Search

The combined use of two or more drugs against HIV may reduce the chances that the virus will become resistant to either drug. This was the result of the ACTG 184 study, which evaluated a new anti-HIV drug called L-697,661. Six HIV-infected patients took L-697,661 and zidovudine and seven took L-697,661 alone. The virus became rapidly resistant to L-697,661 in those who took L-697,661 alone, but this did not occur in those who took both drugs. L-697,661 belongs to the class of drugs called non-nucleoside reverse transcriptase inhibitors.

Background: Among patients who begin receiving zidovudine during intermediate-stage human immunodeficiency virus (HIV) infection, it is unclear whether changing to combination therapy (adding didanosine or zalcitabine) or sequential monotherapy (changing to didanosine or zalcitabine) significantly improves survival. Objective: To determine, among patients who began receiving zidovudine during intermediate-stage HIV infection, the differential effects of changing to combination therapy (zidovudine with didanosine or zalcitabine) or sequential monotherapy (with didanosine or zalcitabine) or continuing zidovudine monotherapy. Patients: 1077 HIV-seropositive men in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study who began receiving zidovudine before an AIDS-defining illness developed. Setting: University-affiliated clinics in Baltimore, Chicago, Los Angeles, and Pittsburgh. Design: Longitudinal cohort study. Treatment groups and important prognostic variables were modeled as time-dependent covariates in Cox proportional hazards models. Measurements: Progression to AIDS and death. Results: Compared with patients receiving continued zidovudine monotherapy, patients receiving combination therapy had a 45% improvement in survival (relative risk, 0.55 [95% CI, 0.41 to 0.74; P < 0.001]) and patients who changed to sequential monotherapy had a 32% improvement in survival (relative risk, 0.68 [CI, 0.52 to 0.89; P= 0.005]). In the landmark analyses, the median prolongation of survival associated with changing therapy was, at best, 3 to 6 months. Survival curves converged at 3.5 years for the 50 cells/mm3 disease-stage landmark, at 4.4 years for the 100 cells/mm3 landmark, and at 4.9 years for the 150 cells/mm3 landmark. Mortality within these periods was 100%, regardless of treatment group or landmark. Conclusions: For patients who began receiving zidovudine during intermediate-stage disease, changing to either combination therapy or sequential monotherapy was associated with a statistically significant survival benefit compared with continuation of zidovudine monotherapy. The absolute increase in survival was modest, however, and long-term survival remained poor. Simultaneous time-dependent adjustment for changes in therapy and in important prognostic variables is necessary to derive relatively unbiased estimates of treatment effects in observational studies of HIV infection., Switching from zidovudine therapy to either therapy with zalcitabine or didanosine or to therapy with a combination of drugs appeared to give equally effective results. However, gains in survival were modest in both cases. Researchers compared outcomes among 263 HIV-infected patients who switched to a different drug and 318 patients who were given combination therapy with 496 patients who continued zidovudine therapy. Patients switching to a different drug had a 29% decrease in the risk of developing an AIDS-defining disease versus a 14% reduction with combination therapy compared with those continuing zidovudine. Similarly, patients switching to a different drug had a 32% reduction in the risk of death versus a 45% reduction with combination therapy compared with those continuing zidovudine. However, average survival rates were extended by only three to six months by changing therapy from zidovudine.

Nevirapine appears to be well tolerated and have some beneficial effect in HIV-infected patients. Nevirapine is an antiviral drug that inhibits enzymes involved in the reproduction of HIV. Researchers conducted a clinical trial of nevirapine alone and in combination with zidovudine, another antiviral drug, among 62 HIV-infected patients. Patients received doses of 12.5, 50 and 200 milligrams (mg) of nevirapine alone or in combination with 200 mg doses of zidovudine every eight hours. By day 7 of the trial, blood levels of HIV infection markers fell to a minimum level in the majority of patients. Blood levels of HIV genetic material decreased by at least 50% after four weeks of treatment in four of ten patients receiving either 50 mg or 200 mg of nevirapine. Most patients experienced fatigue or extreme sleepiness as a side effect of the drug. Other side effects included headache, diarrhea, nausea, fever and rash.

* Objective: To compare the safety and efficacy of continuing zidovudine therapy with that of zalcitabine alone or zalcitabine and zidovudine used together. * Design: A randomized, doubled-blind, controlled trial. * Setting: AIDS Clinical Trials units and National Hemophilia Foundation sites. * Patients: 1001 patients with symptomatic human immunodeficiency (HIV) disease and 300 or fewer CD4 cells/[mm.sup.3] or asymptomatic HIV disease and 200 or fewer CD4 cells/[mm.sup.3] who had tolerated zidovudine therapy for 6 months or more. * Intervention: Patients were randomly assigned to receive zidovudine, 600 mg/d; zalcitabline, 2.25 mg/d; or zidovudine, 600 mg/d, and zalcitabine, 2.25 mg/d. * Measurements: The primary end point was time to disease progression or death. * Results: The median follow-up time was 17.7 months. The estimated 12-month event-free rates were 70%, 67%, and 73%, respectively, for the zidovudine, zalcitabine, and combination groups (P = 0.26). A trend analysis showed significantly lower progression rates for combination therapy compared with zidovudine therapy as the pretreatment CD4 cell count increased (P = 0.027). For patients with 150 or more CD4 cells/[mm.sup.3], those receiving combination therapy were less likely to have disease progression or to die than were those receiving zidovudine (relative risk, 0.51; 95% Cl, 0.28 to 0.93; P = 0.029). We observed no difference between the zalcitabine and zidovudine groups (relative risk, 0.74; Cl, 0.40 to 1.36; P = 0.33). For patients with 50 to 150 CD4 cells/[mm.sup.3] or fewer than 50 CD4 cells/[mm.sup.3], we found no differences among the treatment groups (P = 0.69 and P = 0.57, respectively). Severe toxic effects occurred less frequently among patients with 150 or more CD4 cells/[mm.sup.3]. * Conclusions: We found no overall benefits of zalcitabine used alone or with zidovudine. However, a trend analysis suggested a better outcome for combination therapy compared with zidovudine as the pretreatment CD4 cell count increased., A combination of zidovudine and zalcitabine therapy appears to be more effective than either drug alone in preventing disease progression among HIV-positive patients with higher CD4 cell counts. CD4 cells are components of the immune system and become depleted as HIV disease progresses. A group of 1001 HIV-positive patients who had either CD4 cell counts of 300 or less and were symptomatic or who had CD4 cell counts of 200 or less and were asymptomatic were randomly assigned to receive one or the other drug or a combination of both. Patients were followed for a median of 17.7 months. The percentage of patients living without disease progression over a one-year period was 70% for those taking zidovudine, 67% for those taking zalcitabine, and 73% for those taking the combination regimen. However, for patients with CD4 counts of 150 or more, the risk of disease progression or death on the combination regimen was half that of those on zidovudine alone.

* Objective: To examine the effect of acyclovir use on disease progression and survival in human immunodeficiency virus (HIV)-seropositive persons treated with zidovudine. * Setting: Four university-based or -affiliated clinics. * Design: Prospective cohort study of homosexual and bisexual men with semi-annual follow-up. Intent-to-treat Cox models were fit to determine the relation between the use of acyclovir (modeled as a time-dependent covariate) and disease progression, controlling for baseline and time-dependent clinical and laboratory prognostic variables. The acquired immunodeficiency syndrome (AIDS)-free duration and survival time were calculated from the first use of zidovudine. Analysis included study visits 7 to 17 (from 1987 to 1992). * Patients: 786 HIV-seropositive participants in the Multicenter AIDS Cohort Study who began zidovudine therapy before a clinical diagnosis of AIDS; of these, 515 subsequently received acyclovir. Participants were asked at each visit whether they had 'used any medication for health reasons not related to AIDS or if they had taken any medication to help fight AIDS or the HIV virus'; 488 patients indicated acyclovir use under either or both questions, and 242 patients indicated only the latter use. * Results: The use of acyclovir for any indication was not associated with an effect on progression to AIDS but was associated with a 26% decrease in the risk for death (relative hazard, 0.74; P = 0.07). The use of acyclovir for HIV infection was also not associated with an effect on progression to AIDS but was associated with a 36% decrease in the risk for death (relative hazard, 0.64; P = 0.01). To further investigate these findings, we examined dose, constancy, and timing of acyclovir use. The median daily dose of acyclovir used for HIV infection was between 600 and 800 mg. No apparent dose effect on survival was found. Longer uninterrupted use of acyclovir for any indication was associated with an 18% decrease in the risk for death for three or more consecutive visits (relative hazard, 0.82; P = 0.23), a 28% decrease for four or more consecutive visits (relative hazard, 0.72; P = 0.09), and a 7% decrease per visit based on the cumulative number of visits while the patient received acyclovir (relative hazard, 0.93 per visit increase; P = 0.03). Use of acyclovir for any indication and use of acyclovir for HIV infection were each associated with a 44% decreased probability of death if the drug was used after AIDS developed (P = 0.007 and P = 0.005, respectively) but not before. To further investigate the prolongation of survival, two landmark analyses were done. The first analysis began at a landmark of 1 year after initiation of zidovudine therapy and compared three groups of patients: those who used acyclovir at or before this landmark, those who had never started acyclovir or started the drug after the landmark, and those who had never used acyclovir. The 90% survival times were 1325,1059, and 982 days, respectively. The second analysis began at a landmark of developing either a CD4 count less than 50 cells/[mu]L or clinical AIDS. The 90% survival times for the three groups were 398, 261, and 176 days, respectively. * Conclusions: Our analysis suggests that consistent use of acyclovir at a dose sufficient to suppress herpetic recurrences (that is, 600 to 800 mg/d) has a clinically significant effect on prolonging survival in a well-characterized cohort with extensive previous exposure to herpesvirus infections. Further clinical investigation of low-dose acyclovir with concomitant antiretroviral therapy is warranted., Acyclovir taken with zidovudine (AZT) appears to increase the survival time of HIV-infected patients who subsequently develop AIDS. Daily doses of 600 mg to 800 mg of acyclovir were found to be most effective. Those who took acyclovir in conjunction with zidovudine for any reason experienced a 26% decrease in the risk of death over those who took only zidovudine. Those who took acyclovir in conjunction with zidovudine specifically for the treatment of HIV experienced a 36% decrease in the risk of death compared with those who took only zidovudine. Acyclovir appeared to have no effect on the rate of progression to AIDS. However, those who took acyclovir in conjunction with zidovudine after the onset of AIDS had a 44% decrease in the risk of death compared with those who took only zidovudine.

Patients who are infected with the human immunodeficiency virus (HIV), the agent that causes AIDS, are at risk of developing infections, such as Pneumocystis carinii pneumonia, that do not generally affect people with normal immune function. Most patients with AIDS will experience a bout with Pneumocystis carinii pneumonia which, if left untreated, is invariably fatal. Current drugs of choice do not effectively eliminate this parasite, and episodes of pneumonitis frequently recur, suggesting the need for more effective and long-lasting therapy. A new hydroxynaphthoquinone known as compound 566C80 has demonstrated antiprotozoal activity in experimental animals with murine P. carinii pneumonia; in doses of 100 milligrams per kilogram of body weight per day, 566C80 was fully effective in the prevention and treatment of the disease. Phase 1 multidose studies were conducted in five cohorts of four male patients with AIDS to assess dose levels and ascertain the safety and pharmacokinetics of the drug in humans. Participants had not received medical treatment for P. carinii pneumonia in the previous four weeks, and satisfied other experimental parameters. Daily doses of 100, 250, 750, l,500 and 3,000 milligrams of 566C80 were administered to the 5 cohorts, respectively, for 12 or 21 days, after they ate a standard breakfast. A sixth cohort received another dosage regimen to characterize the pharmacokinetic properties of the new compound. The drug was well tolerated up to the maximum dosage in the trial. No significant abnormal clinical findings were attributed to the new compound. Administration of 566C80 with food enhanced its absorption and produced higher blood levels of the drug. The action of this agent suggests that the parasite was killed rather than inhibited; this is an added advantage in the treatment of immunocompromised patients. The apparent successful application of this new class of compounds provides a new category of potentially effective antiprotozoal drugs and offers hope for an effective treatment for P. carinii pneumonitis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Hypericin, the active compound in St. John's Wort, has antiretroviral activity in vitro. Many HIV-infected persons use St. John's wort. Objective: To evaluate the safety and antiretroviral activity of hypericin in HIV-infected patients. Design: Phase I study. Setting: Four clinical research units. Patients: 30 HIV-infected patients with CD4 counts less than 350 cells/[mm.sup.3]. Intervention: Intravenous hypericin, 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral hypericin, 0.5 mg/kg daily. Measurements: Safety was assessed at weekly visits. Antiretroviral activity was assessed by changes in HIV p24 antigen level, HIV titer, HIV RNA copies, and CD4 cell counts. Results: Of the 30 patients who were enrolled, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 (48% [95% CI, 27% to 69%]) evaluable patients, and dose escalation could not be completed. Virologic markers and CD4 cell count did not significantly change. Conclusions: Hypericin caused significant phototoxicity and had no antiretroviral activity in the limited number of patients studied., Hypericin has no apparent immunological effect in HIV patients, and causes significant skin sensitivity to sunlight. Hypericin is the probable active ingredient in the herbal remedy St. John's Wort, commonly used for depression. In the laboratory, hypericin has shown some antiviral activity. Researchers treated 30 HIV-infected patients with oral or intravenous hypericin. Severe phototoxicity developed in 48% of patients, and no change in CD4 white blood cell levels or other virologic markers was detected.