Prevention of HIV Infection
As with most diseases, an "ounce of prevention is worth a pound of cure." With HIV, prevention is primarily twofold:
- Practice safe sex. Even in cities with strong HIV risk-reduction programs, there is an alarming increase in sexually transmitted diseases, indicating abandonment of safe sex practices. In Seattle, WA, and Los Angeles, there is a sharp increase in syphilis cases in gay men. In San Francisco and Seattle, cases of rectal gonorrhea have risen. In San Francisco, there is an increase in sex with multiple partners and a decrease in condom use (Jaffe 2001). Nationwide in the United States, rates of gonorrhea have increased. This unsettling trend may result from the inaccurate belief that HIV is curable with the new treatments, that those under treatment are not infectious, that practicing safe sex is bothersome, or a fatalistic view that infection is inevitable.
- Properly screen all blood products. In March 1985, a screening test for blood-banked products became available in the United States. At that time, HIV had been transmitted to more than 8000 persons with hemophilia and to 12,000 others who received blood transfusions.
Compared to the two screening tests done on banked blood products in 1981, 10 screening tests are now mandated. In the United States, risk of HIV transmission is now approximately one in every 500,000 units. However, in developing countries, blood supplies are not considered safe. High infection rates and costs of monitoring in these countries currently make ensuring the safety of blood products nearly impossible. Blood-blood transmission also includes needle transmission. In the United States, there are few new infections among IV drug users, resulting from clean needle distribution.
Beyond safe sex practices, there are other strategies for lessening risk, although they are not absolutely preventative. Antimicrobials, such as products containing nonoxynol-9, were once thought to reduce risk, but a study found them to be ineffective (CDC 2000). A major study in Uganda in couples containing only one HIV-positive member showed the chance of viral transmission increases with viral load. The viral load must be very low to prevent transmission. These couples were not being medically treated, and their viral load was low without medication (Jaffe 2001).
It is unclear if inducing a low viral load with medication will similarly lessen risk of transmission. Transmission is less among circumcised males, although a randomized study has not been done in this regard. A Tanzanian trial found a 40% reduction in HIV transmission when other sexually transmitted diseases were routinely treated and partners already known to have HIV were treated when symptoms appeared (Jaffe 2001).
High-risk behaviors have been shown to include the following: sexual activity with a gay man, prostitute, or IV drug user; sex with multiple partners; not using a condom; casual sex encounters; blood transfusions from 1978-1985; and recreational IV drug use.
Anyone who has engaged in any high-risk behaviors, should request a screening test for HIV. Most cities have large community health centers that provide the results with a number instead of an individual's name for confidentiality.Behaviors to Optimize Therapy
Once therapy is begun for HIV, certain behaviors will increase the likelihood of a successful response to treatment. It is essential to strictly adhere to the drug treatment regimen. Even a 10% decrease in compliance with the medical regimen (the equivalent of missing as few as 2 doses of medication a week) doubles the risk of dying. To suppress viral load, a compliance of 80-100% with drug treatment is required. Noncompliance with the drug regimen markedly increases the risk of development of resistant strains of the virus, and treatment then fails. If you are taking HIV therapy, make sure your physician explains the regimen in a way you can understand completely. It may be helpful to write the regimen down yourself, as you understand it, and then show it to your physician to check completeness. Discuss with your physician any lifestyle factors (such as work hours, sleep patterns, and travel requirements) that could impact your treatment regimen. Make sure you are able to keep appointments necessary for monitoring the disease process, the response to therapy, and the appearance of possible side effects to medication. Choose a health care practitioner with whom you have an excellent rapport and with whom you are able to discuss intimate details of your life and habits.
It may be helpful to join an HIV support group. There are many of these in every large city, and community health centers can provide lists of similar resources in less urban areas. There are numerous newsletters to which you can subscribe that offer information about breaking developments in AIDS, new treatments, and research efforts. The Internet is a valuable source of information for HIV, as well as numerous other conditions. It is particularly beneficial to keep yourself informed of progress in HIV, so that you can discuss new therapies and other issues with your physician. Informed patients tend to be more compliant in their medical treatment. Especially with AIDS, compliance improves survival.
Avoiding the use of recreational drugs and alcohol is also necessary to optimize treatment (see the section on Other Causes of Immune Suppression). A good diet that is high in nutrient-dense foods is also advisable.Diagnosis and Testing
Lymphocyte (a type of white blood cell) counts are routinely used to monitor the progression of HIV. There are a variety of subtypes of lymphocytes. Related to HIV, one of the most important is the CD4 cell. The CD4 cell population has the ability to regenerate and will rise and fall with treatment, disease progression or regression, and other factors. In general, a CD4 count below 100 is a very grave sign. The CD4 lymphocyte count is measured in units multiplied by 106 per liter of blood or serum. Treatment is usually started when the CD4 count is below 350 and may be considered in some cases when the count is below 500. Treatment is usually not started if CD4 counts are greater than 500.
Viral load, however, has been found to be an even more important laboratory marker than CD4 lymphocyte counts. An extremely important study (Mellors 1996) followed blood samples from 180 gay men for more than 10 years. In this group, the viral load was significantly more predictive of long-term survival than the CD4 count. Lower viral loads also indicate lower viral transmission rates from patient to patient. According to Quinn et al. (2000), "Viral load is the chief predictor of risk in heterosexual transmission of HIV-1, and transmission is rare among persons with levels of less than 1500 copies of HIV-1 RNA per milliliter." Viral loads are measured in number of copies of virus existing within the patient per volume of blood. HIV is an RNA virus, so viral load is reported as plasma HIV RNA level in copies per cubic centimeter (cc).
With viral loads greater than 30,000 copies of virus per cc, beginning treatment is recommended no matter what the CD4 count. (With viral loads above 5000 copies per cc and CD4 counts from 350-500, initiation of treatment is recommended. With CD4 counts from 350-500 and a viral load less than 5000 copies per cc, therapy is considered but not mandated. With CD4 counts greater than 500 and a viral load below 5000, therapy is deferred. With CD4 counts above 500 and a viral load from 5000-30,000, therapy may be considered but is not mandated. With CD4 counts above 500 and a viral load above 30,000, treatment is definitely recommended.)
The rationale leading to treatment recommendations from the CD4 and viral load ranges above is based on the risk of clinical progression of HIV. The risk of near-term progression is considered to be 3 years. If the patient has a low risk of near-term progression (progression of HIV disease within 3 years), then treatment is deferred until they enter another category based on the viral load counts and CD4 lymphocyte counts listed above. When the viral load dips below 50 copies per cc, the virus is no longer detectable in blood or serum. A viral load below 50 is the goal of therapy but realistically is not often achieved, even with the new therapies.
With the new therapies for AIDS, measures of drug resistance are critical. The development of drug resistance indicates some type of change in therapy is needed. Blood tests that check the sensitivity of an individual patient's HIV to specific drugs used in the treatment regimen are routine.Progression of the Illness (HIV-Positive versus AIDS)
After exposure to HIV from blood, from blood products, or via mucosal surfaces (which includes sexual contact or breast feeding), a person becomes HIV-positive usually within 2-6 weeks and certainly within 6 months. HIV-positive means that the virus is detectable in the blood and tissues of the infected person. However, at this point, there may be no symptoms related to the HIV infection. This state of being positive for HIV continues with few, if any, symptoms until the person has enough copies of the virus to produce an effect on the immune system of the host.
The symptoms of AIDS and progression of the disease process are actually only indirectly related to the virus itself. AIDS causes illness and death via the secondary effects of the virus on the immune system and the resultant development of AIDS-related infections and malignancies. Many of these secondary effects are unusual and difficult to treat. With the appearance of AIDS, we have had an increase in infections that used to be rare, such as P. carinii pneumonia, cytomegalovirus, cryptococcosis, atypical tuberculosis, and others. Malignancies previously commonly found, such as lymphoma and others, are found with AIDS, but unusual tumors, such as Kaposi's sarcoma, are also seen. Because the virus causes disease and symptoms via the occurrence of malignancies and infections (due to the compromising of the host's immune status), treatment focuses on preventing the development of the symptoms and diseases associated with HIV.
AIDS is diagnosed after the person contracts one or more infections or malignancies that are in themselves unusual, that recur, or that are unusually difficult to treat. The time from inoculation with the virus to development of AIDS is highly variable. Within months of a positive HIV test, in some people there may be rapid progression from being HIV-positive to AIDS. There also may be asymptomatic survival in the HIV-positive state for more than 10 years. This variability probably reflects the multiplicity of virus-host interactions (Klein et al. 1995). Within 10 years of becoming HIV-positive, the chance of progressing to full-blown AIDS is 60.2% (Anon. 1998).
In an article, Klein et al. (1995) noted the chance of death within 10 years of becoming HIV-positive was 48.1%. In a multicenter study of HIV-positive gay men with a known date of conversion to being HIV-positive, the median survival time after HIV infection was 12.1 years (Coutinho 2000). Older age is associated with a shorter incubation period before the development of full-blown AIDS and a shorter survival time. However, numerous medical articles note that decades of survival are now possible after becoming HIV-positive. This survival relates to the Highly Active Anti-Retroviral Therapy (HAART) treatments that have decreased the death rate from AIDS. It is difficult to find exact statistics in the literature giving the chance of survival for extended periods. We are also beginning to talk of co-morbidities as causes of death in persons who are HIV-positive. The term co-morbidity refers to the fact that--due to improved survival--the HIV-positive person may actually die of an illness unrelated to AIDS, such as cardiovascular disease.Treatment of HIV/AIDS - Drugs in Use
The first major advance in HIV treatment came with the development of AZT (zidovudine), the first drug approved for the treatment of AIDS in 1987. Then, in the mid-1990s, advances in the treatment of AIDS were made with the development of new drugs and increasing knowledge about HIV itself. Discussions about treatment then considered the possibility of totally eradicating the virus from the patient's system. It was known that the half-life of infected cells was 10-14 days, and this suggested the virus could be eliminated with continued treatment in 2-3 years.
However, newer research has shown that replication of the virus continues, even when viral load counts are below detectable levels (less than 50 copies of virus per cc of blood or serum). Also, the decay half-life of resting memory CD4 lymphocytes containing HIV or its predecessor ("provirus") is in fact very long (from 6-44 months). Calculating the math derived from these figures shows that totally eliminating HIV with antiretroviral therapy is an unrealistic goal. The time required for eradication of the virus would take more than a decade. "Hit early and hit hard," as a philosophy of therapy (beginning treatment as soon as the patient is discovered to be HIV-positive and treating very aggressively), has now been abandoned.
It is, however, essential to emphasize that even though the virus cannot be eradicated at the present time, it is possible to lead a symptom-free life while harboring the virus. Goals of therapy are to prolong this time period as long as possible. Thus, treatment presently does not focus on eradicating the virus but controlling it. Careful monitoring of treatment, lab values (including CD4 counts and viral loads), and symptoms is critical in this process. Successful therapy requires a dedicated physician and a compliant patient--one who adheres exactly to the treatment regimen. With this existing philosophy for the treatment of HIV, based on newer information and research, we have entered a new age of AIDS treatment, the age of HAART.
Three classes of drugs are used to treat HIV: protease inhibitors, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors. Both protease and reverse transcriptase are enzymes that the virus uses to replicate and propagate itself. By interfering with these two enzymes used in viral replication, the reproduction of the virus is crippled and ongoing viral replication is controlled. Whether the compound is a nucleoside or non-nucleoside reverse transcriptase inhibitor refers to its chemical makeup and whether or not it contains RNA or DNA nucleosides. Both the nucleoside and non-nucleoside reverse transcriptase inhibitors interfere with the enzyme reverse transcriptase used in viral replication.
HAART consists of treatment with three drugs from the three different classes mentioned above, although not necessarily one drug from each class. A triple-drug regimen is required to reduce the risk for development of drug resistance, in which case the drug would no longer be effective against the virus, and to control the destruction of the patient's immune system. The current drugs in use attack HIV at two different enzymes, reverse transcriptase and protease. These enzymes are used by the virus in making more copies of itself within the patient.
The nucleoside analogue reverse transcriptase inhibitors (or NRTIs) stop viral replication by masquerading as nucleosides (building blocks) that the virus uses to construct its own RNA from DNA in the patient's cells and to interfere with the enzyme (reverse transcriptase) that is used in this process. This class of drugs includes AZT (zidovudine), didanosine, zalcitabine, stavudine, lamivudine, and abacavir. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) interfere with the same reverse transcriptase enzyme but are not mimics of the DNA and RNA building blocks. This class includes nevirapine, efacirenz, and delavirdine. The protease inhibitors (PIs) interfere with another enzyme that is an HIV-1 specific protease and also necessary for viral production within the host organism. Drugs in this group are saquinavir, ritonavir, indinavir, nelfinavir, amprenavir (Agenerase), and lopinavir/ritonavir (Kaletra).
Initial treatment regimens are usually selected among the following combinations: (1) 2 NRTIs + 1 PI (with or without low-dose ritonavir,); (2) 2 NRTIs + 1 NNRTI; and (3) 2 NRTIs + 1 NRTI. These three regimens are listed in most international and national guidelines. Investigational regimens presently include some three-drug combinations of all NRTIs: 1 NRTI + 1 NNRTI + 1 PI; in addition to some four-drug protocols (Darbyshire 2000). No conclusive data presently exist showing the superiority of one regimen over another. The choice of a regimen is based on several factors, including regimen potency for the individual patient's CD4 count and viral load, side effects and tolerability of the regimen for the patient, likelihood of drug to drug interactions, convenience of regimen and likelihood that the patient will adhere to it, potential for alternative treatment options if the treatment fails, and drug resistance testing results (Carpenter 2000). Drug selection is a complex process and requires close cooperation and discussion between the physician and patient. Patients or prospective patients wishing to be well-informed are encouraged to read "Updated Recommendations of the International AIDS Society--USA Panel" published in JAMA (Yeni et al. 2002). Similarly, there are recommendations published by British and European societies that are easily accessed in the medical literature. A most informative British article, "Therapeutic Interventions in HIV Infection--A Critical Review" (Darbyshire 2000) is found in the Tropical Medicine and International Health article from July 2000.Continued
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