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A new antiviral agent seems to be effective in preventing HIV from reproducing. Researchers tested (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) on mice infected with the murine leukemia virus. This virus causes a mouse form of AIDS called MAIDS. Both PMPA and PMEA initially seemed effective in preventing MAIDS in these mice. However, all of the mice who received PMEA eventually developed MAIDS, whereas only one mouse who received PMPA developed MAIDS.

The Multicenter AIDS Cohort Study, begun in 1984, is a collaborative study by four medical centers of 5000 gay men infected with or at high risk for HIV. The study has provided important information about the natural history and progression of HIV infection and AIDS, and the effects of antiviral therapy. The drug AZT (zidovudine) has been associated with increased survival and a lower risk of developing AIDS dementia.

Background: Surgical resection has been the usual therapy for HIV-infected patients with lymphoepithelial parotid cysts. Objective: To study antiretroviral therapy for lymphoepithelial parotid cysts. Design: Case series. Setting: HIV outpatient clinics. Patients: HIV-infected patients with lymphoepithelial parotid cysts. Intervention: Antiretroviral therapy. Measurements: Change in size of the parotid cyst, CD4 lymphocyte count, and HIV viral load. Results: Nine HIV-infected adults presented with chronic, large parotid cysts, eight of which were bilateral. In at least seven patients, the cysts were the initial sign of HIV infection. In six patients, the cysts resolved completely with combination antiretroviral therapy. Four of these patients also received prednisone. Three patients who did not comply with antiretroviral therapy had partial responses followed by relapses. Conclusions: Parotid cysts are an unrecognized sign of early HIV infection. These cysts respond to combination antiretroviral therapy, with or without corticosteroids. Surgical resection should be reserved for patients in whom medical therapy has failed or those who refuse or are poorly compliant with medical therapy., Many of the commonly used AIDS drugs may be effective in treating cysts in the parotid glands. The parotid glands are located in the cheeks and produce saliva. Researchers followed nine HIV-infected patients who were taking various AIDS drugs, including zidovudine, didanosine, stavudine and protease inhibitors. The cysts completely disappeared in six patients and three patients had a partial response.

The drug FPMPA appears to be as effective in treating feline immunodeficiency virus (FIV) infection as the drug PMEA but without the serious side effects. FIV infection occurs in cats and produces a disease similar to human AIDS. This makes it a useful animal model for testing potential AIDS drugs. FPMPA and PMEA both inhibit the enzyme reverse transcriptase, which is produced by FIV as well as HIV. A study of 27 FIV-infected cats showed that FPMPA improved symptoms and lowered viral blood levels and was not toxic to bone marrow as PMEA often is.

A drug that can enter the cerebrospinal fluid and also lymph nodes may be effective in eradicating HIV. 6-chloro-2',3'-dideoxyguanosine was tested in three Rhesus monkeys with SIV infection, and in two, viral levels in blood, cerebrospinal fluid and lymph nodes decreased. Blood levels of CD4+ and CD8+ cells increased during the treatment.

A vaginal gel containing dextrin sulfate may be well-tolerated by women. Researchers studied 24 women who used dextrin sulfate gel and 12 who used a placebo gel. Although the dextrin sulfate gel caused vaginal redness in 5 women, there was no microscopic evidence of inflammation. The gel did not affect normal vaginal bacteria that may protect women against HIV infection. Although condoms are effective in preventing the transmission of HIV, many women have no control over condom use by their partner. Dextrin sulfate has been effective in preventing HIV infection in experimental cell lines.

Background: Stavudine is a promising antiretroviral agent, but its clinical efficacy has not been determined. Objective: To evaluate the clinical effect of stavudine (2',3'-didehydro-3'-deoxythymidine) monotherapy in patients with human immunodeficiency virus (HIV) infection. Design: Randomized, controlled, double-blind trial. Setting: 56 outpatient clinics in private practices, universities, and contract research organizations in the United States, France, and Italy. Patients: 822 HlV-infected adults who had 50 to 500 [CD4.sup.+] cells/[mm.sup.3] and had previously received at least 6 months of zidovudine treatment. Intervention: Monotherapy with peroral stavudine capsules or peroral zidovudine capsules. Measurements: The primary end point was clinical progression, which was defined as all occurrences of acquired immunodeficiency syndrome (AIDS)-defining events or death. Results: Patients receiving stavudine reached clinical end points at a rate of 26 per 100 person-years, compared with 32 per 100 person-years for patients receiving zidovudine (relative risk, 0.75 [95% CI, 0.58 to 0.98]; P = 0.03). The risk for death alone was 26% lower in the stavudine group than in the zidovudine group, but the comparison was not statistically significant (relative risk, 0.74 [CI, 0.53 to 1.02]; P = 0.066). The benefit of stavudine therapy was seen in all [CD4.sup.+] cell strata ([is less than or equal to] 100 cells/[mm.sup.3], 101 to 300 cells/[mm.sup.3], and [is greater than] 300 cells/[mm.sup.3]) and clinical stages of HIV disease (asymptomatic, symptomatic, and AIDS). Four weeks after treatment began, [CD4.sup.+] cell Counts were 30 cells/[mm.sup.3] higher in the stavudine group than in the zidovudine group; this difference was sustained for 96 weeks (P [is less than] 0.001). Nausea and vomiting were more common in patients receiving zidovudine (P [is less than] 0.01), and neuropathy occurred more frequently in those receiving stavudine (12% in the stavudine group compared with 4% in the zidovudine group; P [is less than] 0.001). Neuropathy resolved completely in many patients (63%) after interruption of stavudine treatment; these patients could resume stavudine therapy at a lower dose. Conclusions: Stavudine was well tolerated and delayed progression of HIV disease in patients who had previously received 6 or more months of zidovudine treatment. Benefits were apparent in all [CD4.sup.+] cell strata and clinical stages of HIV disease. Stavudine is an important agent to consider for trials of combination chemotherapy., Stavudine appears to be effective in treating patients with HIV previously treated with zidovudine. Disease progress was monitored in 822 patients with HIV treated with either stavudine or continued zidovudine. All patients had previously taken zidovudine for at least six months. Patients taking stavudine had higher CD4+ counts, less nausea, and fewer signs of disease progression but more signs of neurological dysfunction that stopped when treatment was either stopped or reduced in strength. The risk for death was slightly lower in the group taking stavudine.

Cidofovir (Vistide) is a newly developed nucleotide analog to treat cytomegalovirus retinitis. Cytomegalovirus retinitis is an infection of the retina caused by cytomegalovirus. Two clinical trials have shown that cidofovir is effective in treating cytomegalovirus retinitis, especially in patients who are resistant to other drugs. Cidofovir can be administered intravenously twice a month and does not require indwelling catheters. However, the drug can damage the kidneys, and so it should be given along with probenecid and saline and the dose should not be exceeded.

Background: Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with the acquired immunodeficiency syndrome (AIDS). If left untreated, it may lead to progressive destruction of retinal tissue and blindness. Cidofovir is a nucleotide analogue of cytosine that has potent, prolonged in vitro and in vivo activity against herpesviruses, including many CMV isolates that are resistant to ganciclovir and foscarnet. Objective: To determine whether intravenous cidofovir delays progression of previously untreated CMV retinitis. Design: Randomized, controlled trial comparing immediate with deferred cidofovir treatment. Patients in the deferred treatment group were eligible to receive cidofovir after progression of CMV retinitis was documented by retinal photography. Setting: Eight academic medical centers and an independent center that read retinal photographs. Patients: 48 patients with AIDS and previously untreated peripheral CMV retinitis who were randomly assigned to immediate (n = 25) or deferred treatment (n = 23). Intervention: Intravenous cidofovir, 5 mg/kg of body weight, once weekly for 2 weeks and then once every other week. To minimize nephrotoxicity, oral probenecid and intravenous hydration with normal saline were administered with each cidofovir infusion. Measurements: Progression of CMV retinitis was assessed by bilateral, full-field retinal photographs that were read by an ophthalmologist who was masked to treatment assignment. Incidence of side effects, changes in visual acuity, effect on CMV shedding in urine and blood, and mortality were also assessed. Results: The median time to progression of CMV retinitis was 22 days (95% Cl, 10 to 27 days) in the deferred treatment group and 120 days (Cl, 40 to 134 days) in the immediate treatment group (P [is less than] 0.001). Neutropenia (15%) and proteinuria (12%), both asymptomatic, were the most common serious adverse events considered to be possibly related to cidafovir. Cidofovir treatment was discontinued in 10 of 41 patients (24%) because of protocol-defined treatment-limiting nephrotoxicity. Transient reactions to probenecid, including mild to moderate constitutional symptoms or nausea, occurred in 23 of 41 patients (56%) and were dose limiting in 3 (7%). Conclusions: Cidofovir was efficacious in delaying progression of previously untreated CMV retinitis. Treatment was associated with manageable side effects; strict adherence to monitoring of renal function before cidofovir was administered and concomitant administration of probenecid and saline hydration appeared to minimize drug-related nephrotoxicity., Cidofovir appears to be effective in delaying eye complications seen in patients with AIDS and untreated cytomegalovirus (CMV) associated retinitis. Forty-eight patients with CMV-associated retinitis were treated with cidofovir either immediately or after the disease had progressed. Immediate treatment with cidofovir delayed the progression of retinitis from 22 days to 120 days. Side effects included low white blood cell count and increased protein levels in the urine.

Background: Cytomegalovirus (CMV) retinitis is a common infection and a major cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). Objective: To evaluate intravenous cidofovir as a treatment for CMV retinitis. Design: Two-stage, multicenter, phase II/III, randomized, controlled clinical trial. Setting: Ophthalmology and AIDS services at tertiary care medical centers. Patients: 64 patients with AIDS and previously untreated, small, peripheral CMV retinitis lesions (that is, patients at low risk for loss of visual acuity). Intervention: Patients were randomly assigned to one of three groups: the deferral group, in which treatment was deferred until retinitis progressed; the low-dose cidofovir group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with cidafovir, 5 mg/kg once every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with hydration and probenecid. Measurements: Progression of retinitis, evaluated in a masked manner by a fundus photograph reading center; the amount of retinal area involved by CMV; the loss of visual acuity; and morbidity. Results: Median time to progression was 64 days in the low-dose cidofovir group and 21 days in the deferral group (P = 0.052, log-rank test). The median time to progression was not reached in the high-dose cidofovir group but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis of the rates of increase in the retinal area affected by CMV confirmed the data on time to progression. The three groups had similar rates of visual loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in the deferral group, 2.8 per person-year in the low-dose cidofovir group (P [is greater than] 0.2), and 6.8 per person-year in the high-dose cidofovir group (P =0.135). No patient developed 4+ proteinuria, but two cidofovir recipients developed persistent elevations of serum creatinine levels at more than 177 [micro] mol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per person-year. Conclusions: Intravenous cidofovir, high- or low-dose, effectively slowed the progression of CMV retinitis. Concomitant probenecid and hydration therapy, intermittent dosing, and monitoring for proteinuria seemed to minimize but not eliminate the risk for nephrotoxicity., Both high and low concentrations of cidofovir treatment appear to be effective in delaying eye complications seen in patients with AIDS and untreated cytomegalovirus (CMV) associated retinitis. Sixty-four patients with CMV-associated retinitis were treated either immediately with a low or high dose of cidofovir or after retinitis had progressed. Low-dose cidofovir delayed retinitis progression from 21 days as seen in the delayed treatment group to 64 days. Half of the group treated with high-dose cidofovir did not progress to CMV-associated retinitis by the study's end.

Background: Therapy for hepatitis B virus (HBV) infection is still unsatisfactory, particularly in patients who are co-infected with the human immunodeficiency virus (HIV) Lamivudine, a retroviral inhibitor, has been shown to have activity against HBV replication in vitro, in animal models, and in studies of immunocompetent persons. Objective: To assess the efficacy of lamivudine in inhibiting HBV replication during a 12-month period in patients with both HBV and HIV infection. Design: Prospective, open study. Setting: University hospital. Patients: 40 consecutive patients (39 men and 1 woman) infected with both HIV and HBV. All had progressive HIV disease; were refractory to or unable to tolerate therapies other than lamivudine; and received lamivudine, 600 mg/d or 600 mg/d followed by 300 mgld, as therapy for HIV disease. Measurements. Serum concentrations of HBV DNA were assessed every 2 months by using molecular hybridization. Polymerase chain reaction (PCR) for HBV DNA was done at baseline and was done at months 2, 6, and 12 only if the HBV DNA concentration was less than 5 pg/mL. Results: Two groups were retrospectively identified at baseline: patients with high HBV replication (serum HBV DNA concentrations > 5 pg/mL) (n = 30) and patients with low HBV replication (serum HBV DNA concentrations, Preliminary tests indicate that lamivudine can be effective in reducing blood levels of the hepatitis B virus (HBV) in patients infected with both HIV and HBV. HBV blood levels were measured every two months in 40 patients infected with both HBV and HIV treated with lamivudine for one year. HBV blood levels dropped to zero among six patients with initial HBV blood levels below 5 picograms per milliliter (pg/mL). Nearly all (96.3%) of the patients with initial HBV blood levels above 5 pg/mL dropped to below 5 pg/mL with treatment. There were no serious side effects reported.

Ribavirin can protect animals against murine acquired immunodeficiency syndrome (MAIDS) but can be toxic to red blood cells in high dosage. An aerosol antiviral drug, Ribavirin resembles the nucleotide guanosine and can be effective against DNA and RNA viruses. The disease in mice, MAIDS shows similarities to HIV in humans except that MAIDS targets B-cells rather than T-cells. If given to mice in 50 milligram per kilogram doses ribavirin can prevent MAIDS and protect the spleen and lymph nodes from infection. Ribavirin caused anemia and toxicity in mice at 50 mg/kg to 100 mg/kg doses.

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.

Objective: To compare the safety and activity of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine in patients with moderately advanced human immunodeficiency virus (HIV) infection who had received zidovudine. Design: A multicenter, randomized, double-blind, three-arm, 24-week study with a blinded extension through at least 52 weeks. Setting: 21 sites in the United States, Canada, and Puerto Rico. Patients: 254 patients who had received zidovudine (median duration of previous therapy, 20 months) and had absolute [CD4.sup.+] cell counts of 100 to 300 cells/[mm.sup.3]. Interventions: Patients were randomly assigned to receive one of three regimens: 150 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (low-dose lamivudine group); 300 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (high-dose lamivudine group); or 0.75 mg of zalcitabine plus 200 mg of zidovudine three times daily (zalcitabine group). Measurements: Immunologic activity was assessed primarily by changes in absolute [CD4.sup.+] cell counts; virologic activity was assessed by changes in plasma HIV RNA levels as measured by reverse transcriptase polymerase chain reaction. Safety of the treatment regimens was assessed through the reporting of adverse events. Results: 78% of patients completed 24 weeks of study treatment, and 63% of patients completed 52 weeks of study treatment. Changes in absolute [CD4.sup.+] cell counts were significantly better for the low-dose and the high-dose lamivudine groups than for the zalcitabine group (median changes at 52 weeks were +42.5 cells/[mm.sup.3] in the low-dose lamivudine group, +23.33 cells/[mm.sup.3] in the high-dose lamivudine group, and -29.58 cells/[mm.sup.3] in the zalcitabine group). Suppression of plasma HIV RNA levels was similar for all groups (median changes at 52 weeks were -0.48 [log.sup.10] copies/mL in the low-dose lamivudine group, -0.51 [log.sup.10] copies/mL in the high-dose lamivudine group, and -0.39 [log.sup.10] copies/mL in the zalcitabine group). No significant differences in safety were seen among the three regimens, although the low-dose lamivudine regimen appeared to be better tolerated than the others. Conclusions: In patients with HIV infection who had previously received zidovudine, 150 mg of lamivudine plus zidovudine resulted in greater immunologic evidence of benefit than did 0.75 mg of zalcitabine plus zidovudine and was better tolerated than 300 mg of lamivudine plus zidovudine., Zidovudine in combination with low-dose lamivudine appears to be more effective and better tolerated than a higher dose combination therapy or when combined with zalcitabine as a treatment for patients with HIV infection. Two hundred fifty-four patients with HIV previously treated with zidovudine were randomly assigned to take zidovudine plus either zalcitabine, low-dose lamivudine, or high-dose lamivudine for 24 weeks or up to 52 weeks. Patients taking zidovudine plus low-dose lamivudine had the highest average increase in CD4 counts and reported the fewest side effects.

Background: Cytomegalovirus retinitis remains a major cause of illness in patients with the acquired immunodeficiency syndrome (AIDS), and existing therapies for this condition are relatively ineffective and toxic. Objective: To evaluate the efficacy of intravitreous cidofovir injections alone for initialand maintenance therapy for cytomegalovirus retinitis. Design: Prospective, nonrandomized, consecutive case series. Setting: University ophthalmology referral clinic. Patients: 22 patients with AIDS and cytomegalovirus retinitis. in 15 of 32 affected eyes, intravitreous cidofovir was administered as the initial treatment for cytomegalovirus retinitis (group A); 17 eyes had previously been treated with intravenous therapy (group B). Intervention: All eyes were intravitreously injected with 20 [mu]g of cidofovir at 5- to 6-week intervals. No patient in either group received systemic anticytomegalovirus therapy at any time during the study period. Measurements: Healing of retinitis was defined as resolution of retinal opacification and cessation of border progression. Progression, the primary end point, was defined as 750 microns of border progression or development of a new lesion. Results: The mean duration of follow-up was 15.3 weeks (range, 5 to 44 weeks). Of the eyes with active retinitis, 100% (95% CI, 87% to 100%) healed in response to the initial injection. In two eyes (6%; CI, 0% to 15%), two episodes of retinitis progression occurred (one in each eye). Both of these eyes were in a patient with clinically resistant retinitis. In 3% of eyes (CI, 0% to 9%), the retina became detached. Mild iritis developed after 14% of the injections that had been preceded by prophylaxis with oral probenecid. Irreversible, visually significant hyflotonia developed in one eye. Conclusion: Treatment and subsequent maintenance of cytomegalovirus retinitis with 20 [mu]g of intravitreously injected cidofovir, given at 5- to 6-week intervals, is safe and highly effective., Cidofovir injections directly into the eye appear to be effective in treating cytomegalovirus infections in the eyes of patients with AIDS. Every five to six weeks doctors injected cidofovir into 32 infected eyes of 22 patients with AIDS. There was no disease progression in the 15 eyes that received cidofovir injections as the first and only cytomegalovirus infection treatment and in all but two of the eyes that had received previous treatment. Treatable iris inflammation occurred in more infected patients previously treated with probenecid than in those not previously treated.

Objective: To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine. Design: A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units. Patients: 398 adults who had HIV-1 infection, had 350 or fewer [CD4.sup.+] T lymphocytes/[mm.sup.3], and had had more than 6 months of previous nucleoside therapy. Intervention: 1) Either nevirapine or placebo (200 mg/d for 2 weeks, then 400 mg/d thereafter) and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing--60 kg). Measurements: [CD4.sup.+] T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA; HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites. Results: After 48 weeks of study treatment, the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% CI, 7% to 29%; P = 0.001), a 0.32 [log.sub.10] lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (CI, 0.05 to 0.59 [log.sub.10] infectious units per million cells; P = 0.023), and a 0.25 [log.sub.10] lower mean plasma HIV-1 RNA level (CI, 0.03 to 0.48 [log.sub.10] RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [CI, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference. Conclusions: Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens., Combining nevirapine, zidovudine, and didanosine appears to maintain CD4 counts and reduce viral load more effectively than zidovudine and didanosine alone. However, patients taking the triple combination were more likely to develop severe rash. Researchers randomly assigned 398 HIV-infected patients with prior prolonged nucleoside therapy and CD4 cell counts of 350 or less to 48 weeks of treatment with either all three drugs or to zidovudine and didanosine plus placebo. CD4 counts declined an average of 15% with the triple combination versus 33% with the double combination. Viral titers in white blood cells declined by 54% and HIV-1 RNA plasma content declined by 20% with the triple combination versus a viral titer decline of 5% and an RNA plasma content rise of 44% with the double combination. However, similar percentages of both groups, 17% and 14% respectively, experienced disease progression or death, and 9% of those taking the triple combination experienced severe rash versus 2% taking the double combination.

The topical application of the drug trifluridine may be effective in treating herpes simplex lesions that are resistant to acyclovir. Twenty-four AIDS patients applied a trifluridine solution to their lesions every 8 hours until some response was observed. Eighty percent had anogenital lesions and the remainder had facial lesions. The lesions healed completely in 29% of the patients within 2.9 to 7 weeks. The lesions shrank more than 50% in 7 patients but did not heal completely. At the end of study, 17 patients had smaller or nonexistent lesions, 2 had experienced no change and 5 had larger lesions. The drug caused no side effects beyond minor stinging in 1 patient.

The drug canventol can block HIV reproduction induced by the Tat protein but this inhibition is independent of the trans-activator response (TAR). Tat usually interacts with TAR, which is an RNA sequence, to activate viral reproduction. The effect of canventol seems to result from inhibition of tumor necrosis factor (TNF), since canventol inhibition can be reversed by TNF. Canventol is effective at very small concentrations, indicating that it could be a very useful drug against HIV.

A new interferon (IFN) class, IFN-tau, appears to have anti-HIV activity more potent than that of IFN-alpha. IFN-tau, also called trophoblastin, is secreted by trophoblasts involved in the pregnancy of cows, sheep and goats. Researchers compared the effects of IFN-tau and IFN-alpha in human immune cells before and after infection with HIV-1. Monitoring the level of activity of an HIV enzyme revealed that IFN-tau was 35 to 100 times more powerful than IFN-alpha in the inhibition of HIV replication in certain immune cells. IFN-tau inhibited the integration of HIV DNA into cellular DNA, indicating the presence multiple sites of action that have been suggested for other IFNs. IFN-tau appears to be less toxic to cells than IFN-alpha, which has been associated with numerous side effects when used by AIDS patients.

The heterosexual transmission of HIV may best be prevented using a combination of drugs targeting both the virus and its means of infection in the vagina. Virucidal agents directly affect the HIV particle, whereas antiviral agents disrupt various processes in the HIV life cycle. A combination of both agents may prevent infection by both free and cell-associated HIV. The action of virucidal agents such as nonoxynol 9 in breaking down the viral membrane might result in side effects involving destruction of the vaginal mucosa and enhancement of HIV infection. Further research on appropriate administration and formulation of these agents, however, may minimize such side effects. Antiviral agents such as polyanions can inhibit the attachment of the virus to cells and subsequent membrane fusion. Other antiviral agents such a reverse transcriptase inhibitors and fusion/uncoating inhibitors may be useful. As heterosexual transmission results in the majority of HIV infections in the world, a female-controlled approach may be crucial in HIV/AIDS prevention programs.

Treatment of primary HIV infection (PHI) should consist of very early drug intervention with the goal of promoting long-term disease stability. Newly infected patients benefit from early drug therapy because of its higher effectiveness, lower toxicity, and better tolerance in the early disease stages. Virus load seems to remain high in the lymphoid tissues even in the initial absence of viremia, suggesting disease activity. Capitalizing on a fairly intact immune system, antiviral therapy immediately after HIV diagnosis can achieve maximum results before immunity disintegrates. Drugs of choice include zidovudine, 3TC, and a protease inhibitor, such as MK-639 or ABT-538. The initial treatment period should be for about one year with special attention focused on patient compliance and the management of toxic side effects.

Testing for triple-drug therapies for patients with human immunodeficiency virus (HIV) may soon begin. Researchers from 15 major drug companies have joined forces in proposing two year-long studies of four triple-drug therapies for patients with HIV. One study would compare the effectiveness of combined zidovudine (AZT), zalcitabine (ddC), and either saquinavir or nevirapine with AZT and ddC alone (controls). The second study would compare the effectiveness of combinations of AZT, didanosine (ddI) and either lamivudine or nevirapine with AZT and ddI alone (controls). Physicians would treat 75 HIV-positive patients with each of these treatment combinations. Enrolled patients should not have received any retroviral drug treatment before enrollment in the study and have CD4 cell counts between 200-500. The studies would evaluate the patients' viral concentrations and resistance, CD4 cell counts, and disease progression.

Early intervention with triple-drug combination therapies that include zidovudine (AZT) may prove effective in treating patients with human immunodeficiency virus (HIV). Researchers analyzed the response of two HIV cell lines to 10 combinations of three-drug therapies each of which included AZT. The other currently available drugs included in the combination tests were dideoxycytosine (ddC), dideoxyinosine (ddI), nevirapine, 3TC, L-735,524, and Ro 31-8959. All 10 of the drug combinations were more effective in reducing cellular HIV disease than any of the drugs used alone or as a double-drug combination. The most effective combination was AZT, ddC, and 3TC. Three of the drug combinations were capable of completely stopping viral reproduction of both cell lines. Treatment was slightly more effective on the HIV-1 3B cell line than the HIV-1 MN cell line. The therapies were less effective with greater concentrations of the viruses.

An antiviral drug must be administered to all nursing home and community-dwelling residents if an outbreak of influenza A infection arises. Whether or not the residents have been previously vaccinated, prophylaxis should also be started. The antiviral agents rimantadine and amantadine, in particular, provide additional protection against the viral infection to older adults. However, rimantadine seems to have lesser side effects to the central nervous system., Risk of influenza mortality is high among older Americans and especially so among those residing in nursing homes. Current recommendations call for annual vaccination of all nursing home residents and [...]

Using polymerase chain reaction (PCR) may be an effective means of assessing drug efficacy in HIV patients. Normally, levels of CD4 T-cells, which are white blood cells depleted in HIV infection, are used to evaluate treatment response. Increases in CD4 T-cell counts may be transitory however, and may not indicate actual changes in the degree of infection. Five HIV-positive patients were treated with a combination of the drugs zidovudine and didanosine. Average CD4 T-cell counts rose from 390 to 505 cells per cubic millimeter after six months of treatment and then dropped to 383 cells per cubic millimeter by 12 months. However, copies of HIV RNA, as measured by PCR, fell from 2,170 copies per millimeter to an undetectable level by one month and remained undetectable after one year. PCR is a simple, cheap procedure and has the added benefit of permitting evaluation in asymptomatic patients.

Vaginal spermicides have microbicidal properties that suggest their usefulness in helping to protect against human immunodeficiency virus (HIV) and other sexually transmitted infections. Laboratory, animal, and clinical investigations also support this notion. Because of the importance of identifying additional methods to protect against these infections, however, better information is needed on these female-controlled methods. A consistent set of laboratory standards is needed to evaluate the in vitro activity of existing and future virucides. Further evaluation of such areas as the actions of virucides and vehicles on different anatomical sites and safety studies to better judge determinants of toxicity are needed. Clinical studies might compare efficacy of spermicides and condoms in prevention of HIV and other sexually transmitted diseases as well as investigate psychosocial considerations that determine suitable candidates for vaginal virucides, how they are used, and how their use might be improved., Vaginal spermicides may help prevent HIV infection and other types of sexually transmitted diseases in women. These preparations are antiseptics with virucidal properties, or the ability to kill different types of viruses. Vaginal spermicides that are used in different contraceptive products include nonoxynol-9, octoxynol-9, benzalkonium chloride and menfegol. They are used in many different forms including foams, jellies, creams, sponges, suppositories and as a coating for condoms. Research studies have found that spermicides have activity against HIV and herpes simplex virus types 1 and 2. They also have activity against the bacteria that cause gonorrhea and syphilis. Their effectiveness in preventing Chlamydia infections is still questionable. Vaginal spermicides offer women a method of protection from infection that can be used independently of their partner.

Antiviral products for non-HIV infections are growing in number and range of uses. Are you up-to-date on the current indications for the new drugs as well as the more familiar [...]

Results are presented from an ongoing study of the safety and effectiveness of zidovudine (azidothymidine), the only drug currently licensed by the Food and Drug Administration for treating human immunodeficiency virus type 1 (HIV-1) infection, which causes AIDS. The study, started in 1987, involved 886 patients at 12 clinical sites. Eligible patients had AIDS or AIDS-related complex (certain symptoms in a patient who has tested positive for HIV antibodies) and levels of CD4-positive T lymphocytes (a type of white blood cell) that were below 250 per microliter (a measure of the extent to which the immune system has been compromised by the disease). Most patients received 200 milligrams of zidovudine six times daily as an initial dose, and then 100 milligrams six times daily. Thirty-two percent of the patients died during the follow-up period; 12-month survival was 83 percent and 18-month survival was 67 percent. Patients who died early were more likely to have a CD4-positive T cell count of less than 150 per microliter, a hematocrit (reflecting the number of red blood cells) of less than 35, low or moderate functional status, and 60 days or more between the time of diagnosis and the time when zidovudine treatment began. Age, sex, race, weight, mode of HIV transmission, and certain other variables were not associated with survival. Anemia (insufficient number, or impaired function, of red blood cells) was the most common reason zidovudine therapy was temporarily interrupted, and serious anemia was the condition most often associated with shorter survival. Since a control group not being treated with zidovudine was not included, it cannot be said with certainty that zidovudine led to lowering of the hematocrit, but this is likely; however, even patients with serious anemia lived longer when they took zidovudine. This detailed, long-term study shows that zidovudine is tolerated for up to two years by most patients with advanced disease due to HIV infection. (Consumer Summary produced by Reliance Medical Information, Inc.)

Phase I and II clinical studies have been conducted to test the safety and potential activity of the reverse transcriptase inhibitor, dideoxycytidine (ddC), in treating human immunodeficiency virus-1-infected patients. Although ddC appears to be active in combating viral infection, as judged by its ability to decrease human immunodeficiency virus-1 p24 antigen titers and increase the number of CD4.[sup].+ lymphocytes, it is also capable of causing severe peripheral neuropathy in a dose-dependent manner. The studies discussed here indicate that low-dose ddC treatment regimens substantially reduce the toxic side effects of this drug, and yet retain the ability to affect p24 antigen and CD4.[sup].+ lymphocyte levels. These studies also define the window of therapeutic usefulness for ddC, and suggest that both safety and activity can be maintained during long-term, low-dose use of ddC., HIV, the human immunodeficiency virus, can be effectively treated with drugs that inhibit the viral enzyme known as reverse transcriptase, which is essential for the replication, or production, of the HIV virus. One such drug is zidovudine, or AZT. Phase I and II clinical trials, which are the initial human studies of a new drug, are currently underway to test the effectiveness and safety of a recently developed reverse transcriptase inhibitor, dideoxycytidine (ddC), for treating HIV-1 infection. This new antiviral agent is effective against HIV-1 infection, as indicated by decreased levels of the p24 antigen, which is an HIV marker, and by increased levels of CD4+ lymphocytes, which are immune cells that are particularly vulnerable to destruction by HIV. However, ddC treatment has been associated with the occurrence of severe peripheral neuropathy, or nerve disease, which is more likely with increasing doses of ddC. Using lower doses of ddC reduces the incidence of adverse drug effects, and the treatment remains effective at decreasing p24 antigen levels and increasing CD4+ lymphocyte numbers. These early clinical studies have been useful in determining the range of safe and effective doses of ddC for treating HIV infection. In addition, the results suggest that the safety and activity can be retained with long-term, low-dose use of ddC. (Consumer Summary produced by Reliance Medical Information, Inc.)

The safety and activity of several antiretroviral agents are being evaluated for treatment of acquired immunodeficiency syndrome (AIDS) in infants and children. Intermittent oral and intravenous regimens and continuous intravenous infusion of the dideoxynucleoside, 3'-azido-3'-deoxythymidine (zidovudine, AZT), have been shown to be beneficial in improving neurodevelopmental function and growth velocity in pediatric patients with AIDS. AZT, however, is limited by the associated development of neutropenia and anemia, which frequently necessitates transfusions. Another dideoxynucleoside, 2',3'-dideoxycytidine (ddC), also shows theoretical promise in the treatment of the pediatric AIDS population. This agent is not associated with the hematologic toxicity induced by AZT but does produce a painful sensory peripheral neuropathy. Sequential therapy with AZT and ddC may limit the toxic effects associated with the use of these drugs individually. Dideoxyinosine and soluble recombinant CD4 are two newer antiretroviral agents that are under investigation for the management of AIDS in infants and children. The activity of recombinant CD4 in preventing the transplacental transmission of human immunodeficiency virus is also being evaluated., Research is underway to develop new medications effective against the human immunodeficiency virus (HIV), which causes the acquired immunodeficiency syndrome (AIDS). It has been discovered that HIV can be suppressed by agents that inhibit the viral enzyme known as reverse transcriptase, which is essential for the replication, or spread, of the virus within the body. Currently, studies are underway to test the effectiveness and safety of several reverse transcriptase inhibitors in treating AIDS in children and infants. The reverse transcriptase inhibitor zidovudine (AZT) is effective in improving nerve development and function, and the rate of growth, in children and infants with AIDS. But AZT treatment has been associated with the development of neutropenia, which is a decrease in the number of neutrophils (a type of white blood cell), and anemia, which is a reduction in the oxygen-carrying capacity of the blood. A chemically similar reverse transcriptase inhibitor, dideoxycytidine (ddC), may also be effective in treating AIDS among pediatric patients. Although ddC does not cause blood disorders, it was shown to cause painful peripheral neuropathy (nerve disease). Treatment with AZT followed by ddC may reduce the incidence of adverse effects caused by these agents individually. Two newer antiviral agents, dideoxyinosine and soluble recombinant CD4, are currently being tested for their activity against HIV in infants and children. The ability of recombinant CD4 to prevent the transmission of HIV from mother to child during pregnancy is also being investigated. (Consumer Summary produced by Reliance Medical Information, Inc.)

The incidence of acquired immunodeficiency syndrome and the number of people infected with the human immunodeficiency virus (HIV) is likely to increase into the 1990s and perhaps beyond. Zidovudine, a 2',3'-dideoxynucleoside approved for the treatment of acquired immunodeficiency syndrome, provides immunologic, virologic, and survival benefits. However, because its hematologic toxicity can be dose-limiting, investigations are ongoing with other 2',3'-dideoxynucleosides. After zidovudine, the first of these agents to be tested was 2',3'-dideoxycytidine (ddC), the most potent inhibitor of HIV reverse transcriptase among the dideoxynucleosides tested thus far. Concentrations of ddC as low as 0.5 [micro]M provide protection against HIV in cultured T cells (and monocytes), even at high multiplicities of infection. Like the other dideoxynucleosides, activation of ddC is dependent on intracellular phosphorylation to its 5'- triphosphate form. Efforts are under way to alter enzymatically the intracellular ratio of ddC-5'-triphosphate to deoxycytidine-5'-triphosphate, its endogenous counterpart. ddC has relatively straightforward pharmacokinetics; it has a plasma half-life of about 1.2 hours and an oral bioavailability of about 87 percent. Approximately 75 percent of the drug is excreted unchanged in the urine. Patients treated with ddC have experienced both immunologic and virologic benefit, although long-term high doses are limited by the development of painful peripheral neuropathy. Significant hematologic toxicity is not evident in most patients; low-dose regimens of ddC alone, as well as alternating or in combination with zidovudine, are being tested in an effort to retain antiviral activity while minimizing treatment toxicities., The incidence of acquired immunodeficiency syndrome (AIDS) and infection by the human immunodeficiency virus (HIV), which causes AIDS, is increasing. HIV can be suppressed by agents that inhibit the viral enzyme called reverse transcriptase, which is essential for the replication, or production, of the virus. One of the first reverse transcriptase inhibitors was zidovudine (AZT), which has been shown to suppress HIV infection and prolong the life of patients with AIDS or AIDS-related complex (ARC). However, AZT causes myelosuppression, the inhibition of bone marrow function, and its widespread use has resulted in the development of HIV strains that are resistant to its effects. A more recently developed antiviral agent, 2',3'-dideoxycytidine (ddC), was shown to be a powerful inhibitor of reverse transcriptase. Doses of ddC as low as 0.5 micromoles per liter (uM/L) protect T cells, a type of immune cell that is particularly vulnerable to destruction by HIV. The activation of ddC depends on its phosphorylation, or the addition of a phosphate group, resulting in the formation of its 5'-triphosphate form. Current research is focusing on changing the ratio of ddC-5'-triphosphate to deoxycytidine-5'-triphosphate within the cell. The time taken to eliminate half of the administered dose of ddC is 1.2 hours. After oral ingestion, the bioavailability, or percentage of drug left for therapeutic action, is 87 percent, and 75 percent of ddC is eliminated unchanged in the urine. This new antiviral agent, ddC, was shown to be effective against HIV infection and to improve immune deficiencies, but causes as a side effect painful peripheral nerve disease. The use of lower doses of ddC with or without AZT may decrease toxicities associated with these antiviral agents, and is currently under investigation. (Consumer Summary produced by Reliance Medical Information, Inc.)

Ribavirin is a drug that is effective against various types of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) viruses, including the human immunodeficiency virus (HIV). Adverse effects of ribavirin include central nervous system side effects and anemia. Isoprinosine, a synthetic derivative of the naturally occurring substance inosine, has been shown to improve immune or natural defense system responses in HIV-infected patients. The effectiveness of a combined regimen of ribavirin and isoprinosine was assessed in 15 HIV-infected homosexual men for up to three months; the subjects had no symptoms of HIV infection. The men were divided into groups receiving 4 grams per day of isoprinosine combined with either 800 or 1,200 milligrams per day of ribavirin. Eight minor HIV-related incidents occurred in six patients during the study. The drug combination did not alter blood levels of p24 antigen, a component of the virus that can activate the immune system, nor did it improve suppressed immune responses. Treatment was associated with the development of lymphopenia, a deficiency of lymphocytes, which are immune cells. The results show that isoprinosine combined with ribavirin causes lymphopenia and does not suppress HIV activity or restore immune functions, which are weakened in HIV-infected patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Cytomegalovirus (CMV) infection may cause retinitis or inflammation of the retina, the inner lining of the eye; this is the most common cause of blindness in patients with acquired immunodeficiency syndrome (AIDS). The drug foscarnet was shown to inhibit viral deoxyribonucleic acid (DNA) polymerase, an enzyme involved in the formation of the viral DNA molecule which carries the genetic information of the CMV microorganism. Studies suggest that foscarnet may be effective in preventing the progression of CMV retinitis. The effectiveness of foscarnet was assessed in 17 patients with CMV retinitis. Foscarnet produced a complete response in eight patients, a partial response in eight patients, and no response in one case. The excretion of CMV in the urine was not decreased by foscarnet in 4 of 12 patients, despite improved retinal lesions. Adverse effects of foscarnet included: kidney failure, reflected by increased blood creatinine levels in 50 percent of patients and also the need for dialysis, the artificial filtration of the blood, in two patients; and anemia resulting in the need for blood transfusion in 10 patients. Among seven patients maintained on foscarnet therapy, four suffered recurrence of CMV retinitis, and only one remained in remission for longer than 24 weeks. The drug zidovudine did not worsen the incidence of side effects due to foscarnet use. Thus, foscarnet is effective in suppressing the activity of CMV in retinitis, although the suppression is not maintained. (Consumer Summary produced by Reliance Medical Information, Inc.)

Trizivir, an antiretroviral drug used in treatment of HIV infection is described and evaluated. Trizivir contains three antiretroviral agents, lamivudine, abacavir sulfate and Zidovudine.