Aging, HIV and the possible effect of nukes
In high-income countries such as Canada, Australia and the U.S. and in regions such as Western Europe, huge advances have been made in the treatment of HIV disease. Researchers increasingly expect that a young person who is diagnosed today and who initiates potent combination anti-HIV therapy (commonly called ART or HAART) and who has minimal co-existing health conditions should have several additional decades of life expectancy.
The combinations of therapies available for the initial treatment of HIV are plentiful. Furthermore, pill taking has been simplified by the availability of the co-formulation of several drugs into one pill, creating an entire regimen in a single tablet. Such single-tablet regimens need only be taken once daily. However, things were not always this way.
A look at the past
Initial treatment for HIV infection, when it became available in the late 1980s, consisted of a single drug—the nuke (nucleoside reverse transcriptase inhibitor) AZT (zidovudine, Retrovir)—given at high doses and taken every four hours. Such a regimen frequently caused headache, nausea, vomiting and damaged the bone marrow.
In the early 1990s, other anti-HIV drugs in the same class became available, including the following nukes:
- ddC (zalcitabine, Hivid)
- ddI (didanosine, Videx)
- d4T (stavudine, Zerit)
These three drugs, commonly called d-drugs, initially appeared to be better tolerated but soon showed their own side effects, such as peripheral neuropathy (painful nerves in the hands, feet and legs). ddC is no longer manufactured and treatment guidelines in high-income countries now discourage the use of d4T and ddI.
In 1996, a new class of anti-HIV drugs became available—protease inhibitors (PIs). When used in combination with nukes, the results were dramatic. For the first time in the history of the AIDS pandemic, people showed sustained recovery from AIDS-related infections.
However, shortly after HAART became available, reports emerged of a strange syndrome of changes in body shape sometimes associated with the loss of the fatty layer just under the skin. This loss of fat, called lipoatrophy, affected all parts of the body but its effect on the face could become most distressing.
Initially, because PIs were the latest class of anti-HIV therapy, they were suspected as the culprits. However, a few years later, researchers began to realize that exposure to d4T and, to a lesser extent, AZT, was linked to lipoatrophy. Today, drugs such as d4T and AZT are generally not recommended as first-line therapy in high-income countries.
In the current era, nukes remain the backbone of many regimens. Nukes commonly used today include the following combinations:
- abacavir + 3TC – sold as a fixed-dose formulation called Kivexa (or Epzicom) and also found in Trizivir
- tenofovir + FTC – sold as a fixed-dose formulation called Truvada and also found in other combinations such as Atripla, Complera and Stribild
A lingering sense of caution
Decisions about starting therapy for HIV infection have always been challenging; both doctors and their patients have weighed the risks and benefits, as well as a person’s ability to take HIV medicines exactly as directed for many years. In the current era, with safer, simpler therapies and more results from clinical trials, the risk–benefit ratio has swung strongly in favour of very early initiation of therapy. The most recent version of the U.S. Department of Health and Human Services’ (DHHS) HIV/AIDS Treatment Guidelines recommends early therapy for all HIV-positive people, for two reasons, as follows:
- At the level of the individual, early treatment can help preserve the immune system and improve health.
- From a public health point of view, treating more HIV-positive people reduces the amount of HIV in their blood, other tissues, and genital fluids. The result is decreased sexual infectiousness. As a result of this reduced infectiousness, at the level of a large urban area or region, widespread use of ART can help to reduce new cases of HIV transmission. This approach of treating people to reduce their infectiousness is called TasP—treatment as prevention.
Despite the general tolerability and safety of Kivexa and Truvada, some HIV-positive people and their doctors remain somewhat wary of nukes in general, given their checkered history, and wonder about the potential of these drugs for causing new, unknown side effects. This latter concern is increased as HIV-positive people age and need to take multiple medications, heightening the potential for drug interactions and side effects.
Emerging research suggests the possibility that nukes can affect the energy-producing parts of cells (mitochondria). However, nuke combinations commonly used in the initiation of therapy today have not been proven to cause mitochondrial damage that is directly linked to the ill health of ART users.
Aging and HIV
Some researchers have found hints of apparently accelerated aging in some HIV-positive people. Specifically, some organ-systems, such as the brain, heart, blood vessels and bones, appear to have aged more quickly than they should.
The cause of this apparent aging is not clear.
If premature or accelerated aging does exist in HIV infection, there may be several potential causes affecting different people, including the following:
- long-term exposure to specific proteins produced by HIV-infected cells
- higher-than-normal levels of inflammation, which accompanies chronic viral infections such as HIV
- substance use
- tobacco smoking
- co-infection with other germs, such as members of the herpes virus family—CMV (cytomegalovirus) and EBV (Epstein-Barr virus)
The immune system and aging
Several research teams have found that, if left untreated, HIV infection does prematurely age the immune system. HIV appears to cause this by repeatedly activating the immune system and producing inflammation. This virus also appears to cause complex and poorly understood changes to the immune system shortly after it enters the body.
ART greatly reduces HIV-related inflammation but cannot entirely eliminate it. Prolonged exposure to higher-than-normal levels of inflammation is associated with many chronic illnesses and it is possible that such inflammation over the long-term may play a role in reports of accelerated aging seen in some HIV-positive people in studies. However, it is important to bear in mind that exposure to unhealthy behaviours—particularly tobacco smoking—also causes inflammation. Separating all the possible drivers of accelerated aging in HIV-positive people will not be easy and will require many studies, some of them quite expensive and daunting in their complexity.
Much caution needed
A research team in Australia has been exploring the theory that nukes somehow contribute to the apparent acceleration in aging in HIV-positive people. Their work, conducted in complex laboratory experiments on cells from HIV-negative and HIV-positive people suggests the possibility that the drug tenofovir (Viread) may accelerate the aging of the immune system. However, we urge our readers to treat this finding with a great deal of caution, if only because the results from the Australian experiments are not definitive. Furthermore, due to built-in limitations of their study’s design (it is cross-sectional in nature), questions remain about the significance of their findings. Next up, we will explore some of the issues related to the Australian study.
—Sean R. Hosein
- Boasso A, Royle CM, Doumazos S, et al. Overactivation of plasmacytoid dendritic cells inhibits antiviral T-cell responses: a model for HIV immunopathogenesis. Blood. 2011 Nov 10;118(19):5152-62.
- Herbeuval JP, Nilsson J, Boasso A, et al. HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS. 2009 Jan 2;23(1):35-40.
- Bestilny LJ, Gill MJ, Mody CH, et al. Accelerated replicative senescence of the peripheral immune system induced by HIV infection. AIDS. 2000 May 5;14(7):771-80.
- Leeansyah E, Cameron PU, Solomon A, et al. Inhibition of telomerase activity by HIV Nucleos(t)ide Reverse Transcriptase Inhibitors: a potential factor contributing to HIV-associated accelerated ageing. Journal of Infectious Diseases. 2013; in press.
- Payne BA, Wilson IJ, Hateley CA, et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nature Genetics. 2011 Jun 26;43(8):806-10.
- Helleberg M, Afzal S, Kronborg G, et al. Mortality Attributable to Smoking Among HIV-1-Infected Individuals: A Nationwide, Population-Based Cohort Study. Clinical Infectious Diseases. 2013; in press.
- Rasmussen LD, Kessel L, Molander LD, et al. Risk of cataract surgery in HIV-infected individuals: a Danish nationwide population-based cohort study. Clinical Infectious Diseases. 2011 Dec;53(11):1156-63.
- Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clinical Infectious Diseases. 2011 Dec;53(11):1120-6.
- Pathai S, Lawn SD, Weiss HA, et al. Increased ocular lens density in HIV-infected individuals with low nadir CD4 counts in South Africa: evidence of accelerated aging. Journal of Acquired Immune Deficiency Syndromes. 2013; in press.
- Smith RL, de Boer R, Brul S, et al. Premature and accelerated aging: HIV or HAART? Frontiers in Genetics. 2012;3:328.
- Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998 May 7;12(7):F51-8.
- van der Valk M, Gisolf EH, et al. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS. 2001 May 4;15(7):847-55.
- Cohen S, Janicki-Deverts D, Turner RB, et al. Association between telomere length and experimentally induced upper respiratory viral infection in healthy adults. JAMA. 2013 Feb 20;309(7):699-705.