Advances in anti HIV medications, prognosis, quality of life

Since the first United States Food and Drug Administration approved zidovudine as medication for HIV in 1987, there has been a total of 37 antiretrovirals developed to date, in single or combined forms. Generic formulations of these drugs have been made available for developing countries as well. These antiretrovirals have helped to significantly reduce the incidence of HIV-related health complications and death. These drugs and its beneficial outcomes have altered the perception of HIV from being a death sentence into a manageable chronic condition. The development of newer drugs with better efficacy has been proven to prolong life, and recent studies out of developed countries have shown that a twenty-year old person living with HIV in the US or Canada is expected to live into their early 70s.

Each antiretroviral targets one of the critical steps in the HIV replication cycle (Fig. 1), and when used in combination, become highly effective in decreasing the amount of virus in the body. Viral suppression, the decrease of the HIV viral load (VL) in the body to levels below that detected by commercially available assays, is the goal of therapy. With persistent viral suppression, the body’s immune function improves, preventing the development of complications brought about by AIDS, leading to prolonged and improved quality of life. Without therapy, the natural course of HIV dictates that in majority of people, there will be a progressively weaker immune system, an increased susceptibility to opportunistic infections associated with AIDS, and eventually a premature death.

The optimal initial regimen for a patient without drug experience consists of two nucleoside reverse transcriptase inhibitors in combination with a drug from one of three drug classes: an non-nucleoside reverse transcriptase inhibitor, a protease inhibitor boosted with ritonavir, or an integrase strand transfer inhibitor. Selection of a regimen is based on evidence demonstrating the regimen’s durable viral suppression, resulting increased CD4 counts, and a favourable safety profile. However, even after achieving viral suppression, antiretrovirals are unable to eradicate the virus from the body. This is due to the HIV virus being established very early on during acute infection, in latent CD4 T-lymphocyte (CD4) cells, or viral reservoirs. These are located throughout the body, including the brain, lymphoid tissue, bone marrow, and the genital tract, and persists with a long half-life, which makes its depletion difficult.

HIV-replication-cycle.svg

Fig 1 HIV Replication Cycle
Author : Thomas Splettstoesser (www.scistyle.com)

The decision to start antiretrovirals in the HIV-reactive patient depends on the current recommendation of scientific guidelines, which take into account the person’s immunologic status, presence of complications, other non-HIV related illnesses, the willingness and readiness of the patient to initiate therapy, and available resources. Most studies suggest that therapy should be started at a CD4 count below 350 or 500 cells/mm3, while a few would say that starting antiretrovirals at any count is an acceptable option. CD4 counts below 200 cells/mm3 is a determinant of being at a higher risk of opportunistic infections, non-HIV related illnesses, and death, compared to others. There is a more urgent need to start therapy among patients that possess these criteria, and prophylactic drugs for the prevention of opportunistic infections may be warranted. Other conditions for which therapy is considered more urgent are: pregnancy, presence of AIDS-defining conditions, acute opportunistic infections, HIV-associated kidney disease, early or acute HIV, co-infection with hepatitis B or C, a drop in the CD4 count of more than 100 points in a year, and a VL of more than 100,000 copies/mL. For patients with a CD4 count higher than 500 cells/mm3, reservations about prolonged exposure to medications and their side effects prevent some physicians from recommending starting therapy at such counts. However, the public health benefit of reduced HIV transmission supports starting antiretrovirals earlier.

Medical literature provides strong evidence for minimal risk of sexual transmission of HIV once viral suppression is achieved while on therapy, due decreased virus levels in genital secretions. The risk of HIV transmission among heterosexual sero-discordant couples in one study was estimated at 0.0 to 0.14 per 100 person-years during viral suppression. This meant that out of 1000 heterosexual sero-discordant couples having sex for a year, only one or two incidences of HIV transmission will occur for as long as the HIV-positive partner was on therapy and achieved viral suppression. Another, and perhaps the most significant, achievement of antiretroviral therapy is the prevention of transmission from mother to child. Starting therapy is presently recommended for all HIV-infected pregnant women. To achieve early diagnosis and treatment, health care providers are encouraged to educate all childbirth-eligible women with HIV on safe sexual practices, options for conception or contraception, and antiretroviral use during conception and pregnancy.

The choice of an antiretroviral regimen is tailored specifically for the individual to maximise treatment efficacy by promoting adherence and minimising risk of drug resistance, interactions with other medications, and adverse drug reactions. Adherence rates of greater than 95% result in best outcomes, while poor adherence may result in a reduced treatment response. Poor adherence may be a result of substance abuse, psychological illness, inaccessible healthcare services, absence of support systems, ignorance of HIV and benefits of treatment, or something as simple as having a complex medication regimen and schedule. Assessing a patient’s readiness to commit and adhere to a lifetime of medications should occur even before initiating therapy. Identifying barriers to adherence and addressing them throughout the course of treatment should be part of the regular visit to the doctor. The HIV-positive patient should be provided with basic knowledge about HIV disease, treatment and prevention, the treatment regimen, need for monitoring VL and CD4 counts, expectations during the course of healthcare, the importance of adherence, and the consequences of failure by the healthcare provider as a means to enhance compliance.

Failure to achieve an undetectable viral load should lead the healthcare provider to inquire about adherence to therapy, interactions with other medications or food that the patient is taking, trends of CD4 and VL values over time, and drug-resistance tests. Substance abuse, dependence, or addiction may be associated with psychiatric conditions such as anxiety and depression, the latter of which being one of the strongest predictors of poor adherence and poor treatment outcome. Addressing depression, providing risk-and harm-reduction strategies and an accessible, non-discriminatory and non-threatening environment for the substance user are practices that can promote adherence. Another subgroup of people living with HIV who may have issues with treatment adherence is the ageing HIV population. They may present with age-related conditions that complicate HIV management, engage in more risky behaviours due to the inconvenience of safe practices, and practice poly-pharmacy. Older people with HIV also possess weaker mucosal and immunologic defence mechanisms, resulting in a decreased immune recovery after illness, and present with an increased risk and prevalence of non-AIDS events such as cancer.

Probably the most common and most significant burden for a person living with HIV on treatment is the occurrence of adverse effects of the antiretroviral drug. Immediate and dramatic reactions to the medications such as rash, with some resulting in Stevens-Johnson syndrome, and hepatotoxicity are the more frequent complaints. These may be affected by concomitant use of medications with additive toxicities or drug interactions, a concurrent medical condition such as hepatitis that may exacerbate adverse effects, and genetic factors that predispose to hypersensitivity reactions. It is important that these adverse drug reactions be reported immediately to the physician for immediate resolution. The discontinuation of medications by the patient may result in drug resistance, and should be avoided. Communication with the healthcare provider is encouraged.

The achievement of HIV treatment goals entails teamwork from patients, their support systems, and healthcare providers. With this concerted effort and optimal drug adherence, the benefits of antiretroviral therapy are maximised and people living with HIV can expect to manage their chronic condition quite well.

Key Terms

DNA: DNA is like the “blueprint” for building living cells.

Enzymes: Enzymes build new proteins, transport materials around the cell, and carry out other important cellular functions.

RNA: Cells use RNA to tell enzymes how to build a specific part of a cell. To make a new protein, enzymes will copy a specific part of the DNA into a piece of RNA. This RNA is then used by other enzymes to build a new protein or enzyme.

Proteins: Building blocks used to make living things.

Nucleus: A small package inside the cell where the genetic material is kept.

CD4: A CD4 cell is a type of lymphocyte. Lymphocytes are a type of white blood cell and they are some of the most important cells in your immune system. There are two main types of lymphocytes are B-cells and T-cells. B-Cells are antibodies while T-Cells are divided into three groups:

  1. Helper T-Cells (also called T4 or CD4+ cells) help other cells destroy infective organisms.
  2. Suppressor T-Cells (also called T8 or CD8+ cells) suppress the activity of other lymphocytes so they don’t destroy normal tissue.
  3. Killer T-Cells (also called cytotoxic T lymphocytes, or CTLs, and are another kind of T8 or CD8+ cell) recognize and destroy abnormal or infected cells.

CD4 cells are responsible for signalling other immune system cells to fight an infection in the body. They are also the prime target of HIV which can cause the number of these cells to decrease over time. Too few CD4 cells means that the immune system will no longer functions like it is supposed to.


Entry Inhibitor

Entry inhibitors work by attaching themselves to proteins on the surface of CD4 cells or proteins on the surface of HIV. In order for HIV to bind to CD4 cells, the proteins on HIV’s outer coat must bind to the proteins on the surface of CD4 cells. Entry inhibitors prevent this from happening.

Nucleoside & Nucleotide Analogues (NRTIs)

NRTIs, sometimes called “nucleoside analogues” or “nukes,” contain faulty versions of the building blocks (nucleotides) used by reverse transcriptase to convert RNA to DNA. When reverse transcriptase uses these faulty building blocks, the new DNA cannot be built correctly. In turn, HIV’s genetic material cannot be incorporated into the healthy genetic material of the cell and prevents the cell from producing new virus.

While nucleotide analogues are technically different than nucleoside analogues, they act very much the same way. In order for nucleoside analogues to work, they must undergo chemical changes (phosphorylation) to become active in the body. Nucleotide analogues bypass this step, given that they are already chemically activated.

Non-Nucleosides Reverse Transcriptase (NNRTIs)

NNRTIs, also known as “non-nucleosides” or “non-nukes” for short, attach themselves to reverse transcriptase and prevent the enzyme from converting RNA to DNA. In turn, HIV’s genetic material cannot be incorporated into the healthy genetic material of the cell, and prevents the cell from producing new virus.

Integrase Inhibitors

After the “reverse transcription” of RNA into DNA is complete, HIV’s DNA must then be incorporated into the CD4 cell’s DNA. This is known as integration. As their name implies, integrase inhibitors work by blocking this process.

Protease Inhibitors (PIs)

When HIV infects a CD4 cell in a person’s body, it copies its own genetic code into the cell’s DNA. The CD4 cell is then “programmed” to make new HIV genetic material and HIV proteins. The proteins must be cut up by the HIV protease—a protein-cutting enzyme—to make functional new HIV particles. PIs block the protease enzyme and prevent the cell from producing new viruses.

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REFERENCES

  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
    Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 20/11/2014.
  2. Samji H, Cescon A, Hogg RS, Modur SP, Althoff KN, et al. (2013) Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada. PLoS ONE 8(12): e81355.
  3. Tsibris AMN and Hirsch MS. Antiretroviral Therapy for Human
    Immunodeficiency Virus Infection. In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Disease Mandell, 7th ed (pp 1833-1853) Philadelphia: Churchill Livingstone.

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