PrEP clinical trials cut short for “futility”

Also: Truvada under fire as early as 2005

All emphasis added by me.

We’ve talked a lot here about the phenomenon, which really spiraled out of control in the early days of AIDS, of researchers cutting clinical trials short because it was considered “unethical” to continue with a placebo. In these cases, the drugs were fast tracked, and the results of the trials themselves excitedly published, regardless of what horrible adverse effects became obvious over time.

One phenomenon we don’t hear much about is the cases in which a clinical trial is abandoned for what is termed “futility”—in other words, the preliminary results were so bad that the trials were aborted and the results largely left unpublished. What implications do these largely unpublished results have for the state of the science regarding these trials?

As we already know, HIV vaccine trials have a long history of being cut short for futility. There are more than ninety such failed trials. Here are just a few examples.

HIV vaccine trials: lessons learned and the way forward (2010)

This one is really interesting because they note that one trial actually showed that the vaccine “might have increased the risk of acquisition of HIV in MSM.”

An effective HIV vaccine is a global health priority. We describe lessons learned from four HIV vaccine trials that failed to demonstrate efficacy and one that showed modest protection as a pathway forward.

The Merck Ad5 phase IIb T-cell vaccine failed to show efficacy and might have increased the risk of HIV acquisition in MSM. While VaxGen gp120 alone was not efficacious in groups at high risk for HIV-1 infection, the RV144 ALVAC prime and gp120 boost regimen showed 31% efficacy in low incidence heterosexuals. All trials demonstrated the limitations of available laboratory and animal models to both assess relevant vaccine-induced immune responses and to predict clinical trial outcome. Analysis of innate and adaptive responses induced in RV 144 will guide future trial design.

Here’s another one:

Major HIV vaccine trial fails (2023)

The only HIV vaccine in a late-stage trial has failed, researchers announced Wednesday, dealing a significant blow to the effort to control the global HIV epidemic and adding to a decadeslong roster of failed attempts.

Known as Mosaico, the trial was the product of a public-private partnership including the U.S. government and the pharmaceutical giant Janssen. It was run out of eight nations in Europe and the Americas, including the U.S., starting in 2019. Researchers enrolled nearly 3,900 men who have sex with men and transgender people, all deemed at substantial risk of HIV.

And here’s the money quote:

Mosaico was particularly challenging to design ethically because of the advent of PrEP, which was first approved in the U.S. in 2012. To prove a vaccine works, researchers must recruit participants who remain at substantial risk of HIV over time. So Mosaico first offered PrEP to those seeking to enroll in the trial and only accepted as participants those who adamantly declined the preventive therapy notwithstanding their risk of HIV.

Yet another trial cut short:

HIV vaccine trial ends in “deep disappointment” (2020)

An analysis of the study showed no significant difference in subsequent HIV infections among the volunteers in the vaccine group versus placebo group. According to NIAID, 129 HIV infections occurred among the vaccine recipients and 123 HIV infections occurred among the placebo recipients. NIAID said that those study participants are being informed of the trial stopping and researchers will continue to follow study participants over time.

These results are certainly underwhelming.

Finally, here’s one last article, The hunt for an AIDS vaccine approaches 40 with hope and caution (2022), which contains all the predictable spin, including lauding the fast tracked Covid vaccines as some sort of medical miracle.

“HIV is a wily virus,” says Dagna Laufer, MD, vice president of clinical development at IAVI, a New York-based nonprofit scientific research organization that develops vaccines and antibodies.

Ah yes, the anthropomorphization of HIV, ascribing to it genius level intellect and the strategic skills of a psychopath. The piece continues on in this vein, attributing to a tiny retrovirus truly mind boggling skills of evasion and camouflage, and it ends with the hope that mRNA technology might be the savior of the apparently near doomed HIV vaccine.

There are many such trials that have failed, but let’s move on.

Given that so many HIV vaccine trials—all of them, so far, among those whose outcomes have been resolved—have failed, one might ask what the state of affairs is regarding the fake vaccines, or PrEP. I’m glad you asked.

It turns out there are more than a few trials for PrEP that have been aborted for “futility.” Consider the paper published in Clin. Investigation (Lond) in 2013, HIV PrEP Trials: The road to success. Here is the abstract:

The global HIV epidemic cannot be controlled by current treatment or prevention strategies. Pre-exposure prophylaxis (PrEP) using antiretrovirals is a promising approach to curbing the spread of HIV transmission. Recently, four clinical trials demonstrated favorable results when antiretroviral PrEP was administered topically or orally. However, two additional trials were unable to demonstrate a benefit, indicating that further study is required to define the populations and conditions under which PrEP will be effective. Adherence is highly correlated with protection, yet the exact level of adherence required is unknown. Future studies may require increased drug exposure testing and more objective methods to monitor adherence in real-time. Although the development of drug resistance in the PrEP trials has been low, it remains a concern, as therapeutic options could be compromised for those who seroconvert while on PrEP.

So, we have one third of the trials being abandoned for “being unable to demonstrate a benefit.” And as a mathematician, I really love the sentence “Adherence is highly correlated with protection, yet the exact level of adherence required is unknown.” Translated this means “the variables scatter in a way that might have a pattern.” Correlated in what way? One assumes they mean linearly, but in that case there ought to be a clear correlation as well between levels of adherence and levels of “protection.”

There are more trials for PrEP drugs that have been cut short for futility, as well as vaccine trials.

PrEP ineffective for women?

A clinical trial investigating the use of pre-exposure prophylaxis (PrEP) to prevent HIV infection among women has been canceled after early results suggested the approach would be ineffective, according to a statement issued by FHI, which implemented the study.

[…]

In the meantime, these findings are likely to make clinicians much more reluctant to prescribe Truvada to HIV-negative women at potentially high risk for HIV. Those who have been skeptical about the widespread use of PrEP will likely welcome this news; some feel the medical community has been too quick to embrace PrEP without fully accounting for its potential downsides. But you can't help but mourn this potentially major setback for PrEP, which, just a couple of months ago, seemed like it might be a promising new tool for women who may not have the option of using condoms with their male sexual partner.

Whatever you do, don’t ever say anything bad about PrEP. Never, you heathen. PrEP is good even when it’s deadly. That’s one commandment of the church of HIV AIDS.

There are more, but I will end with this extremely interesting article.

The abandoned trials of pre-exposure prophylaxis for HIV: what went wrong? (2005)

Read this carefully, because it is very relevant.

New approaches to HIV/AIDS prevention are urgently needed to stem the estimated 5 million new infections that occur worldwide each year. One such promising, novel intervention has been the proposed use of the oral antiretroviral drug tenofovir (Viread) as a pre-exposure prophylaxis (PREP) in high-risk groups (for example, uninfected women who have high-risk commercial sex). However, emerging opposition has halted the progress of at least two important clinical trials of tenofovir as PREP and brought negative attention to tenofovir, somewhat similar to that visited on thalidomide more than four decades ago. This could prove damaging in the long term.

(Tenofovir is an active ingredient in Truvada and Viread.)

The “negative attention” brought to tenofovir was not limited to adverse effects of the medication but also to patient protocols that were ethically dubious. (Is it any surprise that participants are treated poorly in such trials?) I find the phrase they use to describe the “negative attention” brought to tenofovir as “similar to that visited on thalidomide more than four decades ago” extremely—perhaps unwittingly—telling. This statement was perhaps much more accurate than its writer may have imagined. Regardless, unethical clinical trial practices are endemic to “HIV research.”

The dramatic protest against the Cambodian trial at the XV International AIDS Conference in Bangkok, Thailand, caught the world's media attention [2] and brought tenofovir to the forefront of the public's attention (Figures 1 and ​and2).2). The primary reasons cited for the demonstrations included alleged inadequate prevention counseling by the study investigators, a lack of pre- and post-test HIV counseling, and the nonprovision of medical services and insurance for those who seroconverted during the study or experienced adverse events related to the trial drug [3]. Participant activist groups also argue that the safety of tenofovir for long-term use by individuals who are HIV negative has not been established, and that there was limited involvement of the target communities in the trial design [1,3,4]. The activist groups representing the participants argue that the participants take all of the risks and get little of the benefits.

Finally, from the abstract:

If tenofovir is someday proven to be clinically efficacious as a PREP, today's irresponsible reporting and activism surrounding tenofovir could cause those in need to snub the drug if, or when, it becomes licensed for use as a PREP. This unfortunate prospect raises questions about responsible media reporting, responsible conduct on the part of investigators and activists, and what should be done to avert or repair damaging trial-related disputes in the future.

Talk about foreshadowing. This study was published in 2005, fully six years before PrEP was approved and well before the Truvada atrocities became widely known. And I don’t know what to say about the creepy conclusion, that all but demands censorship for a drug that was under fire as long as eighteen years ago and continues to be so to this day.

These are only a few of the trials for so called “HIV preventatives” that have failed, sometimes in a spectacular manner. Given the less than stellar results of the clinical trials that do survive and make it to publication (PrEP is nowhere close to 99% effective in the literature), the fact that so many more such trials didn’t even make it out of the gate ought to ring some alarm bells. Perhaps the reason so many HIV drug and vaccine trials fail is because the HIV AIDS story is a lie, and perhaps we ought to be taking a good hard look at that probability.

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In The Real AIDS Epidemic, I present an analysis of data that falsify the HIV/AIDS hypothesis and warn about the toxic drugs being given to people in the name of that falsified HIV/AIDS hypothesis. In the afterword, I offer constructive suggestions for a paradigm shift in AIDS research and treatment that emphasize the recognition of the massive Non-HIV AIDS epidemic in the general population.

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