Treatment Issues; Vol. 9, No. 3 - March 1995
Gabriel Torres, M.D.

AIDS Now the Leading Cause of Death

Harold Jaffe, M.D., from the Centers for Disease Control and Prevention (CDC), announced (in a lecture comprising conference session no. 3) that the number of AIDS cases reported to the agency in 1994 was 80,691. The total number of reported AIDS cases now exceeds 440,000, and one-quarter million have died. The disease is increasing rapidly among younger gay men, and, especially in the northeastern United States, among women and injection drug users.

AIDS has now surpassed unintentional injury as the leading cause of death for male Americans between the ages of 25 and 44. For women in the same age group, AIDS is fourth behind unintentional injury, breast cancer and heart disease. It outstripped homicide and suicide in 1992.

Tuberculosis Update

A study from Bronx Lebanon Hospital in New York examined the outcome of 39 patients with AIDS and multidrug resistant tuberculosis (MDR-TB) treated at their institution from 1991 to 1994. (abstract no. 102) Overall, 54 percent of the patients responded to treatment. The likelihood of survival was 54 percent at one year and 50 percent at two years. These survival rates compare favorably with previous reports of patients with AIDS and MDR-TB, which had reported death rates of greater than 85 percent.

The resistance patterns of the TB isolates did not affect the clinical response or survival. Response was associated with starting appropriate therapy within four weeks of the diagnosis, receiving at least two weeks of continuous appropriate therapy and disease limited to the lungs. The average delay until the laboratory reported resistance patterns of the TB isolates was one month at this hospital. The authors concluded that prompt initiation and continuation of appropriate therapy can increase both response and survival in AIDS patients with MDR-TB.

Johns Hopkins University researchers (abstract no. 103) examined the relationship between response to the PPD skin test for TB and HIV viral burden. It compared the viral load of HIV-positive drug users who were PPD skin test reactors (skin test reactions greater than 2 mm in diameter but free of active TB) to controls with negative skin test reactions. Researchers concluded that having a positive skin test was not associated with an increase in HIV virus levels and may be a marker of immune function. Lack of active TB disease may be associated with a low TB burden.

Finally, a study from Montefiore Hospital in New York compared the sizes of the skin test reactions of HIV-positive and HIV-negative drug users in a methadone maintenance treatment program (abstract no. 105).

This study suggested that HIV-positive people produce skin test reactions equal to HIV-negative ones if they are immunocompetent enough to react at all. The authors called for a re-evaluation of the present, less strict standard for deciding that a PPD skin test is positive in a patient with HIV.

The present recommendation is to consider PPD skin tests positive in persons with HIV if the bump that appears (induration) is over five millimeters in diameter. For others, the induration has to be ten millimeters or more.

New Ganciclovir Implant Study

Treatment Issues reported on the results from a small phase II study of ganciclovir eye implants as a maintenance therapy for CMV retinitis. The implants, manufactured by Chiron Vision, consist of a small capsule surgically inserted in the eye. They are designed to keep CMV suppressed after two to three weeks of intravenous induction therapy.

A newer, much larger randomized trial was described at the Second National Meeting on Human Retroviruses (abstract no. LB16). In this study, 188 patients with newly diagnosed CMV retinitis in one or both eyes received either a 1 mcg/hour or a 2 mcg/hour ganciclovir implant or continued intravenous ganciclovir infusions. Patients were followed for progression of disease and death.

One hundred forty-eight volunteers completed the protocol. The times to renewed growth of CMV lesions were 194 days for the group receiving the 1 mcg/hour implant, 182 days for the group receiving the 2 mcg/hour implant and 73 days for the group receiving intravenous ganciclovir -- making for a doubling in progression-free time for the groups with the implant.

Complications from the implants included four cases of inner eye inflammation, seventeen retinal detachments and twelve vitreous hemorrhages. By comparison, retinal detachments occur in eighteen percent of the general population with CMV retinitis.

There were no statistically significant differences in terms of time to the onset of CMV in the other eye, yet there was a trend toward less extraocular disease in the group receiving systemic therapy. There were no differences in survival among the groups.

The investigators argued that this study demonstrates the effectiveness of implants in preventing CMV disease progression with low rates of complications, and should probably replace intravenous ganciclovir as maintenance therapy. Most experts estimate that the implants should be exchanged after 32 weeks in order to minimize the chance of patient relapse.

HPMPC for CMV Retinitis

HPMPC or cidofovir is a nucleoside analogue that is under study as a treatment for CMV infection. A multicenter trial has been completed among 48 patients with non-sight- threatening peripheral CMV retinitis who were randomly assigned to receive either immediate or deferred treatment with the drug (abstract no. LB18). Patients in the deferred arm were given cidofovir when their retinitis began to progress.

Treatment consisted of single cidofovir infusions of 5 mg per kg of body weight per week for the first two weeks and every other week thereafter. Probenecid and intravenous rehydration (saline) solution were given to reduce kidney toxicity, which had been seen in previous trials with this drug. The endpoint of the study was the time to retinitis progression, measured by advancement of the edge of an existing retinal lesion as detected by retinal photography. The time to retinitis progression was 22 days in the deferred treatment group compared to 120 days in the immediate group - a very significant difference.

Side effects included loss of protein in the urine in 23 percent of trial participants, neutropenia in fifteen percent and rises in serum creatinine (a kidney function test) in 5 percent.

The study indicated that cidofovir is effective in the treatment of CMV retinitis and that the toxicities can be alleviated by use of probenecid and intravenous saline. It now seems appropriate to consider cidofovir as salvage therapy for those failing ganciclovir and foscarnet and to consider trials comparing these three drugs.

Taxol for advanced Kaposi's sarcoma

Paclitaxel (brand name: Taxol) is a chemotherapeutic drug used widely for the treatment of solid tumors. It works by inhibiting cell division.

In vitro studies have shown that Taxol is cytotoxic to spindle cells obtained from Kaposi's sarcoma lesions. This finding led National Cancer Institute investigators to conduct a pilot study of Taxol in 20 AIDS patients with advanced Kaposi's sarcoma and very low CD4 cell counts (median of sixteen) (abstract no. 134). Taxol was administered as a three-hour intravenous infusion at an initial dose of 135 mg per square meter of body surface escalating to a maximum of 175 mg/m2. Thirty percent of the patients had received prior systemic chemotherapy and 25 percent had pulmonary KS.

Overall, 55 percent of patients had a partial response and 40 percent had stabilization of disease. Four of five patients with KS in their lungs responded with clearance of tumor lesions as demonstrated by serial lung CT (computed tomography) scans. Side effects included neutropenia, hair loss, fever, rashes and catheter-related complications. The duration of the improvement was short (two months on average), but patients responded to retreatment with Taxol when they relapsed.

Loviride

Loviride is a novel non-nucleoside reverse transcriptase inhibitor manufactured by Janssen Pharmaceuticals. The first human data on loviride was presented at the Tenth International Conference on AIDS in Yokohama in August of 1994. An early trial conducted among asymptomatic HIV- positive patients with CD4 counts above 400 observed that the drug was well tolerated and produced moderate CD4 cell count gains of 42 to 60 over 24 weeks of treatment along with temporary reductions in HIV plasma levels.

At the Second National Conference on Human Retroviruses, Michael Youle, M.D., of the United Kingdom reported on the first randomized trial of loviride (abstract no. LB6A). Loviride, zidovudine and the combination of both were compared to placebo in a group of 56 HIV-positive patients with CD4 counts between 200 and 500 and varying degrees of AZT experience.

After six months of treatment, the combination arm showed a sustained increase in CD4 cells as compared to the zidovudine, loviride or placebo groups. The most common side effects were headache, nausea and diarrhea, which occurred most frequently in the first two months.

Point mutations at codon 181 of the gene for reverse transcriptase were detected in several patients after six months of treatment. This change conferred resistance to the drug both in peripheral blood mononuclear cells and plasma samples. The combination of AZT and loviride did not prevent the emergence of resistance-inducing mutations.

Viral load assessments were limited due to a laboratory error that damaged blood samples, but a preliminary assessment of a portion of the available samples showed enhanced viral load reductions with the combination compared to either monotherapy.

Loviride is entering combination trials in Europe: the British Medical Research Council is planning a trial comparing the combination of loviride, AZT, 3TC and ddC versus the combination of AZT and 3TC versus cyclical therapy with each of the four drugs for an eight week period. Glaxo, 3TC's developer, has also started a 1,200-person trial comparing patients' current treatment alone (either AZT or AZT/ddI or AZT/ddC) to current treatment plus 3TC to current treatment plus 3TC and loviride. No information about planned loviride trials in the United States is available.

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