In laboratory cultures, normal blood vessel endothelial cells acquire the characteristic features of KS spindle cells and start to proliferate under the combined influence of Tat plus the inflammatory cytokines and growth factors mentioned above.1They then apparently produce their own plethora of cytokines and growth factors capable of promoting KS cell growth. Among these are some of the usual suspects in triggering KS -- bFGF, VEGF, TNF and IL-6 -- which again act synergistically with Tat to promote further proliferation. Tat also promotes adhesion between KS spindle cells and normal vascular cells, thus recruiting more cells into the KS disease process.2 However, the origin of spindle cells in the body is subject to continued debate since they possess some of the characteristics of the endothelial cells on blood vessel walls as well as other cells types such as smooth muscle cells and macrophages. Also, the experimental findings might explain why KS is particularly aggressive when associated with HIV infection, but they cannot explain the malignancy's epidemiological pattern. If cellular dysregulation was solely responsible for the disease, it is believed that a much larger percentage of HIV-infected patients would suffer from KS, given that cytokine imbalance and extracellular Tat are characteristic of HIV infection.
Because AIDS-related KS is largely confined to gay men, many researchers have suspected all along that a cofactor, such as a transmissible pathogen, may be at play. Such suspicions are strengthened by the geographic and social isolation of non-AIDS KS (elderly Mediterranean men and an epidemic of more virulent non-AIDS KS in Africa).
A number of microbes have been proposed over the years as the causative agent of KS. These include, but are not limited to, cytomegalovirus (which was proposed as the pathogen responsible for the African epidemic of non-AIDS KS); hepatitis B virus; human herpesvirus 6 (HHV-6); human papillomavirus 16 (HPV-16); Mycoplasma penetrans; and a furiously debated suspect, amyl nitrates (poppers). Results from the various studies attempting to confirm the presence of these agents in KS lesions have been unpersuasive at best.
In 1994, a team of researchers at Columbia University identified a novel virus in samples of KS tissues. The newly identified Kaposi's sarcoma herpesvirus (KSHV or HHV-8), was then identified in virtually all KS tissues taken not only from HIV-infected patients, but also from patients with classic African KS and non-HIV-infected gay men with KS.3,4Several more recent studies have indicated that antibodies to KSHV are detectable in 80% to nearly 100% of people with HIV-associated KS. KSHV has also been detected in 30% to 60% of HIV-positive gay men without KS.
Prevalence of KSHV seems to correlate with different population's risk of developing KS. For example, only a few percent of U.S. blood donors are KSHV-positive, and KS is rare here compared to Uganda where half the people test KSHV-positive, whether they have HIV or not.5In a 1996 report, researchers found that 21 HIV-positive patients with KS had started testing positive for KSHV antibodies six to 75 (median of 33 months) months before the tumors' appearance.6Similarly, the San Francisco Men's Health Study has found that after ten years, KS had developed in 50% of those entering the study with positive tests for both HIV and KSHV.7Finally, KSHV has been found in nearly all spindle cells. Most of these cells are in a state of chronic, "latent" infection with no production of new virus particles, just some of the virus proteins. Only a few cells exhibit an acute, "lytic" infection in which active viral reproduction is occurring.8 The debate over KSHV continues. Researchers such as Robert Gallo had claimed in the past that the virus was a ubiquitous one that concentrated in KS tumors as an inoffensive "passenger" virus. Now Dr. Gallo concedes that it may have a role in triggering KS tumor development, but that it does not transform normal cells into malignant ones. It merely adds to the overall inflammatory reaction that eventually leads to excess cell proliferation and then cancerous tissue growth composed of descendents of a single accidentally transformed cell. Others argue that KSHV plays a much more central role in creating KS. They note that the viral genome contains instructions for a large number of homologs to human angiogenic and cell growth factors, including several that would help cancerous cells to escape human immune defenses, for example a molecule that blocks the toxic effects of alpha interferon on cancer cells. At the just concluded 5th Conference on Retroviruses and Opportunistic Infections, reports on KSHV cited several potential cancer-causing genes such as one for a receptor placed on cell surfaces that responds to VEGF by stimulating cell proliferation and vascular growth.9Although most of the possible cell-transforming cancer genes (oncogenes) are expressed only in cells suffering lytic KSHV infection, their products could have widespread effects on neighboring cells. The two differing views on KSHV seem to be coming closer, with the timing and relative significance of the viral role being the main disagreement.
Foscarnet, a broad-spectrum antiviral currently used for the treatment of CMV disease, has played a noteworthy role in the ongoing KSHV debate. In 1995, a brief report from the Centers for Disease Control noted that persons with HIV receiving foscarnet, in most cases for CMV disease, had a risk of developing KS that was only 30% of that in those not taking foscarnet.10A more recent report from two London hospitals found that patients on foscarnet had 62% less risk of contracting KS.11Moreover, early anecdotal reports suggested that foscarnet may effectively treat lesions in HIV-positive patients experiencing early stages of the disease. Three of five patients given foscarnet experienced remission in their KS for a year or more.12 As Treatment Issues reported in January, a CMV trial testing ganciclovir eye inserts with or without systemic oral ganciclovir noted that the oral ganciclovir arm experienced a lower incidence of new AIDS-associated conditions, particularly KS. Because it provides considerably more ganciclovir to the bloodstream, the experimental oral ganciclovir prodrug valganciclovir should show a still greater effect on this malignancy. Positive observations concerning ganciclovir also come from the London hospital report cited above, which found that ganciclovir reduced KS risk to a similar extent as foscarnet in that patient population, although the trend did not reach statistical significance.
Such observations have given researchers the impetus to test antiviral drugs against KSHV. In the test tube, foscarnet is by no means the most potent anti-KSHV agent. Many other broad-spectrum nucleoside analogs have shown considerable activity against the virus. Among these are ganciclovir and Gilead Sciences' phosphated nucleoside analogs cidofovir and PMPA.13,14(The latter is now under development for treating HIV.)
An anti-KS trial with foscarnet was launched in 1996 at New York University. It planned to administer 3- to 14-day cycles of intravenous foscarnet to volunteers with early KS. Foscarnet's manufacturer, Astra Pharmaceuticals, canceled the trial after the first few cycles showed no immediate benefit and the advent of potent anti-HIV therapies threatened to complicate KS trials (see final section). There is an ongoing trial at the National Cancer Institute using intravenous cidofovir infused according to the standard cidofovir regimen for CMV. This trial to date has only enrolled three of 15 to 25 planned participants, so there is very little data available. (Persons interested in volunteering for the trial may call Dr. Richard Little at 800/772-5464, extension 657.)
A trial involving valganciclovir, Hoffman-La Roche's experimental oral prodrug equivalent of IV ganciclovir has also been proposed, but Roche says that it has no plans to test either ganciclovir or valganciclovir in KS. Company spokesperson Bob Posch gave the present low incidence of KS and the availability of other treatments as the reasons for the company's disinterest. The low number of people with KS makes any such trial difficult to design and recruit for, Posch argued.
But the antiviral nucleoside analogs only interfere with the production of new viral DNA, thus protecting uninfected cells by blocking production of new virus in acutely infected cells. They do not at all help cells chronically infected by KSHV. Their effect on established KS therefore depends on whether perpetuating the malignancy requires the continual infection of a number of uninfected cells, which is questionable. Infection of new cells would be required if malignant spindle cells can only be created by infection by KSHV and if these cells cannot proliferate indefinitely. Whatever the answer is here, antiviral drugs at a minimum would have a role in limiting the further spread of KS tumors or preventing the disease in the first place.
While the usefulness of antiviral drugs remains speculative, there has been considerable recent progress on alternate, remedial strategies for controlling KS. These will supplement the old standbys -- localized cryotherapy, radiation therapy and chemotherapy injections into the tumors as well as systemic chemotherapy. The older therapies are short-lived in effect -- new KS tumors eventually emerge. They also are marked by considerable toxicities. This was especially true of the chemotherapies, which function by killing dividing cells. But even the localized therapies have problems, notably pain, ulceration and scarring, and these are compounded by the tendency to overuse local agents in an attempt to chase down all the tumors that appear.
However, a new era is dawning. In the last three years, the Food and Drug Administration (FDA) approved three chemotherapeutics specifically for KS: the liposomal compounds Doxil (liposomal doxorubicin) and DaunoXome (liposomal daunorubicin) plus, just recently, paclitaxel (Taxol). The FDA will review 9-cis-retinoic acid this year, and other potential treatments, such as alpha interferon and human chorionic gonadotropin (HCG), are yielding promising clinical trial results.
Liposomal technology, as characterized by the drugs Doxil and DaunoXome, is a novel approach in treating various neoplasms and systemic infections. These drugs are liposome-encapsulated versions of doxorubicin or daunorubicin, respectively. Liposomal encapsulation, which encloses drug molecules in tiny lipid spheres, dramatically increases the half-life of the drugs. It also results in higher drug concentrations in tumors, which should decrease side effects in uninvolved organs. Standard chemotherapies for KS involve combinations of agents such as daunorubicin, doxorubicin (Adriamycin), vincristine and bleomycin. These drugs can cause significant neutropenia, nausea, vomiting, hair loss (alopecia), and cardiac toxicity. In contrast, the main common side effect associated with either Doxil or DaunoXome appears to be neutropenia (low neutrophil counts). This neutropenia can be reversed through dose reduction or administration of G-CSF (Neupogen). The extent of cardiac toxicity has not been resolved but appears to be less than with the non-liposomal versions of the same drugs.
Doxil has been approved by the FDA for use in patients with advanced KS who have not responded to or are intolerant of prior KS treatments. DaunoXome is approved as a first-line systemic chemotherapy in advanced KS. In practice, both are being used as initial therapy. DaunoXome is administered as a one-hour infusion every two weeks for 24 weeks whereas Doxil administration consists of half-hour infusions every three weeks, again typically over 24 weeks. The cost of DaunoXome and Doxil is high -- respectively 50% and 133% more than the cost of the standard doxorubicin, bleomycin, vincristine combination.
Few large, controlled clinical trials comparing these two drugs with standard combination chemotherapy have been conducted. Approximately eight published papers concern the use of either Doxil or DaunoXome. Response rates (including complete regression, partial regression, and stable disease) have on occasion exceeded 90% of patients treated. Many of these studies enrolled subjects failing standard combination therapy and reported that Doxil and DaunoXome are both effective in treating KS that is nonresponsive to initial chemotherapy (refractory). Note, though, that the duration of response has been limited to about four months. KS progression then resumes, making retreatment necessary. In the long run, neither liposomal nor non-liposomal therapies have been shown to prolong survival.
Past editions of Treatment Issues have carried detailed reports on Doxil and DaunoXome studies (see in particular July/August 1995). One just-published study compared Doxil to bleomycin plus vincristine in 242 persons.15 (See also Treatment Issues, September 1996) The complete and partial response rate to Doxil was 58.7% compared to 23.3% for the combination. Doxil was associated with more neutropenia, whereas the combination resulted in more peripheral neuropathy.
The benefit of combining Doxil or DaunoXome with standard chemotherapeutic drugs has not been proven. Preliminary results from one study (ACTG 286) indicate that a Doxil-containing combination therapy is no better than Doxil monotherapy for the treatment of advanced KS. Over the course of a year, 129 HIV-positive subjects were enrolled and 126 were evaluated in the analysis; 62 received Doxil alone and 64 received a combination of Doxil, bleomycin and vincristine. There were no significant differences in terms of response rates between the two groups, but Ronald Mitsuyasu, M.D., the study's principal investigator, reported that the volunteers receiving combination therapy developed serious toxicities faster than those receiving Doxil monotherapy (7 weeks versus 10 weeks, respectively). They also were much more likely to stop therapy due to the side effects. The investigators have concluded that the addition of standard chemotherapeutic agents, at least bleomycin and vincristine, may increase toxicity and decrease quality of life without substantially improving clinical outcomes.16
Last fall the FDA approved another chemotherapeutic, paclitaxel (Taxol), as a second-line therapy in advanced KS. Two open-label, noncomparative studies of paclitaxel demonstrated that impressive response rates could be achieved in refractory KS patients. The first was a study conducted at the National Cancer Institute on 29 volunteers who were infused with paclitaxel every two weeks at a dose of 135 mg/m2 of body area. The second study was run by researchers at the University of California and Harvard and involved 56 volunteers receiving a biweekly dose of 100 mg/m2.
The volunteers in the two studies had very advanced AIDS. Their combined median CD4 count was only 16 and 73% had organ involvement in addition to cutaneous KS. Fifty-nine of the 85 total volunteers had had prior systemic therapy for KS. Of these 59, 37 (62%) exhibited no new tumors and at least a 50% reduction in either the total number of tumors, the number of raised tumors or in the surface area of specific index tumors. (These criteria have become the standard definition of a "partial response.") Counting from the first day of treatment, the median time to progression among the responders was 9.1 months, compared to 6.2 months for the entire 59-person, treatment-experienced subcohort. (This is a dubious comparison since the responders may well have had disease that progressed more slowly than the nonresponders even in the absence of treatment.)
As in other types of cancer, paclitaxel is effective for KS but tremendously toxic. Low white blood cell counts (leukopenia) occurred in 62% of the volunteers and anemia in 29% of them. Paclitaxel is supposed to be taken along with G-CSF to control bone marrow suppression. Other common side effects include hair loss (91% of volunteers); weakness or debility (84%); diarrhea (79%); nausea or vomiting (69%); muscle or joint pain (64%); and peripheral neuropathy (58%). The drug is as costly as Doxil and DaunoXome.
Camptothecins are potent anticancer compounds that inhibit the cellular enzyme topoisomerase I. (Topoisomerases uncoil the tightly wound DNA in cells' nuclei so that DNA replication and cell division can take place.) Camptothecins have incidental antiviral activity, including against HIV, although that activity does not seem related to topoisomerase. (For more details on topotecan, see Treatment Issues, April 1995)
A trial of topotecan (9-aminocamptothecin), a compound approved for certain types of cancer and manufactured by SmithKline Beecham, is currently underway in HIV-positive volunteers with KS. The study will measure the effect of the compound on both KS tumors and HIV viral load, but the data on topotecan will be a long time in coming. The trial, located at UCLA and UC San Francisco, has only enrolled a couple of people in the last 18 months.
The trial requires five-day continuous infusions, which makes recruitment problematic, especially given the new treatment options. Otherwise, topotecan's greatest drawback is severe bone marrow suppression, leading to life-threatening neutropenia. SmithKline has created two topotecan analogs that are active against HIV, at least, and supposedly safer. These underwent initial lab evaluation over a year ago, and there has been no visible progress since then.
Less toxic chemotherapies would be very useful in treating KS. Since chemotherapies by their nature poison normal proliferating cells as well as malignant ones, scientists have been looking at so-called antiangiogenesis factors that would block the growth of new blood vessels in tumors, thus starving the malignancy. Such drugs seem tailor-made for KS since it is composed precisely of proliferating vasculature.
A new way to use doxorubicin in this fashion was proposed this year.17Researchers from the Burnham Institute in La Jolla, California have developed several short peptides that stick to certain receptors found on cell walls in new blood vessels, including those making up Kaposi's sarcoma tumors. (Some of these receptors are ones for the growth factors suspected of stimulating KS.) The peptides can be conjugated with doxorubicin to make a drug that is far more specific, and presumably safer, than Doxil. Tests with the peptides found that they zeroed in on KS tumors in a mouse model. In mouse models of human breast cancer, the conjugate achieved dramatic results compared to doxorubicin alone. In one test, four of the six conjugate-treated mice were alive after 120 days, whereas all six of the mice treated with doxorubicin alone had died by day 75.
Other compounds have been under investigation for some time because of their antiangiogenetic properties. Since most of these do not actually kill cells, they would seem to only hold out hope of preventing further growth of the tumors.
Several years ago two promising agents, TNP-470 and SP-PG, sparked interest for the treatment of KS. These have fallen by the wayside, at least as anti-KS drugs, due to a lack of observed efficacy. Two other compounds are still under investigation at the National Cancer Institute (NCI), and small trials are actively enrolling.
Thalidomide is a sedative that has been around for decades but had never been considered for use in cancer treatment until the last few years. It is thought that the drug inhibits the growth of blood vessels, which may be what causes the limb deformities in fetuses whose mothers take thalidomide. Oral thalidomide is now in clinical trials in London and at the NCI for the treatment of HIV-related KS, and the initial responses look promising. The NCI phase II dose-escalating study has enrolled 13 participants to date with a median CD4 count of 255 at baseline. Dosing starts at 200 mg/day and increases to 1,000 mg/day. Eleven participants have been evaluated. Four attained a partial response. Two of those have not progressed at 42 and 22 weeks and the other two progressed after 16 and 24 weeks. Five patients who did not meet the criteria for partial responders (50% reduction in tumors for at least four weeks) had stable disease to date with no other KS treatment, one for 52 weeks. Side effects included sedation in five patients that resolved on dose reduction. Three of the original 13 participants experienced toxicities (rash with fever, muscle inflammation or mental depression) requiring treatment termination.
Richard Little, M.D., of the NCI, feels that results are encouraging and hopes that enrollment will pick up. Entry requirements include a history of cutaneous KS that has progressed over the two months prior to enrollment. Anyone interested in participating may contact Dr. Little at 800/772-5464, ext. 657.
The second compound under study at the NCI is IL-12. This cytokine is best known for its ability to promote the response by CD8 cells to viral infection, but it also has antiangiogenetic properties, which is why it generated interest as a KS treatment. The NCI trial has only enrolled six or seven participants so far. Dr. Little noted that although there have been no partial responses to date, there has been some disease stabilization that might be due to the drug. Trial participants are dose-escalated from 100 nanograms/kg, given by subcutaneous injection, to 500 nanograms/kg. The study period is twelve weeks with an extension to 28 weeks in those with no disease progression. IL-12 has been well tolerated so far. Anyone interested in participating may contact Dr. Little at the above-mentioned number.
Other antiangiogenesis compounds are in preclinical development. Robert Yarchoan, M.D., of the NCI, is hoping that antiangiogenesis agents will constitute a new generation of KS therapy. "My feeling about KS is that we now have some good chemotherapy drugs with Doxil and Taxol," he said. "Most patients keep KS under control, and now is the time to use some of these other less toxic antiangiogenesis drugs that focus on sites of activity. The hypothesis was that these compounds could only stabilize disease but in fact, we're finding some disease regression. These compounds could be used by themselves for mild KS. I think for more severe disease an approach that's worth testing would be to get a response with something like Taxol and then to come in with something like thalidomide or another antiangiogenesis agent to maintain the response."
An alternative strategy in fighting KS is to use natural hormones and cytokines as tools to alter the inflammatory milieu supporting tumor growth. The first attempts of this order were made with alpha interferon (IFN-a), which was approved in 1988 as a systemic anti-KS therapy for "selected" patients (those who do best are otherwise asymptomatic, with no prior opportunistic infections, and have CD4 counts over 200). Cells secrete alpha interferon in response to viral invasion. Its effect on KS has not been mapped out completely. Among other things, alpha interferon stimulates cells to inhibit viral replication and malignant proliferation.
Alpha interferon research has most recently focused on its activity when combined with antiretrovirals -- in most cases, the nucleoside analogues. Most studies completed thus far have tested alpha interferon combined with AZT monotherapy. In 1996, University of Miami investigators reported a study of alpha interferon in combination with AZT for the treatment of KS. Results from the study were promising for participants with CD4 counts less than 200 cells/mm3. Such people previously had exhibited consistent response rates below 10% when treated with high-dose alpha interferon monotherapy.18But the alpha interferon and AZT combination induced KS regression in approximately 30% of subjects enrolled in the Miami study.19 High rates of neutropenia have been reported in the majority of studies of alpha interferon and AZT. Research has now shifted slightly to examine the effects of alpha interferon in combination with nucleoside analogs that suppress the bone marrow less, such as ddI. One such trial, ACTG 206, has recently closed to accrual after enrolling approximately 75 HIV-positive subjects with CD4 counts greater than 100. Participants originally were randomized to receive standard doses of ddI monotherapy with either a low dose (1 million units/day) or a high dose (10 million U/day) of alpha interferon. (The trial ahs been amended to allow participants to switch to whatever antiretroviral combination their doctor recommended.) According to the protocol chair, Dr. Susan Krown, of New York's Memorial Sloan-Kettering Hospital, patients seem to be responding to both doses of alpha interferon. The incidence of neutropenia appears to be much lower than those seen in trials of alpha interferon and AZT, and no other dose-limiting toxicities have yet been reported. It is too early to tell whether or not one study arm has an efficacy advantage over the other, though. Another multicenter study is now enrolling through the AIDS Malignancy Consortium looking at alpha interferon in combination with ritonavir and two reverse transcriptase inhibitors (ACM 004). Anyone interested in participating may call Jeannette Lee at 205/934-5165.
Human chorionic gonadotropin is a naturally occurring hormone that is produced by women during pregnancy. It is an approved therapy for treating infertility in women and cryptorchidism (failure of the testicles to descend) in boys. Interest in HCG was stimulated by anecdotes of KS regression in two pregnant women. Researchers at Robert Gallo's laboratory at the National Cancer Institute then noticed that HCG triggered regression in a mouse model of KS.20 Pamela Harris, a Washington, D.C. physician, reported on KS remissions in patients that she treated with high-dose HCG (200,000 international units three times a week of Serono's Profasi brand HCG at a weekly cost of $3,600). However, the KS flared up when treatment was terminated.21,22 To put these findings to the test, Parkash Gill, M.D., and colleagues at the University of Southern California attempted to treat 36 volunteers with AIDS-related Kaposi's sarcoma.23The first 24 received four different doses of HCG (6 persons each). All subjects were treated intralesionally -- two tumors were injected with HCG while a third was injected with saline solution. A double-blind study in 12 additional persons was conducted to determine the efficacy of the highest dose study used in the initial study. Six volunteers had two of their lesions treated intralesionally while the remaining six had two tumors injected with saline.
Treatment was well tolerated at all doses studied (250, 500, 1,000, and 2,000 IU given three times a week for two weeks). Of the 12 tumors treated with 2,000 IU, ten responded to intralesional therapy; complete tumor regression was observed in one lesion each at the 250 IU and 500 IU doses, in two lesions given the 1,000-IU dose, and in five tumors given the 2,000 IU dose. In the blinded study, none of the 12 lesions in the six patients injected with saline had responses, as compared with 10 of the 12 lesions in the six patients injected with HCG (these data are statistically significant).
The trial was conducted with Wyeth-Ayerst's brand of HCG because it was found superior to the others, including Serono's, in test-tube experiments. Purified HCG did not work at all, but some fragments of the molecule did. The real active substance in commercial HCG, dubbed HAF for HCG-Associated Factor, has yet to be identified. In the lab experiments and human topical trial, KS cells died after contact with the HCG preparation through the process of apoptosis. (Apoptosis is a normal cytokine-driven process for killing unwanted or defective cells in which enzymes break down cells' chromosomes.)
The tumors responding to topical HCG tended to be the smaller ones. Topical preparations are in any case impractical for persons with widespread KS. Investigators have now moved on to testing systemic HCG. Results of a trial of subcutaneous HCG (Wyeth-Ayerst brand) were published by Parkash Gill and colleagues in December.24Eighteen male volunteers without internal KS were divided into three dose groups: 5,000 IU daily, 10,000 IU three times a week and 10,000 IU daily. HCG was administered until a maximal response was observed. Six of the eighteen volunteers achieved either a complete remission or a partial one (50% or greater reduction in number or size of tumors). Nine others had their disease stabilized for ten weeks or more. Notably, two volunteers at the highest dose had complete remission that has lasted for a year -- although they have been off treatment for 210 and 310 days. (But the other four volunteers at this dose did not do particularly well. Two had stable disease for only 71 or 77 days and the other two had disease progression within 60 days of starting treatment.) Results did not seem related to use of protease inhibitors or baseline CD4 count. The most common side effects were considered positive ones, including substantially increased weight, libido, energy, appetite and testosterone levels.
There have been some suggestions that HCG also inhibits HIV activity.25Robert Gallo announced last June26that a factor derived from HCG, which he called HAF-C had shown itself capable of reducing viral loads by 80% to 99% in a pilot study. No consistent effect on HIV was evident in the subcutaneous HCG trial, however.
Another study of systemic therapy, this time in people with internal, or visceral, KS and CD4 counts below 100 is still in press. It achieved a partial or complete response rate of 35% to 45%, according to Dr. Gallo.
Another hormonal treatment for KS is 9-cis-retinoic acid. Its developer, Ligand Pharmaceuticals plans to apply within the next few months for FDA approval to market this product as a topical gel to treat KS. The company is also investigating use of 9-cis-retinoic acid, which it calls "Panretin," in a variety of other malignancies and noncancerous conditions, but its exact mechanism of action is unknown. 9-cis-retinoic acid is a natural hormone that activates a series of six cellular receptors, three of which trigger cell growth and development while the others cause death by apoptosis in superfluous or apparently malfunctioning cells. (Ligand also is conducting early trials of the synthetic "Targretin," which only affects the apoptosis receptors.) Ligand has sponsored two major phase III trials of Panretin gel. Both trials, one in North America and the other in Australia and Europe, were 12-week, placebo-controlled trials in which volunteers applied the gel at home to cutaneous KS lesions. Thirty-five percent of those receiving Panretin in the 268-person North American trial experienced partial or complete reduction of six index KS lesions compared to 18% of those using the placebo. Interim results from 78 participants in the international trial were even better: 42% in the treatment arm versus 7% in the placebo arm witnessed at least a partial response to treatment. These results were so clear-cut that the international trial was terminated at this point, although the original plan had been to enroll 270 volunteers as in the North American trial. (Full disappearance of the index lesions constitutes a complete response. A partial response was defined as a 50% shrinkage in a product of the index lesions' two diameters or observed flattening in 50% of those lesions.) In both trials, side effects were confined to occasional skin irritation on the lesions themselves -- healthy skin was unaffected.
Whatever its mode of action, 9-cis-retinoic acid needs direct contact with the KS cells to work. Tumors resolve layer by layer from the outside in when Panretin is applied. Both these trials include extended open-label phases in which further healing of tumors was observed. Kenneth Washenik, M.D., of New York University Medical Center reports that an interim analysis of the North American trial's open-label phase found that 49% of the study participants were now showing some benefit from the gel.
Besides Targretin, Ligand is also developing an oral version of Panretin. This capsule version is now in clinical trials for KS and other conditions. In KS, data from two open-label phase II trials will be available later this year. The two trials will involve a total of 56 people treated for 16 weeks. Volunteers must be on stable anti-HIV therapy from six weeks before starting until four weeks after stopping the oral Panretin.
The requirement that study participants remain on existing therapy from well before the trial starts is indicative of the important influence anti-HIV therapy is thought to have on KS. In fact, the initial presentations on the Panretin gel trials have been criticized for not separating out factors such as anti-HIV therapy that might have reduced the volunteers' KS with or without Panretin. The company says such a multifactor analysis will be presented at the 12th International Conference on AIDS this summer, if its submission is accepted.
As indicated previously, the confounding effects of HIV therapy are already complicating the analysis of present KS trials. Now that there are treatments that deeply cut HIV viral load, hopefully immune competence will return while the putative KS-supportive environment (the excess of growth factors plus Tat protein) fades away. KS stabilization or regression will be much more frequent than in the past even in the absence of specific KS treatment. It will be necessary to run larger trials, all with placebo controls to properly test KS therapies. And this requirement arises right at the time when the pool of available volunteers with KS is reduced.
The hope that the new highly active antiretroviral therapies (HAART) will control KS as they suppress HIV remains to be validated. There was a flurry of reports on the subject in February at the 5th Conference on Retroviruses and Opportunistic Infections. They painted a complex picture. First of all, a French survey of 60,000 patients with HIV found a two-thirds reduction in the incidence of KS between 1996 and 1997 (abstract 182). Then the previously mentioned San Francisco Men's Health Study review concluded that increased HIV viral load as well as decreased CD4 count were independent factors promoting KS development in those infected with KSHV (abstract 430). This observation certainly suggests that reducing HIV levels therapeutically would reduce KS. Both a French and an Argentinean report (abstracts 431 and 434, respectively) did show examples of people whose KS went into remission after initiating HAART.
A Chicago study (abstract 433) found that the KS response to HAART was not uniform. It concluded: "A very consistent worsening of KS appears to occur approximately two months following a clinically significant rise in HIV RNA levels, while the improvement of KS following a fall in [HIV] levels is more variable." In one case described in a conference lecture by Andrew Carr, M.D., a man in an early monotherapy trial of the protease inhibitor ritonavir experienced rapid increase in pain and swelling of existing KS tumors plus the appearance of new ones. At the same time, his HIV viral load had fallen 1.7 logs (98%) while KSHV in his blood sank down below detectable levels. His CD4 count went from 180 to 285. Dr. Carr's conclusion was that the man's immune response to KS had increased but was still insufficient to control the disease.
It may turn out that anti-HIV therapy decisively prevents new cases of KS but that its effect on established KS is limited. Such a situation would parallel another anecdotal report by Dr. Carr on microsporidiosis and cryptosporidiosis,27two intestinal parasites that are difficult to treat. According to the report, HAART resulted in the cessation of the diarrhea caused by these two microbes in nine patients, but four of them relapsed during the 13-month observation period.
Adding HAART will clearly have a big impact on KS, but it does not always suppress HIV and may not always cause KS regression even when it does. New KS treatments and new KS trials are still necessary despite HAART's contribution to limiting this puzzling and recalcitrant malignancy.