CROI: Tenofovir microbicide stops rectal infection in monkeys better than PrEP

Gus Cairns, Michael Carter
Published: 27 February 2007

Two-thirds of monkeys treated with a tenofovir-containing rectal microbicide were protected from repeated rectal challenge with a pathogenic variety of SIV, the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles heard on Monday.

This rate of protection is an improvement on a previous study where oral tenofovir pre-exposure prophylaxis delayed but did not prevent infection in rectally-challenged monkeys.

However another poster at the conference (Garcia-Lerma) demonstrated that complete protection was possible using injected tenofovir and FTC and that oral tenofovir/FTC was as effective as the microbicide formulation.

Furthermore, a second poster analysing the six ‘breakthrough’ infections in this study found that monkeys that had become infected despite receiving PrEP developed viral loads that were, and continued to be 2 logs (100-fold) lower than control animals, indicating that PrEP could have a disease-modulating effect even if it does not stop infection.

Protective effect of PrEP is dose-dependent

In the second study of antiretroviral chemoprophylaxis, the team of investigators led by Walid Heneine, who presented a study using tenofovir and FTC as PrEP at last year’s CROI, gave three versions of PrEP to 18 monkeys.

They used larger concentrations of the drug(s) than in the microbicide study – 20mg/kg of FTC and 22mg/kg of tenofovir but also used a more pathogenic challenge virus, the artificially-created SHIVsf162p3 human/monkey chimeric virus.

Six monkeys were given daily subcutaneous injections of FTC along; six were given oral tenofovir/FTC; and six were given subcutaneous injections of tenofovir and FTC. Eighteen control monkeys were not given any treatment.

Seventeen out of the 18 control monkeys were infected, 50% of them after just two challenges and over 75% after eight.

In contrast all six given the subcutaneous FTC/tenofovir were protected from infection, meaning that there was no infection after 14 weekly viral challenges and a washout period of another four weeks. “This shows that full protection against rectal challenge is possible”, say the investigators, though clearly daily subcutaneous injections are never likely to be a practical form of PrEP.

Four out of the six (67%) given oral tenofovir plus FTC were protected from infection but just two out of the six given subcutaneous FTC.

Of the two monkeys (33%) given oral tenofovir/FTC that were infected, one was infected after nine challenges and one after 12. Of the four given subcutaneous FTC that were infected, one infection each occurred at weeks five, ten, twelve and 13. (In the study of oral tenofovir presented two tears ago, three out of four monkeys were infected by week nine.)

Thus the protection rate offered by oral ‘combination PrEP’ in this study was the same as that offered by a tenofovir-alone microbicide in the other one.

Tenofovir microbicide protects two-thirds of monkeys

The study of a tenofovir-containing microbicide gel (dosed at 1mg/kg body weight) was a placebo-controlled study that tested the efficacy of the microbicide at three intervals relative to rectal challenge with SIV - two hours or 15 minutes before or two hours afterwards.

Twenty monkeys were used in the study. Six were given the gel 15 minutes before challenge, three two hours before, and three two hours after. In addition four were given a placebo gel 15 minutes before rectal SIV challenge, while four were challenged with SIV but given no other treatment. The investigators used SIVmac32H, a ‘reasonably pathogenic’ monkey virus, as challenge.

Six of the nine monkeys given tenofovir gel before challenge (67% - four of the six dosed 15 minutes before and two of the three dosed two hours before) were protected from infection, meaning that evidence of viral infection was detected in lymphoid tissues tested 20 weeks after challenge. One of the three monkeys given the gel two hours after challenge was also protected, but this 33% rate of protection was not seen as significant by the investigators.

Three of the four macaques that received the placebo, became infected with SIV and all four of the untreated monkeys.

An immune response to the gag protein of SIV was observed in four of the seven monkeys protected from infection by the microbicide; in other words they became exposed seronegatives, having ‘seen’ the virus without becoming infected.

Partial protection, consisting of intermittent detection of SIV which gradually decayed, was observed in two of the other macaques treated with the gel before viral exposure.

One intriguing aspect of the study was that the degree of protection offered by the gel correlated with plasma tenofovir levels – despite the fact that systemic penetration is not seen as desirable in microbicides. The four given tenofovir gel 15 minutes before challenge that were not infected had plasma tenofovir levels over 119 nanograms per millilitre (ng/ml); the two that were not protected in this group had tenofovir levels below 74 ng/ml.

‘Unsuccessful’ PrEP lowers viral load

One of the most interesting aspects of this study, however was that, as with the tenofovir microbicide, the viral load in the monkeys that had ‘breakthrough’ infections despite PrEP were lower than those given no treatment. In fact from the start of infection, the mean viral loads in the breakthrough infections were at least two logs (100-fold) lower than those in the challenged and untreated monkeys. Peak viremia in untreated monkeys was eight million and had declined to 80,000 by eight weeks after infection, reaching a ‘set point’ by week ten. In contrast peak viremia in the ‘breakthrough’ monkeys was 80,000 and had declined to just 315 by week eight.

This offers the prospect that even PrEP that is unsuccessful at preventing infection could limit subsequent viral load enough to prevent or considerably delay progression to AIDS.

Martin Cranage, presenter of the microbicide study, commented: “traditionally, the fields of vaccines and microbicides have run parallel. We may be seeing them begin to draw together.”

PrEP of moderate efficacy could cut infections by a quarter

In another presentation, investigators from Imperial College, London, and the University of Pittsburgh (Abbas) developed a mathematical model to determine the potential of PrEP to avert new HIV infections in resource limited settings.

Factors included in the model were the effectiveness of PrEP, the proportion of the population taking PrEP, the proportion of individuals who stopped taking PrEP, HIV drug resistance as a result of PrEP use, and the extent to which the use of PrEP lead to an increase in sexual activity involving a risk of HIV transmission.

The most optimistic scenario, with PrEP being 90% effective, and taken by 75% of the population, would, the investigators calculated, lead to a 74% drop in new HIV infections over ten years.

A more realistic scenario, however, with PrEP of 60% efficacy, would lead to a 25% drop in infections over the same time period.

When the model was modified to assume the same level of effectiveness, but use by only the most sexually active groups (16% of the population in the initial model), the percentage of number HIV infections averted would drop by 29% if PrEP was 90% effective and only 7% if it was 60% effective. However because fewer people would have to receive PrEP the cost per infection averted in the ‘optimistic’ scenario would drop from $6812 to $638 for tenofovir alone and $974 for tenofovir/FTC.

In terms of a possible disinhibiting effect on behaviour if PrEP was introduced, it was calculated that if the number of risky sexual encounters doubled, the number of infections would actually increase if PrEP was less than 50% effective.

References

Cranage M et al. Pre-exposure prophylaxis in macaques against rectal SIV challenge by mucosally applied PMPA: potential for complementation of microbicide and vaccination strategies. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 29, 2007.

Garcia-Lerma JG et al. Higher ARV drug potency correlates with increased protection against rectal SHIV transmission. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 986, 2007.

Garcia-Lerma JG et al. Blunted viremia in macaques failing chemoprophylaxis with FTC or FTC/TDF combination. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 985, 2007.

Abbas U et al. Potential effect of ARV chemoprophylaxis on HIV-1 transmission in resource-poor settings. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 32, 2007.

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