CROI: Successful PREP trial in monkeys sparks call for more research

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A successful trial of ‘combination pre-exposure prophylaxis’ (PREP) in monkeys using tenofovir (Viread) and FTC (emtricitabine, Emtriva) has resulted in community advocates calling for more studies to see how the concept might be applied to humans.

Researchers from the Centers for Disease Control (CDC) in the United States successfully protected monkeys from repeated rectal challenges with SHIV (a recombinant human/monkey immunodeficiency virus), the Thirteenth Conference on Retroviruses and Opportunistic Infections heard.

Dr Walid Heneine and colleagues gave six out of twelve rhesus macaques daily subcutaneous injections of 22mg/kg of tenofovir and 20mg/kg FTC. After a nine-day lead-in period they then started challenging the monkeys, plus another six control animals who did not receive PREP, with weekly rectal inoculations containing 380,000 viral particles, equivalent to the highest seminal viral loads seen in acute infection.

Glossary

rectum

The last part of the large intestine just above the anus.

equivalence trial

A clinical trial which aims to demonstrate that a new treatment is no better or worse than an existing treatment. While the two drugs may have similar results in terms of virological response, the new drug may have fewer side-effects, be cheaper or have other advantages. 

plasma

The fluid portion of the blood.

acute infection

The very first few weeks of infection, until the body has created antibodies against the infection. During acute HIV infection, HIV is highly infectious because the virus is multiplying at a very rapid rate. The symptoms of acute HIV infection can include fever, rash, chills, headache, fatigue, nausea, diarrhoea, sore throat, night sweats, appetite loss, mouth ulcers, swollen lymph nodes, muscle and joint aches – all of them symptoms of an acute inflammation (immune reaction).

simian human immunodeficiency virus (SHIV)

An artificial form of HIV adapted to cause infection and disease in monkeys. It combines elements of a virus that affects monkeys (SIV) with the envelope protein of HIV itself. Researchers study SHIV as a way to learn more about HIV.

The plasma level of tenofovir achieved was somewhat higher than that seen in a therapeutic dose in humans, but the FTC levels were equivalent to the therapeutic dose, the conference heard.

Four out of six control animals became infected after four challenges while a fifth became infected after 14 challenges. In contrast none of the animals given tenofovir and FTC became infected within 14 challenges. The researchers also repeated the experiment using FTC alone. In this case one animal out of six given FTC became infected after five challenges and another after ten. In contrast 14 out of 14 control animals became infected in the same time period.

The results from this trial are superior to results announced at last year’s retrovirus conference (Subbarao), where four out of four animals given tenofovir alone were infected after 14 weeks of challenge with SHIV.

Dr Heneine told aidsmap that although the rectal challenge model was intended to mimic human sexual exposure, the unusual method of drug administration by subcutaneous injection was designed primarily to achieve predictable levels of the antiretrovirals in plasma. “This is a proof-of-concept study and was not intended to imitate what might happen in humans,” he said.

“It was established in the early 1990s that two drugs offered more protection against progression to AIDS than one, but the same has never been established for protection against infection.” He added that the CDC intended to conduct further animal trials which more closely mimicked oral dosing in humans.

He also criticised interpretations of PREP trials that viewed any infection of treated animals as a ‘failure’ of the concept. “Unless you have an intervention that is 100% effective, all treated animals will eventually be infected if you repeat challenges,” he said.

“But the fact is that animals treated with FTC alone needed seven times the amount of viral challenge than the control animals in order to get infected, and presumably considerably more with both drugs.”

One concern often expressed about single-drug PREP is that if it fails to prevent infection, drug resistance might develop rapidly and widescale PREP might ‘seed’ previously rare mutations in the population.

A poster by the same team of researchers underlined some of these fears. The signature resistance mutation to tenofovir is K65R, which also confers resistance to many other NRTIs. However it has not arisen very frequently in tenofovir-treated patients and had not badly affected viral resistance, so it was thought it might only appear slowly in patients ‘accidentally’ given tenofovir monotherapy.

However, Heneine’s team found that out of eleven SIV-infected monkeys given a high (30mg/kg) dose of tenofovir, the K65R mutation appeared within a week in four animals.

In four others it appeared by six weeks of treatment and in the other three by week nine, despite an interruption of tenofovir treatment.

These resistance data will underline caution about using PREP. However the concept, which has previously aroused opposition among AIDS activists questioning the ethics of PREP trials, received backing from one US prevention advocacy group.

The US Community HIV/AIDS Mobilisation Project (CHAMP) issued a press release urging more studies of PREP in both animals and humans. They said: “We are concerned that PREP research utilising tenofovir has not yet developed a community constituency. We must swiftly and ethically answer the question: does tenofovir PREP work?”

CHAMP called for a full panel of trials with the statistical power to answer questions about the safety and efficacy of PREP “in various populations and with respect to various modes of transmission.”

References

Garcia-Lerma J et al. Prevention of rectal SHIV transmission in macaques by tenofovir/FTC combination. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 32LB, 2006.

Johnson J. Rapid emergence of drug-resistant SIV in tenofovir-treated macaques: implications for tenofovir prophylaxis against HIV. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 609, 2006.

Subbarao S. Chemoprophylaxis with oral tenofovir dispropoxil fumarate delays but does not prevent infection in rhesus macaques given repeated rectal challenges of SHIV. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 136LB, 2005.