HIV rebound

The paper that I’m writing about today is “The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption” by Li et al. I will quote passages from the paper, and then try to explain what all of those fantastically long words mean.

Objectives:

Therapies to achieve sustained antiretroviral therapy-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying biomarkers that predict time to viral rebound could accelerate the development of such therapeutics.

This is one of a whole host of papers that deals with identifying biomarkers that can aid in the permanent treatment of HIV-positive patients. What does permanent treatment mean? When HIV-positive patients are put on an active treatment regimen, the treatment is often spectacularly successful…..until the treatment stops. Then, patients see a violent relapse. However, there are some patients (we’ll call them super-patients) that don’t see a relapse at all. Researchers are now trying to figure out what it is about these patients that helps them not relapse when treatment is stopped, and whether these conditions can be re-created in all patients. Simple.

Methods:

Cell-associated DNA (CA-DNA) and CA-RNA were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay.

What is single-copy assay? Here is a direct quote from this paper:

This assay uses larger plasma sample volumes (7 ml), improved nucleic acid isolation and purification techniques, and RT-PCR to accurately quantify HIV-1 in plasma samples over a broad dynamic range (1–106 copies/ml). The limit of detection down to 1 copy of HIV-1 RNA makes SCA 20–50 times more sensitive than currently approved commercial assays.

Essentially it is a new-and-improved method of measuring the amount of HIV RNA in your blood plasma.

What are the results of this experiment?

Results:

Participants who initiated antiretroviral therapy (ART) during acute/early HIV infection and those on a non-nucleoside reverse transcriptase inhibitor-containing regimen had significantly delayed viral rebound. Participants who initiated ART during acute/early infection had lower levels of pre-ATI CA-RNA (acute/early vs. chronictreated: median <92 vs. 156 HIV-1 RNA copies/106 CD4þ cells, P < 0.01). Higher preATI CA-RNA levels were significantly associated with shorter time to viral rebound (4 vs. 5–8 vs. >8 weeks: median 182 vs. 107 vs. <92 HIV-1 RNA copies/106 CD4þ cells, Kruskal–Wallis P < 0.01). The proportion of participants with detectable plasma residual viremia prior to ATI was significantly higher among those with shorter time to viral rebound.

So people who start HIV treatment early have a more successful treatment overall, and it takes a longer time for the disease to rebound even when the treatment is stopped. This largely aligns with common sense and disease rebounds seen in other diseases like cancer. What is more surprising is that patients on the non-nucleoside reverse transcriptase inhibitor-containing regimen also see the same kind of success. Let us explore some of the words in this phrase. A nucleoside is a nucleotide, which is the basic building block of DNA and RNA, minus the phosphate group. Reverse transcriptase is the process of constructing complementary DNA sequences from RNA sequences (reverse transcription, because regular transcription constructs RNA from DNA). So constructing DNA from RNA without the help of nucleosides helps in treating HIV? Maybe this newly constructed DNA helps the immune system figure out how to fight the HIV RNA in the plasma? I’m not sure.

Moreover, higher levels of cell-associated HIV RNA lead to a shorter rebound time after treatment is stopped (ATI). This also makes sense. Treatment should only be stopped when RNA levels have decreased considerably. This is something I also came across in the book “The Emperor of Maladies” by Siddhartha Mukherjee. Cancer treatment, whether it be chemotherapy or a strict drug regimen, is often stopped when the patient supposedly feels cured for a duration of time. However, the cancer often rebounds very quickly. This tells us that treatments, whether they be for cancer or HIV, should be carried on for much longer than they are today, and the patient feeling “fine” is not a good marker for when the treatment should be stopped.

Conclusion:

Higher levels of HIV expression while on Antiretroviral Therapy (ART) are associated with shorter time to rebound after treatment interruption. Quantification of the active HIV reservoir may provide a biomarker of efficacy for therapies that aim to achieve ART-free remission

This is a repetition of the above. Stop treatment only when HIV RNA levels are low. This will increase the time it takes for the disease to rebound. Essentially, disease treatment aligns with common sense. Who knew.

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Graduate student

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