nutren, Ensure Plus, and Sustacal 
can increase caloric intake for individuals who are having trouble 
consuming enough calories. Because both individuals' needs and the 
products' compositions vary, one supplement may be better suited 
than another for a particular situation. Patients should consult their 
physicians or a nutritional counselor before adding nutritional 
drinks to their diets. Little data from controlled trials exist, though, 
so it is difficult to assess the actual benefit of supplementation.
Lipisorb is a food supplement containing medium chain triglycerides 
that may benefit patients with fat malabsorption. Elemental 
(predigested) diets are comparatively easy to absorb in the GI tract 
and reportedly have helped lessen diarrhea and stabilize weight.[18]
In patients unable to eat, data from two studies suggest that enteral 
gastrostomy feeding (feeding through a tube placed directly into the 
stomach through the skin) can result in weight gain and increased 
lean body mass.[19]

Total parenteral nutrition (TPN) is a form of liquid nutrition infused 
directly into the bloodstream. Studies indicate that patients 
receiving TPN gain significant amounts of body cell mass and weight 
if they are free of systemic infections. Other studies have shown 
that administering TPN during secondary infection can increase 
weight gain and improve the quality of life by improving the 
individual's ability to fight infection.[20] Investigators also have 
reported that TPN has favorable effects on immune cell 
responsiveness.[21] But TPN can cost up to $13,000 a month in a home 
care environment. It is usually used to support someone through a 
limited period of acute illness but may be required for more lengthy 
periods.

Exercise

Exercise can promote protein formation in tissues throughout the 
body. It is a helpful therapy when physical health permits. To build 
up lean body mass, resistance exercises (such as weight lifting) are 
more important than aerobic exercises, although aerobic exercise 
can also be beneficial. Exercise promotes muscle formation by 
increasing the number of testosterone receptors. Proper timing of 
food intake is also important in weight lifting. It is a good idea to 
eat well but not immediately prior to lifting weights and to eat a 
high protein food one to two hours after lifting.

Conclusion

A variety of therapeutic strategies are available for different 
aspects of HIV-associated wasting. There is a strong correlation 
between proper weight, good nutritional status and survival.[22] 
Individuals should chart their weight, noting any significant change, 
and physicians should take determined steps to diagnose and treat 
major weight loss. Correct diagnosis and aggressive treatment can 
improve quality of life and prolong survival.

1 Kotler DP et al. American Journal of Clinical Nutrition. Sept 1989; 
50(12):444-7.

2 Lombard RP et al. Clinical Immunology and Immunopathology. 1989; 
50:374-84.

3 Jones PD et al. Journal of Acquired Immune Deficiency Syndromes. 
Dec 1992; 5:1266-71.

4 Landman A et al. Thirty-second Interscience Conference on 
Antimicrobial Agents and Chemotherapy. Oct 1992; abstract 568.

5 Coodley GO et al. Journal of Acquired Immune Deficiency 
Syndromes. Jan 1994; 7(1):46-51.

6 Flynn N et al Eighth International Conference on AIDS Jul 1992; 
8(2): B205. abstract PoB3687.

7 Grunfeld C et al. Eighth International Conference on AIDS Jul 1992; 
8(2): B230. abstract PoB3835.

8 Krentz AJ et al. Journal of Acquired Immune Deficiency Syndromes. 
Mar 1993; 6(3):245-251.

9 Mulligan K et al. Journal of Clinical Endocrinology and Metabolism. 
Oct 1993; 77(4):956-62.

10 Dezube BJ et al. Journal of Acquired Immune Deficiency 
Syndromes. Jul 1993; 6(7): 787-94.

11 Landman A et al. Thirty-second Interscience Conference on 
Antimicrobial Agents and Chemotherapy. Oct 1992; abstract 568.

12 Mole L et al. Journal of Acquired Immune Deficiency Syndromes. 
May 1994; 7(5):520-1.

13 Lahdevirta J et al. American Journal of Medicine. Sept 1988; 
85(3):289-91.

14 Armitage K et al. Archives of Internal Medicine. Dec 1992; 
152(12):2497-9.

15 Soave R et al. Thirty-third Interscience Conference on 
Antimicrobial Agents and Chemotherapy. October 1993; abstract 
405.

16 Hecker LM et al. Nutrition Reviews. Nov 1990; 48(11):393-401.

17 Torres G, personal communication.

18 Hickey MS. Surgical Clinics of North America. Jun 1991; 
71(3):645-64.

19 Kotler DP et al. American Journal of Clinical Nutrition. 1991; 
53(1):149-54.

20 Campelli A et al Eighth International Conference on AIDS. Jul 
1992; 8(2): 63.

21 Singer P et al. Journal of Parenteral and Enteral Nutrition. Jan-
Feb 1991; 15(1):75-9.

22 Guenter P et al. Journal of Acquired Immunodeficiency 
Syndromes. Oct 1993; 6(10):1130-8.

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Nutritional and Wasting Reports at the Tenth International Conference
 by Dave Gilden

Although the Tenth International Conference on AIDS in Yokohama 
last month was particularly poor in information about the 
nutritional aspects of AIDS, researchers did present several 
significant reports on treating AIDS wasting syndrome.
Morris Schambelan, M.D., of the University of California San 
Francisco described very positive results from a trial utilizing 
recombinant human growth hormone (rHGH) produced by Serono 
Laboratories.[1] Although rumors about this trial had circulated 
before, Dr. Schambelan's account was the first official disclosure of 
the data, which covered an initial twelve weeks of placebo-controlled 
observation and up to two years of further follow-up in which all 
trial participants received rHGH.

In the trial's first phase, the 90 trial participants receiving human 
growth hormone (at a rate of 0.1 mg per kilogram of body weight) 
gained an average of 1.5 kilograms. Their lean body mass went up 
three kilograms, and they lost 1.5 kilograms of fat. These people's 
treadmill performance also increased ten percent. A full quality of 
life assessment has yet to be done. In comparison, the 88 people 
originally on placebo at first gained a pound in weight on average, 
but by the end of the twelve weeks, their weight was back to 
baseline.

These figures suggest that rHGH works as expected, by reorienting 
the body's metabolism to building protein stores and breaking down 
fat rather than just adding weight. During the extended follow-up 
period, trial participants continued to regain weight, with some 
increasing by more than twenty pounds to reach their pre-illness 
mass. Since human growth hormone is very expensive to produce, the 
question now is whether the extra weight and lean tissue can be 
maintained if therapy is stopped.

Dr. Schambelan further noted that levels of insulin-like growth 
factor (IGF) rose substantially during the first twelve weeks of 
rHGH therapy. Much of growth hormone's effect may be due to IGF. 
But in another presentation at the conference, researchers from 
Genentech, Inc. reported negative results from a trial using small 
amounts of its version of rHGH plus IGF.[2] The effects on 52 trial 
participants appeared to be minimal after six weeks, and Genentech 
says it has no plans for further trials concerning wasting syndrome. 

A cheaper alternative to human growth factor and insulin-like 
growth factor may be thalidomide. Thalidomide interferes with the 
production of tumor necrosis factor (TNF), excessive amounts of 
which are suspected of accelerating weight loss as well as HIV 
replication. In a small study conducted in Mexico City,[4] an average 
weight gain of eight percent was recorded after twelve weeks on 
thalidomide, compared to an average loss of eight percent in the 
trial's placebo arm. A similar study conducted in Thailand[3] found 
that trial participants increased their weight by 4.5 percent after 
21 days. Nearly half the people in the Thai trial also had 
tuberculosis, which like HIV is known to cause very high TNF 
production. Neither trial could measure any effect on HIV levels or 
CD4 counts. The trials also did not collect detailed body composition 
data.

(A trial of thalidomide for HIV wasting is just getting under way at 
Rockefeller University in New York and several other sites around 
the country. Note that because of thalidomide's notorious history of 
causing birth defects, women "of child-bearing potential" have been 
excluded from thalidomide trials. This is an issue that raised 
considerable controversy during one of the Conference sessions.)
The necessity of analyzing body composition and not just weight 
gain was underscored by two posters at the conference concerning 
the appetite stimulant Megace.[5,6] Both studies found that although 
Megace triggered significant weight gains in men with HIV-related 
wasting, most or all of that gain was composed of fat. The lack of 
increase in lean tissue may be at least partly explained by the 
reduction in serum testosterone associated with Megace that the 
first study detected.

Another nutritional strategy that received some limited support at 
the Tenth International Conference on AIDS was vitamin 
supplementation. An eight-year observation of 280 gay or bisexual 
HIV-positive men forming part of the United States' Multicenter 
AIDS Cohort Study (MACS)[7] tracked survival rates according to 
intake of specific vitamins. High intakes of vitamins B1, B2, B6, C 
and niacin were associated with decreased mortality rates. In 
particular, those who at the beginning of the study were taking 
vitamin B6 supplements equal to at least two times the RDA had a 
40 percent lower death rate during the eight-year period. Zinc 
supplementation, on the other hand, was associated with an 
increased death rate.

1 Schambelan M et al. Tenth International Conference on AIDS 
Abstract Book. Aug 7-12 1994; II:35, oral presentation 432B.

2 Bukar JG et al. II:223, poster PB0903.

3 Reyes-Tern G et al. II:65, oral presentation 536B.

4 Klausner JD et al. I:221, poster PB0312.

5 Engelson ES et al. II:222, poster PB0900.

6 Stute A et al. II:223, poster PB0907.

7 Tang A et al. II:220, poster PB0894.

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Donald Kotler on the Gut, Inflammation and HIV 

> Donald Kotler, M.D., is Associate Professor of Medicine at Columbia 
University College of Physicians and Surgeons. He is one of the 
world's foremost experts on AIDS-related gastrointestinal 
conditions and weight loss. Over the years he has co-authored more 
than 100 reports related to AIDS and HIV. His current AIDS research 
concerns malnutrition, protein loss, anabolic agents, infections of 
the digestive tract and the role HIV itself plays in digestive 
ailments. <

Diagnosing GI Disorders

TI: Are there things that concern you about how people are being 
treated for HIV-related gastrointestinal disorders?

Kotler: Yes. If a doctor says, "You have malabsorption," and the 
doctor was smart enough to test for it specifically and find it, then 
I think the patient should listen to whatever the doctor says. Most 
doctors don't know malabsorption from hemorrhoids, and diarrhea 
becomes a common wastebasket designation. Diarrhea comes from 
the small intestine or the large intestine. And when it comes from 
the small intestine, it may well be malabsorption. When it comes 
from the large intestine, it may well not be malabsorption.
If you're trying to feed someone, it is absolutely important to know 
whether the small intestine is working or not. Most doctors ignore 
that. If you have a doctor who ignores it, then you probably can't 
trust what he or she is going to say in terms of nutritional advice. If 
you have a doctor who does not ignore it and actually makes that 
determination, that's probably a doctor who will refer you to a good 
nutritionist. 

The biggest mistake that I've seen is that patients with 
malabsorption are told to eat as much as they want of anything that 
they want to try, to maximize the calories that go in.

TI: Why is that bad?

Kotler: Usually you maximize the symptoms that occur and in 
maximizing the symptoms, there is a big push to not eat. So patients 
are left in a horrible situation of being very hungry, but knowing 
that whatever they eat is going to give really bad symptoms.
In fact, if you look at the typical malabsorption syndromes, the 
amount of calories that are malabsorbed are not huge. People should 
just be able to eat a little bit more and overcome that. But they do 
not, either because the symptoms prevent the eating, or there are 
unconscious signals not related to symptoms which prevent food 
intake.

So in fact, the typical malabsorber doesn't eat enough. And the richer 
the diet you give them, the less they end up eating, especially of 
calories that will be absorbed. Someone who has a malabsorption 
syndrome and who starts the day with a big ice cream soda because 
it has a lot of calories is probably going to have great difficulty 
eating lunch at all and may not get any appetite back until late at 
night.

TI: So, often people are not getting proper workups?

Kotler: Right. And if they do have an assessment which shows 
malabsorption, they need to be treated with a special diet, and even 
that might not even work. For that, I often have to resort to 
intravenous feeding, but I'm now doing a study to see if I can get 
away from intravenous feeding.

TI: What does a patient need to know about getting a good GI workup? 

Kotler: The workup has to lead to some answer. If it doesn't, then it's 
not an actual workup. A patient who has a problem and goes for an 
evaluation and is told simply, that it is not A, B, or C - that patient 
hasn't finished their evaluation. It's very important to know what or 
at least where it is. There must be an explanation for the symptoms 
whether or not it can be treated.

Sometimes, there is damage and you can't find the causative 
organism, but you can at least localize the damage. And you treat 
based upon localizing the damage because you might not be able to 
cure the underlying process -

TI: What does "localize the damage" mean? 

Kotler: Cryptosporidiosis affects the small intestine and is causing 
malabsorption. Since we can't cure cryptosporidiosis, we try to 
treat the malabsorption to minimize the symptoms and improve the 
nutrition. There are people who have small intestinal damage that's 
as bad as you'd see by cryptosporidiosis, but there's no bug. 
The evaluation ends up saying, "You don't have crypto." Well, that's 
not good enough. The evaluation should end up saying, "You have no 
cryptosporidiosis, but you have damage to your small intestine that 
gives malabsorption, just as if you did have crypto." The patient can 
be treated nutritionally, just as if he had cryptosporidiosis because 
the damage has been localized in the small intestine.

TI: So the idea is to correct for the malabsorption?

Kotler: If the damage is such that it prevents the proper digestion of 
lactose and fat, the idea is to remove lactose and fat from your diet. 
It's not to add lactose and fat just because they are great sources of 
calories and you should at least absorb something - that doesn't 
work. And it is certainly not enough to say, "Well, there's no 
cryptosporidiosis. Good bye."

TI: You have said that you try to get people off of IV feeding. How do 
you do that?

Kotler: By adjusting the diet. If somebody has intestinal damage and 
can't deal with food given the regular way, the two possibilities to 
get around the problem are to give food in a different way - 
intravenously - or to give a different food.

To give a different food means to give medium chain triglyceride, 
rather than long chain fats; less complex carbohydrates rather than 
more complex carbohydrates; no lactose and use sugars that are 
much easier to digest and absorb. And then see if this changed diet 
is as good as feeding intravenously. We know that feeding 
intravenously can improve nutrition.

Inflammation and HIV

TI: What behavioral things can people do to really extend their life?

Kotler: Oh, I would look at it the other way around. Patients should 
avoid certain things - like being reinfected over and over again.

TI: Do we know for a fact that "reinfection" [with HIV] occurs?
Kotler: No, we don't know anything. We don't know the effect of 
inflammation. But the guy who gets gonorrhea twenty times in the 
course of a year-and-a-half and each time inflames his intestine, 
which happens to have HIV in it, and the inflammation stimulates 
the intestine and drives the T-cells into the intestine to fight the 
inflammation where they get lost - I truly think that that sped the 
disease along in the past. Do I know that? No.

TI: Is the inflammation of the intestines central to HIV progression?

Kotler: Well, this is my personal and speculative view of disease 
progression:

Take it from the intestine and to a different, but similar group of 
structures - the mucous membranes. They have facets that are 
different than any place else in the body. They're an interface 
between a very clean and pristine, internal environment and a filthy, 
contaminated, external environment. Think about the rectum, the 
vagina, especially the cervix. The mouth isn't so much better. It's a 
very fine membrane separating an immune system from bugs of all 
types.

The body, over millennia, has learned to react promptly to any type 
of invasion of organisms. Membranes of bacteria or other organisms 
are perhaps the strongest immune stimulators you could ever find.
Any break in the lining of a mucous membrane will tend to bring 
those bugs in direct contact with the immune system. So the 
inflammation would be prompt and strong. That wouldn't happen in 
the kidney or the adrenal gland because there's no bugs around to 
cause that rapid stimulation. But in the intestine, in the other 
mucous membranes, they are there all the time.

So if anything like gonorrhea - or a cold - breaks the lining and 
opens up its pores for permeability and schmutz gets in and the body 
responds with a very strong inflammatory response, that 
inflammatory response will, at the same time, recruit lymphocytes 
that activate each other. It becomes self-perpetuating. So the 
inflammation reproduces the initial insult - weakening of the 
barrier. As long as the inflammation is there, the barrier will 
continue to be weakened. Stuff will continue to get in. The 
inflammation will continue to go on. So having bugs around and a 
weak barrier becomes like an amplifier. 

Now, the normal immune system has shut-off mechanisms. For every 
yin there's a yang. For everything that turns something on, there is 
something that will turn it off again. And early in the disease, this 
may happen - the immune system is intact enough so that it will 
limit [its reaction] and localize it and shut it off. There may come a 
point during the weakening of the immune system where the turnoff 
switch is missing, and then there's nothing to hold it back.
Think of it. You salivate because you get some stimulus. Unless there 
was something to shut that off, once you started salivating, you 
would just continue to salivate until you dehydrated yourself and 
died. You need the shut-off valve to make you stop salivating.

TI: So you want to avoid getting any additional bugs that survive. 
Which raises the common question, should people not be drinking 
water in major urban areas, such as New York City?

Kotler: I'm not sure that bottled waters are better. I recommend a 
good filter that gets changed often. You usually won't see chronic 
cryptosporidiosis unless the CD4 cells fall below 200. 

Boiling is okay [but] difficult to do, to make big boiled water tanks. I 
suspect that most bottled water is free of contamination. But it is 
insufficient if you wash your lettuce or make your ice from tap 
water. 

TI: What about salad bars and fresh vegetables?

Kotler: Stay away, unless you're going to clean them with a water 
source that's okay.

There's a lot of stuff written. And it's best coming from dietitians. 
Your cutting board shouldn't be wood, so that stuff gets caught in it. 
If you're cutting raw meat, use different cutting boards for other 
foods.

Therapies for HIV-Wasting 

TI: What role do anabolic hormones, like testosterone and 
oxandrolone [a synthetic testosterone-like steroid with reduced 
masculininzing effects], have in therapy?

Kotler: It seems clear that anabolic agents, under certain 
circumstances, can allow people to build back their protein and 
muscle stores, and in doing so, feel a whole lot better. Low 
testosterone levels have to be looked at as a natural response to 
chronic inflammation.

Anabolic steroids shunt the amino acids back to the muscles to make 
them grow. The body can't be asked to do two things at once - to 
give up its protein [to support the inflammatory response] and at the 
same time make bigger pecs. Now, it may not be so important any 
more, since God's Love We Deliver [a New York City meal delivery 
group] can give you all the amino acids you need. But the body's 
metabolic machinery was set up in a different millennium [when 
protein and energy sources were scarce].

TI: What about exercise?

Kotler: Absolutely. You can perhaps maximize the effect of an 
anabolic steroid by using resistance-training exercise. On the other 
hand, you might be able to get pretty far without using any anabolics 
at all and just using resistance-training exercise.

TI: And what role can recombinant human growth hormone play?

Kotler: That's another anabolic. I think in both cases, the more you 
use, the better response you get, and that you're going to have to 
supply the energy and the nutrients along with it to have them work. 
Then after that, I don't know.

TI: Can women use anabolic steroids?

Kotler: There's only one that's ever been recommended in women 
because the others appear to have too much androgen activity, but 
I'm not really sure. Estrogen and progesterone do not seem to act as 
anabolic steroids in women. It's really unclear what is an analogous 
anabolic agent for women. 

In fact, it may go back to a chemical that was bandied around in 
AIDS circles years ago and then pretty much neglected recently - 
that's DHEA [dehydroepiandrosterone]. DHEA is a precursor to the 
anabolics and it may be that one of the reasons the anabolic levels 
fall is because DHEA metabolism is diverted to something else 
rather than anabolics. Perhaps, if you're given DHEA, you can 
overcome that.

The people who did DHEA studies did nothing to see if it had an 
anabolic effect. Although some people taking DHEA looked pretty 
good, it was all being looked at as an antiretroviral agent or an 
immune modulator. It didn't really show very much that way, but it's 
conceivable that it is an anabolic agent. And it might well be that 
early on, that might be the best one to use, but no one studied it that 
way.

Reducing the Inflammatory Response

TI: Let's talk more about inflammation. Is there anything that 
patients could do to cut down on inflammation in a beneficial way?
Kotler: You can cut down on inflammation with an anti-inflammatory 
agent - we're doing a study right now with aspirin. The rationale is 
that several of the inflammatory signals directly stimulate HIV. 
Tumor necrosis factor [TNF] and interleukin-1 [IL-1], which are the 
messengers of the inflammatory response, happen to activate HIV.
A number of compounds, like aspirin and thalidomide, inhibit 
inflammatory signals. There are many anti-inflammatories, some 
may be perfect, some awful. There's a difference between the 
aspirin-type and the Motrin-type agents. 

Another consequence of inflammation is what's called "oxidative 
stress," which uses up the body's naturally available antioxidants. 
There are people who are using antioxidants in an attempt to 
compensate for that loss. 

It may be that the body's oxidative balance relates directly to how 
HIV grows, so that people who take salicylate [aspirin] or 
antioxidant therapies - vitamin E or C - may inhibit the virus to 
some extent.

TI: What is your present research with anti-inflammatory therapies?

Kotler: Our anti-inflammatory agent study originally was related to 
inflammation and HIV expression in the gut. We found that aspirin-
like anti-inflammatories seemed to dampen both the inflammation 
and its symptoms and decrease the expression of HIV viral proteins 
in the GI tract. 

I was unable to get further funding to study this in the gut and 
instead got funding to do the systemic study of aspirin in a group of 
HIV-infected people. That's being done at Community Research 
Initiative on AIDS [CRIA] in New York.

TI: When do you expect to have some data from the aspirin study?

Kotler: Don't know. The techniques we were using were insufficient 
to show the changes that we were looking for. We are now using a 
much more sensitive assay to measure viral load (the branched chain 
DNA), but only a few people have started the study and we want at 
least 50. We've already screened 35. With a more sensitive assay we 
probably would have needed 25 or 35 in the study. Once the study 
accrues, it's only a two-month study.

It's very difficult to get funding for an aspirin study. There's no 
patent at the end of the road. Nobody's going to make a lot of money, 
so the research money is limited. 

TI: The dose being used is equivalent to how many aspirin per day?

Kotler: Twelve, like the arthritis dose. It's big-time aspirin as a 
drug, leading to [high] blood levels, not aspirin as a headache remedy.

TI: What do you think aspirin does, specifically? What's its mode of 
action?

Kotler: A recent paper in Science says it inhibits a cellular activity 
promoter - NFkappaB - that is turned on by TNF and other signals. 
It also may be a free radical scavenger and act as an antioxidant. 
Certain salicylates do that. But in fact, I really don't know how it 
might work. People have been using aspirin for hundreds of years, 
and the mechanism of action was worked out, I believe, in the early 
seventies.

Reforming Research

TI: Let's talk about antiretroviral therapy. What do you tell your 
patients?

Kotler: My own feeling is that people should be on therapy early, that 
if they're willing, an antiviral therapy can be part of that, and that 
consideration of a combination therapy should come up early rather 
than late.

TI: What other therapy would be part of the combination, if not an 
antiviral?

Kotler: Besides behavior modification, good diet, and lots of sleep 
and stress reduction, I often use NAC [n-acetyl cysteine, a precursor 
to the cellular antioxidant molecule glutathione] and moderate doses 
of vitamins and minerals, including the antioxidants. There's a little 
bit too much "either/or" in AIDS treatment these days. You know 
people are put on AZT and just kept on it until they turn terrible and 
their doctors are virtually forced to change therapy out of 
embarrassment and shame.

TI: Where should we be putting our AIDS research dollars?

Kotler: Alternate hypotheses for pathogenesis. The hypotheses of the 
effects of inflammation. The effects of oxidative stress. They're 
here. There are drugs on the shelf that can be used right now if we 
knew they were good. These therapies took the back seat to the 
antiretrovirals. So a huge amount of data was, and still is, being 
generated about antiretrovirals in ways that're unbelievably 
confusing.

We've been let down. After all this time, what's the proper dose of 
AZT? What's the blood level you really need? Do you really need a 
blood level or do you need a level in CD4 lymphocytes? If so, what is 
that level? Basic answers aren't known.

TI: Why is it so hard to get studies funded?

Kotler: They're expensive. Somebody has to lay out the money for 
them. And the people who were making the decisions, came down 
hard on the side of the chemotherapeutic agent and antiretroviral 
agents, seeking the precise molecule to take out HIV altogether and 
bring about a cure. 

They're still looking at new single agents that will hold HIV off 
altogether, indefinitely. And every new drug that comes out, it 
seems like it's being looked at in exactly the same way.
Can you imagine a baseball game where the home team is down three 
to two in the sixth inning, and everybody tries to hit a home run, but 
they all strike out? Nobody tries to get to first base. That's my view 
of AIDS drug development. Everybody is looking for a $2-billion a 
year drug and nobody is looking for things that might just help.

TI: Whose responsibility is it to change that - private industry or 
government?

Kotler: I don't know. Probably the patients. You've been pushing 
things along pretty well up to now. If there's a change, you're 
probably going to have to be the ones to force the change. I wouldn't 
leave it to the people who are now in charge because they benefit 
from the status quo. From their point of view, things might be going 
okay. But from a different point of view, things are not going so well 
at all.

