translation agency

Being Alive
The Top 10 HIV/AIDS Stories of 1997
Mark Katz, M.D.
February 5, 1998
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 courage! 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 Pentamidine 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 with HIV/AIDS.

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 remember." 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.

Not anymore! 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 combination.) 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 suppression.

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 optimal!) 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 trials.) 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 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 point.

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.