HIV: Where Are We Now?

Clinical Management of HIV

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Early Identification of HIV Infection

One of the most important factors that influence patient outcomes is early identification of HIV infection. Too often patients present to the clinic or emergency department with complaints of symptoms consistent with any viral illness. The most common symptoms of HIV infection include fever, headache, rash, fatigue, anorexia, pharyngitis, lymphadenopathy, nausea, vomiting, and diarrhea. If HIV is not suspected or considered in the differential diagnosis, the patient will be sent home with the usual instructions: rest, drink plenty of fluids, and take Tylenol as needed for fever. After about one week symptoms may resolve with no further treatment, and the patient can resume their normal activities of daily life. If these activities include unprotected sex or intravenous drug use, new cases of HIV infection will occur. The importance of taking a complete assessment for HIV risk factors can't be overemphasized. Patients don't usually volunteer personal information unless asked. Someone coming in for a symptomatic illness may not think to tell you about a recent divorce or change in relationship. They will focus on the current problem.

A person who is newly infected with HIV can live eight to ten years with no distinct symptoms of the illness. They may have a cold more often than their co-workers or take longer to recover from an infection, but overall they continue to look healthy until one day they become very sick and eventually a diagnosis of HIV infection is made. Patients who are diagnosed at later stages of the disease usually have Acquired Immune Deficiency Syndrome or AIDS. This is a condition caused by HIV which involves symptoms consistent with severe suppression of the immune system. Patients with AIDS are at risk for developing opportunistic infections. These infections are caused by pathogens that are ubiquitous in the environment and only cause illness when the immune system is too compromised to prevent infection.

Two markers are monitored to determine the prognosis of the patient with HIV. The first, the T lymphocytes or CD4 count is a marker of the prognosis of the patient. This provides a rough estimate of the condition of the immune system. Lower values are indicative of more severe immune suppression. In clinical practice, these values are used to determine the need for antiretroviral therapy and prophylaxis against opportunistic infections. Usual normal laboratory values for CD4 counts range from 350- 1200 cells/mm3. When someone reaches 200 cells/mm3 their classification changes from HIV to AIDS. There are other illnesses that are considered to be AIDS defining and also change a person's status from HIV to AIDS. These include, but are not limited to:

• Candidiasis of the lungs, esophagus or trachea
• Cytomegalovirus of the eye
• HIV associated dementia
• Invasive cervical cancer
• Kaposi's sarcoma
• Pneumocystis pneumonia
• Progressive multifocal leukoencephalopathy
• Toxoplasmosis of an internal organ

The second marker is the HIV viral load (VL). This value is an estimation of the number of copies of HIV in the body. Since it is estimated rather than an actual number, it may vary from day to day and/or from morning to night. Patients should be reassured if this happens.

Antiretroviral Therapy (ART)

The decision to initiate ART is based on a number of factors. While there are recommendations for the use of ART meant to guide treatment, patients should be evaluated personally before making the decision when to treat and what to treat with. In many instances, these decisions will be based not only on medical facts, but also on mental health and socioeconomic variables. The most efficacious treatment will not be effective if the person is not adherent with dosing directions. Missing doses of ART can lead to viral resistance, not only to the one medication missed, but also to other ART medications in the same or other classes of drugs. This phenomenon is known as "cross resistance." Prior to beginning any ART, patients should be educated about the medication, possible adverse side effects, the importance of adherence, and potential drug-drug or drug-food interactions. Whenever possible, regimens should be chosen to best meet the needs of the individual.

Classes of Antiretroviral Medication

There are currently five classes of antiretroviral medications. Each class of drugs works to interrupt viral replication at a distinct step in the process. The use of combination therapy has been shown to be more effective at controlling the virus than mono (one medication) or dual therapy (two medications). Combination therapy increases the sites where drugs can interrupt the viral replication cycle and effectively lower the viral load. The five classes of ART are:

• Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
• Protease Inhibitors
• Non-Nucleoside Reverse Transcriptase Inhibitors
• Integrase Inhibitors
• Entry/Fusion Inhibitors

There is no known cure for HIV at this time. A person with an undetectable viral load still has HIV and can still spread the virus. They are not cured, but they are less likely to infect someone following exposure than someone with a large viral load.

How ART Works

Like other viruses, HIV needs to replicate inside another cell. It has proteins on its surface that are attracted to receptors on the outside of the CD4 cell's surface. When the two surfaces meet, they bind which allows entry of the RNA from the HIV to enter the CD4 cell. This is the point where fusion and entry inhibitors attempt to interrupt the replication process by preventing the two cells from binding together.

Once the HIV viral capsid enters the cell a viral enzyme called reverse transcriptase is released. The reverse transcriptase enzyme has a major role in transcribing viral RNA into DNA, the genetic material found in human cells. It is at this point in the replication cycle that nucleoside/ nucleotide and non-nucleoside reverse transcriptase inhibitors work to interrupt the viral replication cycle.

Once the viral RNA is transcribed into DNA the genetic material is transported into the nucleus of the CD4 cell. After this happens, the viral enzyme integrase facilitates insertion into the DNA of the CD4 cell so that when the cell replicates it makes viral cells instead of CD4 cells. In fact, the CD4 cell which previously helped to protect the body from invasion with harmful organisms is turned into a "viral factory." It is during this process that the integrase inhibitor attempts to interrupt the viral replication cycle. The class of integrase inhibitors is one of the newer classes of ART.

Viral assembly begins when long strings of proteins are cut into smaller pieces by the protease enzyme and assembled into HIV structural elements and enzymes. When this process is complete, they bud off of the CD4 cell to become new virons. After maturation, these virons can infect new CD4 cells and continue the process of immune suppression. Protease inhibitors target this portion of the process to attempt to interrupt the viral replication cycle.

Much research has been conducted in order to understand which medications have the most efficacy in different circumstances. As a result of these studies, CDC and other Infectious Disease organizations have made recommendation on when to begin ART and what order to use the drugs that are available. Again, these recommendations are simply guidelines, not solid rules, and the unique needs of each patient should be assessed prior to beginning or switching medications.

The viral load is used to monitor the effectiveness of ART. Once on effective antiretroviral therapy, the HIV viral load (VL) should be "undetectable." This value is determined by the type of test used by the laboratory. The most common values considered to be undetectable can vary from 4 to 400 copies. CD4 and VL laboratory tests are monitored carefully by the provider and should be checked every three to six months.

If the HIV viral load becomes detectable a discussion should be held with the patient to determine if all ART is being taken appropriately at the correct dose and time interval. The most common reason for the development of viral resistance is non-adherence. If the patient is non-adherent it is important to stress the importance of taking ART properly. Studies have shown that drug resistance can develop if less than 95% of ART is taken correctly. On occasion, the virus will naturally mutate to detectable levels. In either case a HIV genotype should be ordered to determine if genetic mutations have occurred, and another ART regimen should be initiated if needed based on these results.

Adherence to ART is important on two levels, for the patient who is HIV infected, non-adherence can lead to drug resistance and greatly increase the possibility of death. Drug resistant HIV viruses are transmitted to newly infected patients from source patients. A person who is newly diagnosed with HIV/AIDS can have few if any choices for effective ART, increasing the possibility of a poor prognosis. The development of multidrug resistant strains of HIV is a real concern in the field of medicine and Public Health.

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