Isoprinosine is an immune modulating drug which increases the secretion of the cytokines interleukin-1 and interleukin-2 in vitro and the production of natural killer cells (cells which destroy virally infected and cancerous cells).

It is also known as inosine pranobex or by the tradename Methisoprinol.

Current use

Early laboratory studies of isoprinosine were conducted in cells that were not infected with HIV. Tests in HIV-infected cell lines in vitro have found conflicting evidence as to whether isoprinosine has a direct anti-HIV effect.

One large placebo-controlled study of isoprinosine found no evidence that it delayed disease progression or affected immunological or virological markers. Another study suggested that treatment did delay progression from asymptomatic infection to AIDS, but found no effect on progression to non-AIDS symptomatic disease or on markers such as p24 antigen levels or CD4 count.

Isoprinosine is remarkably free of side-effects and was a popular drug in the treatment `underground' in the USA in the late 1980s but no further reports on its use have been published since 1992.

Use in combinations

Isoprinosine has been used safely in combination with AZT, although there is no evidence that this increases the efficacy of AZT. A study of isoprinosine in combination with ribavirin found no evidence of beneficial immunological or virological effects, but participants experienced a generalised loss of white blood cells, including CD4 cells, which partially recovered one month after the drugs were discontinued.

Getting it

Isoprinosine comes as a crystalline powder which can be partly dissolved in water. It is no longer available from buyers' clubs in the USA.

Key research

Pompidou (1985) reported that isoprinosine (200µg/ml) reduced HIV reverse transcriptase activity in PBL by 48%. However, Hansen reported that in vitro isoprinosine did not inhibit HIV infection at any concentration. Isoprinosine had no effect on the production of infectious virus and did not inhibit syncytia formation in chronically infected H9 cells. Hansen concluded that isoprinosine has no direct effect on HIV in vitro.

Two major double-blind placebo-controlled trials of isoprinosine in HIV-infected subjects have yielded conflicting results.

696 HIV-positive asymptomatic/early ARC people with CD4 counts between 200 and 400/mm³ were enrolled in a multicentre double-blind placebo-controlled USA/UK trial. Patients received isoprinosine 4 g/day by mouth or placebo for 6 months, then all patients received isoprinosine for 6 months. Sztein reported that after 6 months, no effects on virological or immunological markers were seen among the 79 participants at one centre. At another centre Phair also saw no significant immunological or clinical effects. The manufacturer reported that overall, isoprinosine had no effect on disease progression as compared to placebo.

Pedersen (1990b) enrolled 866 HIV-positive asymptomatic/early ARC individuals in a multicentre double-blind placebo-controlled isoprinosine trial in Denmark and Sweden. Patients were randomized to receive isoprinosine 3 g/day by mouth for 6 months or placebo. Of the 833 evaluable subjects, 2/412 (0.5%) isoprinosine-treated patients progressed to AIDS as compared with 17/421 (4%) placebo recipients. However, no difference in progression to symptomatic disease besides AIDS was observed and no difference in the decrease in CD4 cell count or p24 antigenaemia level was detected. In an accompanying editorial, Kweder suggested that a confirmatory trial be conducted before claims of efficacy for isoprinosine are accepted.

Thorsen (1992) reported that 596 participants in the above study continued on open treatment. All patients were evaluated with regard to progression to AIDS and/or death. Within 48 weeks, 10/412 (2.4%) patients assigned isoprinosine and 27/420 (6.4%) patients assigned placebo progressed to AIDS. Intention-to-treat analysis showed identical results. Viewing the open treatment phase in isolation revealed no difference in progression rates between those treated and those not receiving the drug, perhaps reflecting the higher proportion of patients receiving zidovudine or PCP prophylaxis in the latter group. No severe adverse reactions or toxicities were observed.

Teglbjaerg (1992) analysed samples from 642 people who received isoprinosine and 334 who received placebo in the Scandinavian multicentre placebo-controlled isoprinosine study, comparing HIV-antigen levels before and during treatment. During the study 17 placebo recipients progressed to AIDS, compared with 2 treated with isoprinosine. The proportion of HIV-antigen-positive patients who developed AIDS during treatment was significantly higher than the proportion of HIV-antigen-negative patients in whom AIDS developed (6% vs 2%). No significant changes in HIV-antigen levels were observed between the isoprinosine and the placebo-treated group of HIV-antigen-positive patients. Median HIV-antigen levels did not change significantly in either the isoprinosine or the placebo-treated group. The researchers conclude that the lack of effect of isoprinosine on HIV antigen indicates that any beneficial effect of the drug is not the result of a direct antiviral activity against HIV.

De Simone (1989) enrolled 553 people with HIV in a randomised, multicentre trial of isoprinosine (two 500 mg tablets every 6 hours for 3 months) versus no treatment. Isoprinosine was associated with a slightly improved clinical condition or with a trend in that direction, as compared to the untreated group. Treated participants also experienced a preservation of the CD4/CD8 cell ratio values, a decrease in the CD8 cells and an increase in the Leu 2-7+ cell number better than in the untreated individuals. No serious or adverse effects were observed.

Pedersen (1990a) treated 8 HIV-positive, healthy patients with isoprinosine (3 g/day for 28 days); six patients received no treatment but were examined in parallel and two patients were withdrawn. Isoprinosine significantly enhanced the lymphoproliferative response after stimulation with phytohaemagglutinin (PHA) and purified derivative of tuberculin (PPD), while isoprinosine had no effect on the following immune parameters: the expression of surface markers on blood mononuclear cells including CD2, CD3, CD4, CD8, CD14, CD19, CD20, CD25, leu-8 and HLA-DR. Furthermore isoprinosine did not influence the ability of IL-2 to stimulate the proliferation of lymphocytes or the natural killer (NK) cell activity either unstimulated or stimulated in vitro with interferon alfa, IL-2, or indomethacin. Neither did isoprinosine affect the in vitro production of IL-1 alpha or beta, IL-2, IL-6, or tumour necrosis factor.

Grieco administered isoprinosine (4 g/day) to 5 people with AIDS and 4 with ARC. There was no significant association of isoprinosine treatment and CD4/CD8 ratio alterations in either group. In addition, there was no significant enhancement of lymphocyte proliferative responses to mitogens in 5 people with AIDS. However, the mean lymphocyte proliferative responses to phytohaemaglutinin and concanavalin A in patients with ARC increased after 28 days of treatment.

Schulof evaluated the clinical, immunologic and virologic effects of oral treatment with ribavirin and isoprinosine for up to 3 months in asymptomatic, HIV-culture-positive gay men. 15 men received isoprinosine 4 g/day and 800 mg/day (9 men) or 1200 mg/day (6 men) of ribavirin. Five men in each ribavirin dosage group completed at least 2 months of treatment. No unexpected toxicities were observed. Eight minor HIV-related events occurred in six men while on study. All men remained HIV-positive and time to positive culture decreased by at least 4 days in three men from each treatment group. Serum p24 levels did not change in two men who were p24 antigenaemic and received 800 mg/day of ribavirin. Treatment was associated with a generalized lymphopenia affecting all lymphocyte subsets including CD4, which was partially reversible 1 month after stopping treatment. Most of the men remained anergic on DTHS skin testing. No improvements were noted in in vitro lymphoproliferative responses to antigens or in NK cell activity (which decreased significantly in the 1,200 mg/day ribavirin group). Although well tolerated at the doses employed, the combination of ribavirin and isoprinosine produced an unexpected generalized lymphopenia and did not exhibit HIV-suppressive or immunorestorative effects.

References

De Simone C et al. Clinical and immunological assessment in HIV+ subjects receiving inosine-pranobex. A randomised, multicentric study. Med Oncol Tumor Pharmacother 6(1):63-67, 1989.

Grieco MH et al. In-vivo immunomodulation by isoprinosine in patients with the acquired immunodeficiency syndrome and related complexes. Ann Int Med 101(2):206-207, 1984.

Hansen J-E et al. No effect of isoprinosine on HIV infection in vitro (letter). AIDS 4:1033-1042, 1990.

Kweder SL et al. Inosine pranobex - is a single positive trial enough? NEJM 322(25):1807-1809, 1990.

Pedersen BK et al. Effects of isoprinosine treatment of HIV-positive patients on blood mononuclear cell subsets, NK- and T-cell function, tumour necrosis factor, and interleukins 1, 2, and 6. Scand J Immunol 32(6):641-649, 1990.

Pedersen C et al. The efficacy of inosine pranobex in preventing the acquired immunodeficiency syndrome in patients with human immunodeficiency virus infection. NEJM 322(25):1757-1763, 1990a

Phair J. Inosine pranobex therapy in HIV seropositive patients at risk of developing AIDS. 5th Intl Conf AIDS, Montreal, abstract WBP 313, 1989b.

Pompidou A et al. In-vitro inhibition of LAV/HTLV-III infected lymphocytes by dithiocarb and inosine pranobex (letter). Lancet ii(8469/70):1423, 1985.

Schulof RS et al. Clinical, virologic, and immunologic effects of combination therapy with ribavirin and isoprinosine in HIV-infected homosexual men. JAIDS 3(5):485-492, 1990.

Sztein M et al. Immunologic and virologic parameters in 100 HIV-infected patients (PTS) treated with isoprinosine (ISO) or placebo (PLB) as part of a multicenter phase III clinical trial. 5th Intl Conf AIDS, Montreal, abstract WBP 308, 1989.

Teglbjaerg L et al. Effect of isoprinosine on HIV antigenaemia. AIDS 6:199-201, 1992.

Thorsen S et al. One-year follow-up on the safety and efficacy of isoprinosine for human immunodeficiency virus infection. J Intern Med 231(6):607-615, 1992.