The Conference on Retroviruses and Opportunistic Infections held in early March in Seattle, Washington, featured over a thousand scientific research presentations primarily focused on HIV, but also TB, hepatitis and other infections. Some of them were very high impact, like the news of the HIV patient who is possibly cured. Most, however, while not ground-breaking, were nevertheless important in revealing new strategies that could improve the management of HIV patients.
I will highlight a few studies that are important regarding the effects of our HIV medicines and some new ways that could possibly improve complications of HIV Infection.
Déjà vu?
This conference presented new data from multiple sources that is raising concern among clinicians. A number of studies and evaluations seem to have identified an issue of significant weight gain occurring in patients starting integrase inhibitors. There have been earlier reports that hinted about this occurring but we are now beginning to see more clearly that this could be problematic.
It seems that patients starting integrase inhibitors experience weight gain and this can happen whether they are switched to integrase inhibitors from another HIV regimen (treatment experienced) or whether they are started on an integrase inhibitor-containing regimen as their very first HIV regimen. The integrase inhibitors in use are Raltegravir (the first integrase approved for use in 2007), Elvitegravir (included in combinations Genvoya and Stribild), Dolutegravir (included in combinations Triumeq and Juluca) and Bictegravir (included in the combination Bictarvy).
The integrase inhibitors are currently the most powerful drugs we have in suppressing HIV infection and they became recommended as first-line agents because of their tolerability and their low-side effect profile, or so we thought.
The reason I subtitled this section “Déjà vu” relates to what happened to the HIV treatment community about 20 years ago. We were celebrating the availability of the protease inhibitor drugs which allowed us to suppress patients to undetectable levels of virus when combined with other drugs.
The problem was that the older drugs in this class had many side-effects and required multiple doses. Using drugs like Indinavir, Nelfinavir and later, Lopinavir (Kaletra), we soon began to see changes in our patients’ body composition. Most disturbing was abnormal fat distribution where patients would accumulate weight in the belly (visceral adiposity) and in the back of the neck (“buffalo hump”), at the same time losing fat in the limbs and the face (termed lipoatrophy).
We later learned that loss of fat was likely due to drugs in the nucleoside class like Stavudine (D4-T, Zerit) and Didanosine (ddI, Videx). These changes in fat distribution put patients at risk for diabetes and the cosmetic impact affected their self-esteem. Fortunately, safer protease inhibitors like Atazanavir (Reyataz) and Darunavir (Prezista) became available as well as better nucleosides like Tenofovir (Viead) and Abacavir (Ziagen).
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We do not fully understand why and how the integrase inhibitors are doing this. Increasing weight is generally not a good thing, except for patients who have experienced weight loss or wasting from advanced HIV infection. HIV patients are at higher risk of heart disease and diabetes, and many patients experience these conditions already, unrelated to HIV infection. Increasing weight can worsen this.
It also seems that all integrase inhibitors are not created equal in causing this problem. It was consistently shown that Dolutegravir was the worst culprit and Elvitegravir was the least, with Raltegravir somewhere in the middle. There was no data presented on Bictegravir.
If you have been taking any of the integrase inhibitors and have gained weight, be sure to talk to your medical provider. Your weight is recorded whenever you have a clinic visit so they should have some accurate numbers on how much weight you have actually gained. Develop a plan to increase physical activity and exercise and meet with a nutritionist to improve your diet. If all else fails, discuss changing your HIV medicines to ones that don’t cause this problem.
Teaching an Old Dog New Tricks
Metformin is an oral drug used to treat diabetes in patients who don’t require insulin. Many patients who are HIV-infected and also have diabetes may be treated with metformin. It has been available in the US for a couple of decades.
Two research teams identified actions of metformin, separate from its actions in diabetes, that may help with HIV disease. The researchers found that at a dose of 850 mg of metformin twice a day, a number of benefits were observed which included less inflammation in the intestines (a common feature of HIV disease), fewer lymphocytes entering the intestines and other changes in blood cells that reduce the chance of them being infected by the virus.
It will be interesting to see if these effects lead to long term benefits in HIV patients. The patients who were in this study were HIV infected but did not have diabetes.
Probiotics
A couple of studies show some positive effects of probiotics in HIV disease. In an article I wrote, HIV and the Gut Microbiome: Prebiotics and Probiotics, I described a phenomenon where HIV causes gut damage and gut bacteria can slowly leak into the bloodstream causing inflammation ( a process we call microbial translocation). In one study use of probiotics decreased the number of cells related to gut damage and improved the diversity of bacteria in the gut.
In another study, 2 sachets of a probiotic product called Vivomaxx taken daily lead to improvements in the gut damage that would result in reduced gut leakage of bacteria and less inflammation.
Possible benefits of mineral supplementation?
Patients with low levels of serum zinc were randomized to receive supplementation with zinc gluconate at either 45mg/day or 90 mg/day. After 4 months, the supplementation with zinc led to reduced levels of inflammation in the body because the chemicals that promote inflammation had been reduced.
These chemicals involved in inflammation have been linked to the development of cardiovascular disease, the risk for metabolic disease and other complications of HIV. Importantly, these chemicals remain at higher levels than normal in HIV patients even when they are controlled on HIV medicine. Zinc supplementation should be studied to determine if complications of inflammation in the body are reduced over time.
More studies are needed to determine how valuable these interventions are. Any changes you plan to make should be discussed with your medical providers. In the next article, I will present some new drugs that target HIV and may be very powerful in combination with the treatments we currently have.
Dr. Crawford has over 25 years of experience in the treatment of HIV. While at Howard University School of Medicine, he worked in two HIV-specialty clinics at Howard University Hospital. He then did clinical research as a visiting scientist with the AIDS Clinical Trials Group (ACTG) at Johns Hopkins University School of Medicine. He served as the Assistant Chief of Public Health Research with the Military HIV Research Program where he managed research studies under the President’s Emergency Plan for AID Relief (PEPFAR) in four African countries.
He is currently working in the Division of AIDS in the National Institutes of Health. He has published research in the leading infectious diseases journals and serves on the Editorial Board of the journal AIDS. Any views and perspectives in his articles on blackdoctor.org are not representative of any agency or organization but a reflection of his personal views.
