HIV/AIDS

Quality of life for HIV/AIDS patients has dramatically improved in recent years with the advent of sophisticated new therapies, and scientific innovation is unraveling the mysteries of the human immunodeficiency virus at an expeditious rate. Cutting-edge treatments under investigation at the frontiers of science are redefining the discussion of HIV/AIDS and “cure” is no longer a four letter word in the minds of some leading HIV researchers (Singh 2011).

Having identified multiple aspects pivotal in controlling HIV infection and developing antiretroviral drugs to target many of them, the scientific community has made tremendous strides in the management of latent HIV. The mortality rate for HIV-positive individuals has declined considerably and continues to do so (Killian 2011; Bhaskaran 2008; Giusti 2011).

Alas, the indispensable antiretroviral drugs themselves cause a number of troubling side effects. Patients treated with long-term antiretroviral therapy usually develop, among other concerns, lipodystrophy, insulin resistance, and increased cardiovascular risk. Unfortunately, these drug-induced conditions diminish patients’ quality of life and contribute to an increased rate of cardiovascular events and diabetes (Escote 2011; Tien 2008; Tebas 2008; Palios 2012).

Life Extension believes that a major gap in conventional HIV treatment regimens is the failure to aggressively manage patients’ cardio-metabolic risk by using evidence-based drugs like metformin, and scientifically studied natural compounds like green coffee extract and omega-3 fatty acids from fish oil. Moreover, hormone restoration therapy appears to promote healthy fat redistribution and improve body composition in male HIV patients, and is associated with lower risk of death in HIV-positive women.

In this Life Extension protocol you will learn some basics of the biology of the human immunodeficiency virus and how it destroys the immune system of its host. You will also discover a number of natural compounds that may improve your quality of life by targeting several antiretroviral drug-related side effects, and read about avant-garde medical therapies that aim to improve outlook for HIV patients even further in the not-so-distant future.

Understanding HIV/AIDS

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS) by destroying CD4+ "helper T cells". In healthy individuals, helper T cells organize immune responses that protect the body from infection. When HIV invades the human system, it binds to co-receptors (typically CXCR4 or CCR5) on the surfaces of CD4+ cells and macrophages, and introduces viral genetic material into these cells.

Once HIV has gained entry into the host cell, viral RNA is reverse transcribed into viral DNA and combines with the DNA of the host cell—so as the infected cell replicates, so, too, does the virus (Campbell 2008). Reverse transcription from viral RNA to viral DNA is a target for some antiretroviral drugs. As CD4+ cell levels become depleted with advancing HIV infection, viral replication within macrophages, dendritic cells, and other cell types sustains viral load.

HIV can be categorized based on its interaction with surface co-receptors during attachment and entry into host cells. Three primary entry methods comprise a large percentage of HIV cases – R5, which utilizes the receptor CCR5 to gain entry, X4, which uses the CXCR4 co-receptor, and X4R5, which uses both (Coakley 2005).

Given the dependency upon these cell-surface co-receptors for entry, some strains of HIV are unable to infect individuals who harbor mutations in the gene encoding the co-receptor. These people are resistant to the subtype(s) of HIV that would normally utilize a wild-type receptor to gain entry into host cells.

In addition to attacking the immune system, HIV has the ability to escape immune attack. During cell replication, some HIV viruses mutate at such a rapid rate that they become unrecognizable to the immune system. This enables the virus to keep multiplying and also allows for further mutations. Furthermore, viral DNA that enters the chromosome of the infected cell (where it combines with the cell's own DNA by the action of the HIV-integrase enzyme) may remain in a latent state. As a result, it can remain undetected by the immune system (Agosto 2011; Campbell 2008). This has presented a tremendous obstacle for achieving complete elimination of the disease.

As HIV continues to survive and replicate within its human host, it eventually weakens the immune system; this leaves the infected individual susceptible to opportunistic infections, including Pneumocystis pneumonia (PCP), tuberculosis, herpes simplex virus, and Kaposi's sarcoma (Onyancha 2009; Campbell 2008).

Distinguishing HIV-1 and HIV-2

The widely used term, "HIV", generally refers to HIV-1, the most prevalent form worldwide. However, two types have been identified: HIV-1 and HIV-2. Both are transmitted via the same routes (Markovitz 1993), both are associated with similar opportunistic infections, and both cause AIDS (de Silva 2008). However, HIV-2 has a lower viral load (Popper 1999; de Silva 2008; MacNeil 2007), is less pathogenic (Popper 1999; MacNeil 2007), generally progresses more slowly than HIV-1 (MacNeil 2007; Foxall 2011), and is mostly confined to West Africa.

The breakdown of the immune system from HIV-2 infection is less dramatic and occurs at a slower rate than it does with HIV-1 (Pepin 1991). Also, neutralization escape—that is, the ability to mutate and dodge an attack from neutralizing antibodies—is less common in HIV-2 infections (Shi 2005). Thus, characteristics of HIV-1 including a higher viral load, greater pathogenicity, and the ability to escape neutralization more often, contribute to its widespread prevalence.

Both types of HIV appear to have originated from simian immunodeficiency viruses (SIV) in chimpanzees (Pan troglodytes) and sooty mangabeys (Cercocebus atys; SM) (Chan 2010; Hahn 2000). SIV are retroviruses that infect primates; certain strains of SIV are thought to have mutated into HIV and subsequently infected humans (Chan 2010; Gao 1999).

Transmission

HIV can be transmitted via exposure to contaminated body fluids, such as blood (Pilcher 2007; Cohen 2008), semen (Pilcher 2007; Kaul 2008), or breast milk (Salazar-Gonzalez 2011; Gantt 2010; Permar 2010; Gray 2011). Potential routes of transmission include blood transfusions (Dwyre 2011), intravenous drug use (Raguin 2011; Cohen 2008), and unprotected sexual intercourse (Boily 2009); HIV-infected females can transmit the virus to their children in utero (Marinda 2011; Arya 2010), during delivery (Arya 2010), or via breastfeeding (Liang 2009).

Anal sex is associated with a much higher risk of HIV transmission than vaginal sex. One factor that may contribute to this is that the rectum contains a thin membrane (the lamina propria) that harbors an abundance of HIV target cells—and only one layer of tissue separates these target cells from the rectal lumen (Royce 1997; McGowan 2008).

Although oral sex generally presents a relatively low risk of HIV transmission (Baggaley 2010), the risk of transmitting HIV increases if the mouth or genitals contain cuts or open sores (e.g., recent dental work) that could provide an entryway for the virus (Saini 2010). Similarly, the risk of transmission during anal or vaginal sex increases in the presence of sexually transmitted diseases, such as herpes or syphilis, that produce ulcers or sores that compromise mucosal integrity, leaving the individual more susceptible to infection (Sandlin 2011; Corbett 2002). Additional risk factors include sexually transmitted infections such as gonorrhea or chlamydia, which produce genital inflammation that can weaken mucosal barriers that would normally help shield the body from infection. Gonorrhea also interferes with CD4 cell activation and proliferation, potentially increasing the opportunity for infection (Boulton 2002).

Uncircumcised men are at higher risk of contracting HIV than those who are circumcised. This may be because the foreskin possesses numerous Langerhans cells, which contain a protein called Langerin. Langerin helps protect the body from HIV infection by quickly degrading the virus. However, if a viral onslaught occurs and the cells run out of available Langerin, these cells become viral transporters for infection and deliver the virus to lymph nodes. Thus, removing the foreskin diminishes the opportunity for the Langerhans cells to promote viral infection as transporters (Pask 2008; Donoval 2006).

Symptoms/Course of Disease

HIV progression comprises the acute, latent, and late/advanced stages. The acute stage comprises the first few weeks after infection, during which time the patient may experience "flu-like" symptoms including headache, nausea, sore throat, or fever (Bell 2011); other possible symptoms include swollen lymph nodes, muscle pain, and oral and esophageal sores. As HIV enters and replicates within CD4+ cells in the immune system, the viral load increases sharply, and there is a corresponding dip in the number of CD4+ cells, and an increase in CD8+ cells in the blood. During this stage, the patient is extremely infectious.

This phase usually ends a few weeks later, when the immune system is able to mount an effective response: The viral load decreases, and the number of CD4+ rises again, marking the beginning of the latent stage. At this point, the disease enters a period of clinical dormancy that could last for many years, although it can be much shorter in some patients. During this time, there may be no symptoms, and the carrier may be entirely unaware that he or she is carrying HIV. The virus, however, still continues to progress.

As CD4+ cell count decreases below 350 cells/µL, patients often develop constitutional symptoms, such as fatigue and night sweats, and become more prone to various infections. When the immune system is no longer able to fight off the infection, the advanced stage begins and is characterized by CD4+ cell counts below 200 cells/µL, the development of opportunistic infections, and a severely impaired immune system, all of which culminate into AIDS (Bell 2011).

Figure 1: HIV timecourse (Pantaleo 1993)

Diagnosis

The diagnosis of HIV typically begins with a test that detects natural antibodies produced against the virus. If the antibody test result is positive, a more sensitive test is performed, such as a Western blot analysis or indirect immunofluorescence assay (a test that uses fluorescent compounds so that HIV antibodies present in the blood glow fluorescent green when placed under ultraviolet light).

The human body generally does not produce HIV antibodies until several weeks after infection, so if antibody tests are administered prior to that point, they may return false-negative results. This is particularly worrisome given that people with HIV appear to be most infectious during the acute stage (Hollingsworth 2008; Wawer 2005; Pilcher 2004). Consequently, patients with a negative test result are encouraged to be tested again three months later, as well as six months later. Virologic tests, which detect the actual virus or components thereof, are useful for identifying acute infection in patients who test negative for HIV antibodies (Read 2007).

Current diagnostic options for detecting HIV include:

• Viral Load Tests: These tests measure the quantity of HIV in the blood. Examples include the polymerase chain reaction (PCR) test, which can identify HIV by detecting its genetic material.
• P24 Antigen Test: This test detects the p24 antigen, a protein produced by HIV. Detectable levels of p24 are produced during the early stages of HIV infection, making this a useful test in cases where an asymptomatic patient is suspected to have HIV (because of high-risk behaviors, for example) and tests negative for antibodies (Pilcher 2010).
• Fourth Generation Assay: In 2010, the FDA approved a new, "fourth generation" test, called the ARCHITECT HIV Ag/Ab Combo Assay. This test detects both the p24 antigen and HIV antibodies, with the goal of facilitating early diagnosis of the infection. It has demonstrated high diagnostic sensitivity and specificity in detecting HIV (Chavez 2011; Bischof 2011; Pandori 2009).
• Nucleic Acid Tests: Nucleic acid tests (NAT) can identify HIV infection approximately 12 days before antibodies become detectable (Fiebig 2003). This allows for earlier detection of the virus, which could prevent the spread of the infection due to early awareness. In a study of more than 3,000 people who were tested for HIV, using NAT improved the detection yield by 23% compared with a rapid HIV test (Morris 2010).
• Rapid Tests: Rapid HIV tests present an affordable option that allows for easy sample collection (e.g., via oral swab or finger prick) and produces results in just 15 minutes. However, they are associated with a high rate of false-positive results. Consequently, patients who test positive with a rapid test should then be checked via a conventional HIV test to confirm the diagnosis.
  
  Once an HIV infection has been diagnosed, key measures used for evaluation and monitoring are:
• CD4+ Cell Count. This is considered the hallmark of disease progression. In healthy individuals, CD4 count usually range from 500 to more than 1,000 cells/µL; when these levels drop below 200, it is a criterion for AIDS (Schneider 2008). In addition to being an indicator of disease progression, CD4 count can help to assess when to start antiretroviral therapy. A recent trial found that a combination of clinical monitoring and CD4+ cell count testing was the most effective strategy for monitoring HIV progression (UCSF 2011).
  
  The World Health Organization recommends that patients with HIV begin treatment when their CD4 count falls to ≤350 cells/µL, even if they don't have symptoms. Although, recent evidence indicates that if HIV-infected individuals initiate antiretroviral therapy sooner they are much less likely to transmit the disease to others (Cohen 2011).
• Viral Load. If the patient adheres to his/her medication regimen and the antiretroviral therapy is effective, the viral load will generally drop to less than 50 copies/mL in 16 to 24 weeks, depending on the level before treatment was initiated (Rizzardi 2000). If viral load does not appear to decrease with treatment, this could be a sign of drug resistance.
• Drug Resistance. These tests determine whether a strain of HIV is resistant to any anti-HIV medications. During genotypic testing, for example, the genetic structure of the HIV sample is studied for mutations that are recognized as creating HIV resistance to certain drugs. During phenotypic testing, the HIV is exposed to different concentrations of various antiretrovirals to determine resistance.

Patients who test positive for HIV should also undergo screening for other conditions that are associated with HIV, including other sexually transmitted diseases, tuberculosis, and hepatitis B (Aberg 2009).

Treatment

Patients today have access to an arsenal of powerful antiretroviral drugs to decrease the viral load:

• Entry Inhibitors: These drugs bind to CCR5 receptors on immune cells, preventing HIV from attaching to them and initiating infection. Example: maraviroc (Selzentry®).
• Fusion Inhibitors: Fusion inhibitors block the gp41 protein on the surface of HIV, which prevents it from fusing with the host cell (Cervia 2003). Example: enfuvirtide (Fuzeon®).
• Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs/ NtRTIs): These medications interfere with HIV’s ability to be imported into the DNA of healthy immune cells by limiting reverse transcription of viral RNA into viral DNA. Examples: abacavir (Ziagen®), emtricitabine (Emtriva®), lamivudine (Zeffix®), tenofovir (Viread®), zidovudine (Retrovir®).
• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): These drugs also inhibit reverse transcription of viral RNA. Examples: etravirine (Intelence®), efavirenz (Sustiva®), nevirapine (Viramune®).
• Integrase Inhibitors: These medications inhibit integrase, an enzyme that facilitates the insertion of viral DNA into the DNA of infected cells (Jegede 2008). Example: raltegravir (Isentress®)
• Protease Inhibitors: These drugs inhibit protease, an enzyme that is used to help assemble HIV after it has been incorporated into host DNA. Examples: atazanavir (Reyataz®), fosamprenavir (Lexiva®), ritonavir (Norvir ®), darunavir (Prezista®).

A variety of these drugs, and others, are often used in combination to manage HIV; this strategy is referred to as highly active antiretroviral therapy, or HAART. Drug regimens are typically chosen based on a number of factors, including patient tolerability, patient genetic background, and physician experience.