July 26th, 2023

REPRIEVE Trial Highlights Shift in HIV Care from ID to General Medicine

Australian White Ibis. Not an exotic bird in Brisbane!

The biggest news this week at the 12th IAS Conference on HIV Science here in Brisbane, Australia, was the results of REPRIEVE, a large randomized clinical trial conducted in people with HIV.

It’s not a study of novel antiretroviral regimens, or of treatment or prevention of opportunistic infections, or of an HIV eradication strategy using latency-reversing agents or immunotherapy.

Nope — it’s a study of cardiovascular prevention with an exotic class of drugs called statins.

(Sarcasm alert.)

That’s right, statins. As noted here several years ago, REPRIEVE recruited stable people with HIV age 40 or older, on ART, and at low to moderate risk of cardiovascular disease — people for whom a statin would generally not be prescribed. Since HIV confers up to a 2-fold increased risk of CVD compared to people without HIV, the hypothesis was that a statin would reduce the risk of a major adverse cardiovascular event compared to placebo.

The drug chosen was pitavastatin, since it doesn’t interact with any ART regimen. 7769 people enrolled at study sites throughout the world, with diverse demographics and broad geographic representation. It was a “simple” (nothing this size is really simple) study design, with randomization to pitavastatin or matching placebo.

After a median follow-up of approximately 5 years, the data and safety monitoring board overseeing the study stopped the study early because of a highly significant benefit of pitavastatin — the risk reduction for pitavastatin vs. placebo was 35%.

The benefits of pitavastatin were consistent across baseline demographics and medical issues, with point estimates favoring the intervention over placebo in virtually every group. Overall, this translated to a 5-year number needed to treat (NNT) to prevent a major cardiovascular event of 106 (95% CI, 64 to 303), in line with or better than other widely adopted interventions (treatment of hypertension, or aspirin) to prevent this complication.

Presenting the study results to a packed conference room at the IAS meeting, lead investigator Dr. Steven Grinspoon highlighted several uncertainties that await further study, among them:

  • What is the mechanism of this risk reduction? The magnitude was greater than would have been expected solely based on the lipid-lowering effect, implying the anti-inflammatory property of the statin also played a major role.
  • Is the higher incidence of diabetes with statin therapy enough to counter any of these favorable results? This risk is in line with what has been observed in other statin studies, though in some regions where diabetes is very common, this could be an issue.
  • Are there certain subgroups likely to have more or less benefit? Oddly, people with hypertension did not appear to benefit as much — probably just a fluke. And we’ve been tracking certain antiretrovirals with CV risk for many years; it will be fascinating to see if any specific regimens confer excess risk, with or without pitavastatin.
  • How will we interpret absolute vs. relative risk in clinical practice? Not surprisingly, those at lowest cardiovascular risk have a higher NNT (200) to benefit one patient. Even if pitavastatin lowers the risk by 35% in this group, does the low absolute risk make it worthwhile to add another drug?
  • Would another statin have comparable results? After all, pitavastatin is rarely prescribed today, as generic statins are much less expensive. The drug is also not available in many countries.
  • What was the impact of COVID-19 on outcomes? The study started enrolling in 2015, and completed in 2023. That means a lot of participants got COVID-19 during the study, both before and after vaccines became available.
  • Would we get the same result in people without HIV? Not saying that REPRIEVE is going to answer this question — just wondering. The “put statins in the water” camp certainly believe this!

Numerous substudies are ongoing or planned to try and tease out the answer to these and other questions. As we await them, we can congratulate Steve (whom I’ve known for years as a thoughtful and collaborative investigator) and his large research team for completing this remarkable study.

We can also again reflect on how far we have come in HIV medicine in making PWH rock-solid healthy, so that non-ID health issues, in particular diseases of aging, dominate their wonderfully long lives. Steve is an endocrinologist; the protocol co-chair (Dr. Pamela Douglas) is a cardiologist. And while there are ID doctors on the leadership team (hello Drs. Carl Fitchenbaum and Judy Aberg!), it’s notable that major advances in HIV research have drifted away from an ID doctor’s typical areas of focus.

More importantly, a conversation about the risks and benefits of statin use is mainstream general medicine discourse, something that happens thousands if not millions of times a day in primary care. Stable people with HIV are overwhelmingly just that — stable.

These provider-patient discussions will have nothing to do with complex resistance genotypes, novel antiretroviral drug classes, or life-threatening opportunistic infections. About the most complicated aspect of this discussion from the ID/HIV standpoint will be the drug interactions if your patient is still on a regimen containing the pharmacokinetic boosters ritonavir or cobicistat, a rapidly dwindling patient group, and you choose to use atorvastatin.

(That’s easy — just start with a low dose, 10 milligrams daily.)

Now I still enjoy the general medicine that comes with longitudinal HIV follow-up, but I do understand if some ID doctors opt out. And whether these statin yea-or-nay discussions should be in the domain of ID specialists, or general internists, or both, is another topic entirely.

Notably, Australia has never put HIV care in the sole domain of ID specialists. It’s a model we should look at increasingly over the next years-to-decades, thanks to the success of HIV treatment.

6 Responses to “REPRIEVE Trial Highlights Shift in HIV Care from ID to General Medicine”

  1. Josep M Llibre says:

    The benefit of pitavastatin in reducing major CV events was not statistically significant for those with very low CVD risk scoring 0 to 2.5%: HR 0.51 (0.23-1.16). Neither was it for those with low CVD risk from 2.5 to 5% (HR 1.30; 0.73-2.30).
    It was only significant for those with a CVD risk score beyond 5% (HR 0.48; 0.32-0.71).
    In addition, no significant benefit was seen in those with HTN (0.91; 0.63-1.31), an unexpected finding, or in current smokers. (0.75; 0.49-1.14). These two subpopulations should probably be those that we should insist more in putting them on a statin.
    Finally, there was a significant increase in diabetes mellitus: IRR 1.35 (1.09-1.66).
    Well, I certainly would tone down a bit the enthusiasm.
    Obviously, the authors deserve all the congratulations for conducting such an important study.
    Josep M Llibre
    Barcelona, Spain

    • Paul Sax says:

      Excellent points, Josep. It would be hard to justify prescribing for that lowest risk group in particular.


  2. Loretta S says:

    “pitavastatin is rarely prescribed today, as generic statins are much less expensive”. Pitavastatin is the generic form of Livalo. While it isn’t usually the first statin we reach for (it’s moderate-intensity), it is prescribed more than rarely in the US. That’s due in part to its relatively few drug interactions (thanks to UGT metabolism) and anecdotally, it is sometimes the only statin patients can tolerate.

    • Paul Sax says:

      Hi Loretta,

      Interesting you have this experience! Agree about the few drug interactions, but I surveyed a bunch of people at this conference, and none of them had ever prescribed pitavastatin. In the USA, no generic is available yet (Livalo is the brand name), and it’s much more expensive than generic atorvastatin which you can get from places like Mark Cuban pharmacy for < $5 for a 90 day supply.

      Here's what goodrx has to say about pitavastatin pricing:



      • Loretta S says:

        Agree that pitavastatin is more expensive than atorvastatin. But both Livalo (pitavastatin + calcium) and Zypitamag (pitavastatin + magnesium) have fairly inexpensive copay programs, even for uninsured patients, described on their websites. Definitely way cheaper than the GoodRx prices, if you’re inclined to prescribe either med for your patients. (I am NOT trying to be a salesperson for either medication here! 🙂 ) Of course, as always, people with Medicaid, Medicare, etc. may not be eligible. Unfortunately.

  3. Samuel Stampfer says:

    Very interesting! Perhaps this might be an argument for co-formulating pitavistatin in a single tablet in combination with ART? At that low dose it would not significantly impact pill size. Might be tricky logistically and from a regulatory standpoint, but that seems like the easiest way to add a low risk medication with a high NNT.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.