• #1 Cold Turkey: Federal Panel Gives Imprimatur to Cessation of Antibiotic, Antiviral Preventive Therapies After T-cell Rise
• #2 Desperately Seeking Rx: I Say Salvage, You Say Rescue
• #3 HIV Antiretrovirals in Development
• #4 Summary of TAG Policy Statement on NDA 20-993, Gilead Sciences' Application for Approval of Preveon adefovir dipivoxil for Treatment of HIV

Bye-bye, OIs?
Michael Marco braved the perennial ennui and premature cannecule of our nation's capitol in order to attend a joint PHS/IDSA meeting whose express purpose it was to draft revisions to the 1997 federal guidelines for the prevention of opportunistic infections in HIV-infected individuals. Specifically, the panel members were asked to address the cessation of OI prophylaxis in the, as it's come to be called, "age of HAART."

The final United States Public Health Service (USPHS)/Infectious Diseases Society of America (IDSA) revisions were recently published in the MMWR. Working group member Michael Marco reports on the major changes.

I felt like I was at the OI Senior Prom. It was this past spring when infectious disease dignitaries and OI prophylaxis and treatment mavens gathered for a day and a half at the monstrous Bethesda Pooks Hill Marriott (where they won't cook a hamburger under medium-well for fear of a massive E. coli breakout) to revise the U.S. Public Health Guidelines for the prevention of opportunistic infections in HIV+ individuals. And, yes, it was time for this panel to reconvene to discuss the numerous studies and case reports recently published (or presented at AIDS conferences) which have examined the natural history of OIs in the era of potent combination antiretroviral therapy (frequently -- if inexactingly -- referred to as "HAART").

More specifically, the panel reconvened to scrutinize the consequences (to date) of discontinuing primary prophylaxis (most commonly, PCP prophylaxis) and secondary prophylaxis (more familiarly thought of as "maintenance therapy") in HIV-infected individuals who have experienced increases in their CD4 cells above the threshold warranted for such prophylaxis.

Many individuals on combination antiretroviral therapy who have had robust CD4 cell increases have already stopped taking primary and secondary prophylaxis ("maintenance therapy") for opportunistic pathogens such as Pneumocystis carinii, Mycobacterium avium and cytomegalovirus. Thus, the most important questions addressed at this meeting were, "Is it safe to discontinue OI prophylaxis in individuals whose CD4 cells have risen above the given threshold for its initiation?" and, "Can we stop both primary and secondary preventive measures in such an environment?"

I found it interesting that these researchers (a majority were former members of the ACTG's celebrated OI Committee) who had been responsible for the landmark OI studies which gave us information on who should start OI prophylaxis (and with which drugs), were now meeting to decide who could stop. It was as if they were undoing their work of the past 10-15 years, but that was clearly not the case. All were pleased that the rate of OIs (especially PCP, MAC and CMV) in this era of potent combination antiretroviral therapy has decreased to single digits and obviously had looked forward to the day when effective antiretroviral therapy would markedly halt or slow the progression of HIV infection.

In the mean time, this group kept hundreds of thousands of people alive during the many sad and hopeless years of AZT, ddI and ddC-even though their life-saving OI studies would never be as sexy as the antiretroviral research which, over those same years, cried "Eureka" at the promise of "convergent combination" therapy or crowed "It's never too early!" in its undue enthusiasm over nucleoside mono- and bi-therapy.

As a quick reminder, the 1997 USPHS/IDSA OI prophylaxis guidelines made the following recommendation for the therapeutic prevention of PCP, MAC and CMV:

1. PCP prophylaxis for HIV-positive individuals with fewer than 200 CD4 T-cells/mm³ and a history of thrush (oropharyngeal candidiasis) or unexplained fever for two weeks or more;
2. MAC prophylaxis in HIV-infected individuals with fewer than 50 CD4 T-cells/mm³; and
3. CMV (cytomegalovirus) retinitis maintenance therapy (also referred to as "secondary prophylaxis"); that is, continual CMV treatment (most likely with oral or intravenous ganciclovir, in order to prevent further progression or development of CMV infection in the retina) for life. Below are the major (draft) changes for PCP, MAC, and CMV prophylaxis, the three most common OIs, and the scientific data used to substantiate them.

The USPHS/IDSA guidelines panel is also planning-for the first time-to draft OI treatment guidelines. After all, this only makes sense: if the panel can advise physicians on when and how to prevent occurrences (and reoccurrence) of HIV-associated opportunistic infections, then it should not be so difficult to come up with recommendations for their treatment, should need be. We eagerly await those guidelines as well.

While initial estimates of HAART success hovered around eighty percent, treatment regimens are failing left and right. Recent studies of salvage regimens (or "rescue therapy," as the always-touchy-feely West Coast activists have dubbed it) have not been encouraging. However, at a number of recent conferences and workshops, researchers, activists and industry have been rolling up their sleeves and trying to figure out what we're going to do about treatment failure.

In recent results from ACTG 359, presented at the Second International Workshop on Salvage Therapy for HIV Infection, individuals who had received extensive indinavir therapy were randomly assigned to receive various combinations of ritonavir, saquinavir, nelfinavir, adefovir and delavirdine. In this study, only about thirty percent of participants had achieved undetectable plasma HIV RNA levels after sixteen weeks of treatment. Ritonavir and nelfinavir were approximately equivalent in their ability to suppress RNA levels. Delavirdine was superior to adefovir, and the combination of the two drugs was no better than delavirdine alone.

In a similar finding from ACTG 372, (which tested combinations of abacavir, efavirenz, adefovir, nelfinavir, and older nucleoside analogues), nelfinavir was found to be superior to placebo, but abacavir was no better than older nucleoside analogues in pre-treated patients. Again, only about 30% of participants achieved "undetectable" plasma HIV RNA levels after sixteen weeks of treatment.

Following that meeting, TAG co-sponsored a workshop on trial design for clinical studies in heavily pre-treated patients with Project Inform, the Forum for Collaborative HIV Research, and the Division of AIDS at the National Institutes of Health. Such studies can be difficult to conduct because, as participant Dr. Julio Montaner eloquently put it, "standard-of-care sucks." As a consequence, few individuals are willing to be randomized to studies which include standard HAART regimens to which they are likely to be resistant. Participants outlined a number of methodologies for overcoming these methodologic obstacles, including distinguishing short-term screening trials and longer-term treatment "strategy" trials. There were also calls for virologists to work more quickly to clarify the interpretation of resistance assays.

This workshop generated a number of new study efforts, including a team of researchers and activists who are pursuing "strategic therapeutic interruptions" (the high-tech name for what we used to call "not taking your drugs"), as well as mega-HAART studies and studies of combinations of experimental drugs. Significantly, FDA's Heidi Jolson, who directs the agency's Division of Antiviral Drugs, informed companies that the regulators have no problem with combining experimental agents in salvage therapy studies.

At the recent Third International Workshop on Drug Resistance and Treatment Strategies in San Diego, data were presented on a variety of new treatments that may be useful in the salvage therapy setting. A few of the more notable studies are summarized below.

In a study of Pharmacia-Upjohn's new protease inhibitor, known as tipranivir, samples of virus were collected from 135 individuals with resistance to one or more currently marketed protease inhibitors. Using the Virco phenotypic assay (AntiVirogram), 107 samples were resistant to three or four protease inhibitors, while 28 had single protease resistance mutations. All viruses were also sequenced prior to phenotypic analysis. According to Virco's Brendan Larder, 96 out of 107 (90%) of the highly protease inhibitor-resistant samples maintained complete susceptibility to tipranivir. Eight samples showed intermediate levels of resistance, and three showed high-level tipranivir resistance. This study also suggested that saquinavir-resistant virus may exhibit hypersensitivity to tipranivir. [N.B. Actual results may differ.]

The ACTG's Dr. Connie Benson reported data from a study sponsored by Abbott Laboratories of its new protease inhibitor ABT-378. While ABT-378 shares some resistance mutations with ritonavir and indinavir, small amounts of ritonavir can dramatically increase levels of 378 to the point at which moderate-level resistance can be overcome.

This study took NNRTI-naïve individuals who had plasma HIV RNA levels 1,000-100,000 copies/mL during treatment with their first protease inhibitor, and treated them with two weeks of ABT-378 administered with either 100 or 200 mg of ritonavir twice daily. Then they added nevirapine (Viramune) and one new nucleoside analogue. At baseline, sixty-four percent of individuals had four-fold or greater loss in susceptibility to their previous protease inhibitor; and thirty-three percent had four-fold or greater loss of susceptibility to three or more protease inhibitors (using the Virco phenotypic assay). More than 90% of study individuals had 3TC resistance (M184V), and 45% had AZT resistance. Six individuals discontinued treatment during the course of the study.

During the initial two-week ABT-378 treatment period, 95% of the study participants showed at least a 0.5 log decrease in plasma viral load. After twenty-four weeks of treatment, 77% of study participants had plasma viral load levels <400 copies/mL. A few cases of serious diarrhea were reported.

In what is perhaps a sign of the times, Gilead has filed an application for approval of its drug Preveon (adefovir) as salvage therapy (see inset, left). While early studies have shown that adefovir is generally unimpressively active against HIV in vitro, data collected by Gilead suggest that 3TC-resistant virus may be hypersensitive to the drug.

Because adefovir can cause serious kidney toxicities in substantial numbers of patients, however, many observers are skeptical about the drug's real-world utility. Adefovir was originally studied at a dose of 120 mg/day. In study GS-408, 1% of patients taking adefovir at this dose had grade three or four proximal renal tubular dysfunction (PRTD) at week 24, however by 48 weeks, approximately 33% of patients were affected with PRTD.

In CPCRA 039 almost 40% had stopped the drug by one year. And in the Expanded Access program (which had enrolled almost 9,000 individuals as of September 1999), the median duration of therapy was only six months, so the ultimate incidence of PRTD appeared low. [As TAGLine goes to press, an FDA Advisory Panel votes against adefovir approval. The panel expressed concern that adefovir-related nephrotoxicity required dialysis in some cases and that the number of patients for which the company had submitted data was quite limited. While the panel's vote is not binding, it is rare that the FDA goes against the recommendation of its expert advisors.] Gilead also has a similar drug in development, known as PMPA (tenofovir), which may have a broader therapeutic window than adefovir has.

In order to facilitate further "salvage" studies, TAG has joined hundreds of other AIDS advocates in the Coalition for Salvage Therapy, a group which works with companies and regulators to ensure that heavily pre-treated patients are not left behind in the mad scramble for drug approval. The coalition is currently working with Abbott, Pharmacia & Upjohn and Gilead regarding the availability of their new products for salvage therapy studies, and through expanded access programs. ¤

The adefovir accelerated NDA poses a number of difficult issues. The drug's antiviral activity is far from impressive, especially in pre-treated patients, who are just those for whom the sponsor seeks approval to market the drug. Moreover, the cumulative incidence of renal dysfunction at the more heavily studied 120 mg dose appears to be over one third at one year. The incidence appears to be delayed at the 60 mg dose for which the sponsor seeks approval. However, the database on the 60 mg dose is small and short-term. According to the sponsor, the median time (50% of drug discontinuers) to study drug discontinuation in the randomized study 417 was 26 weeks at the 120 mg dose and 30 weeks at the 60 mg dose. Thus, for those in this study who developed renal dysfunction, the lower dose afforded about four more weeks of antiviral activity before toxicity required drug discontinuation.

TAG's Position
Based on data that have been publicly presented at medical conferences, as well as data provided by the sponsor and on our analysis of the relevant legislative and regulatory standards and guidelines, TAG cannot endorse approval of adefovir at this time, as current data do not indicate that Preveon, at the dose regimen proposed for approval, is safe or effective according to the accelerated approval regulatory standard.

However, because we recognize that the need for therapies for pre-treated patients is strong, we believe that Gilead should continue to study the drug in this patient population, and should continue to make the drug available to patients lacking other treatment options through expanded access programs. Moreover, should FDA grant accelerated approval for the current application, recognizing that the need for therapies for pre-treated patients is strong, we believe the approval should be with a very narrow indication focused on heavily pre-treated patients. At the same time, Gilead should continue to study the drug in this patient population, with particular focus on patients who have the lamivudine resistance mutation which preliminary studies have suggested may confer hypersensitivity to adefovir. In this case, special safeguards should be put in place, such as registering physicians who prescribe the drug, as is done with thalidomide, and monthly monitoring and reporting of renal function.

TAG would also like to note that, while the therapeutic margin for the use of adefovir against HIV seems to be relatively small, the drug has shown great promise in the treatment of hepatitis B, where the antiviral activity seems to be much greater, allowing for use of lower doses, and potentially reduced incidence of renal toxicity. TAG strongly encourages Gilead Sciences to continue studying the drug as a therapy for hepatitis B.

For access to TAG's complete position paper on the adefovir application, visit our web site at www.aidsinfonyc.org/tag.¤