AIDS medical therapy

Overview
Acquired immune deficiency syndrome (AIDS) is a collection of symptoms and infections resulting from the specific damage to the immune system caused by the human immunodeficiency virus (HIV) in humans, and similar viruses in other species (SIV, FIV, etc.)

Anti-HIV medications (also called antiretrovirals) are grouped into six drug classes according to their mechanism of action. The six classes are as follows:


 * 1) Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
 * 2) Nucleoside reverse transcriptase inhibitors (NRTIs).
 * 3) Protease inhibitors (PIs).
 * 4) Fusion inhibitors.
 * 5) CCR5 antagonists.
 * 6) Integrase inhibitors.

Multidrug regimen has proved to be very beneficial because of reduction in progression to AIDS, opportunistic infections, rate of hospitalizations and deaths.

Goals of therapy
DHHS ART Guidelines present the following goals for therapy:
 * Durable suppression of HIV viral load ( to <50 cells/mL ).
 * Restoration of normal CD4 cell count.
 * Prevention of transmission of the disease.
 * Prevention of building of drug resistance.
 * Improvement in quality of life of the patient.

Uncontrolled viremia causes inflammation and immune activation, which has an overall effect on cardiovascular, renal and hepatic systems. Controlling viremia also controls these effects.

Indications
The DHHS guidelines currently recommend the follwing:

A. US Department of Health and Human Services (DHHS)
DHHS have published guidelines for initial ART based on data from randomized controlled trials. Current optimal HAART options consist of combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents.

Typical regimens consist of: Following regimens are recommended by DHHS:
 * Two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) PLUS
 * Either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI).
 * An NNRTI, efavirenz plus 2 NRTIs OR


 * A boosted PI: atazanavir (ATV/r) once daily or darunavir (DRV/r) once daily plus 2 NRTIs OR


 * An integrase inhibitor, raltegravir (400 mg twice daily) with 2 NRTIs.

The recommended NRTI coformulation is tenofovir/emtricitabine (TDF/FTC) in all of the above combinations. In treatment-naive patients, four drug regimen is not found to be more efficacious than three-drug regimens and is associated with more adverse events.

B. International AIDS Society-USA (IAS-USA) guidelines
In agreement with the DHHS guidelines mentioned above, IAS-USA recommend the following:
 * Fixed-dose TDF/FTC as the preferred NRTI for combination ART.
 * If HLA B5701 testing is negative, then abacavir/lamivudine is used as an alternative choice.

Treatment-naive patients
The DHHS Guidelines recommend that therapy should be initiated in the following patient populations:


 * Patients with history of an AIDS-defining illness or with a CD4 count of less than 350/µL.


 * Pregnant women with HIV infection.


 * Patients with HIV-associated nephropathy.


 * Patients with HIV and hepatitis B virus (HBV) coinfection who require treatment for HBV infection.

Fusion inhibitors (eg, enfuvirtide) are not approved for treatment-naive patients.

Treatment-experienced patients
Treatment failure is defined by the following factors:
 * Virologic failure: which is defined as suboptimal viral suppression or loss of suppression (>50 HIV-1 RNA copies/mL).


 * Immunologic failure : which is defined as failure to achieve or maintain CD4 cell count recovery despite effective viral suppression.


 * Development of new opportunistic infections or neoplasms despite apparent CD4 count recovery.

Initial HIV therapy
NNRTI, PI, or integrase inhibitor-based regimen in combination with dual NRTIs is considered as an initial HIV therapy. Currently, CCR5 inhibitors are not recommended due to lack of sufficient published data. The particular choice of agent depends on the following factors:
 * Side effect profiles.
 * Comorbidities in patient.
 * Potential drug interactions.
 * Allergy history.
 * Pregnancy status.
 * Patient convenience.

Highly Active Anti-Retroviral Therapy

 * Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART. This has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available.


 * In developed countries where HAART is available, doctors assess the viral load, rapidity in CD4 decline, and patient readiness while deciding when to recommend initiating treatment.


 * In the absence of HAART, progression from HIV infection to AIDS occurs at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.


 * HAART is thought to increase survival time by between 4 and 12 years. This average reflects the fact that for some patients – and in many clinical cohorts this may be more than fifty percent of patients – HAART achieves far less than optimal results. This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV.
 * Non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to get any benefit from and develop resistance to HAART.
 * The side effects include lipodystrophy, dyslipidaemia, insulin resistance, an increase in cardiovascular risks and birth defects.

Special Considerations

 * HAART allows the stabilization of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped. Moreover, it would take more than the lifetime of an individual to be cleared of HIV infection using HAART. Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality.

HIV in children
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 are more aggressive for children than for adults.

Alternate Therapies
Various forms of alternative medicine have been used to treat symptoms or alter the course of the disease. In the first decade of the epidemic when no useful conventional treatment was available, a large number of people with AIDS experimented with alternative therapies. The definition of "alternative therapies" in AIDS has changed since that time. Then, the phrase often referred to community-driven treatments, untested by government or pharmaceutical company research, that some hoped would directly suppress the virus or stimulate immunity against it. Examples of alternative medicine that people hoped would improve their symptoms or their quality of life include massage, stress management, herbal and flower remedies such as boxwood, and acupuncture; when used with conventional treatment, many now refer to these as "complementary" approaches. Despite the widespread use of complementary and alternative medicine by people living with HIV/AIDS, the effectiveness of these therapies has not been established.

Treatment Adherence
Adherence is taking the correct dose of each anti-HIV medication at the correct time and exactly as prescribed. Adherence is very important for successful HIV treatment. The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues, along with side effects that create intentional non-adherence, also has a weighty impact.

Difficulty in adherence
There are several reasons why adhering to an HIV treatment regimen can be diicult. Most treatment regimens involve taking several pills every day with or without food, or before or after other medications. Other factors that can make treatment adherence diicult include:
 * Diiculty taking medications (such as trouble swallowing pills).
 * Side efects from medications (for example, fatigue or diarrhea).
 * Daily schedule issues (including a busy schedule, shift work, or travel away from home).
 * Being sick or depressed.
 * Alcohol or drug abuse.

Importance of adherence
Adherence afects the success of HIV treatment in two ways:
 * Good adherence to an HIV treatment regimen helps anti-HIV medications work efectively to reduce the viral load. Skipping medications, even occasionally, gives HIV to multiply rapidly. Preventing the virus from multiplying is the best way to stay healthy.
 * Good adherence to an HIV treatment regimen also helps prevent drug resistance. One or more anti-HIV medications in a treatment regimen can become inefective as a result of drug resistance.

Skipping medications makes it easier for drug resistance to develop. HIV can develop resistance to the anti-HIV medications in a person’s current regimen or to other, similar anti-HIV medications not yet taken, limiting options for successful HIV treatment. And drug-resistant strains of HIV can be transmitted to others, too. Although there are many diferent anti-HIV medications and treatment regimens, studies show that a person’s first regimen ofers the best chance for long-term treatment success. Adhering to the regimen from the start will help ensure that the HIV treatment is successful.

Patient monitoring during antiretroviral therapy
A patient monitoring system is the backbone of clinical care, treatment and prevention by the clinical team caring for groups of patients.

Visit Frequency
Patients who are started on ART should generally have follow-up within one to two weeks. Patient should be asked about the following:
 * Adverse effects.
 * Adherence.
 * Prevention of transmission.

Visit frequency of patients who are clinically stable on their ART regimen, can be decrease to every three months.

General laboratory investigations
The following lab tests are adviced at baseline and at scheduled follow-up:


 * Complete blood count with differential
 * BUN and creatinine
 * Liver function tests

More frequent testing is indicated in the following conditions:
 * If mild or moderate abnormalities are detected and the medication is continued.
 * Depending on the drug prescribed
 * In patients on nevirapine, some experts recommend monitoring at 0, 2, 4, 8, 12 weeks and then every 3 months.
 * Women in childbearing age-group, should have a pregnancy test, before initiation of potential teratogenic drugs like efavirenz.
 * In patients taking zidovudine, hematologic monitoring is important as the drug causes bone marrow suppression.
 * In patients taking tenofovir, which can cause renal insufficiency, monitoring of creatinine and urinalysis every six months is necessary.

Virologic Response
The most reliable indicator of response to ART is plasma HIV RNA and should be measured in all patients at baseline and regularly during therapy. It is thus useful in predicting clinical progression.

Viral load reduction may be more rapid in following patients:
 * Having high CD4 cell count.
 * Having lower levels of baseline viremia.
 * In treatment-naive patients.

Transient increase in the viral load can be present in acute illness and vaccinations.

Virologic failure
It is defined either as primary failure to achieve a viral load <50 copies/mL or any sustained recurrence of viremia to >50 copies/mL after initial viral suppression.

Two main causes of the failure are:
 * 1) Drug resistance.
 * 2) Failure of the drugs to reach the target site.

Viral blips
It refer to an isolated low-level of detectable HIV RNA (>50 to 500 copies/mL) that occurs during long-term monitoring on a stable ART regimen.

Department of Health and Human Services (DHHS) have suggested that viral blips do not require intervention with a new regimen unless the viral load is sustained at >200 copies/mL.

Indications for modification of therapy
Common indications for the change of therapy are as follows:
 * Virologic failure : It should be confirmed with a second test before any treatment modification is considered.
 * Toxicity
 * Intolerance
 * Inconvenience

Related Chapters

 * HIV Treatment
 * Antiretroviral drug
 * Antiretroviral therapy in pregnancy
 * Immune reconstitution inflammatory syndrome