Being Alive 1998 Feb 5: 1
For the eighth time in as many Januarys, I have the privilege
of recording one person's perception of the top strides in
HIV/AIDS over the previous twelve months. As in the past, these
focus on clinical (epidemiological and treatment-related)
issues, but once again the merits of political activismsuch as
the autumn 1997 announcement of dozens of human volunteers for
a live HIV vaccine trialrate a perennial award for advocacy and
Nostalgic at the mere thought of doing this column once again,
I dusted off my old Being Alive Newsletters and, before
proceeding, want to share the top story from each preceding
year of this decade:
1990: Prophylaxis for Opportunistic Infections
1991: Clear Superiority of Oral PCP Prophylaxis Over
1992: The Democratic Election Victory
1993: The Concorde Study
1994: AZT Reduces Transmission in Pregnancy
1995: First Protease Inhibitor Approved
1996: The "E" WordEradication
And, now, on to the year which I shall personally remember as
"The Year of `Titanic'"
1. AIDS: Is It Over -- Or Isn't It?
Most readers of this column agree with meit's not!but this year
saw the release (and promulgation by the mass media) of reports
of marked reductions in new AIDS cases as well as deaths. The
missing piece in so many of the reports was a simple one: If
fewer people are dying from aidsthen more persons are living
Alleged evidence of an increasing incidence of unsafe
sexparticularly in the gay male communityfueled a major debate
sparked by writers and spokespersons such as Larry Kramer,
Gabriel Rotello and Michelangelo Signorile.
Although the epidemic remains very much with us in its 17th
year, inpatient hospitalizations plummeted in 1997.
Opportunistic infections once commonplace are now rarities;
when was the last time you saw a case of cryptococcal
meningitis or cryptosporidial diarrhea? This summer, when I
asked a Los Angeles primary care provider with hundreds of HIV
patients in his practice, "When was the last time an AIDS
patient you were following died?" he told me, "I can't
2. "Don't Just Add Or Change One!"
It's hard to believe that just one year ago, if you were on a
double nucleoside regimen (usually AZT/3TC or d4T/3TC) with a
formerly undetectable viral load which had now risen to
detectable and significant levels, the general course was to
simply add a protease inhibitor.
We came to realize early this year that adding a single drug to
a failing regimen might be akin to giving monotherapy (i.e.,
you might already be resistant to both drugs already being
takenhence the rise in viral load)and this is sure to fail.
So, we now try to change as many components of a failing
regimen as possible, especially when adding a protease
inhibitor. Dr. Steven Deeks of San Francisco presented data at
September's ICAAC Conference that you are 15 times more likely
to fail a new protease-containing regimen if the accompanying
two reverse transcriptase inhibitors are not changed as well.
(Since many HIV-infected persons had been taking AZT/3TC, 1997
thus saw an increased popularity of the alternative d4T/ddI
3. Resistance, Resistance, Resistance
This concept received considerable attention at medical
conferences and in publications throughout the year. While
virologic resistance is a, perhaps the, major reason why
anti-HIV drug regimens fail, it's important not to forget that
other factors might be playing a role as welle.g., is the drug
being appropriately taken and absorbed? is the intracellular
metabolism normal, or somehow flawed?
Nevertheless, most intermediate and advanced "students" of HIV
now know that the codon 184 mutation is associated with
high-grade 3TC resistance, or that there is significant overlap
of resistance patterns (so-called "cross-resistance") between
indinavir and ritonavir, or nevirapine and delavirdine.
Genotypic testingin which a virus' mutations are displayed
thanks to computer technology, is increasingly used but not
anywhere near approval by the FDA. It may yield some helpful
information on whether to switch or maintain a therapeutic
regimen, but experts seem to be clearer that the future lies
with phenotypic testingwhich is more expensive and even less
well-developed. With this technique, the person's virus is
tested directly against different therapeutic regimens (singly
and in combination) to ascertain which one gives the best viral
More on that in 1998.
4. The Eradication Balloon Puckers
No, it hasn't burst, but 1996's elation over the "E" word was
met with some tempering this year, as the identity of Dr. David
Ho's "third compartment" became clearer: While current
therapies can suppress most HIV activity/replication, there
appears to be a reservoir of infected lymphocytes (so-called
CD45RO memory cells), perhaps only 0.1% of the total, which
still harbor the virus after prolonged administration of HAART
(highly active antiretroviral therapy).
We also know more definitively that when therapy is stopped, an
undetectable viral load will rather quickly rebound (as early
as several days, most likely within a couple of weeks) to
pre-therapy levels in some patients. The take-home message
here: If HIV as an organism is continuously active and potent,
so must be the therapeutic approaches thereto!
Also, towards year's end, Dr. Douglas Richman of San Diego
indicated that patients with viral loads which were
undetectable with the usual tests (which have sensitivity
levels of 500 copies/ml)but still detectable with tests which
read down to 50 copies/ml (which will become more widespread in
1998)showed microscopic evidence that viral mutations were
occurring, albeit very slowly. (Whether a viral load suppressed
from 499 to 49 will result in any significant change in a
person's clinical course with HIV remains to be seenfor the
time being, an "undetectable" viral load, even with a test
sensitivity of 500 copies/ml, is considered adequate if not
5. Life in the HAART Lane
While HAART has demonstrated clinical and ultimate survival
advantages, this year we saw the announcement of new cases of
diabetes in several dozen patients on protease inhibitors.
Likewise, abnormalities in lipid levels (such as marked
triglyceride elevations) may occur, and this past fall, a
syndrome known as "buffalo hump" also thought to be due to an
as-of-yet-undefined metabolic alteration, was described in
certain persons with HIV. (The latter syndrome was at first
thought to be due to protease inhibitors, but has been seen as
well in persons with HIV who have never taken a PI.) Methods to
increase patient adherence are receiving much attention, and
the two most commonly prescribed protease inhibitorsindinavir
(Crixivan) and nelfinavir (Viracept)are, at year's end, both
being studied at simplified dosing regimenstwice daily instead
of the present three times per day. Other anti-HIV medications
besides protease inhibitors are also being studied at new doses
and dosing regimens to allow for greater patient compliance:
1998 may see more ddI (Videx) dispensed at 300-400 mg once
daily, and nevirapine (Viramune) at 400 mg once daily. In 1997,
two new formulations of existing medications were
approvedCombivir (which contains AZT plus 3TC) and the more
bioavailable form of saquinavir, Fortovase.
6. FDA Approval of Viracept
March saw the FDA approval of the fourth protease inhibitor,
nelfinavir, developed and marketed by Agouron Pharmaceuticals.
There was strong anticipation that Viracept would quickly rise
to the top of the protease piledue to its purported favorable
resistance pattern (claimed to be significantly different from
that of the 3 already approved PIs), minimal side effects (only
diarrhea was seen in more than 2 to 5% of patients), and
favorable dosing (could be taken with food). In reality, while
it has registered a strong showing in the antiviral market in
the 10 months since its approval, patients who have failed on
it have not necessarily been able to succeed in suppressing
viral load with other PI-containing regimens, and the incidence
of diarrhea is generally accepted to be significantly higher
than originally stated. (This latter phenomenon is often seen
after drugs are FDA-approvedand may have to do with the fact
that patients who use a pharmaceutical after approval are on
the average more ill than those who used it during clinical
The only other antiviral approved in 1997 was delavirdine
(Rescriptor), approved in April and bringing the total number
available to 11five nucleoside reverse transcriptase inhibitors
(RTIs), two non-nucleoside RTIs (NNRTIs), and four PIs. Whether
or not you like the drugs themselves, the companies which
manufacture them, or the FDA which regulates them, it's
unarguable that the number approved has quickly risen. In
November 1995 there had been only four anti-HIV medications on
the U.S. marketthe other seven were to be approved over the
ensuing 18 months.
7. The Pipeline Lengthens
While the period from mid-1997 to early 1998 may see no
additional anti-HIV drugs attain FDA approval, several
medications are likely to become available shortly thereafter.
Already available via expanded access programs are abacavir
(Glaxo-Wellcome's new RT inhibitor); efavirenz (Sustiva,
Merck's NNRTI); and the first representative of a new
subdivision of reverse transcriptase inhibitors known as the
nucleotide analogsGilead's adefovir (Preveon).
Further down the road-in-development are new protease
inhibitors by Glaxo- Wellcome (amprenavir, formerly 141W94) and
Abbott (ABT-378) and another nucleotide analog known currently
as PMPA. New target sites for anti-HIV activity are also being
sought out with HIV binding inhibitors (e.g., TP-20) and the
ongoing development of integrase inhibitors (e.g., zintevir).
8. Guidelines Posted on the Internet
The standardization of anti-HIV guidelines to a federal level,
a formidable task in itself, was no doubt made easier by 1990's
computer technology. June saw the issue of a document entitled
Report of the NIH Panel to Define Principles of HIV Infection
and a companion document, Guidelines for the Use of
Antiretroviral Agents in HIV-Infected Adults and Adolescents.
The latter, released by the U.S. Department of Health and Human
Services, was significant for several reasons: It demonstrated
an attempt towards a national standardization of HIV care. It
was released not through publication in a journal or letter,
but on the World Wide Web.
The expert panel which formulated the guidelines included
HIV-infected persons sitting alongside well-known HIV
physicians such as Drs. Anthony Fauci and John Bartlett.
A revised version of the guidelines was subsequently released
in November, now including combination ritonavir-saquinavir
(the most widely studied and commonly used protease combination
to date) as one of the options for the protease-containing
portion of a first-line antiviral regimen. (These guidelines
can be viewed at http://www.hivatis.org)
9. Support Widens For Nutrition-Based Therapies
Nineteen-ninety-seven saw the publication of at least three
studies in well-respected, peer-reviewed scientific journals,
each of which involved a potential HIV therapy which would be
considered "alternative" or "holistic." Tang et al. published
(Journal of Nutrition, January) their study of more than 100
HIV-infected persons whose vitamin B� levels were measured.
Those with levels lower than a defined cut-off point progressed
to AIDS in half the time as those whose levels were above this
Herzenberg et al. published (Proceedings of the National
Academy of Sciences, March) their results of the first
controlled trial of NAC (N-acetylcysteine) therapy for HIV.
This medication, FDA-approved for other purposes, restores
depleted glutathione levels, and was associated with improved
survival in this cohort.
Lastly, Baum et al. studied (Journal of AIDS, August) 125
seropositive drug users and found that deficiency of the trace
mineral selenium was associated with shortened survival.
The ultimate clinical and therapeutic implications of these
three correlations remain to be completely understood, but the
elevated consciousness of the role they may play is an
important development of this year.
10. Post-Exposure Prophylaxis (PEP)
An editorial in an April issue of The New England Journal of
Medicine (Katzno relation!and Geberding) raised an important
issue: Should persons who sustain a potential or actual
exposure to HIV via unprotected sex or needle-sharing be
treated with the same triple antiviral regimen now offered to
health care workers who sustain a potential exposure? The
question brings up many more which are still being debatede.g.,
Who will pay? Should partners be treated as well? What if
patients continue to relapse, i.e., continue to have
unprotected sex and ask for subsequent month-long antiviral
treatment? Already PEP is being used increasingly for victims
of sexual assault and for persons in emergency departments and
clinic settings who ask for it.