Ampligen is a synthetic RNA molecule. Test tube studies showed that it stimulates the cellular immune system by encouraging interferon production and activating natural killer cells.

Ampligen and AZT (zidovudine, Retrovir) are synergistic in test tube studies.

The manufacturer reports that ampligen treatment in conjunction with AZT may switch immune responses from a Th2 type, characterised by humoral immune responses such as the production of antibodies, to a Th1 type, characterised by cell-mediated immune responses.

Ampligen is manufactured by HemispheRx Biopharma under the tradename Atvogen.

Current use

Ampligen is an unlicensed, experimental drug. Phase I studies of ampligen have produced conflicting results. One trial in ten people suggested that the drug reduced levels of HIV in the blood and stabilised or increased CD4 cell counts, while another study in 39 people found no evidence of any anti-HIV effects, but stabilisation of CD4 cell counts at higher dose levels. A new trial was started in Texas in 1997, studying ampligen's effect on HIV viral load in HIV-positive people with CD4 cell counts greater than 400 cells/mm³ who are not receiving any other anti-HIV drugs.

In October 1988 a large-scale phase III clinical trial was halted after at least as many ampligen recipients as placebo recipients progressed from AIDS-related complex to AIDS. The manufacturer subsequently claimed that this was because the drug interacted with the plastic bags it was stored in. A small trial in 1991 did suggest that the drug stored in glass ampoules might have beneficial effects on the CD4 cell count.

Side-effects of the drug are minimal, but may include mild, transient, flu-like symptoms, flushing, chest tightness, transient neutropenia and malaise.

Retrogen is a similar drug with efficacy in test tube, which has not yet been tested in animals.

An oral form of ampligen called Oragen has been developed. Tests in mice suggest that it is effective against the mouse hepatitis virus.

Use in combinations

Trials of the combination of ampligen and AZT have not yet produced any definitive results, although in the test tube the combination seems to be very effective against strains of HIV that have developed resistance to AZT.

Getting it

Ampligen is only available through clinical trials, but none is currently taking place in the United Kingdom.

Key research

Ampligen is a mismatched, double-stranded RNA molecule. It is a polynucleotide derivative of poly I - poly C with occasional uracil residues to provide RNase cleavage sites. Mitchell reported that in vitro ampligen and AZT are synergistic.

Montefiori reported that pre-treatment with ampligen (10-50 µg/ml) afforded significant protection against subsequent HIV infection to the highly HIV-permissive T-cell line C3 and to the T-lymphoblastoid cell line CEM in vitro. Antiviral activity was increased by the continued presence of ampligen in cultures following virus challenge. A one-time exposure to ampligen (50 µg/ml) provided greater antiviral activity than either a one-time exposure to recombinant IFN-alpha (250 international units/ml), IFN-beta (250 IU/ml), or IFN-gamma (50 IU/ml) in cultures of CEM cells, or a one-time exposure to a combination of all three IFNs (150 IU each per ml) in cultures of C3 cells. Ampligen had no effect on cell division, RNA and protein synthesis, or virus replication in all T-cell lines examined.

Hendrix conducted a randomized, double-blind, cross-over study in four healthy volunteers in which participants received either ampligen (single 200mg intravenous dose) or placebo for seven days each. No clinical, immunologic or laboratory effects were noted.

Carter treated ten people with ARC or AIDS with ampligen. A reduction in HIV RNA in peripheral blood mononuclear cells, a reduction of HIV load as measured by co-culture, an increase in or maintenance of the number of CD4 cells and augmentation of delayed-type skin hypersensitivity reactions were observed. No toxic reactions were reported.

Armstrong enrolled 39 people with asymptomatic HIV infection or early ARC and CD4 counts below 500 in a phase Ia/Ib open-label trial (ACTG 038). Participants received ampligen (10mg, 40mg, 120mg, 270mg, 405mg or 570mg/m²) intravenously twice a week for 9 to 25 weeks. No significant anti-HIV effect could be detected by virological tests. Participants who received the two lower doses had a significant decline in their CD4 count, but in those receiving higher doses (more than 120mg/m² intravenously twice a week) no significant CD4 decline occurred which was dose related.

A multicentre double-blind placebo-controlled Phase III study known as AMP101 was halted after 20 participants with ARC progressed to AIDS, 12 of whom were receiving ampligen. The manufacturer subsequently claimed that the plastic bags in which ampligen was stored during this study caused structural changes in the drug.

Strayer (1990) treated 20 people with ARC or pre-ARC (mean CD4 count 196) with Ampligen formulated in glass bottles (100-200mg intravenously twice weekly) for 4.5-36 months. 1/20 developed an OI after 16 months. The frequency of OIs was compared to a similar cohort of ARC/pre-ARC patients who received placebo in a multicentre study of ampligen (AMP101, above). Ampligen increased time to OI, decreased p24 and increased CD4 count compared to placebo. In contrast similar patients receiving ampligen formulated in plastic IV bags developed OI at a rate no different from placebo recipients. Physiochemical studies showed that the plastic bag formulation yielded a drug with a higher sedimentation value, shorter RNase resistant cores and reduced ability to activate 2'-5' oligoadenylate synthetase, suggesting that the similar progression rates in the placebo and ampligen arms in the AMP101 study was related to structural changes in ampligen upon exposure to plastic bags.

Strayer (1993) assigned 16 AZT-treated people with CD4 counts between 300 and 500 to receive intravenous infusions of ampligen (400 or 700mg twice weekly) or placebo. One ampligen recipient and 4 placebo recipients progressed to AIDS during the 48 week course of the study.

Hendrix reported that a single 200mg intravenous injection of ampligen had no immunological effects.

References

Armstrong JA et al. A phase I study of ampligen in human immunodeficiency virus-infected subjects. JID 166(4): 717-722, 1992.

Carter W et al. Clinical, immunological, and virological effects of Ampligen, a mismatched double-stranded RNA, in patients with AIDS or AIDS-related complex. Lancet i:1286-1292, 1987.

Hendrix C et al. Immunologic effect after single dose atvogen (ampligen) in healthy volunteers. Fifth International Conference AIDS, Montreal, abstract MCP 85, 1989.

Mitchell WM et al. Mismatched double-stranded RNA (ampligen) reduces concentration of zidovudine (azidothymidine) required for in vitro inhibition of human immunodeficiency virus. Lancet (8538): 890-892, 1987.

Montefiori DC et al. Antiviral activity of a mismatched double-stranded RNA (Ampligen) against human immunodeficiency virus in vitro. PNAS 84: 2985-2989, 1987.

Strayer DR et al. Improvement in T4 level and decrease in opportunistic infections and lymphomas (OI/L) in ARC/pre-ARC patients (T4=60-300) receiving ampligen compared to placebo. 6th International Conference AIDS, San Francisco, abstract SB 490, 1990.

Strayer D et al. Placebo (Pla) controlled study of ampligen (AMP) in HIV disease: inhibition of progression to category C HIV infection (AIDS). First National Conference on Human Retroviruses, Washington, abstract 117, 1993.