The human immunodeficiency virus (HIV) attacks the body’s immune cells, specifically the CD4+ T-cells (lymphocytes). The virus replicates within these immune cells and destroys it. In this way the body’s immune defenses are gradually diminished over months and years until a point is reached where the immune protection is almost totally depleted. This late stage is known as acquired immune deficiency syndrome (AIDS). Although HIV/AIDS is incurable, certain types of drugs can slow down the virus from replicating and therefore save the body’s immune defenses for a longer period of time. It essentially retards the infection but cannot stop it altogether. These drugs are known as antiretroviral drugs or ARVs.

What are antiretroviral drugs?

Antiretroviral drugs (ARVs) are pharmaceutical substances that are active against the human immunodeficiency virus (HIV) and are useful in treating acquired immunodeficiency syndrome (AIDS). By doing so, these drugs slow down the progression of the infection. These drugs have become more effective with ongoing research and advancements in HIV treatment. Several new antiretroviral drugs are available now and some of the older antiretroviral drugs are less used at present due to safety concerns or inferior activity against the virus.

When to use ARVs?

The progression of the HIV is monitored the amount of viral genetic material (HIV RNA) in the blood and the CD4+T-cell count. It has been found that the risk of disease progression is low in the short term when :

  • CD4+ cell count is more than 350 cells/mm3, and
  • plasma HIV RNA count is below 50,000 copies/mL

The aim of antiretroviral therapy is to :

  • increase the CD4 count above 350 cells/mm3, and
  • suppress the HIV multiplication as long as possible – reflected by the reduction in plasma HIV RNA concentration below 50,000 copies/ml and preferably to undetectable levels of less than 50 copies/ml.

An effective antiretroviral therapy also aims at preventing resistance in the virus and of HIV-related complications.

Different Types of ARVs

Three established classes of antiretroviral drugs and three newer less established antiretroviral drug classes are currently approved for use. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs) are the well established classes of antiretroviral drugs, while the newer classes include fusion inhibitors, CCR5 antagonists, and HIV integrase inhibitors. Almost all the available antiretroviral drugs can only prevent infection of susceptible cells of the patient while these drugs have no impact on cells that are already infected by HIV. Emergence of drug resistance is common with treatment using single drug (monotherapy) and hence multidrug therapy (combination therapy) is the standard treatment approach.

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

NRTIs inhibit the HIV reverse transcriptase enzyme which is responsible for conversion of viral RNA into DNA. This DNA is incorporated into the infected person’s cell chromosome and the human immune cell is utilized as a host to produce new virus particles.

List of Names

NRTIs also terminate the elongation of DNA synthesized by the virus. Most of NRTIs are active against both HIV-1 and HIV-2. The available NRTIs include :

  • emtricitabine
  • lamivudine
  • tenofovir
  • abacavir
  • stavudine
  • zidovudine
  • didanosine
  • zalcitabine

Of all the NRTIs currently available tenofovir alone is a nucleotide while all other NRTIs are nucleosides. Tenofovir requires phosphorylation only twice to get activated compared to nucleosides which require phosphorylation thrice. Resistance to NRTIs can develop due to mutations.

Side effects

  • anemia
  • bone marrow suppression which is most severe with zidovudine
  • peripheral neuropathy which is most severe with stavudine, didanosine and zalcitabine
  • myopathy
  • cardiomyopathy
  • pancreatitis
  • hyperpigmentation which is common with emtricitabine and zidovudine
  • rash
  • fever
  • nausea
  • vomiting
  • diarrhea
  • flatulence
  • headache
  • dyspnea
  • fatigue
  • optic neuritis
  • abnormal cholesterol levels
  • insulin resistance

Rarely some of the NRTIs can cause lactic acidosis (more with stavudine and zidovudine), neuromuscular weakness (more with stavudine), mucosal ulceration (more with zalcitabine), fat wasting (with stavudine), renal dysfunction (with tenofovir), liver enlargement, fatty liver and myocardial infarction.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

The NNRTIs directly and noncompetitively inhibit the reverse transcriptase enzyme similar to the NRTIs. Unlike the NRTIs though, the NNRTIs do not require activation. NNRTIs are minimally active against HIV-2. The virus can develop rapid resistance against NNRTIs if administered alone.

List of Names

  • efavirenz
  • nevirapine
  • rilpivirine
  • etravirine
  • delavirdine

Side effects

NNRTIs are generally associated with high incidence of :

  • skin rash
  • gastrointestinal disturbances

Rarely these drugs are involved in severe rash such as erythema multiforme and Stevens-Johnson syndrome. Other possible adverse effects are :

  • headache
  • fatigue
  • nausea
  • vomiting
  • diarrhea
  • raised liver enzyme levels
  • high cholesterol levels.

NNRTIs (prominently efavirenz) are associated with central nervous system adverse effects like dizziness, drowsiness, insomnia and psychiatric symptoms like depression and psychosis. Nevirapine can occasionally cause fatal hepatitis. NNRTIs are also involved in numerous drug interactions with other antiretroviral drugs which limit extensive use of the group in combination therapy.

Moderate to severe hepatic impairment is a contraindication for use of drugs like nevirapine. Efavirenz is contraindicated in first trimester of pregnancy and in women with significant childbearing potential.

Protease Inhibitors

Protease is an enzyme responsible for cutting large protein molecules to produce the smaller structural proteins of the mature virus. Protease inhibitors prevent the processing of the viral proteins into functional components. This results in the production of non-pathogenic viral particles which are harmless to the host. Protease inhibitors have activity against both HIV-1 and HIV-2. Development of resistance is common when used alone and hence it is always used in combination.

List of Names

Important protease inhibitors currently available include :

  • atazanavir
  • darunavir
  • indinavir
  • amprenavir
  • fosamprenavir
  • lopinavir
  • nelfinavir
  • tipranavir
  • ritonavir
  • saquinavir

Ritonavir causes inhibition of liver enzymes resulting in reduced metabolism of other drugs and for this reason ritonavir is usually combined with other antiretroviral drugs to improve the effects of these drugs. Fatty meal can improve absorption of some protease inhibitors like nelfinavir and lopinavir.

Side effects

Long term use of protease inhibitors (except atazanavir) is associated with central obesity, buffalo hump (fat deposition in the back of neck), increased cholesterol and blood sugar levels. Other adverse effects are diarrhea, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, abnormal sensations (paresthesias), reduced white blood counts, increased liver enzymes and skin rash. Increased bilirubin is seen with atazanavir and indinavir. Kidney stones and crystaluria are common with indinavir. Another major concern with use of protease inhibitors is the high potential for drug interactions (most prominent with ritonavir).

Fusion inhibitors

Fusion inhibitors are a group of drugs that block the entry of the virus into the cells of the affected individual (host). The drugs that block entry of virus to host cell are generally called as entry inhibitors. The entry of the virus into the host cell is complex. It involves binding of viral glycoprotein envelope to CD4 receptor of the host cell, conformational changes of the viral envelope, fusion of the viral envelope to the host cell membrane and finally the entry of the viral particle into the host cell.

Enfuvirtide is the only currently available fusion inhibitor. It prevents fusion of the viral and cellular membranes. It is only active against HIV-1. Unlike other antiretroviral drugs enfuvirtide is administered by subcutaneous injections and it has to be given twice daily. Virus can develop resistance to enfuvirtide through mutation.

The high cost of the drug, the need for administering the drug by injection twice daily, and high incidence of local reactions has not made the drug popular. The drug is generally reserved for HIV-1 patients who are not responding to regular antiretroviral regimens.

Injection site reactions like pain, redness and swelling are the most important side effects of the fusion inhibitor enfuvirtide. The use of the drug is also known to cause enlargement of lymph nodes and increased incidence of pneumonia. Hypersensitivity reactions are also seen with enfuvirtide. Hypersensitivity to the drug is a contraindication for enfuvirtide.

CCR5 receptor antagonist

CCR5 receptor antagonists also prevent entry of virus into the host cell like fusion inhibitors. Maraviroc is the only currently available CCR5 antagonist. Maraviroc is useful against HIV-1. Resistance for maraviroc can result from mutations.

Adverse effects of CCR5 receptor antagonists include diarrhea, upper respiratory tract infections, fever, rash, abdominal pain, cough, muscular and joint pain, disturbances in sleep, and elevation of liver levels. Maraviroc is contraindicated in patients with severe renal dysfunction.

HIV integrase inhibitors

HIV integrase is an enzyme essential for the replication of the HIV. Raltegravir is the only available HIV integrase inhibitor at present. It is approved for use in treatment in HIV-1 patients resistant to multiple drug regimens. Mutations can lead to resistance against raltegravir.

Diarrhoea, dizziness, nausea, vomiting and headache are some of the possible adverse effects of raltegravir. Creatine phosphokinase can be elevated with its use.


Article reviewed by Dr. Greg. Last updated on February 24, 2012