Why Would Doctors Consider a Nuc-Sparing Regimen for HIV Treatment?

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Question: Why Would Doctors Consider a Nuc-Sparing Regimen for HIV Treatment?

These days, people with HIV are living long, full lives, and people older than 50 are one of the fastest-growing groups of HIV-infected people. Effective HAART options have enabled this change from the early days of the HIV epidemic, but it has come with a price -- long-term use of HIV drug cocktails can have some serious side effects.

Extended treatment with HAART can cause a number of problems including lipodystrophy (changes in fat distribution), kidney disease, and what some describe as premature aging. However, some classes of drugs may be more likely to cause these side effects than others. Two types of drugs that have been associated with particularly significant health risks are nucleotide and nucleoside reverse transcriptase inhibitors - a class collectively known as NRTIs. Recently, there has been a growing interest in the use of therapeutic regimens that do not include these classes of drugs. Such treatments are known as nuc-sparing regimens.


Two of the side effects associated with NRTI use are mitochondrial toxicity and telomere shortening.

Mitochondria are the energy generators of the cell. Although they generally become damaged and less effective with age, this process seems to be accelerated in individuals with HIV.

NRTIs seem to speed the damage along even more quickly, since the same nucleotides used by HIV reverse transcriptase are also used in mitochondrial DNA replication. It has been hypothesized that mitochondrial damage contributes to a picture of premature aging seen in HIV infected adults.

However, mitochondrial toxicity isn't the only connection between HIV and premature aging.

There is also telomere damage. Telomere length is a marker of aging in humans, and individuals with HIV who are taking NRTIs have abnormally shortened telomeres. This damage may be explained, at least in part, by the fact that the enzyme telomerase, which extends telomeres in healthy cells, is a form of reverse transcriptase similar to that made by HIV. Therefore NRTIs can inhibit its function to some degree as well as interfering with HIV replication.

Currently all recommended HIV treatment regimens include NRTIs in combination with protease inhibitors and other types of drugs. However, there has been a growing interest in the possible use of nuc-sparing regimens for treating HIV - HAART regimens that do not contain NRTIs. There are several potential concerns with this approach.

  1. There is concern that a drug cocktail consisting of a smaller number of drugs without NRTIs might be more likely to give rise to viruses with significant drug resistance.
  2. Nuc-sparing regimens may not be as effective at controlling HIV infection as regimens that contain NRTIs.
  1. It is uncertain whether nuc-sparing regimens would actually be an effective way of reducing side effects in long term HAART users.

Although scientists have attempted to address these questions, the results of their research have been mixed. While some studies have shown a reduction in side effects on nuc-sparing regimens, other studies have not seen similar benefits. In addition, several reports have found that nuc-sparing regimens may have a higher virologic failure rate than treatments which contain an NRTI. Virologic failure refers to the inability of the drug to help a patient maintain a low, or undetectable, viral load.

As such, nuc-sparing HIV treatment regimens remain both experimental and controversial. Some scientists have suggested that they may be better suited to patients who have been on HAART for an extended period of time and whose infection is already well under control. However, there has not been a great deal of research on whether late-treatment for HIV needs to be the same as early-treatment. To date, most studies have focused on maintaining viral control rather than on reducing long-term medication side effects. There's a practical reason for that oversight. It is extremely expensive to fund studies for long enough periods to understand long-term effects.


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