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Decmber 1996

  1. Potential breakthrough in the treatment of KS
  2. Update: Interleukin-2 to boost immune system
  3. How HIV penetrates CD4 cells
  4. A comeback for sulfated polysaccharides?
  5. F.D.A. warning on use of cidofovir

Potential breakthrough in the treatment of KS

Tumor regression achieved with injections of hCG hormone

To date, treatment of Kaposi's sarcoma, the most common cancer seen in patients with HIV disease, has been palliative, not curative. The accepted treatments for KS -- interferon alfa, systemic chemotherapy, and radiation therapy -- have achieved only modest success in shrinking lesions and slowing disease progression. Moreover, the usefulness of all forms of chemotherapy, including interferon, has been limited by their toxicity -- particularly in patients receiving antiretroviral therapy. Although progress has been made in identifying the causative agent in KS (see Vol. 1, No. 1, page 8), little progress has been made in eradicating this neoplasm in afflicted individuals.

The recently published results of a two-phase clinical trial suggest that certain preparations of human chorionic gonadotropin (hCG), when injected directly into cutaneous KS lesions, may result in complete regression of those superficial tumors. While this therapeutic modality has obvious practical limitations -- especially in patients with scores, even hundreds of lesions -- it does suggest a new avenue of approach to treating what has been a frustratingly refractory cancer in AIDS patients.

In the dose-escalation phase of this small trial, 24 male subjects with the purplish skin lesions that characterize KS but no evidence of visceral disease were assigned to receive intralesional injections of 250, 500, 1000, or 2000 IU of hCG. The six patients in each of the four cohorts were given thrice-weekly injections for two weeks. In each case hCG was injected into two lesions, and an inert dilutent was injected into a third lesion.

The investigators report that treatment was well tolerated, although one study subject in the 2000-IU arm did drop out after his initial treatment, complaining of pain at the injection sites. In general, side effects -- including dizziness, nausea, and headache -- were mild, and the remaining 23 subjects completed the two-week study.

The effects of treatment were strongly dose-related, with only one of 12 lesions in the 250-IU arm responding to hormone therapy, versus 5 of 12 lesions in the 500-IU arm and 10 of 12 in the 2000-IU arm. This response appears to be the result of hCG-induced apoptosis: injections of 250 IU of the hormone fragmented and destroyed less than 30% of the cells in the target lesion, while injections of 2000 IU destroyed 90% to 100% of the cells.

In the second, double-blind phase of this trial, 12 additional subjects were randomized to either 2000 IU of hCG or the inert dilutent. As in the Phase 1 study, lesions were injected three times a week for two weeks, this time into two nodular lesions per patient. No regression was seen in any of the 12 lesions injected with dilutent, but 10 of the 12 hCG-treated lesions did respond to therapy. Apoptosis was seen only in treated lesions, and the percentange of cell death increased in a dose-dependent fashion.

Although these injections were made directly into the target lesions with a fine needle -- and although the hCG was released just under the skin and directly over the lesion, to raise a wheal that would cover the entire lesion -- the treatment appears to have had some systemic benefits. Investigators did not expect to see such benefits, given the short duration and site-specific nature of the treatment, but they report complete resolution of five dilutent-treated lesions -- a systemic antitumor response which, they speculate, "may be due to a systemic effect of the hormone when it is injected locally."

Significantly, treated patients seemed to experience other systemic benefits of hCG therapy. Increased appetite was reported by five subjects, and three patients gained as much as six pounds. Increases in energy and libido were also reported. These unanticipated ancillary benefits suggest that hCG may have a broader role to play in the treatment of HIV disease.

Gill PS, Lunardi-Iskandar Y, Louie S, Tulpule A, et al. The effects of preparations of human chorionic gonadotropin on AIDS-related Kaposi's sarcoma. N Engl J Med 1996; 335: 1261-9.

Dr. Judith A. Aberg, a member of the editorial advisory board of HIV Newsline, comments:

A gamma-2 herpesvirus -- referred to as Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) -- has recently been recognized as a co-factor in the development of KS. Little is known about the transmission or pathogenesis of this virus, but the low prevalence rates in hemophiliacs and injection- drug users, and the high rates in HIV-positive gay men, suggest that HHV-8 is predominantly transmitted through sex, not parenterally. A study published two months ago in The Lancet found that HHV-8 seroprevalence rates vary from country to country, and while not all infected individuals develop KS, virtually all patients with KS are seropositive for this new herpesvirus.

The fact that KS occurs much more often in men than in women -- coupled by the fact that it cannot be induced in nude athymic mice while they are pregnant -- has suggested to some that hCG confers some sort of protection against infection. On the other hand, pregnancy does not protect HIV-infected women from developing KS, nor does it appear to slow its spread, so the production of hCG, in and of itself, cannot explain the benefits achieved in this small study.

Commercial preparations of hCG vary markedly in strength and purity, and it remains to be determined what substance, in the preparation used by these investigators, was active against the study subjects' tumors. Dr. Susan E. Krown, in an editorial that accompanied the report by Gill et al., postulates that it may well have been a contaminant, possibly a ß-hCG peptide, that was actually responsible for the tumor regression that was seen.

In any event, intralesional injections of hCG have only a limited and largely cosmetic role in the treatment of Kaposi's sarcoma. At a cost of roughly $250 for a 20,000-IU vial, hCG is simply too expensive to be a viable treatment for patients with dozens of KS lesions, especially those individuals with lesions larger than the relatively small ones treated in this study. Moreover, this modality is of no value in the treatment of visceral KS, which produces much more morbidity and mortality than skin lesions, no matter how large or numerous they may be. However, if it can be demonstrated that higher parenteral doses of hCG do extend the benefits of localized therapy to untreated lesions, then hCG may indeed prove useful in the treatment of this common malignancy in patients with HIV disease.

Krown SE. Kaposi's sarcoma -- What's human chorionic gonadotropin got to do with it? N Engl J Med 1996; 335: 1309-10.

Simpson GR, Schulz TF, Whitby D, Cook PM, et al. Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 1996; 349: 1133-8.

Update: Interleukin-2 to boost immune system

Intermittent infusions result in substantial -- and sustained -- elevations in CD4 counts

A preliminary, dose-ranging study of the effects of interleukin-2 -- a T-cell-derived lymphokine that regulates the proliferation of CD4 cells -- established that intermittent infusions of IL-2 could reverse some of the deleterious effects of HIV on the immune system in patients with CD4 counts above 200 cells/mm3 (see "Interleukin-2 boosts CD4 counts," Vol. 1, No. 2, pages 27-28). The N.I.H. team that conducted that preliminary study recently reported the results of a larger, longer, controlled trial of IL-2 in a similar group of patients. Their findings suggest that bimonthly infusions of high doses of IL-2 can produce substantial and sustained increases in CD4 counts.

Investigators randomized 60 patients to IL-2 plus antiretroviral therapy or antiretroviral therapy alone. One patient in the IL-2 arm dropped out before receiving his initial infusion; the other 59 subjects remained in the 14-month study until its conclusion, and some of those original volunteers have now been followed for up to 50 months. Antiretroviral therapy consisted of ZDV, ddI, ddC, or d4T, alone or in combination, and could be altered at any time during the course of the study. IL-2 was administered every 8 weeks, in cycles lasting 5 days, at an initial dosage of 18 million IU per day by continuous IV infusion. Over the 14 months of the trial dosages of IL-2 were progressively stepped down with each cycle, to 8 million IU per day by Cycle 6.

IL-2 therapy produced fatigue and malaise in virtually all treated patients, and 33% of patients experienced transient, asymptomatic elevations in serum bilirubin. (In the control group, 10 of 29 patients reported one or more severe clinical side effects possibly related to therapy, suggesting that at least some of the fatigue, nausea, fever, and diarrhea seen in both study arms could be attributed to antiretroviral therapy, or even to HIV disease itself.) As the dosages of IL-2 were reduced with successive cycles, the adverse effects of therapy were also reduced.

In patients who received IL-2 infusions, CD4 counts rose from a mean of 428 cells/mm3 at baseline to a mean of 916 cells/mm3 after a year of treatment. In the control arm, by contrast, the mean CD4 count was 406 cells/mm3 at baseline and declined to 349 cells/mm3 over the course of the trial. There were no significant differences between the two arms in serial measurements of viral load (HIV-1 RNA by bDNA) or p24 antigen levels.

After 14 months of therapy all of the study subjects were eligible to receive IL-2 during the extended, open-label phase of the trial, and 45 of the 59 remaining subjects elected to do so. During long-term follow-up, four patients died of AIDS-related illnesses. Only one of them had been in the IL-2 cohort originally, and he was a non-responder who died roughly a year after his last cycle of IL-2. In the rest of the IL-2 cohort, CD4 counts have remained at approximately twice baseline values for 30 months, and CD4 counts have risen in those members of the control group who elected IL-2 therapy during open-label follow-up (Figure).

The investigators note that toxicity was substantially lower in this trial than in their earlier, dose-escalation study, and they conclude that intermittent infusions of IL-2 "have a profound and sustained effect on CD4 counts in HIV-infected patients with baseline CD4 counts above 200 cells per cubic millimeter."

Kovacs JA, Vogel S, Albert JM, Falloon J, Davey RT, Walker RE, et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 1996; 335: 1350-5.

Dr. W. David Hardy, a member of the editorial advisory board of HIV Newsline, comments:

Many things -- more clearly defined by the impressive results reported by Kovacs et al. -- make the concept of immunomodulation by interleukin-2 therapy appealing. Although HIV RNA assays give us direct evidence of the efficacy of antiretroviral therapy, CD4 cell counts are an important indicator of how well antiretroviral therapy is decreasing the rate of immune cell destruction. They are also a direct measurement of immune competence -- and, therefore, of the body's capacity to resist AIDS-related opportunistic infections.

It is still not entirely clear whether increases in CD4 cell counts lead to increased resistance to OIs. Although this relationship would seem to make sense, anecdotal reports to the contrary challenge this concept -- as do preliminary data from in vitro immunologic studies, which demonstrate a predominance of mature memory CD4 cells, rather than pluripotent naïve cells, after IL-2 infusions.

It should be noted, however, the work of Kovacs et al. did clearly demonstrate that the best, most feasibly attainable, results with IL-2 will be obtained in highly motivated, highly compliant patients with more than 200 CD4 cells/mm3 and well-controlled HIV replication (i.e. low viral load). In their study the mean CD4 cell count after 12 months of IL-2 therapy -- 916 cells/mm3 -- is in the normal range, even for HIV-negative individuals, and Kovacs et al. noted that two of their patients chose to skip several cycles of IL-2 infusions because their CD4 counts were above 3000 cells/mm3. This type of prolonged, enhanced response to IL-2 may allow for even more intermittent and individualized cyclic regimens of IL-2, with reduced adverse effects. There are early indications, from these and other investigators, that the response to intermittent IL-2 therapy is enhanced when it is combined with an antiretroviral regimen that includes a protease inhibitor such as indinavir. The addition of a protease inhibitor to patients' regimens may make it possible to achieve results comparable to those reported by Kovacs et al. with lower, less toxic doses of IL-2.

Because IL-2 acts on the immune system itself, not on HIV, its efficacy should not be affected by the viral enzymatic mutations that produce resistance to antiretroviral agents. Indeed, the long-term data on some of the patients in this study seem to bear out that expectation: Kovacs et al. report that some individuals have continued to respond to IL-2 therapy for more than four years. For these patients, certainly, the inconvenience of having to be hospitalized every other month for five days of IV or subcutaneous therapy, and the high cost of that therapy, may be worthwhile in light of the benefits achieved.

How HIV penetrates CD4 cells

The saga continues

The precise mechanism by which HIV enters white blood cells has been a mystery since the virus was discovered more than a decade ago. It is known that the CD4 molecule is the principle passageway through which HIV invades the intracellular space. However, laboratory models have shown that when CD4 receptors are inserted into the membranes of non-human cells those cells are not susceptible to HIV infection. This finding suggested that other molecules are involved in this complex physiological process.

Last spring, researchers from the National Institute of Allergy and Infectious Diseases announced the discovery of a lymphocyte surface protein they named "fusin". Fusin acts as an accessory molecule in cellular infection by facilitating the merging of HIV's envelope with the CD4 receptor. It contains genetic sequences that are homologous to a class of surface proteins known as "G" proteins -- which receive messages from the extracellular space, initiating a cascade of events that serve to amplify the original signal.

Researchers at the National Cancer Institute and the F.D.A. recently published data suggesting that CD4 interacts with fusin only after gp120, a protein in HIV's outer envelope, binds to the receptor and induces a conformational change. Pre-treatment of cells with a chemical called phorbol myristate acetate (PMA) prevented the interaction of the CD4-gp120 complex with fusin. Since the natural function of fusin is unknown, some researchers have expressed concern about the wisdom of developing drugs that alter the protein. However, the discovery that PMA prevents interaction between fusin and CD4 suggests that it may be possible to lock HIV out of cells without interfering with the normal functions of fusin.

Other cell surface molecules involved in HIV infection have been discovered. In our last issue, we reported on the protective effects of a mutant version of the chemokine receptor known as CRK5 (see "Genetic mutation appears to confer immunity to HIV," Vol. 2, No. 5, pages 114-115). This receptor interacts with intracellular messengers called RANTES, MIP-1a and MIP-1b. When inherited from both parents, this fortuitously mutant version of CRK-5 gene conferred protection from HIV infection in men repeatedly exposed to the virus. Inheriting the gene from one parent did not prevent HIV infection, but it did slow disease progression. Taken together, these advances in our understanding of how HIV penetrates CD4 cells suggest new avenues of investigation and new modalities for thwarting the virus's ability to replicate.

Lapham CK, Ouyang J, Chandrasekhar B, Nguyen NY, Dimitrov DS, Golding H. Evidence for cell-surface association between fusin and the CD4-gp120 complex in human cell lines. Science 1996; 274: 602-5.

Dr. Paul A. Volberding, the editor-in-chief of HIV Newsline, comments:

We once hypothesized that we might be able to eradicate HIV by flooding a patient's circulation with "decoy" CD4 cells. The hope was that the virus would attach itself to these man-made decoys, thereby sparing the host's own CD4 lymphocytes. Unfortunately, this subterfuge, which worked in the test tube, did not work in human subjects -- and soluble CD4 decoy therapy joined the long list of in vitro successes that have failed in vivo. Since the disappointing results of trials using soluble CD4 were announced, no significant advances have been made in the development of antiretrovirals that prevent entry of HIV into CD4-expressing cells. The isolation of fusin and CRK5 is likely to breathe new life into a strategy that had been largely abandoned.

A comeback for sulfated polysaccharides?

Calcium spirulan shown to inhibit p24

Several years ago, a sulfated polysaccharide, dextran sulfate, demonstrated potent anti-HIV activity in vitro. Dextran was not commercially available in the United States, but an oral formulation was manufactured by a Japanese pharmaceutical company. Shortly after the test tube results were revealed, so-called buyers' clubs began providing their clients with dextran sulfate, and thousands of people began taking the drug without clinical supervision. Subsequent clinical trials showed that oral dextran sulfate is very poorly absorbed -- which may well have accounted for the disappointing anti-HIV effects seen in both the research setting and the community at large.

However, the rumors that sulfated polysaccharides were dead as a potential antiretroviral treatment may have been exaggerated. Another drug in the same class, calcium spirulan, has received favorable test-tube evaluation for its activity against HIV and two herpes viruses. Researchers exposed mouse cells to those viruses after the laboratory animals had received intravenous injections of calcium spirulan, which is derived from sea algae. Even at low concentrations, calcium spirulan was shown to inhibit p24 antigenemia. Moreover, the drug seemed to inhibit syncytia formation. This may be an important finding, because it is the formation of syncytia -- giant aggregates of CD4 cells -- facilitates cell-to-cell viral transmission. The inhibition of this process would make calcium spirulan particularly useful in the early stages of HIV infection, by protecting uninfected CD4 cells. In addition, calcium spirulan proved efficacious against both HSV-1 and CMV, common pathogens in individuals with HIV infection.

Although the administration of sulfated polysaccharides such as dextran sulfate has been associated with adverse side effects, these effects appear to be diminished or non-existent in the case of calcium spirulan, which also has a considerably longer half-life than dextran. Furthermore, the well-known anticoagulant activity of other sulfated polysaccharides, notably heparin, does not appear to be significant in blood exposed to the drug.

Overall, calcium spirulan has demonstrated in vitro antiretroviral activity that is comparable to that achieved with dextran sulfate. This particular study showed that the new drug has advantages over dextran, particularly in terms of its side effects profile, which may permit the administration of higher therapeutic doses. Although the task of developing an oral formulation with good bioavailability is a daunting one, given the poor GI absorption of polysaccharides, there will certainly be further studies of this promising compound.

Hayashi K, Hayashi T, Kojima I. A natural sulfated polysaccharide, calcium spirulan, isolated from spirulina platensis: in vitro and ex vivo evaluation of anti-herpes simplex virus and anti-human immunodeficiency virus activities. AIDS Research and Human Retroviruses 1996; 12 (15): 1463-71.

F.D.A. warning on use of cidofovir

IV treatment for CMV retinitis may lead to severe renal impairment

In the April issue of HIV Newsline we reported that an F.D.A. advisory panel had unanimously recommended approval of cidofovir, a new and more convenient treatment for CMV retinitis (see Vol. 2, No. 2, pages 31-32). As we noted at the time, the advantage of cidofovir, in patients whose cytomegalovirus infection is unresponsive to oral ganciclovir, is its dosing schedule. Unlike IV ganciclovir and foscarnet, which are generally administered in daily infusions through an indwelling catheter, intravenous cidofovir can be administered in a single infusion given every other week. This regimen eliminates the need for a surgically-placed port, thereby reducing both the risk of catheter-associated infections and the physical restrictions that accompany the placement of such ports.

The potential nephrotoxicity of cidofovir -- which Gilead Sciences markets as Vistide® -- was well recognized at the time the drug was approved, and treated patients were given oral probenecid and saline hydration to ameliorate the nephrotoxic effects of cidofovir therapy. Despite these precautions, two treated patients have developed acute renal failure after the administration of only one or two infusions of cidofovir. Both patients had risk factors for nephrotoxicity, and these cases have prompted the F.D.A. to issue a warning regarding the administration of cidofovir in AIDS patients. The purpose of this warning letter is four-fold:

  • To emphasize the importance of judicious selection of candidates for therapy

  • To reiterate the approved treatment protocol, including coadministration of probenecid and adequate hydration during and immediately following each infusion

  • To remind clinicians that renal function in treated patients must be very carefully monitored

  • To provide two additional contraindications for cidofovir use that were not included in the original package labeling

Those contraindications include laboratory values suggesting renal malfunction: serum creatinine levels greater than 1.5 mg/dL, creatinine clearance less than or equal to 55 mL/min, or a urine protein level greater than or equal to 100 mg/dL. Cidofovir use is also contraindicated in patients taking drugs that have nephrotoxic potential, such as amphotericin B, NSAIDs, IV pentamidine, and aminoglycoside antibiotics. Patients who have received, or are currently receiving, IV foscarnet are also at increased risk of renal impairment on cidofovir therapy.

To reduce the risk that treated patients will develop renal dysfunction, Gilead Sciences will provide all practitioners who call 1-800-GILEAD-5 with a log for monitoring renal function, plus detailed guidelines for its use. Clinicians who encounter nephrotoxicity in cidofovir-treated patients are asked to report those cases to Gilead or to the F.D.A.'s MedWatch Program (1-800-FDA-1088).

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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.