566C80 (Atovaquone): FDA Advisory Committee Recommends Approval for Pneumocystis Treatment

On September 24 the FDA Antiviral Drug Products Advisory
Committee also recommended approval of 566C80 (also called
atovaquone), a drug developed by Burroughs Wellcome Company, for
treating pneumocystis. The committee recommended that the drug
be used as second-line treatment, if
trimethoprim/sulfamethoxazole (TMP/SMX, commonly known as Septra,
or Bactrim) could not be tolerated or failed to work. Trials had
shown that TMP/SMX was more likely than 566C80 to be effective
against pneumocystis, but also more likely to be discontinued
because of side effects. The importance of 566C80 is to offer
another pneumocystis treatment option for those times when it is
needed.

566C80 might also be useful in treating toxoplasmosis.

FDA approval of 566C80 is expected in the next several weeks
or months. Meanwhile, a Burroughs Wellcome "treatment IND"
program which started in November 1991 will continue to be
available for those who need the drug now; there is also a
similar "compassionate release" system for use outside North
America. More than 800 patients have been treated in these
programs. To enroll a patient in the treatment IND, physicians
can call 800/755-2020, 7 days a week 24 hours a day.

****** Warning: "Poppers" Return, More Evidence of Harm

by John S. James

"Poppers" are nitrite inhalants which have been used in the
gay community as a sexual aid. Following research reports that
these chemicals might be contributing to immune problems in AIDS
or to the development of Kaposi's sarcoma, they were banned in
the United States in 1988. But now they are coming back, being
sold allegedly for such purposes as removing fingernail polish,
in sex clubs, bars, through the mail, and by advertisements in
gay publications. One concern is that promoters of new
preparations, in an effort to get around the law, could replace
banned chemicals with substitute ones, with completely unknown
effects when deliberately inhaled; one unlucky choice of
ingredient could cause widespread damage. Efforts are under way
to analyze inhalants now being sold to determine what they
contain.

[The 1988 law, section 8 of the Consumer Product Safety Act,
banned the manufacture for sale, distribution in commerce, or
importation of various forms of "butyl nitrite." Manufacturers
then substituted isopropyl nitrite, and in 1990 Congress amended
the law to also ban "volatile alkyl nitrites that can be used for
inhaling or otherwise introducing volatile alkyl nitrites into
the human body for euphoric or physical effects." We do not know
if the current products have substituted other chemicals in order
to evade this language.]

In most of the world poppers are not illegal or regulated,
and they have remained in widespread use in some countries.

According to Hank Wilson, a well-known AIDS activist with
ACT UP/Golden Gate who fought poppers years ago and recently
brought the current resurgence to our attention, one problem in
alerting the gay community to the dangers is that some gay
newspapers are reluctant to report negative news about poppers
because they carry advertisements for these preparations. As a
result, young people now entering the gay community often do not
know that there ever was a health issue or controversy about the
use of these drugs. (A San Francisco law requiring a warning
sign where poppers are sold took effect in January 1984. But
today the traffic is underground, so this warning law isn't
working.)

The issue of poppers in the gay community first surfaced in
1981, and some observers suspected that poppers themselves might
cause AIDS. Later, those theories were largely dismissed, but
confusion occurred because some people thought the issue was
finished. The remaining concerns are that poppers might be a
cofactor in the development of AIDS, or could lead to relapse to
unsafe sex, or make HIV infection more likely by causing changes
in blood vessels(1), or possibly cause poisoning if unknown
chemicals are substituted in an effort to evade the law. And
some of the chemicals are known to degrade over time, so there
could be harmful byproducts as well. Some researchers also
suspect that the body may metabolize the nitrites to
nitrosamines, which are strongly carcinogenic(1).

Because of the high profit margin -- it costs about 25 cents
for the chemical which sells for about $10 retail -- this issue
is expected to remain with us for some time.

Recent Studies of Popper Use

Poppers have not been conclusively proven to be harmful;
absolute proof would require a large clinical trial with people
randomly assigned to take a placebo or each of the various
chemicals in use, clearly an ethical impossibility. One recent
study(2), however, gave repeated doses of amyl nitrite to
volunteers and found suppression of immune functions, especially
of natural killer cells, following moderate inhalation. The
number of these cells did not decrease, but their activity
decreased about 30 percent, and remained low until several days
after the use of the drug was stopped. (The volunteers were
HIV-negative men who had used poppers previously. The
researchers' institutional review board would not allow the test
to be repeated on HIV-positive volunteers, because of the risk of
harm their health.)

An epidemiological study in Vancouver published in May
1992(3) followed a cohort of 353 gay men and found that those who
used nitrite inhalants were 2.3 times more likely to develop
Kaposi's sarcoma than those who did not. Because such an
association could be caused by factors other than the chemical
effect of the nitrites (for example, those who used poppers might
also have had more unsafe sexual contacts), the data was
statistically adjusted for known HIV risk factors. Poppers use
was still associated with increased risk of KS.

However, an English study of 65 gay men(4) failed to find an
association between poppers use and KS.

An epidemiological study in Boston(1) found that poppers use
increased the risk of HIV infection, especially during unsafe
sex. And the same Vancouver research group mentioned above
reported, at the 1991 International Conference on AIDS in
Florence, that gay men who practiced unsafe sex were more likely
to use poppers than those who did not(5).

Two 1990 articles from the U. S. National Institute of Drug
Abuse(6,7) called nitrite inhalants a leading candidate as a
cofactor for the development of KS in persons with AIDS, and
urged physicians to encourage patients to avoid their use.

However, a report from the San Francisco City Clinic Cohort
Study(8) did not find differences in nitrite use among AIDS
patients with KS vs those who did not have KS.

A study of gay men in the Paris area found that poppers use
was associated with increased risk of being HIV positive, even
after the data was adjusted for known risk factors(9).

In an animal study, mice exposed to isobutyl nitrite 45
minutes a day for 14 days showed several kinds of immune
suppression(10).

This list is far from complete; there are many other
medical-journal articles on poppers, most of them reporting
evidence of health risks. We only included the ones which were
published in 1990 or later, and which seemed most important.
Therefore our list entirely omits the earlier medical-journal
warnings about poppers which led to the law against them in the
United States.

Comment

We may never have final answers to the questions about
health hazards of poppers; some of the articles cited here did
not find evidence of harm. But the weight of the evidence
strongly suggests that poppers are certainly not safe and
probably do cause damage to health, especially to persons with
HIV. Since these drugs are coming back into use despite the U.
S. law against them, people will have to make their own
decisions. It is important that the available information be
widely circulated in the gay community and among other users of
such inhalants.

Note: Anyone who wants to work on the poppers issue can
call Hank Wilson at 415/441-4188, or write to him at 55 Mason
Street, San Francisco, California 94102.

References

(1) Seage GR 3rd, Mayer KH, Horsburgh CR Jr, Holmberg SD, Moon
MW, and Lamb GA. The relation between nitrite inhalants,
unprotected receptive anal intercourse, and the risk of human
immunodeficiency virus infection. American Journal of
Epidemiology. January 1, 1992: volume 135, number 1, pages 1-
11.

(2) Dax EM, Adler WH, Nagels JE, Lange WR, and Jaffe JH. Amyl
nitrite alters human in vitro immune function. Immunopharmacology
and Immunotoxicology. 1991: volume 13, number 4, pages 577-587.

(3) Archibald CP, Schechter MT, Le TN, Craib KJ, Montaner JS, and
O'Shaughnessy MV. Evidence for a sexually transmitted cofactor
for AIDS-related Kaposi's sarcoma in a cohort of homosexual men.
Epidemiology. May 1992: volume 3, number 3, pages 203-209.

(4) Beral V, Bull D, Darby S, and others. Risk of Kaposi's
sarcoma and sexual practices associated with faecal contact in
homosexual or bisexual men with AIDS. Lancet. March 14, 1992:
volume 339, pages 632-635.

(5) Willoughby BC, Schechter MT, Craib KJ, and others.
Characteristics of risk takers among seronegative men in a gay
cohort. VII International Conference on AIDS, Florence, June
16-21, 1991 [abstract # W. C. 3003].

(6) Haverkos HW. The search for cofactors in AIDS, including an
analysis of the association of nitrite inhalant abuse and
Kaposi's sarcoma. Progress in Clinical and Biological Research.
1990: volume 325, pages 93-102.

(7) Haverkos HW. Nitrite inhalant abuse and AIDS-related Kaposi's
sarcoma. Journal of Acquired Immune Deficiency Syndromes. 1990:
volume 3, supplement 1, pages S47-S50.

(8) Lifson AR, Darrow WW, Hessol NA, and others. Kaposi's
sarcoma among homosexual and bisexual men enrolled in the San
Francisco City Clinic Cohort Study. Journal of Acquired Immune
Deficiency Syndromes. 1990: volume 3, supplement 1, pages S32-
S37.

(9) Messiah A, Bucquet D, Mettetal JF, and Rouzioux C. Sexual
practices associated with increased risk of HIV infection: the
danger of self-defined safer-sex? VI International Conference on
AIDS, San Francisco June 20-23, 1990 [abstract # S. C. 686].

(10) Soderberg LSF and Barnett JB. Exposure to inhaled isobutyl
nitrite reduces T cell blastogenesis and antibody responsiveness.
Fundamental and Applied Toxicology. 1991: volume 17, pages 821-
824.