Introduction

NNRTIs pictureIt is estimated that approximately 38.6 million people worldwide are currently living with human immunodeficiency virus (HIV) infection. HIV infection specifically affects a certain type of white blood cell, known as CD4+ T cells which is essential for a functioning immune system. If left untreated, HIV will eventually compromise all CD4+ T cells in an individual, causing widespread immune dysfunction and making them vulnerable to a wide range of other infections, disorders and cancers. While the diagnosis of being “HIV-positive” refers to the presence of HIV replicating in the bloodstream, AIDS (acquired immunodeficiency syndrome) is an advanced stage of HIV infection, where the CD4+ T cell counts drop too low (generally, below 200 cells per microlitre of blood). At this point, individuals with HIV are at high risk of developing a wide range of “AIDS defining conditions” that emerge due to the low level of immune cells, such as the HIV wasting syndrome, certain types of pneumonia and Kaposi’s sarcoma (a type of tumour on the skin caused by human herpes virus), amongst others.

HIV infection cannot be cured. However, the infection can be controlled using a class of drugs known as antiretrovirals (ARVs). ARVs are the best available treatment for HIV and it has been proven that complying with antiretroviral therapy (ART) reduces the rate of AIDS-defining conditions and the rate of death due to HIV/AIDS.

There is a wide range of ARV drugs available. ART regimens vary from person to person, depending on resistance of that particular HIV strain to different drugs, how well it can be tolerated, how it interacts with other medications or illnesses the person may have, cost, and individual preference. There are four main classes of ARV drugs, namely:

  • Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and tenofovir;
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine, delavirdine, efavirenz and etravirine;
  • Protease inhibitors (PI) such as saquinavir mesylate, fortovase, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, atazanavir, tipranavir and darunavir; and
  • Drugs that interfere with viral entry into host cells such as fusion inhibitors (enfuvirtide) and CCR5 antagonists (aplaviroc, vicriviroc and maraviroc).

The World Health Organization (WHO) recommends all people with HIV who are eligible for treatment receive a combination of two types of ARV drugs. As a first-line therapy, this is generally two NRTIs and a NNRTI. Second-line ART therapy generally consists of a ritonavir-boosted protease inhibitor, plus two NRTIs. However, consulting with a specialist to determine the most appropriate combination of ARVs is essential.

If a HIV infection is susceptible to the prescribed ARV regimen and the drugs are taken as directed, the replication of the HIV virus is reliably suppressed in 80% of cases who have not received ARV treatment before. If an individual does not take the medications as directed (taking them occasionally or intermittently), then this benefit cannot be guaranteed and a treatment-resistant HIV strain is more likely to emerge. This can make future treatment of the infection much more difficult.


How does it work?

Once the HIV virus enters the bloodstream it can commence its reproductive cycle, known as viral replication. HIV binds to certain receptors on the surface of a CD4+ T cell. Using these receptors it can introduce itself into the immune cell, where it moves into the cell nucleus and inserts itself into the human DNA strand through the use of specific viral enzymes such as viral reverse transcriptase and viral integrase. Once it is incorporated into human DNA, the virus can then exploit the cell’s own machinery to manufacture more infective HIV particles, with the help of yet another HIV-derived enzyme called viral protease. These new particles are released into the bloodstream to invade more CD4+ T cells. As more and more cells are invaded, the HIV replication cycle increases exponentially, eventually expending all normal CD4+ T cells and leaving the individual without a normal immune defence system.

All ARV drugs target a particular step in this HIV replication cycle. NRTIs were the first drug classes licensed for treating HIV. As their name implies, they target the HIV viral reverse transcriptase, slowing the integration of the HIV nucleic acid into the human DNA strand. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) act in a similar fashion, albeit in a slightly different location on the same enzyme. By using NRTIs and NNRTIs together, researchers have discovered these two classes of drugs have a synergistic effect (where the combined effect of the drugs is greater than the sum of the effects of the drugs when they are used alone) on reducing HIV replication.


For more information on the other classes of anti-retroviral therapies, see Antiretroviral Therapy (Anti-HIV Drugs).


How well does it work?

NNRTIs pictureOn the whole, NNRTIs are very effective for reducing HIV replication when used in combination with NRTIs; however, they are not without their side effects. The main NNRTIs recommended by the WHO in guidelines for treating HIV are efavirenz and nevirapine, as well as the newer drugs etravirine and rilpivirine. These drugs are all generally used in combination with NRTIs.

WHO guidelines recommend that HIV-positive individuals who have not taken ARV drugs before should receive two NRTIs (preferably zidovudine or tenofovir, plus lamivudine) and either efavirenz or nevirapine as a first-line therapy. The WHO also recommends that HIV-infected pregnant women receive zidovudine plus lamivudine (NRTIs) with either nevirapine or efavirenz as a first-line therapy. However, efavirenz should not be initiated in the first trimester because it has been shown to carry a risk of malformation to a developing foetus.

When studying how effective an ARV drug is, investigators often measure the CD4+ T cell count in people before, during and after treatment. Because infection with HIV generally destroys CD4+ T cells, an effective treatment will result in the treated individual’s CD4+ T cell count increasing. Another way of assessing the effectiveness of an ARV drug is to measure how many viral particles can be detected in a blood sample taken from an individual. Because an effective ART will prevent the virus from replicating, the amount of virus detected in an individual after receiving treatment should decrease.


Efavirenz

Two major clinical trials of efavirenz have demonstrated that it is an effective treatment for HIV infection when added to other NRTIs. One trial of 1,266 patients compared three different combinations of ARV drugs and found that when patients received efavirenz as part of their treatment, HIV levels at approximately 1 and 3 years were significantly lower than for those who did not. Another trial was conducted in 196 patients who had previously received other ARV drugs – the researchers found that efavirenz use was associated with an increase in the levels of CD4+ T cells, as well as better suppression of the HIV infection after 48 weeks of treatment.


Nevirapine

Two trials of nevirapine established its effectiveness. 2,249 patients in a randomised trial comparing nevirapine, lamivudine and background therapy consisting of other standard ARV drugs, to lamivudine alone plus background therapy. The addition of nevirapine to background therapy (with lamivudine) was associated with significantly greater improvements in CD4+ cell counts after 1 year of therapy. After 2 years, patients who used nevirapine had lower rates of progressing to AIDS or death. In a smaller trial of nevirapine with zidovudine and didanosine, the addition of nevirapine made HIV suppression more effective (after 48 weeks). Yet another trial examined nevirapine use in children. 47% of children with HIV (3 months to 16 years of age) who received 48 weeks of nevirapine therapy had a HIV level of less than 400 copies/mL.


Etravirine

Two large trials of etravirine are currently ongoing; however, the benefit of etravirine after 48 weeks has been seen in both of these trials. Of individuals receiving etravirine, 70.8% achieved a HIV level of < 400 copies/mL, compared to only 46.4% of patients receiving placebo. The average CD4+ cell count also increased following etravirine use over placebo.


Rilpivirine

Two similar trials of rilpivirine have established that after 48 weeks of treatment, the average CD4+ cell count increase from baseline (the cell count observed before beginning treatment) was greater for individuals with rilpivirine added to their treatment regimens, compared to those without. 


Side effects

Use of ARV drugs is not without its side effects, and these can vary depending on the ARV used.

Efavirenz

The most significant side effects following efavirenz use are dizziness, nausea, headache, fatigue and rash. In trials, nearly 20% of individuals using efavirenz experienced moderate to severe nervous system symptoms, compared to 9% in the groups not using efavirenz. Similarly, 26% of treated adults experienced a new-onset rash after starting treatment, compared to 17% in control groups. The rate of rash reached 46% in children. Rarely, serious psychiatric side effects can occur, such as severe depression, paranoia and mania.

Nevirapine

The rate of side effects following nevirapine treatment are similar in adults and children. The most common are rash, fever, nausea, headache, fatigue, tiredness, vomiting, diarrhoea, abdominal pain and muscle pain. Rash is the most frequent; however, it is usually mild or moderate and occurs only 9% of the time. Nevirapine can rarely adversely effect the liver, so individuals starting on nevirapine should have their liver function checked 6 weeks after commencing therapy.

Etravirine

Etravirine use in clinical trials was most commonly associated with rash (10% of people treated), which was generally mild or moderate and more common in women. Other side effects include diarrhoea (7.0%), high triglyceride levels (6.3%) and nausea (5.2%).

Rilpivirine

The most common side effects after starting rilpivirine were depression (3.5%), rash (3%), insomnia (2.9%), headache (2.6%), nausea (1.2%) and dizziness (0.7%). Decreased levels of the stress hormone cortisol and increased serum creatinine (associated with decreased kidney function) and serum lipids have also been recorded.


Conclusion

Several trials of NNRTI use are still ongoing, particularly exploring the newer NRTIs (such as etravirine and rilpivirine) and the risks and benefits of different combinations of NRTIs and NNRTIs. It is important that the appropriate ARV regimen for HIV treatment is carefully selected, depending on medical history, other illnesses, prior HIV treatment, stage of the infection and individual preferences. People with HIV are strongly advised to work with a specialist HIV service to optimise their treatment.

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