HIV drug resistance

Last updated

HIV drug resistance occurs when microevolution causes virions to become tolerant to antiretroviral treatments (ART). ART can be used to successfully manage HIV infection, but a number of factors can contribute to the virus mutating and becoming resistant. Drug resistance occurs as bacterial or viral populations evolve to no longer respond to medications that previously worked. In the case of HIV, there have been recognized cases of treatment resistant strains since 1989, with drug resistance being a major contributor to treatment failure. [1] While global incidence varies greatly from region to region, there has been a general increase in overall HIV drug resistance. The two main types of resistance, primary and induced, differ mostly in causation, with the biggest cause of resistance being a lack of adherence to the specific details of treatment. These newly created resistant strains of HIV pose a public health issue as they infect a growing number of people because they are harder to treat, and can be spread to other individuals. [2] For this reason, the reaction to the growing number of cases of resistant HIV strains has mostly been to try to increase access to treatment and implement other measures to make sure people stay in care, as well as to look into the development of an HIV vaccine or cure. [3] [4]

Contents

Mechanisms of resistance

HIV is considered resistant when it no longer respond to known treatments. [5] Because currently there is no known cure for HIV, the goal of treatment is to reduce an infected individual's viral load to the point where it is no longer detectable in order to alleviate their symptoms and reduce their risk of infecting others. [6] HIV drug resistance poses an issue because it reduces the possible HIV medications a person can take due to cross resistance. In cross resistance, an entire class of medication is considered ineffective in lowering a patient's HIV viral load because all the drugs in a given class share the same mechanism of action. [7] Therefore, development of resistance to one medication in a class precludes the use of all other medications in the same class. A blood test can be done to determine which drugs may be effective prior to initiation of treatment or during treatment to ensure resistance has not developed. [7]

Types of resistance

Induced resistance

One of the two types of HIV drug resistance is induced resistance. Induced resistance refers to resistance that occurs as a result of drug therapy. HIV is a retrovirus that replicates quickly using reverse transcriptase, known for its lack of error correcting mechanisms, resulting in a high mutation rate. Mutations that confer a substantial selective advantage to HIV survival can therefore quickly replicate within an individual, creating a new, resistant strain. [8] [5] These mutations accumulate over generations and in populations, resulting in the great genetic variation within populations of HIV, and an increased probability of a virion developing an evolutionary selective advantage over other virions. [5] Natural selection then acts on HIV by selecting for virions with higher fitness, as all others are eventually killed off by drug treatments. [9] The virions that are able to escape the harmful effects of the drug then create an entirely new, drug resistant population. The selected-for virions continue reproducing until the patient's viral load returns to pre-treatment levels, creating a cycle in which treatment is initially successful in reducing the viral load, but becomes less effective as the virus becomes resistant and virion levels once again increase. [10]

Primary resistance

The other type of HIV drug resistance is primary resistance. Primary resistance refers to resistance that is not incurred as a result of ART therapy. It is thought that some strains of HIV-1 are naturally resistant to ART drugs, and that the prevalence of these strains varies across the globe. [8] Primary resistance is acquired when an individual's initial infection with HIV comes from an already resistant strain. [3] An individual infected by a resistant strain begins their course of treatment with already limited drug options, which can pose problems later down the line if they develop additional resistance. [10]

Causes of resistance

Importance of drug regimen adherence

As previously described, mutations occur as a result of random mutations that are especially prevalent in HIV due to characteristic elements of the viral reproductive process, namely the use of reverse transcriptase. Several mechanisms of resistance have been identified, including mutations that block the incorporation of nucleosides, a class of HIV drug, into the viral DNA. [11] One known cause of HIV drug resistance is lack of adherence to the prescribed drug regiment. Low levels of adherence can be attributed to lack of access to healthcare, stigmatization of HIV, and a lack of availability of drugs due to prohibitive cost or other factors. Missing doses of medication or taking them late poses a major issue because it can allow for the virus to once again begin to replicate inside the body. Proper adherence also greatly reduces the risk of the spread of the virus, thereby improving general public health and lowering health care spending. [12] Some drugs are known to have lower incidences[ spelling? ] of resistance and may be preferable for individuals known to have difficulty adhering to a drug routine, but these benefits have to be weighed with the potential risks, including severity of side effects. [13]

Potential limited effects of current drugs

In 2004, one study estimated the percentage of the American HIV positive population with some form of drug resistance to be 76.3%. [14] A more recent study in South Korea estimated that 50% of their HIV positive population had multi-drug resistant strains of HIV, while 10% had multi-class resistant strains. Multi-class resistant strains pose a larger problem because each class includes many drugs, and eliminating use of an entire class of drugs severely limits treatment options. [15] These studies indicate that the incidence of resistance varies greatly based on geographic location.[ citation needed ]

In their 2017 HIV Drug Resistance Report, the World Health Organization conducted surveys in 14 countries to estimate the prevalence of resistance to HIV medications. One subgroup included only HIV-positive patients who had just initiated antiretroviral therapy in order to assess the prevalence of HIV drug resistance in treatment-naive patients, deemed "pretreatment drug resistance." Resistance to NNRTIs in this patient population ranged from 2.7% (in Myanmar) to 15.9% (in Uganda). Resistance to NRTIs ranged from 0.3% (in Namibia) to 6.8% (in Nicaragua). Resistance to protease inhibitors ranged from 0.3% (in Cameroon and Myanmar) to 2.6% (in Mexico). Resistance to NNRTI + NRTI combination therapy ranged from 0.2% (in Myanmar) to 4.6% (in Uganda). [16]

Contemporary treatment issues

Current medical and scientific opinion is mixed on the most effective treatment methods, but is focused on drug cocktails and the importance of first-line regimens. [17] The World Health Organization advocates a public-health approach to HIV treatment in order to make treatment uniform and available to patients around the world. [18] As of July 2017, the WHO is implementing the Global Action Plan on HIV drug resistance 2017–2021. It is a 5-year initiative intended to help countries around the world manage HIV drug resistance. [19]

Among treatment methods, the World Health Organization acknowledges the importance of successful first-line treatments. [18] First-line treatments are known to affect the virus' future response to other treatments, making the effectiveness of first-line treatments an issue of vital importance. [18] The most successful treatments are combinations of three drugs used simultaneously, as this greatly reduces the probability of the virus developing resistance. [20]

ART use in developing countries

Shortly after the advent of ART therapy, there was much controversy about how to make the drugs accessible to the developing world in countries where the disease was most widespread. Because of the strict regimen that had to be followed in taking the drugs, critics were hesitant to distribute the drugs in under-resourced countries where they worried patients would be unwilling or unable to follow the regimen. [21] However, studies comparing drug regimen adherence rates between high and low income countries showed that individuals in low income countries were no less likely to correctly follow drug instructions. In one study, 77% of African patients were found to satisfy the standard of adherence, compared to just 55% of North American patients studied. [12] These high adherence rates in resource-poor countries can be attributed to the success of community-based approaches like the HIV Equity Initiative in Haiti, which employed local workers and trained them in how to safely distribute HIV medication, as well as programs such as that in Brazil, in which generic drugs are able to be mass-produced and distributed for little to no cost. [22] [21]

Future steps to control HIV resistance

The number of people with resistant strains of HIV are growing, making the matter a more pressing issue for health care officials. If current trends continue, infection rates will rise, as will government spending on HIV/AIDS. [23] HIV drug resistance also has the potential to disrupt the progress being made in the global fight against AIDS, such as with the "90-90-90" target to diagnose 90% of cases, provide treatment to 90% of infected individuals, and successfully suppress the viral load in 90% of the treated individuals. [3] New classes of drugs are constantly being researched and produced to help address the issue of resistance, as well as to try to alleviate the steep costs associated with managing HIV. [24] However, UNAIDS believes that the issue is currently under control, with ART treatment being effective for a majority of patients. Instead, they support research into developing a vaccine or cure as being more central to the mission of reducing the spread of AIDS. [25]

See also

Related Research Articles

<span class="mw-page-title-main">Antiviral drug</span> Medication used to treat a viral infection

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.

<span class="mw-page-title-main">Zidovudine</span> Antiretroviral medication

Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

<span class="mw-page-title-main">Stavudine</span> Chemical compound

Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. However, it is not a first-line treatment. It is given by mouth.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

<span class="mw-page-title-main">Efavirenz</span> Antiretroviral medication

Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is sold both by itself and in combination as efavirenz/emtricitabine/tenofovir. It is taken by mouth.

<span class="mw-page-title-main">Darunavir</span> Antiretroviral medication

Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or cobicistat to increase darunavir levels. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth once to twice a day.

Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) co-infection is a multi-faceted, chronic condition that significantly impacts public health. According to the World Health Organization (WHO), 2 to 15% of those infected with HIV are also affected by HCV, increasing their risk of morbidity and mortality due to accelerated liver disease. The burden of co-infection is especially high in certain high-risk groups, such as intravenous drug users and men who have sex with men. These individuals who are HIV-positive are commonly co-infected with HCV due to shared routes of transmission including, but not limited to, exposure to HIV-positive blood, sexual intercourse, and passage of the Hepatitis C virus from mother to infant during childbirth.

HIV superinfection is a condition in which a person with an established human immunodeficiency virus infection acquires a second strain of HIV, often of a different subtype. These can form a recombinant strain that co-exists with the strain from the initial infection, as well from reinfection with a new virus strain, and may cause more rapid disease progression or carry multiple resistances to certain HIV medications.

<span class="mw-page-title-main">Resistance mutation (virology)</span>

A resistance mutation is a mutation in a virus gene that allows the virus to become resistant to treatment with a particular antiviral drug. The term was first used in the management of HIV, the first virus in which genome sequencing was routinely used to look for drug resistance. At the time of infection, a virus will infect and begin to replicate within a preliminary cell. As subsequent cells are infected, random mutations will occur in the viral genome. When these mutations begin to accumulate, antiviral methods will kill the wild type strain, but will not be able to kill one or many mutated forms of the original virus. At this point a resistance mutation has occurred because the new strain of virus is now resistant to the antiviral treatment that would have killed the original virus. Resistance mutations are evident and widely studied in HIV due to its high rate of mutation and prevalence in the general population. Resistance mutation is now studied in bacteriology and parasitology.

HIV Resistance Response Database Initiative (RDI) is a not-for-profit organisation established in 2002 which states its mission as "To improve the clinical management of HIV infection by developing a large clinical database and bioinformatic techniques that predict accurately any individual's response to any combination of HIV drugs."

The cost of HIV treatment is a complicated issue with an extremely wide range of costs due to varying factors such as the type of antiretroviral therapy and the country in which the treatment is administered. The first line therapy of HIV, or the initial antiretroviral drug regimen for an HIV-infected patient, is generally cheaper than subsequent second-line or third-line therapies. There is also a great variability of drug prices among low, middle, and high income countries. In general, low-income countries have the lowest cost of antiretroviral therapy, while middle- and high-income tend to have considerably higher costs. Certain prices of HIV drugs may be high and difficult to afford due to patent barriers on antiretroviral drugs and slow regulatory approval for drugs, which may lead to indirect consequences such as greater HIV drug resistance and an increased number of opportunistic infections. Government and activist movements have taken efforts to limit the price of HIV drugs.

<span class="mw-page-title-main">HIV/AIDS research</span> Field of immunology research

HIV/AIDS research includes all medical research that attempts to prevent, treat, or cure HIV/AIDS, as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.

<span class="mw-page-title-main">Fostemsavir</span> Chemical compound

Fostemsavir, sold under the brand name Rukobia, is an antiretroviral medication for adults living with HIV/AIDS who have tried multiple HIV medications and whose HIV infection cannot be successfully treated with other therapies because of resistance, intolerance or safety considerations.

HIV in pregnancy is the presence of an HIV/AIDS infection in a woman while she is pregnant. There is a risk of HIV transmission from mother to child in three primary situations: pregnancy, childbirth, and while breastfeeding. This topic is important because the risk of viral transmission can be significantly reduced with appropriate medical intervention, and without treatment HIV/AIDS can cause significant illness and death in both the mother and child. This is exemplified by data from The Centers for Disease Control (CDC): In the United States and Puerto Rico between the years of 2014–2017, where prenatal care is generally accessible, there were 10,257 infants in the United States and Puerto Rico who were exposed to a maternal HIV infection in utero who did not become infected and 244 exposed infants who did become infected.

Treatment as prevention (TasP) is a concept in public health that promotes treatment as a way to prevent and reduce the likelihood of HIV illness, death and transmission from an infected individual to others. Expanding access to earlier HIV diagnosis and treatment as a means to address the global epidemic by preventing illness, death and transmission was first proposed in 2000 by Garnett et al. The term is often used to talk about treating people that are currently living with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) to prevent illness, death and transmission. Although some experts narrow this to only include preventing infections, treatment prevents illnesses such as tuberculosis and has been shown to prevent death. The dual impact on well-being and its 100% effectiveness in reducing transmission makes TasP the most important element in the HIV prevention toolkit. In relation to HIV, antiretroviral therapy (ART) is a three or more drug combination therapy that is used to decrease the viral load, or the measured amount of virus, in an infected individual. Such medications are used as a preventative for infected individuals to not only spread the HIV virus to their negative partners but also improve their current health to increase their lifespans. Other names for ART include highly active antiretroviral therapy (HAART), combination antiretroviral therapy (cART), triple therapy and triple drug cocktail. When taken correctly, ART is able to diminish the presence of the HIV virus in the bodily fluids of an infected person to a level of undetectability. Undetectability ensures that infection does not necessarily have an effect on a person's general health, and that there is no longer a risk of passing along HIV to others. Consistent adherence to an ARV regimen, monitoring, and testing are essential for continued confirmed viral suppression. Treatment as prevention rose to great prominence in 2011, as part of the HPTN 052 study, which shed light on the benefits of early treatment for HIV positive individuals.

Viral load monitoring for HIV is the regular measurement of the viral load of individual HIV-positive people as part of their personal plan for treatment of HIV/AIDS. A count of the viral load is routine before the start of HIV treatment.

Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. One tablet, taken orally once daily, contains 50 mg bictegravir, 200 mg emtricitabine, and 25 mg tenofovir alafenamide. It was approved for use in the United States in February 2018, and for use in the European Union in June 2018.

Semzuvolimab, formerly known as UB-421 is an experimental HIV antibody, under development by United Biomedical, Inc. (UBI), headquartered in Hauppauge, New York, U.S. for use in the treatment of HIV infection. By blocking the CDR2 domain of the CD4 receptor of the virus, it prevents initial viral attachment to the host T cell and entry into the host immune cell via a competitive inhibition mechanism. The antibody is unlikely to promote resistance to itself via generation of CD4-independent virus, and has performed well in phase 2 open-label trials. Additionally, it offers hope to HIV patients whose infection has become multi-drug resistant. Furthermore, the antibody has shown long term suppression, which requires the patient to be treated less often, which improves treatment adherence. Previous experimental infusions of broadly neutralizing antibodies (bNABs) have suppressed HIV for about two weeks by targeting proteins on the virus itself, but the rapid mutation rate of HIV induces antibody-resistant strains that render the treatment ineffective. UB-421 theoretically avoids this possibility by blocking a stable human protein that HIV uses to infect T cells. Its advantages include its competitive inhibition, a high affinity of UB-421 to CD4 T cells which is 100 times stronger than HIV, its neutralization of multiple sub-types of HIV, its inhibition of both cell-to-cell and cell-free transmission of HIV, and its immune modulation of training the immune system to better attack HIV, all of which provide potential as monotherapy.

References

  1. ↑ Larder B (2001). "Mechanisms of HIV-1 drug resistance". AIDS. 15 Suppl 5: S27–34. doi: 10.1097/00002030-200100005-00005 . PMID   11816171.
  2. ↑ "HIV and drug resistance". unaids.org. Retrieved 30 October 2018.
  3. 1 2 3 HIV drug resistance report 2017. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO.
  4. ↑ "Antiretroviral Drug Discovery and Development". National Institute of Allergy and Infectious Diseases. Retrieved 25 October 2018.
  5. 1 2 3 Freeman S, Herron JC (2007). "Evolutionary Analysis.". A case for evolutionary thinking: understanding HIV (4th ed.). San Francisco, CA: Pearson Benjamin Cummings.
  6. ↑ "Treatment Goals Adult and Adolescent ARV". AIDSinfo. Archived from the original on 31 August 2020. Retrieved 9 November 2018.
  7. 1 2 "Drug Resistance". AIDSinfo. U.S. Department of Health and Human Services. Retrieved 31 October 2017.
  8. 1 2 Clavel F, Hance AJ (March 2004). "HIV drug resistance". The New England Journal of Medicine. 350 (10): 1023–35. doi:10.1056/nejmra025195. PMID   14999114.
  9. ↑ Kozal MJ (January 2009). "Drug-resistant human immunodefiency virus". Clinical Microbiology and Infection. 15 Suppl 1: 69–73. doi: 10.1111/j.1469-0691.2008.02687.x . PMID   19220361.
  10. 1 2 Pascu ML (2017). Laser Optofluidics in Fighting Multiple Drug Resistance. Bentham Science Publishers. p. 119.
  11. ↑ "Mechanisms of HIV-1 drug resistance : AIDS". LWW. Retrieved 30 October 2018.
  12. 1 2 Nachega JB, Marconi VC, van Zyl GU, Gardner EM, Preiser W, Hong SY, Mills EJ, Gross R (April 2011). "HIV treatment adherence, drug resistance, virologic failure: evolving concepts". Infectious Disorders Drug Targets. 11 (2): 167–74. doi:10.2174/187152611795589663. PMC   5072419 . PMID   21406048.
  13. ↑ "Adherence Limitations to Treatment Safety and Efficacy Adult and Adolescent ARV". AIDSinfo. Retrieved 9 November 2018.
  14. ↑ Richman DD, Morton SC, Wrin T, Hellmann N, Berry S, Shapiro MF, Bozzette SA (July 2004). "The prevalence of antiretroviral drug resistance in the United States". AIDS. 18 (10): 1393–401. doi: 10.1097/01.aids.0000131310.52526.c7 . PMID   15199315. S2CID   15960179.
  15. ↑ Choi JY, Kwon OK, Choi BS, Kee MK, Park M, Kim SS (June 2014). "The prevalence of antiretroviral multidrug resistance in highly active antiretroviral therapy-treated patients with HIV/AIDS between 2004 and 2009 in South Korea". Journal of Clinical Virology. 60 (2): 154–60. doi:10.1016/j.jcv.2014.02.004. PMID   24680255.
  16. ↑ "HIV drug resistance report. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO" (PDF).
  17. ↑ "Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection". World Health Organization. Retrieved 1 November 2017.
  18. 1 2 3 Gilks CF, Crowley S, Ekpini R, Gove S, Perriens J, Souteyrand Y, Sutherland D, Vitoria M, Guerma T, De Cock K (August 2006). "The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings". Lancet. 368 (9534): 505–10. doi:10.1016/S0140-6736(06)69158-7. PMID   16890837. S2CID   22499739.
  19. ↑ "Global action plan on HIV drug resistance 2017–2021". World Health Organization. Archived from the original on 23 July 2017. Retrieved 1 November 2017.
  20. ↑ Cane PA (September 2009). "New developments in HIV drug resistance". The Journal of Antimicrobial Chemotherapy. 64 Suppl 1: i37–40. doi: 10.1093/jac/dkp258 . PMID   19675018.
  21. 1 2 Rosenberg T (28 January 2001). "Look at Brazil". The New York Times. Retrieved 9 November 2018.
  22. ↑ Dugger CW (29 November 2003). "Rural Haitians Are Vanguard in AIDS Battle". The New York Times. Retrieved 25 October 2018.
  23. ↑ "WHO urges action against HIV drug resistance threat". World Health Organization. Retrieved 25 October 2018.
  24. ↑ "Antiretroviral Drug Discovery and Development | NIH: National Institute of Allergy and Infectious Diseases". niaid.nih.gov. Retrieved 25 October 2018.
  25. ↑ "HIV and drug resistance". unaids.org. Retrieved 30 October 2018.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.