Antiretroviral Therapy for HIV and AIDS

Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs act at different stages of the HIV life cycle.

Combination of several (typically three or four) antiretroviral drugs is known as Highly Active Anti-Retroviral Therapy (HAART).

Classes of antiretroviral drugs
Antiretroviral drugs are broadly classified by the phase of the retrovirus life-cyle that the drug inhibits. There are thus five broad classifications of antiretroviral drugs in development, though only the first three classes currently have licensed examples:
* Reverse transcriptase inhibitors (RTIs) target construction of viral DNA by inhibiting activity of reverse transcriptase. There are two subtypes of RTIs with different mechanisms of action: nucleoside-analogue RTIs are incorporated into the viral DNA leading to chain termination, while non-nucleoside-analogue RTIs distort the binding potential of the reverse transcriptase enzyme;
* Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for final assembly of new virons;
* Fusion inhibitors block HIV from fusing with a cell's membrane to enter and infect it;
* Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial but none are commercially available;
* Entry inhibitors block HIV-1 from the host cell by binding CCR5, a molecule on the viral membrane termed a co-receptor that HIV-1 normally uses for entry into the cell;

Fixed dose combinations
Fixed dose combinations are multiple antiretroviral drugs combined into a single pill.

Synergistic enhancers
Synergistic enhancers usually do not possess any antiretroviral properties alone, but when they are taken concurrently with antiretroviral drugs they enhance the effect of that drug. These include ritonavir. Ritonavir is per se an antiretroviral drug which belongs to the class of protease inhibitors. It can however be administered at a "baby" dosage to reduce the liver metabolism of other antiretroviral drugs. This principle was first exploited in the drug Kaletra (Abbott), which is a combination of ritonavir with the protease inhibitor lopinavir at a ratio (v/v) of 1:5. Ritonavir is also used as an enhancer of other protease inhibitors such as saquinavir and atazanavir, and of the investigational integrase inhibitor, GS-9137. Other synergistic enhancers are being investigated for this purpose.

Combination therapy
The life cycle of HIV can be as short as about 1.5 days: from viral entry into a cell; through replication, assembly, and release of additional viruses; to infection of other cells. HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Its short life cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability of HIV. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more active copies of the virus, the greater the possibility that one resistant to antiretroviral drugs will be made, so antiretroviral combination therapy defends against resistance by suppressing HIV replication as much as possible.

Combinations of antiretrovirals create multiple obstacles to HIV replication to keep the number of offspring low and reduce the possibility of a superior mutation. If a mutation arises that conveys resistance to one of the drugs being taken, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result the standard of care is to use combinations of antiretroviral drugs. Combinations usually comprise two nucleoside-analogue RTIs and one non-nucleoside-analogue RTI or protease inhibitor.

Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations. For example, ddI and AZT inhibit each other, so taking them together is less effective than taking either one separately. Other issues further limit some people's treatment options from antiretroviral drug combinations, including their complicated dosing schedules and often severe side effects.

In recent years drug companies have worked together to combine these complex regimens into simpler formulas, termed fixed dose combinations. For instance, two pills containing two or three medications each can be taken twice daily. This greatly increases the ease with which they can be taken, which in turn increases adherence, and thus their effectiveness over long term. Lack of adherence is a primary cause of resistance development in medication-experienced patients. The highly mutanegenic nature of HIV demands 98% adherence to drug cocktails for the drugs to be totally effective (that means missing less than 6 doses per year).[citation needed] Patients able to adhere at this rate and higher can maintain one regimen for up to a decade without developing resistance. This greatly increases chances of long-term survival, as it leaves more drugs available to the patient for longer periods of time.

According to Reference 5 below, "HIV treatment should reduce your viral load to the point at which it is undetectable. An undetectable viral load does not mean that your HIV infection is gone; it simply means that the test is not sensitive enough to detect the small amount of HIV left in your blood," and "Successful HIV treatment can lower your viral load, which may reduce the risk of HIV transmission."

Current treatment guidelines
Antiretroviral drug treatment guidelines have changed many times. Early recommendations attempted a "hit hard, hit early" approach. A more conservative approach followed, with a starting point somewhere between 350 and 500 CD4+ T cells/mm³. The current guidelines use new criteria to consider starting HAART, as described below. However, there remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the patient and their doctor.

The current guidelines for antiretroviral therapy (ART) from the World Health Organization reflect the 2003 changes to the guidelines and recommend that in resource-limited settings (that is, developing nations), HIV-infected adults and adolescents should start ART when HIV infection has been confirmed and one of the following conditions is present):
* Clinically advanced HIV disease;
* WHO Stage IV HIV disease, irrespective of the CD4 cell count;
* WHO Stage III disease with consideration of using CD4 cell counts less than 350/µl to assist decision making;
* WHO Stage I or II HIV disease with CD4 cell counts less than 200/µl;

The treatment guidelines in the USA are set by the United States Department of Health and Human Services (DHHS). The current guidelines for adults and adolescents were stated on October 6, 2005:
* All patients with history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4+ T cell count receive ART;
* Antiretroviral therapy is also recommended for asymptomatic patients with less than 200 CD4+ T cells/µl;
* Asymptomatic patients with CD4+ T cell counts of 201 - 350 cells/µl should be offered treatment;
* For asymptomatic patients with CD4+ T cell of greater than 350 cells/µl and plasma HIV RNA greater than 100,000 copies/ml, most experienced clinicians defer therapy but some clinicians may consider initiating treatment;
* Therapy should be deferred for patients with CD4+ T cell counts of greater than 350 cells/µl and plasma HIV RNA less than 100,000 copies/mL;

The preferred initial regimens are:
* efavirenz + zidovudine + lamivudine;
* efavirenz + tenofovir + emtricitabine;
* lopinavir boosted with ritonavir + zidovudine + lamivudine;
* lopinavir boosted with ritonavir + tenofovir + emtricitabine;

In countries with a high rate of baseline resistance, resistance testing is recommended prior to starting treatment; or, if the initiation of treatment is urgent, then a "best guess" treatment regimen should be started which is then modified on the basis of resistance testing. In the UK, there is 11.8% medium to high level resistance at baseline to the combination of zidovudine + lamivudine + efavirenz, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine.

Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations from the DHHS have been more aggressive in children than in adults.

In 2005, the Centers for Disease Control and Prevention in the United States recommended a 28-day HIV drug regimen for those who have been exposed to HIV (HIV Postexposure Prophylaxis [PEP]). The drugs have demonstrated effectiveness in preventing the virus nearly 100% of the time in those who received treatment within the initial 24 hours of exposure. The effectiveness falls to 52% of the time in those who are treated within 72 hours; those not treated within the first 72 hours are not recommended candidates for the regimen.

Related topics
* Sexual Health Advice & Leaflets