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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”


    

HIV/AIDS: Epidemic Update for Florida

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The purpose of CME Resource is to provide challenging curricula to assist physicians, nurses, dentists, psychologists, and allied healthcare professionals to raise their level of professional expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

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INTRODUCTION


As we begin the 21st century, the amount that has been learned and written about HIV infection and disease and its influence on individuals and society is staggering. Since the discovery of HIV, scientists have made major inroads in understanding modes of transmission, infectivity, and pathogenicity. Knowledge about the characteristics and behavior of this human retrovirus and its complex mechanisms of immunopathogenesis has helped to develop targeted therapeutic interventions and vaccine strategies. Sophisticated techniques have been and are being developed to diagnose infection, to monitor immune decline, to monitor response to therapy and disease progression, and to accurately detect and diagnose opportunistic diseases. Therapeutic alternatives, especially the nucleoside analogue antiretroviral drugs, have been tested, approved, and are providing benefit to many who are HIV-infected. Much has been learned about the complexities of caring for HIV-infected persons, how to keep them disease-free longer, and how to manage their symptoms more effectively. In addition, the development of new knowledge from HIV-related research also has helped to clarify aspects of the human immune response, behavioral interventions, public health strategies, and social and ethical approaches that contribute to the understanding and management of other diseases and health conditions.

Healthcare professionals will continue to play a major and significant role in preventing the spread of HIV infection and in caring for those who are infected or affected by HIV. As the demographics of HIV infection evolve, both in the United States and around the world, it is clear that all healthcare professionals in all practice settings will be involved to some extent with HIV infection. To be effective and provide compassionate care, adequate and up-to-date information about transmission, prevention, diagnosis, treatment, and care of HIV-infected individuals must be obtained by all healthcare professionals. They must feel comfortable with this knowledge in order to provide care, educate patients and others, and fulfill their professional obligations without undue fear or anxiety.
 


EPIDEMIOLOGY


GLOBAL IMPACT

The epidemiology of HIV infections is presented as it appears in Africa, Asia, Europe, and the United States. Analysis reveals that the HIV pandemic continues to escalate throughout developing countries compared to a notable stabilization in new cases and fatalities in some developed countries. The established healthcare community became aware of the illness that has since become known as AIDS in 1981. The tasks of slowing the HIV pandemic and decreasing the mortality rate are being accomplished by efforts such as progressive treatment of sexually transmitted diseases (STD), increased condom distribution, and utilization of needle exchange programs. In order to further decrease HIV transmission, there are increased efforts to strengthen public health infrastructures, to support HIV/STD prevention programs, to introduce microbicide, to use inexpensive antiretroviral drug therapy for treatment and prevention of transmission, and to improve educational campaigns [19].

Two human immunodeficiency viruses, HIV-1 and HIV-2, have been identified and both cause AIDS. Researchers in America and England have traced the ancestry of the HIV-1 virus to two strains found in African red-capped mangabeys and greater spot-nosed monkeys. The strains most likely combined in chimpanzees that ate the monkeys, resulting in the chimpanzees developing simian immunodeficiency virus (SIV). Chimpanzees then transmitted the virus to humans, as early as 1930. Genetic studies suggest that the lower monkeys first became infected with SIV 100,000 years ago [29]. HIV-2 is believed to be endemic in West Africa. Several well-documented cases of HIV-2 infection have been reported in Europeans and among West Africans residing abroad. By 1991, there were only 18 reported cases of HIV-2 in the United States, and all were associated with immigration from, or travel to, West Africa. Differences in the global spread are attributed to differences in transmissibility and duration of infectiousness [7].

Many countries owe acquisition of HIV infection in their population to contact with American blood products that were exported before the 1985 HIV screening procedures, or to sexual transmission.

Worldwide epidemiologic studies indicate that there are three broad but distinct geographic patterns of AIDS transmission. In pattern I, typical of industrialized countries with large numbers of reported cases, most cases occur among men who have sex with men (MSM) and among urban injecting drug users (IDUs). A smaller percentage of cases is attributed to heterosexual transmission, but this percentage is increasing. Transmission due to exposure to HIV-contaminated blood or blood products occurred between the late 1970s and 1985, but this has since been largely controlled through routine blood screening procedures. The overall population seroprevalence is less than 1%, but this is significantly higher (up to 50% higher) in high-risk behavior groups such as injecting drug users and men with multiple male sex partners [7].

Pattern II is seen in areas of central, eastern, and southern Africa and in some Caribbean countries. Most cases occur among heterosexuals. Transmission through injecting drug use and MSM transmission either does not occur or occurs at a very low rate. The overall population seroprevalence is estimated to be over 1%, and in a few urban areas up to 25% of all sexually active people are infected. Transmission through contaminated blood and blood products remains a significant problem [7].

Pattern III occurs in areas of eastern Europe, the Middle East, Asia, and most of the Pacific basin. It appears that HIV has been introduced to these areas only since the mid-1980s, and only small numbers of cases have been reported. Generally, cases have occurred among those who have traveled to endemic areas or who have had sexual contact with individuals from endemic areas, such as MSM and prostitutes. Only a small number of cases have been reported due to receipt of imported HIV-contaminated blood [7].

Data from prevalence surveys and from HIV and AIDS case surveillance continue to reflect the disproportionate impact of the epidemic on racial/ethnic minority populations, especially women, youth, and children. At the same time, prevalence surveys suggest that young men who have sex with men remain a population at high risk for HIV infection. Declines in AIDS incidence and deaths, first reported in 1996, continued through 1997 and provides evidence of the widespread beneficial effects of new treatment regimens. AIDS incidents decreased 18% between 1996 and 1997 and 11% from 1997 to 1998. These data highlight the importance of HIV prevention strategies such as promoting knowledge of HIV risk behaviors and ways to reduce the risk of infection. By increasing the number of HIV-infected people who are aware of their status, thereby improving access to effective care and treatment programs to improve health and survival among persons who are already infected [6].

According to the United Nations, an estimated 42 million individuals worldwide were living with AIDS at the end of 2002, approximately 50% of which were women. Europe and Central Asia have the fasted growing epidemic. In China, there is an estimated one million people infected; the number could possibly increase to ten million at the end of the decade if controls are not put in place. It is important to note that despite increases in certain geographic areas and demographic groups, overall, the rate of new infections is declining. This is due, it part, to lower prices for anti-AIDS drugs [30]. Recently, the U.S. government decided to allow generic drugs to fight the disease in Africa, where over three-quarters of the 42 million infected with AIDS are living [31].

UNITED STATES STATISTICS

In the United States, approximately 850,000 to 950,000 individuals are infected with HIV [32]. At the end of 2001, an estimated 362,827 individuals were living with AIDS, representing a 14% increase from the end of 1999 [33]. One should keep in mind, when reviewing trends in HIV transmission, that the widespread use of antiretroviral therapy has resulted in fewer deaths and longer survival.

In terms of sheer number of cases, New York, Los Angeles, and San Francisco continue to be the hardest hit areas. The metropolitan areas with the highest numbers of AIDS cases in 1999 were New York, Los Angeles, San Francisco, Miami, Washington DC, Chicago, Houston, Philadelphia, Newark and Atlanta. The rate of infection within the population of these metropolitan areas in 2000 demonstrates its impact. In rank order, they are New York, Miami, San Francisco, Newark, Houston, Atlanta, Philadelphia, Washington, D.C., Los Angeles and Chicago [6].

According to the CDC there are several trends evident from the period between 1996 to 2001[33]:

  • By region, 39% of the persons living with AIDS lived in the South, 29% in the Northeast, 19% in the West, 10% in the Midwest, and 3% in U.S. territories
  • Of persons living with AIDS, 42% were black, 37% were white, 20% were Hispanic, 1% were Asian/Pacific Islander, and <1% were American Indian/Alaska Native
  • Of the 282,250 adult and adolescent men with AIDS, 57% were MSM, 24% were IDUs, 9% were exposed through heterosexual contact, and 8% were MSM/IDUs.
  • Of the 76,696 adult and adolescent women living with AIDS, 59% were exposed through heterosexual contact and 38% were exposed through injection drug use.

In 2003, the CDC published new guidelines for medical professionals to integrate HIV prevention into the regular medical care of those living with HIV. The three major components of the recommendation are: screening for HIV transmission risk behaviors and STDs, providing brief behavioral risk-reduction interventions in the office setting and referring selected patients for additional prevention interventions and other related services, and facilitating notification and counseling for sex and needle-sharing partners of infected persons [34]. Also in 2003, the CDC, in partnership with other U.S. Department of Health and Human Services agencies and other government and nongovernment agencies launched a new initiative, Advancing HIV Prevention: New Strategies for a Changing Epidemic [35]. The new initiative was a response to recent increases of HIV infections among men who have sex with men (MSM), as well as, heterosexuals.

As a result of both the new prevention initiative and the prevention guidelines, several disturbing trends regarding HIV/AIDS have come to light. The CDC's findings were announced at the 2003 National HIV Prevention Conference in Atlanta. Among the most disturbing trends in HIV/AIDS were:

  • A 2% increase in the number of new AIDS cases.
  • New HIV diagnoses for gay and bisexual men increased by 18% since the lowest point in 1999.
  • Twenty percent of African Americans and Latinos are not aware that effective HIV treatments are available.
  • HIV from injection drug use has increased by 15% in youth and young adults, with the greatest increase in the 13 to 15 year old age group.
  • Among gay men, the numbers who meet partners online are increasing and more than three-quarters of these men are likely to report high risk sex with those partners. Thirty-nine percent reported having unprotected anal sex with those partners [36].

The CDC also announced a new national system for measuring the rate of HIV infections in the U.S. The Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS) will be able to more accurately monitor the number of new HIV infections in 35 locations in the U.S. This will allow better targeting for prevention in those populations most in need [37].
 


CHARACTERISTICS OF HIV DISEASE


The immune deficiency characterizing HIV disease is manifested by markedly depressed T lymphocyte functioning, with a reduction of helper T cells (T4), impaired killer T cell activities, and increased suppressor T cells (T8). By selectively invading and infecting T cells, the virus damages the very cell whose function it is to orchestrate the identification and destruction of the virus as antigen. Other cells with the same molecular makeup might also become infected. Eventually, the individual's supply of functional T cells becomes depleted. In a person with a competent immune system, the number of T4 cells ranges from 600-1,200 per mm3, whereas the patient with HIV might have 0-500 per mm3 T4 cells [14].

VIRAL INVASION

HIV was known formerly as human T cell lymphotropic virus (HTLV-III). The HIV virus is a retrovirus, carrying genetic information in ribonucleic acid (RNA) rather than in deoxyribonucleic acid (DNA). It infects the T cell by binding to it at the CD4 receptor site and inserting its RNA into the T cell. Through an enzyme called reverse transcriptase, the HIV RNA is converted to DNA. When the T cell is activated to reproduce, its genetic information is now programmed to produce more of the HIV virus, and functional T cells diminish rapidly. Most antiretroviral drugs now being tested or used in treatment regimens work by inhibiting the action of reverse transcriptase. Azidothymidine (zidovudine/AZT) is one of the few drugs carrying FDA approval for this use [14].

HIV SCREENING

The antibody to this virus has been identified and can be used for screening purposes. However, the latency period, the time the body takes to recognize non-self and program antibodies to the virus, is longer than with many other infectious organisms. In order to diagnose HIV infection, laboratory tests such as enzyme-linked immunosorbent assay (ELISA), a test that was developed to screen the nation's blood supply, and the Western Blot test are used to detect the presence of HIV antibodies, which infected persons have in measurable quantities. ELISA is quick, easy to perform, and extremely sensitive; however, it has a high rate of false-positive results. There can also be false-negative results with ELISA if the test is done before the person develops antibodies or if the person is too sick to produce the antibody. When the ELISA test is positive it should be repeated. If positive again, the Western Blot test, is used to confirm the presence of HIV antibodies. The Western Blot test uses an expensive process called electrophoresis so it is used only as a confirmatory test [17]. The latency period for blood-transmitted HIV infection is thought to be within 4 to 7 weeks, and antibody formation for infection through sexual contact is thought to be from 6 to 14 months. The prolonged latency period thus effectively reduces the accuracy and immediacy of host identification. One of the theories concerning this prolonged latency period is that HIV invades T cells and, in effect, sequesters itself from view of the body's surveillance system, meanwhile multiplying anomalous T cells that are ineffective for purposes of immunity [14].

In November 2002, the FDA approved the OraQuick HIV rapid test. The test, developed by OraSure Technologies, Inc., was categorized as waived under the Clinical Laboratory Improvement Amendments. OraQuick detects the presence of antibodies to HIV-1 and produces results within 20 minutes from a single drop of blood. Positive results require confirmation by Western Blot or immunofluorescence assays [35].

Screening for the antibody is helpful only to the extent that individuals who have been exposed to HIV can be identified. However, not all of these individuals actually carry the virus, nor will all of them show signs of illness. Therefore, several situations are possible.

Exposure

An individual may be exposed to the virus but neither carry it nor contract the disease.

Carrier

The individual may carry the virus with the capability of infecting others but without accompanying signs and symptoms.

Terminal Disease

The individual may be infectious, symptomatic, and terminal. HIV disease becomes AIDS when the immune system is so damaged that the number of CD4+ T-lymphocyte cells is below 200 per mm3 or an opportunistic infection occurs.

Some suggest that the average incubation period for HIV, that is, from infection to clinical symptoms, is from 4 to 6 years. It is also thought that carriers of the virus who test positive for the antibody can remain as carriers for years with the virus in a dormant state. Although approximately one third of those who now test positive for the disease eventually will begin to show clinical manifestations, it is thought by some investigators that the percentage of those who go on to develop the disease will eventually approach 100% [14].

CLINICAL MANIFESTATIONS

Clinical manifestations of HIV generally are related to opportunistic infections preying on an impaired immune system. These diseases include Pneumocystis carinii pneumonia (PCP), tuberculosis, and others. The HIV patient commonly succumbs to uncontrollable infection, becoming increasingly debilitated, feverishly ill, malnourished, and often in pain. Lymphadenopathy, pulmonary infiltrates, wasting syndrome, and neurologic abnormalities; such as dementia, tremors, and encephalitis; contribute to the debilitated state. Because the HIV travels from cell to cell rather than through the bloodstream, it is usually not susceptible to circulating antibodies of the body's remaining immune system B cells. To date, there is no predictable course of curative treatment [14].
 


TRANSMISSION OF HIV


Transmission of HIV results from intimate contact with blood and body secretions, excluding saliva and tears. The most common modes of transmission are sexual contact, administration of contaminated blood and blood products, contaminated needles, and mother-to-fetus. Although blood transfusions of whole blood, packed cells, and fresh frozen plasma are most unlikely to be the cause of transmission with the more sophisticated crossmatching and antibody screening measures, individuals needing specific blood components (such as factor VIII and frequent plasma replacement) are more at risk because of the large numbers of donors needed to produce adequate quantities of these components. The risk of acquiring the virus increases with the numbers of potential carriers involved, just as multiple sexual contacts create higher risk [14].

RISK CATEGORIES 

On the basis of newly reported cases, the current risk categories from greatest risk to least risk are approximately as follows: MSM, injecting drug users, MSM who inject drugs, heterosexual transmission, blood transfusion, perinatal transmission, and no reported risk category [6]. The risk of sustaining HIV infection from a needle stick with infected blood is approximately 1 in 300. In the absence of prophylactic treatment, to be discussed later, approximately 30% to 50% of children born to HIV-infected mothers will contract HIV infection.

In summary, the basic concept of HIV transmission, cellular transformation, epidemiology, treatment, and outcome has been discussed. Great strides have been made in the last few years in an attempt to understand this disease and to begin to research its detection, treatment, and cure [14].

SEXUAL TRANSMISSION OF HIV

HIV has been isolated from blood, seminal fluid, preejaculate, vaginal secretions, urine, cerebrospinal fluid, saliva, tears, and breast milk of infected individuals. Whether HIV infects spermatozoa is controversial. Recent reports of the removal of infected cells from semen, allowing artificial insemination without seroconversion, support the idea that spermatozoa are not infected. No cases of HIV infection have been traced to saliva or tears. The virus is found in greater concentration in semen than in vaginal fluids, leading to a hypothesis that male-to-female transmission could occur more easily than female-to-male. Sexual behavior that involves exposure to blood is likely to increase transmission risks. Transmission could also occur through contact with infected bowel epithelial cells in anal intercourse, in addition to access to the bloodstream through breaks in the rectal mucosa. Although all HIV-seropositive people are potentially infectious, there is widespread variation in the seropositivity and seroconversion of their sexual partners. Factors that could explain this variability include differences in sexual practices and numbers of sexual contacts, susceptibility of the partner, differences in viral strains, changing degrees of infectiousness of the HIV-infected person over time, co-factors that enhance or limit transmission, genetic resistance, or a combination of these factors. AZT may play a small role in preventing transmission. Posing the highest risk of infection is anal receptive intercourse, followed by vaginal intercourse. Risk is reduced through the use of latex condoms. For the wearer, latex condoms provide a mechanical barrier limiting penile exposure to infectious cervical, vaginal, vulvar, or rectal secretions or lesions. Oil-based lubricants may make latex condoms ineffective and should not be used. Water-soluble lubricants are considered safe. Natural membrane condoms (made from lamb cecum) contain small pores and do not block HIV passage in laboratory studies. A meta-analysis of several studies of HIV transmission found that latex condom efficacy was 69% overall. Abstinence from sexual intercourse is the sole safe way to prevent transmission. Over a period of time, precautions tend to fail due to breakage of condoms or failure to maintain precautions. Sexual activity in a mutually monogamous relationship in which neither partner is HIV-infected and no other risk factors are present is considered safe [7].

Oral Sex

Numerous studies have demonstrated that oral sex can result in the transmission of HIV and other sexually transmitted diseases (STDs). While the risk of HIV transmission through oral sex is much smaller than the risk from anal or vaginal sex, there are several co-factors that can increase this risk, including oral ulcers, bleeding gums, genital sores, and the presence of other STDs. Prevention includes the use of latex condoms, plastic food wrap, condom cut open, or a dental dam, all of which serve as a physical barrier to transmission [38].

BLOOD DONOR PRODUCTS

It has been estimated that an HIV-infected drop of human blood contains 1 to 100 live virus particles. In comparison, a drop infected with hepatitis B virus has 100 million to 1 billion organisms. Even so, blood transmission of HIV does occur, primarily through sharing of contaminated needles among injecting drug users and through blood transfusion. Transmission of HIV-1 has occurred after transfusion of the following components: whole blood, packed red blood cells (including washed and buffy coat poor), fresh frozen plasma, cryoprecipitate, platelets, and plasma-derived products, depending on the production process. With the implementation in March 1985 of a donor screening program of the nation's blood supply, blood transfusion is now even safer; the current risk of transmission of AIDS through this route is estimated to be 1 in 225,000. A somewhat higher estimate of 1 in 40,000 to 1 in 60,000 is reported from areas that have a high prevalence of HIV-1 infection. It is possible that before blood screening implementation, more than 12,000 people were infected. A large percentage of hemophiliacs acquired HIV in this manner. Donor screening, HIV testing, and heat treatment of the clotting factor have greatly reduced the risks. To further decrease the possibility of HIV transmission through transfusion of blood and blood products, patients scheduled to undergo elective surgery are increasingly advised to make predeposited blood donations for intraoperative autotransfusion. Current screening tests cannot detect either recently HIV-1-infected people who have not yet developed antibody (the "window period") or HIV antibody-negative patients who have AIDS. Donating procedures include an interview for risk factors and the ability of the potential donor to exclude their blood from being used. Although no transfusion-related cases of HIV-2 infection have been reported in the United States, as of June 1, 1992, all U.S. blood centers test donations for antibodies to both HIV-1 and HIV-2. Clinicians should recommend HIV-1 antibody testing for all people transfused between January 1978 and March 1985 [7].

NEEDLE SHARING

Transmission of HIV among injecting drug users occurs primarily through contamination of injection paraphernalia with infected blood. Behavior such as needle sharing, "booting" the injection with blood, and performing frequent injections increases the risk. Cocaine use (by injection or smoking) is associated with a higher prevalence of HIV infection. This may in part be attributed to the exchange of crack for sex. Sharing of equipment is common due to legal and financial restrictions and cultural norms. Geographically, the rate of infection varies; 80% of New York City addict needle sharers are infected, as opposed to much lower rates in other metropolitan area clusters. Secondary transmission occurs to women, children, and sexual partners. Preventative strategies include drug treatment, on-site medical care in a drug treatment program, recruitment of "street" outreach workers for intensive drug and sex "risk reduction" educational campaigns, teaching addicts to sterilize their equipment between use, the free provision or exchange of sterile injection equipment (as allowed by law), distribution of condoms and bleach to clean drug use equipment, or a combination of these interventions [7].

OCCUPATIONAL EXPOSURES

Transmission due to occupational exposure of healthcare workers has occurred in needlestick accidents and blood splashes to the oral mucosa. Needlestick is the most common route. Thousands of healthcare personnel who were so exposed have been studied, and only 57 cases of well-documented infection have been reported in the United States [25]. The risk of infection through this route is low, and every effort should be made to decrease the exposure rate. Educational efforts, implementation of engineering controls in needled and sharp-edged medical devices, the use of hard plastic needle disposal units where these devices are most frequently used, and the development of procedural details to avoid blood and body fluid contact would greatly reduce the exposure rate. Healthcare personnel must apply universal precautions to all activities to avoid contact with potentially HIV-infected human fluids. Safer medical equipment, particularly needled and sharp-edged devices, must be designed [7].

POSTEXPOSURE PROPHYLAXIS (PEP)

This section, Postexposure Prophylaxis, is from the Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis (as reported in MMWR, May 15, 1998 [5], and updated in June, 2001 [22]).

Definitions of Healthcare Personnel and Exposure

"Healthcare personnel" (HCP) is defined as persons (e.g., an employee, student, contractor, attending clinician, public-safety worker, or volunteer) whose activities involve contact with patients or with blood or other body fluids from patients in a healthcare, laboratory, or public safety setting. An "exposure" that may place HCP at risk for HIV infection and therefore requires consideration of PEP is defined as a percutaneous injury (e.g., a needlestick or cut with a sharp object), contact of mucous membrane or nonintact skin (e.g., when the exposed skin is chapped, abraded, or afflicted with dermatitis), or contact with intact skin when the duration of contact is prolonged (i.e., several minutes or more) or involves an extensive area in contact with blood, tissue, or other body fluids. Body fluids include: (a) semen, vaginal secretions, or other body fluids contaminated with visible blood that have been implicated in the transmission of HIV infection; and (b) cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids, which have an undetermined risk for transmitting HIV. In addition, any direct contact (i.e., without barrier protection) to concentrated HIV in a research laboratory or production facility is considered an "exposure" that requires clinical evaluation and consideration of the need for PEP.

HIV PEP

The following recommendations apply to situations where HCP have had exposure to a source person with HIV or where information suggests that there is a likelihood that the source person is HIV-infected. These recommendations are based on the risk for HIV infection after different types of exposure and limited data regarding efficacy and toxicity of PEP. Because most occupational HIV exposures do not result in the transmission of HIV, potential toxicity must be carefully considered when prescribing PEP. When possible, these recommendations should be implemented in consultation with persons having expertise in antiretroviral therapy and HIV transmission.

Explaining PEP to HCP

Recommendations for chemoprophylaxis should be explained to HCP who have sustained occupational HIV exposures (Figure 1). For exposures for which PEP is considered appropriate, HCP should be informed that: (a) knowledge about the efficacy and toxicity of drugs used for PEP is limited; (b) only zidovudine (ZDV) has been shown to prevent HIV transmission in humans; (c) there are no data to address whether adding other antiretroviral drugs provides any additional benefit for PEP, but experts recommend combination drug regimens because of increased potency and concerns about drug-resistant virus; (d) data regarding toxicity of antiretroviral drugs in persons without HIV infection or in pregnant women are limited for ZDV and not known regarding other antiretroviral drugs; and (e) any or all drugs for PEP may be declined by the HCP. HCP who have HIV occupational exposures for which PEP is not recommended should be informed that the potential side effects and toxicity of taking PEP outweigh the negligible risk of transmission posed by the type of exposure.

Factors in Selection of a PEP Regimen

Selection of the PEP regimen should consider the comparative risk represented by the exposure and information about the exposure source, including history of and response to antiretroviral therapy based on clinical response, CD4+ T-lymphocyte counts, viral load measurements, and current disease stage. Most HIV exposures will warrant only a two-drug regimen, using two nucleoside analog reverse transcriptase inhibitors (NARTIs), usually ZDV and lamivudine (3TC). The addition of a third drug, usually a protease inhibitor (PI) (i.e., indinavir or nelfinavir), should be considered for exposures that pose an increased risk for transmission or where resistance to the other drugs used for PEP is known or suspected.

Timing of PEP Initiation

PEP should be initiated as soon as possible. The interval within which PEP should be started for optimal efficacy is not known. Animal studies have demonstrated the importance of starting PEP within hours after an exposure. To assure timely access to PEP, an occupational exposure should be regarded as an urgent medical concern and PEP started as soon as possible after the exposure (i.e., within a few hours rather than days). If there is a question about which antiretroviral drugs to use, or whether to use two or three drugs, it is probably better to start ZDV and 3TC immediately than to delay PEP administration. Although animal studies suggest that PEP probably is not effective when started later than 24 to 36 hours postexposure, the interval after which there is no benefit from PEP for humans is undefined. Therefore, if appropriate for the exposure, PEP should be started even when the interval since exposure exceeds 36 hours. Initiating therapy after a longer interval (e.g., 1 to 2 weeks) may be considered for exposures that represent an increased risk for transmission; even if infection is not prevented, early treatment of acute HIV infection may be beneficial. The optimal duration of PEP is unknown. Because 4 weeks of ZDV appeared protective in HCP, PEP probably should be administered for 4 weeks, if tolerated.

PEP if Serostatus of Source Person is Unknown

If the source person's HIV-serostatus is unknown at the time of exposure (including when the source is HIV-negative but may have had a recent HIV exposure), use of PEP should be decided on a case-by-case basis, after considering the type of exposure and the clinical and/or epidemiologic likelihood of HIV infection in the source (Figure 1). If these considerations suggest a possibility for HIV transmission and HIV testing of the source is pending, it is reasonable to initiate a two-drug PEP regimen until laboratory results have been obtained and later modify or discontinue the regimen accordingly.

PEP if Exposure Source is Unknown

If the exposure source is unknown, use of PEP should be decided on a case-by-case basis. Consideration should include the severity of the exposure and the epidemiologic likelihood that the person was exposed to HIV.

PEP for Pregnant HCP

For pregnant HCP, the evaluation of risk and need for PEP should be approached as with other HCP who have had HIV exposures. However, the decision to use any antiretroviral drug during pregnancy should involve discussion between the woman and her healthcare provider regarding the potential benefits and potential risks to her and her fetus.

Certain drugs should be avoided in pregnant women. Because teratogenic effects were observed in primate studies, efavirenz (EFV) is not recommended during pregnancy. Reports of fatal lactic acidosis in pregnant women treated with a combination of d4T and ddI have prompted warnings about these drugs during pregnancy. Because of the risk of hyperbilirubinemia in newborns, indinavir (IDV) should not be administered to pregnant women shortly before delivery.

Postexposure Testing and Follow-Up

HCP with occupational exposure to HIV should receive follow-up counseling, postexposure testing, and medical evaluation regardless of whether they receive PEP. HIV-antibody testing should be performed for at least 6 months postexposure (e.g., at 6 weeks, 12 weeks, and 6 months). It is unclear whether an extended follow-up period (e.g., 12 months) is indicated in certain circumstances. If PEP is used, drug-toxicity monitoring should be performed at baseline and again 2 weeks after starting PEP. Clinical judgement, based on medical conditions that may exist in the PEP regimen, should determine the scope of testing.

Recommended Protocol for PEP

Two regimens for PEP are provided in the Public Health Services Guidelines for management of HCP exposures to HIV (Table 1): first, a basic 2-drug regimen that should be appropriate for most HIV exposures; second, an expanded 3-drug regimen that is indicated for exposures that pose an increased risk for transmission (Figure 1) where resistance of one or more of the antiretrovirus agents is suspected.

 

Basic and Expanded Postexposure Prophylaxis Regimens

 Source: Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis [5; 22]

Regimen Category

Application

Drug Regimen

Basic 

Occupational HIV exposures for which there is a recognized transmission risk (Figure 1)

 4 weeks (28 days) of both zidovudine, 600 mg every day in divided doses (i.e., 300 mg twice a day, 200 mg three times a day, or 100 mg every 4 hours), and lamivudine 150 mg twice a day. 

Alternate Basic 

Occupational HIV exposures for which there is a recognized transmission risk (Figure 1).

 4 weeks (28 days) of both lamivudine, 150 mg twice a day, and stavudine, 40 mg twice a day (if body weight is <60 kg, 30 mg twice a day).

4 weeks (28 days) of both didanosine, 400 mg daily on an empty stomach (if body weight is <60 kg, 125 mg twice a day) and stavudine, 40 mg twice a day (if body weight is <60 kg, 30 mg twice a day).

Expanded

Occupational HIV exposures that pose an increased risk for transmission (e.g., larger volume of blood and/or higher virus titer in blood)

Basic regimen plus either indinavir, 800 mg every 8 hours, or nelfinavir, 750 mg three times a day.*

Basic regimen plus efavirenz 600 mg every day at bedtime.

Basic regimen plus abacavir 300 mg twice a day. 

*Indinavir should be taken on an empty stomach (i.e., without food or with a light meal) and with increased fluid consumption (i.e., drinking six 8 oz. glasses of water throughout the day); nelfinavir should be taken with meals.

Source: [5; 22]

Table 1

 


Postexposure Registries

Healthcare providers in the United States are encouraged to enroll HCP who receive PEP in a confidential registry developed by CDC, Glaxo Wellcome, Inc., and Merck & Co., Inc., to assess toxicity. The telephone number is (888)737-4448, (888)PEP-4HIV, or write the HIV PEP Registry, 1410 Commonwealth Drive, Suite 215, Wilmington, NC 28405. Unusual or serious and unexpected toxicity from antiretroviral drugs should be reported to the manufacturer and/or FDA by calling (800)332-1088.

Healthcare providers also should report instances of prenatal exposure to antiretroviral agents to the Antiretroviral Pregnancy Registry. The registry is an epidemiologic project to collect observational, nonexperimental data on antiretroviral drug exposure during pregnancy to assess potential teratogenicity. Referrals should be directed to the Antiretroviral Pregnancy Registry, 1410 Commonwealth Drive, Suite 215, Wilmington, NC 28405. The telephone numbers are (800)258-4263 or (800)722-9292, ext. 39437, and the fax number is (800)800-1052. A protocol has been developed to evaluate HIV seroconversion in HCP who received PEP. These events can be reported to the CDC, by calling (404)639-6425.

Resources for Consultation

Clinicians who seek consultation on HIV PEP for assistance in managing an occupational exposure should consult local experts in HIV treatment as much as possible. In addition, the National Clinicians' Post-Exposure Prophylaxis Hotline (PEPline), (888)448-4911, has been created to assist clinicians with these issues. Other resources and registries include the HIV Postexposure Prophylaxis Registry, the Antiretroviral Pregnancy Registry, FDA, and CDC. Hearing or speech-impaired may call TTY (502)564-6530 from 8:00 a.m. to 4:30 p.m. (EST) [5].

OLDER PEOPLE WITH HIV

While nearly 10% of diagnosed cases of AIDS occur in people 50 years old and older, there has been little attention given to this group in the areas of prevention, education, psychosocial support, or treatment because HIV/AIDS is thought to be the disease of the young and sexually active. Evidence points to many infected older people contracting the disease through MSM or same sex contact. Also, older people are often finding themselves dating again due to divorce or being widowed, and engaging in sexual activity without protection [11]. With AIDS death rates plummeting and people who are infected surviving longer, "the number of people over 50 living with HIV will mushroom," said David Blatt, MD, director of the HIV program at Illinois Masonic Medical Center in Chicago. Because older people typically are not targeted by HIV prevention and education campaigns, the number of sexually transmitted cases among the elderly is expected to skyrocket. Studies indicate that at-risk people over 50 are one-sixth as likely as younger at-risk adults to use condoms during sex, and one-fifth as likely to be tested for HIV [18]. Elderly people presenting with confusion or altered mental status or having severe bouts of pneumonia may first be evaluated for other possibilities before HIV is considered. Many physicians don't suspect HIV in their older patients and miss the opportunity to suggest testing, which can result in delayed diagnosis and treatment. A study in the May/June 1997 Archives of Family Medicine, of primary care doctors in Texas found that 40% rarely or never asked patients older than 50 about HIV risk factors, while only 7% rarely or never asked patients younger than 30 [18]. According to Lisa Calpaldini, MD and colleagues in the November 30, 1998 issue of Patient Care, early possible signs of immunosuppression that are frequently overlooked or mistakenly attributed to aging include thrush and skin problems, especially seborrheic dermatitis, herpes zoster, and recurrent herpes simplex virus type 2, in a person who does not have a history of it. When HIV isn't recognized and treated, the most typical opportunistic infections are Pneumocystis carinii pneumonia (PCP) and recurrent bacterial pneumonia, cytomegalovirus (CMV) and Mycobacterium tuberculosis or Mycobacterium avium complex. PCP can look like bacterial pneumonia, bronchitis, or congestive heart failure. Early HIV symptoms in the elderly, such as fatigue and weight loss, may appear to be a normal part of aging, and AIDS-related dementia is often mistaken for Alzheimer's disease. Fran Wallach, MD, assistant professor at Mt. Zion Medical Center, says, "Because older patients tend to have underlying diabetes, cardiac disease or hypertension, some of our newer therapies like protease inhibitors may either unmask or compound the disease that the patient already has" [18].

MATERNOFETAL TRANSMISSION

HIV is transmitted to infants by transplacental spread from mother to fetus in utero, during parturition, or through breast feeding after birth. Because infants have under-developed natural resistance systems, they are highly susceptible to many infections, including HIV. In vivo transmission is the most common route. Both uninfected and infected infants have been born to mothers who have previously borne an infected infant. Studies have dramatically shown the beneficial effect of treating pregnant women and newborns with AZT to prevent transmission to the child resulting in dramatic declines in the incidence of perinatally acquired AIDS [7]. The use of the OraQuick test to screen pregnant women will hopefully result in a reduced transmission of HIV to infants.

Worldwide, perinatal (i.e., mother to infant) transmission accounts for most HIV infections among children; in the United States, of the approximately 7,000 infants born to HIV-infected mothers each year, 1,000-2,000 are HIV-infected. Strategies for reducing perinatally acquired HIV infection have included preventing HIV infection among women and, for HIV-infected women, avoiding pregnancy or refraining from breastfeeding their infants. On February 21, 1994, the National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Child Health and Human Development (NICHD) announced preliminary results from a randomized, multicenter, double-blind clinical trial of ZDV to prevent HIV transmission from mothers to their infants. This report summarizes the interim results of that trial, which indicate effectiveness of ZDV for prevention of perinatal transmission.

The study was initiated in April 1991 by the Pediatric AIDS Clinical Trials Group (PACTG) of NIAID in collaboration with NICHD and the National Institute of Health and Medical Research (INSERM) and the National Agency of Research on AIDS (ANRS), France. Eligible participants were HIV-infected pregnant women who had received no antiretroviral treatment during their current pregnancy, had no clinical indication for maternal antepartum antiretroviral therapy in the judgment of their healthcare provider, and who had a CD4+ T-lymphocyte count >200 cells/microliter at time of entry into the study. Enrolled women were randomized to receive either a ZDV or placebo regimen. The ZDV regimen included antepartum ZDV (100 mg given orally five times daily) initiated at 14 to 34 weeks' gestation and continued for the remainder of the pregnancy; intravenous ZDV during labor (administered intravenously as a loading dose of 2 mg per kg body weight given over one hour, followed by continuous infusion of 1 mg per kg body weight per hour until delivery); and oral administration of ZDV to the newborn (ZDV syrup at 2 mg per kg body weight per dose given every six hours) for the first six weeks of life, beginning 8 to 12 hours after birth. The placebo regimen was given on the same schedule. Blood specimens were obtained for HIV culture from all infants at birth and at ages 12 weeks, 24 weeks, and 78 weeks. A positive viral culture was considered indicative of HIV infection. Infants also were tested for HIV antibody at ages 15 months and 18 months.

Based on analysis of data for 364 births through December 1993, ZDV therapy was associated with a 67.5% reduction in the risk for HIV transmission; the estimated rates of transmission were 25.5% (95% confidence interval [CI] = 18.3% - 33.7%) among the 184 children in the group receiving the placebo regimen compared with 8.3% (95% [CI] = 3.8% - 13.8%) among the 180 children in the group receiving ZDV (Kaplan-Meier estimate at age 18 months; p = 0.00006). Although the ZDV regimen was well tolerated by mothers and infants, hemoglobin levels were lower for infants in the ZDV group (mean decrease in hemoglobin was <1 g/dL); however, this problem resolved without therapy following completion of ZDV treatment. The incidence of reported side effects was similar among mothers and infants between the two randomized groups.

Based on these interim findings, NIAID accepted the recommendation of an independent data and safety monitoring board to terminate enrollment into the trial and to offer ZDV to women in the group who had received the placebo but had not yet delivered, and to their infants aged <6 weeks [50]. An NIAID Clinical Trials Alert summarizing the trial is available by calling (800)874-2572.

CONSIDERATIONS FOR ANTIRETROVIRAL THERAPY IN THE HIV-INFECTED PREGNANT WOMAN

Guidelines for antiretroviral therapy and for initiation of therapy in pregnant HIV-infected women should be the same as those delineated for non-pregnant adults. Women who are in the first trimester of pregnancy and who are not receiving antiretroviral therapy may want to consider delaying initiation of therapy until after 10 to 12 weeks gestation. This is the period when the embryo is most susceptible to the potential teratogenic effects of drugs; the risks of antiretroviral therapy to the fetus during that period are unknown.

HIV counseling and the offer of HIV testing to pregnant women have been universally recommended in the United States and are now mandatory in some states. Care of the HIV-infected pregnant woman should involve a collaboration between the HIV specialist caring for the woman when she is not pregnant, her obstetrician, and the woman herself. Treatment recommendations for HIV-infected pregnant women are based on the belief that therapies of known benefit to women should not be withheld during pregnancy unless there are known adverse effects on the mother, fetus, or infant that outweigh the potential benefit of the woman [15].

    

Antepartum

Oral administration of 100 mg ZDV five times daily, initiated at 14 to 34 weeks gestation and continued throughout the pregnancy. Acceptable alternative: 200 mg ZDV three times daily or 300 mg ZDV two times daily.

Intrapartum

During labor, intravenous administration of ZDV in a 1-hour loading dose of 2 mg per kg of body weight, followed by a continuous infusion of 1 mg per kg of body weight per hour until delivery.

Postpartum

Oral administration of ZDV to the newborn (ZDV syrup at 2 mg per kg body weight per dose every 6 hours) for the first 6 weeks of life, beginning at 8 to 12 hours after birth (Note: intravenous dosage for infants who cannot tolerate oral intake is 1.5 mg per kg body weight intravenously every 6 hours).

A study sponsored by the Pediatric AIDS Clinical Trials Group (PACTG) and funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development (NICHD), reported in the January 13, 1998 issue of The Journal of the American Medical Association, the following:

"Children exposed to zidovudine (ZDV, AZT) in utero and as newborns and who escaped acquiring HIV from their infected mothers show no cancers or other adverse health effects up through preschool age, according to a new study from the National Institutes of Health (NIH). It is the first report to assess the late effects of AZT exposure in healthy HIV-uninfected children born to mothers who took the drug to prevent transmitting HIV to their offspring."

Anthony S. Fauci, MD, NIAID Director, reported that these findings are reassuring and that these data are critically important because the current recommendation is to treat HIV-infected pregnant women with regimens that include AZT to prevent perinatal HIV transmission.

The international Antiretroviral Pregnancy Registry, sponsored by Burroughs Wellcome Co. (Research Triangle Park, North Carolina) and Hoffmann-LaRoche Foundation, Inc. (Nutley, New Jersey), is collecting observational, nonexperimental data on exposure to ZDV and dideoxycytidine (ddC) during pregnancy. Women who have been treated with either of these drugs at any time during pregnancy for any duration are eligible for registry enrollment. Patients can be enrolled by contacting the registry. The telephone number is (800)722-9292, ext. 8465, and the fax number is (919)315-8981.

ORGAN TRANSPLANTATION

Because these procedures are less common than other transmission-related activities, there have been very few case reports of HIV acquisition by this route. HIV has been transmitted via the kidneys, liver, heart, pancreas, bone, and, possibly, skin grafts and through artificial insemination. HIV testing is used in these circumstances to rule out infection. Most cases of transmission through transplants of organs, bone, or tissue occurred before HIV screening was available. As with blood transfusions, donors testing antibody seronegative may pass HIV infection on to recipients [7].
 


NATURAL HISTORY AND CLASSIFICATION OF HIV INFECTION


ACUTE HIV INFECTION

HIV is a protracted infection which passes through several stages and, if untreated, carries an 80% mortality rate at 10 years. The initial event, reported in 50% to 90% of patients, is an acute retroviral syndrome characterized as an infectious mononucleosis-like illness. Symptoms include fever, sore throat, malaise, rash, diarrhea, lymphadenopathy, mucocutaneous ulcerations and weight loss averaging 10 pounds. A variety of neurologic syndromes including encephalitis may occur. The illness begins one to three weeks after viral transmission and is self-limited with an average duration of two to three weeks. Laboratory abnormalities include lymphopenia, atypical lymphocytosis, and a decreased CD4 cell count. During this early phase HIV antibody tests are negative and the diagnosis rests on the demonstration of HIV P24 antigen or, preferably, quantitative plasma HIV RNA. Concentrations of HIV RNA in the blood (viral load) are high during the acute syndrome. Following the host immune response there is seroconversion with positive serology and the viral load decreases considerably, reaching a relatively stable level at about six months. At this juncture the degree of viral load will dictate the subsequent course. Patients having high viral concentrations such as 105 copies/ml or higher will have a relatively rapid course. The prolonged and progressive infection of target lymphocytes results in an annual average decrease in CD4 count of about 50 per cubic millimeter.

ASYMPTOMATIC HIV INFECTION

Early stage HIV infection, in this form, is characterized by a near complete absence of symptoms and relatively normal laboratory studies. However, there is a gradual decline in CD4 count with positive serologic and virologic studies indicating past infection and persistent viral activity. Patients may be subclassified based on a laboratory evaluation that includes a complete blood count with differential white blood cell count and a platelet count. Immunologic tests, such as the T-lymphocyte helper and suppressor cell counts, are also an important part of the overall evaluation. Patients with test results that are within normal limits and those who have not yet had complete evaluations should be differentiated from patients whose test results are consistent with HIV-associated defects, lymphopenia, thrombocytopenia, and a decreased number of T-helper (T4) lymphocytes [7]. The duration of this asymptomatic stage is variable depending on the level of viremia as measured by HIV RNA and ranges from six to ten years.

PERSISTENT GENERALIZED LYMPHADENOPATHY 

Patients may have persistent but painless generalized lymphadenopathy (PGL) but without further disease findings. PGL is defined as palpable lymph node enlargement of 1 cm or greater at two or more extra-inguinal sites that persists for more than three months in the absence of a concurrent illness or condition other than HIV infection to explain the findings. In some cases, lymphadenopathy regresses as HIV disease advances, probably because the architecture of the lymph node is gradually destroyed [7].

DISEASE PROGRESSION AND CLASSIFICATION

Symptomatic infection can be expected to supervene after the CD4 count has decreased to less than 200/mm3 as this represents the stage of severe immunodeficiency. The Centers for Disease Control and Prevention (CDC) defines late Stage HIV infection as AIDS on the basis of two criteria: characteristic AIDS-defining illness such as Pneumocystis carinii pneumonia, central nervous system (CNS) toxoplasmosis, or other opportunistic infections or tumors (Kaposi's sarcoma). A variety of clinical syndromes may supervene at this juncture including dementia, peripheral neuropathy, wasting syndrome, and chronic diarrhea. In the U.S., the prevalence of AIDS-defining opportunistic diseases is as follows: pneumocystis carinii pneumonia (64%), Kaposi sarcoma (21%), candidiasis (13%), cryptococcosis (7%), cryptosporidiosis (6.2%), cytomegalovirus (5%), atypical mycobacteriosis (4%), systemic herpes (4%), toxoplasmosis (3%), and tuberculosis (3%) [39].

In the absence of antiviral therapy, the average survival is approximately 3.5 years once the patient's CD4 count has reached 200/mm3 and 1.5 years for the patient who has developed an AIDS-defining diagnosis. The natural history has been dramatically altered by highly active antiretroviral therapy especially since the introduction of protease inhibitors and non-nucleoside reverse transcriptase inhibitors in 1996.

For individuals who acquired AIDS through injection drug use, co-infection with the hepatitis C virus (HCV) is common (50% to 90%). Approximately one quarter of HIV-infected persons in the U.S. are also infected with HCV [40]. HCV is one of the most common causes of chronic liver disease in the U.S. and for those individuals co-infected with HCV and HIV, liver damage progresses more rapidly. The U.S. Public Health Service/Infectious Diseases Society of America (USPHS/IDSA) guidelines recommend that all HIV-infected persons be screened for HCV infection [40].

Intervention and treatment of opportunistic diseases and infections is dependent on the ability of the health provider to diagnose, monitor, and educate patients at risk. The main challenge to health providers is choosing those interventions that will alleviate suffering and morbidity, while not exceeding the financial and technical capabilities of the health system [39].
 


MANAGEMENT OF HIV INFECTION


Primary physicians in consultation with specialists are playing an increasing role in the care of HIV-infected individuals. It is not possible for all care to be delivered by infectious disease and oncology specialists. Moreover, with early antiretroviral therapy and prophylaxis for opportunistic infections, HIV disease shares features of other multisystem, chronic diseases characterized by acute exacerbations and end-stage manifestations.

Primary care physicians should provide risk factor assessment of their patients and, when appropriate, screening for HIV infection with pre-test and post-test counseling. Pre-test counseling should include review of risk factors for HIV infection, discussion of safe sex, and the meaning of a positive test. Post-test counseling should include a review of the importance of safe sex practices. For persons who test positive, information on available medical and mental health services should be provided as well as guidance for contacting sexual or needle-sharing partners [13]. Patients with HIV infection should be seen at regular intervals by a primary care provider to perform periodic physical examinations, monitor prognostic markers (e.g., CD4 count, viral load), initiate and monitor antiviral and prophylactic therapy, provide supportive counseling and offer assistance with terminal care. Specialists should be consulted for patients intolerant of standard drugs, those in need of systemic chemotherapy, and those with complicated opportunistic infections. In many cases a single consultation with follow-up to the primary care physician will provide the needed expertise while ensuring continuity of care.

Standard laboratory tests for patients with HIV infection include the following:

  • HIV serology. Standard HIV serologic testing by the ELISA method and confirmation by the Western Blot test carries a sensitivity and specificity exceeding 99%. Suspect patients with negative or indeterminate results should have repeat serologic testing in 2 to 3 months.
  • Quantitative HIV RNA. The measurement of HIV RNA in plasma is extremely important for determining prognosis and monitoring response to antiretroviral therapy. Combination antiretroviral regimens used at the present time will usually produce a 50% decrease in total body HIV within just a few days. HIV RNA assays should be performed approximately one month after initiation of new treatment and at 4-month intervals thereafter.
  • CD4 count. The CD4 count is essential for evaluating the status of the immune system. In healthy adults levels average approximately 600-400/mm3. It is recommended that CD4 counts be performed at 4-month intervals for most patients.
  • Complete blood count (CBC). Anemia, leukopenia, and thrombocytopenia are common in HIV patients in relation to progressive primary viral infection, super-infection with disseminated opportunistic pathogens, and as a complication of anti-retroviral therapy. The CBC should be repeated at three to four month intervals or more frequently if the patient's clinical course is unstable or there is prior evidence of bone marrow suppression.
  • Chest x-ray. Standard chest x-ray should be performed on the initial evaluation of persons found to be HIV-positive. This provides a baseline reference for a patient population at high risk for opportunistic pulmonary complications.
  • Hepatitis serology and liver chemistry panel. These are indicated in the early evaluation of most patients because of the high incidence of concurrent hepatitis. Appropriate tests include detection of serologic markers for hepatitis B and C.
  • Syphilis serology. Standard serologic testing for syphilis is recommended annually in patients who are sexually active.
  • PPD skin test. The PPD tuberculin skin test should be performed annually in patients in high-risk categories including those with HIV infection. Induration greater than or equal to 5 mm is defined as a positive result in patients with HIV infection.

ANTIRETROVIRAL THERAPY

Strategies for the treatment of HIV infection are based on an understanding of the molecular biology of HIV and the life cycle of the virus within the host cell. Antiviral agents have been developed that act predominately on processes specific to the virus particle in order to preserve the integrity of the host cell. Several potential strategies specifically aimed at interruption of the viral life cycle have been defined, including:

1.      Preventing the virus from attaching to the CD4 receptor of the T4 lymphocyte

2.      Interfering with uncoating of the virus within the cell, the first essential step in proviral integration into cellular DNA

3.      Inhibiting reverse transcriptase (RT), a viral enzyme specific to retroviruses, which enables the virus to make a DNA copy from single-stranded viral RNA prior to integration into cellular DNA

4.      Blocking viral regulatory and transactivating proteins, which are involved in the transcription and translation of viral RNA proteins from proviral DNA as the virus goes from the quiet, integrated state to active replication

5.      Inhibiting protease, a viral enzyme responsible for the cleaving of viral proteins both before proviral integration and as the viral particles recombine into functional proteins needed for viral maturation

6.      Preventing viral assembly and budding out of the cell

Highly active antiretroviral therapy or HAART combines three classes of agents, nucleoside analog reverse transcriptase inhibitors, non-nucleoside analog reverse transcriptase inhibitors, and protease inhibitors. Initiated in 1995 in the U.S., the HAART regimen has been effective in dramatically decreasing HIV-related morbidity and mortality and should be considered for all HIV-infected persons who qualify for such therapy. In addition to combination therapy, the sequencing of drugs and the preservation of future treatment options are also important. Three types of combination regimens may be employed as initial therapy. These include: NNRTI-based regimens that are PI sparing, PI-based regimens that are NNRTI sparing, and triple NNRTI regimens that are both PI and NNRTI sparing. The goal of a class-sparing regimen is to "save" one or more classes of drugs for later use [41]. There are now 22 different antiretroviral formulations and 19 separate drugs available to HIV-infected individuals. The U.S. Department of Health and Human Services, in their revised guidelines for the use of antiretroviral agents in HIV-infected adults and individuals, have made the distinction between NNRTI-based regimens and PI-based regimens. Treatment is also classified as "preferred" or "alternative." These changes may simplify therapeutic decisions for clinicians [42].

Prior to 1996 only one class of antiviral drugs, the nucleoside analogs, were available for treatment of HIV infection. Nucleoside analogs act against only one step in the virus life cycle, inhibiting reverse transcriptase (RT). The introduction of non-nucleoside RT inhibitors and protease inhibitors, which act at a different site or by a different mechanism, has revolutionized strategies for the treatment of this infection. For the first time, combination drug regimens employing two or more classes of antiretrovirals have achieved the goal of no detectable virus, resulting in prolonged survival in many previously untreated patients. Currently there are three major classes of antiretroviral drugs, discussed briefly below.

Nucleoside Analog Reverse Transcriptase Inhibitors (NARTI) used singularly or in combination can increase the CD4 count, decrease viral load, and prolong survival. Sequential monotherapy is followed eventually by clinical failure based on the emergence of drug resistance in HIV. Combinations of two NARTIs result in better viral suppression, more sustained CD4 counts and decreased emergence of resistance. Available NARTI agents include: abacavir (Ziagen, ABC); zidovudine (Retrovir, ZDV, AZT); didanosine (Videx, ddl); stavudine (Zerit, d4T); lamivudine (Epivir, 3TC); zalcitabine (HIVID, ddc); tenofovir (Viread, PMPA).

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) have a high affinity for the active site of HIV-RT. When used as a single agent this class is associated with rapid emergence of resistance in as little as six weeks. Thus, these drugs should not be used as single agents but are best employed in combination regimens for patients who have not received prior antiretroviral therapy. Available agents include: efavirenz (Sustiva, EFV); delavirdine (Rescriptor, DLV); and nevirapine (Viramune, NVP).

Protease Inhibitors (PI). Development of mature infectious virus depends upon enzymatic cleavage of HIV transcribed polyprotein by HIV protease. In binding to the active site of the HIV protease, PIs interrupt the formation of mature infectious particles and reduce viral replication by as much as 99%. Resistance to PIs develops rapidly when these agents are used alone. However, in combination with nucleoside analogs the effect can last for years, often resulting in a reduction of viral load to undetectable levels. Available agents include: amprenavir (Agenerase, AMP); indinavir (Crixivan, IDV); nelfinavir (Viracept, NFV); ritonavir (Norvir, RTV); saquinavir (Invirase, SQV-hgc; Fortovase, SQV-sgc); lopinavir/ritonavir (Kaletra).

The decision to initiate antiretroviral therapy is one that requires careful discussion with the patient, usually in consultation with an infectious disease specialist or other physician well versed in the use of antiretroviral drug combinations. Both physicians and patients alike need to be aware of the advantages, potential toxicities, and complexity of monitoring therapy. At the present time, the most active triple-drug regimen (for example two nucleoside analogs and a protease inhibitor) in a previously untreated patient can be expected to reduce the viral load below detectable levels, increase CD4 counts by an average of 100-150/mm3, reduce the risk of HIV-associated complications, and prolong survival. However, the ability to achieve this advantage depends on the patient's willingness to accept a complex medical regimen that requires "many pills," rigorous compliance, frequent follow-up, and moderate risk for drug toxicity. In reaching a decision it is helpful to bear in mind that prognosis is determined by viral load and the CD4 count. Those patients having a viral load in excess of 60,000 copies per milliliter have a relatively rapid course and average survival of a little over four years. In contrast, those with less than 6,000 copies per milliliter have an average survival of more than ten years. The CD4 count is also a prognostic factor, as counts less than 350 indicate severe damage to immune function and corresponding risk for opportunistic infection.

Patient compliance may be improved with a regimen of either Combivir or Trizivir therapy. Both therapies combine more than one drug into a single pill, making it easier for patients to comply with their medication regimen. Trizivir is a fixed-dose combination of Ziagen (abacavir/ABC), Retrovir (zidovudine/AZT), and Epivir (lamivudine/3TC). Trizivir is not recommended for treatment in adults or adolescents who weigh less than 40 kilograms because it is a fixed-dose tablet. Combivir is a combination of zidovudine/AZT and lamivudine/3TC [26; 27].

The current recommendation is to offer therapy to any patient with CD4 count less than 500/mm3 or viral burden exceeding 10,000 copies per milliliter. At the present time, most authorities prefer a regimen of two nucleoside analogs plus a protease inhibitor. These regimens result in maximum reduction of viral load for the longest period of time. When used as initial therapy these regimens will achieve the goal of no detectable virus in approximately 60% to 80% of patients.

PREVENTION OF OPPORTUNISTIC INFECTIONS

Depending on the CD4 count and other risk factors, asymptomatic patients may benefit from treatment to prevent opportunistic infections. Recommendations for anti-microbial prophylaxis of opportunistic infections are summarized in Table 2 according to guidelines provided by the U.S. Public Health Service and Infectious Diseases Society of America. Prophylactic therapy for these conditions is strongly recommended because these infections are relatively common in HIV patients, preventive therapy is simple and cost effective, and efficacy has been established in clinical studies. In addition, all patients should be vaccinated with pneumococcal vaccine. Hepatitis B vaccination should be considered in those patients whose serologic testing indicates susceptibility.

The CDC has developed guidelines for the prevention of opportunistic infections among HIV-infected individuals. The report offers guidelines specific to each type of opportunistic infection. The current 2002 report can be viewed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5108a1.htm .

 

Prophylaxis to Prevent First Episode of Opportunistic Disease Among Adults and Adolescents Infected with Human Immunodeficiency Virus (HIV)

Preventive Regimen

Pathogen

Indication

First Choice

Alternative

Strongly recommended as standard of care

Pneumocystis carinii

CD4 counts of <200/µL or oropharyngeal candidiasis

Trimethoprim-sulfamethoxazole (TMP-SMZ), 1 double-strength tablet (DS) by mouth, daily (AI) or TMP-SMZ, 1 single-strength tablet (SS) by mouth daily (AI)

Dapsone, 50 mg by mouth, twice daily or 100 mg by mouth daily (BI); dapsone, 50 mg by mouth daily plus pyrimethamine, 50 mg by mouth weekly plus leucovorin, 25 mg by mouth weekly (BI); dapsone, 200 mg by mouth plus pyrimethamine, 75 mg by mouth plus leucovorin, 25 mg by mouth weekly (BI); aerosolized pentamidine, 300 mg monthly via Respirgard IIä nebulizer (manu-factured by Marquest, Englewood, Colorado( (BI); atovaquone, 1,500 mg by mouth daily (BI); TMP-SMZ 1 DS by mouth three times weekly (BI)

Mycobacterium tuberculosis, Isoniazid-sensitive

Tuberculin skin test (TST) reaction >5 mm or prior positive TST result without treatment or contact with person with active tuber-culosis, regardless of TST result (BIII)

Isoniazid, 300 mg by mouth plus pyridoxine, 50 mg by mouth daily for 9 mos (AII) or isoniazid, 900 mg by mouth plus pyridoxine, 100 mg by mouth, twice weekly for 9 mos (BII)

Rifampin, 600 mg by mouth daily (BIII) for 4 mos or rifabutin 300 mg by mouth daily (CIII) for 4 mos; pyrazinamide, 15–20 mg/kg body weight by mouth daily for 2 mos plus either rifampin, 600 mg by mouth daily (BI) for 2 mos or rifabutin, 300 mg by mouth daily (CIII) for 2 mos

Toxoplasma gondii

Immunoglobulin G (µgG) antibody to Toxoplasma and CD4 count of <100µL

TMP-SMZ, 1 DS by mouth daily (AII)

TMP-SMZ, 1 SS by mouth daily (BIII);dapsone, 50 mg by mouth daily plus pyrimethamine, 50 mg by mouth weekly plus leucovorin, 25 mg by mouth weekly (BI); dapsone, 200 mg by mouth plus pyrimethamine, 75 mg by mouth plus leucovorin, 25 mg by mouth weekly (BI); atovaquone, 1,500 mg by mouth daily with or without pyrimethamine, 25 mg by mouth daily plus leucovorin, 10 mg by mouth daily (CIII)

 Mycobacterium avium complex

CD4 count of <50/µL

Azithromycin, 1,200 mg by mouth weekly (AI) or clarithromycin, 500 mg by mouth twice daily (AI)

Rifabutin, 300 mg by mouth daily (BI); azithromycin, 1,200 mg by mouth daily plus rifabutin, 300 mg by mouth daily (CI)

Source: [52] CDC, MMWR Recommendations and Reports, June 14, 2002/51 (RR08;1-46) Guidelines for Preventing Opportunistic Infections Among HIV-Infected Persons–2002: Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America.

Table 2

 


TB AND HIV

People dually infected with HIV and tuberculosis (TB) have a 100 times greater risk of developing active TB and becoming infectious compared to people not infected with HIV. CDC estimates that 10% to 15% of all TB cases and nearly 30% of cases among people ages 25 to 44 are occurring in HIV-infected individuals [5].

HIV-1 and M.tuberculosis are two intracellular pathogens that interact at the population, clinical and cellular levels. Initial studies of HIV-1 and TB emphasized the impact of HIV-1 on the natural progression of TB, but mounting immunologic and virologic evidence now indicates that the host immune response to M.tuberculosis enhances HIV replication and might accelerate the natural progression of HIV infection [53].

In addition to CDC's current recommendations, new guide-lines include information about:

  • Directly observed therapy (DOT) for all patients with HIV-related TB
  • Rifabutin-containing antituberculosis regimens (or a streptomycin-based alternative regimen that does not contain rifamycin) for treating TB among patients taking antiretroviral drugs that have interactions with rifampin
  • Monitoring responses to antituberculosis treatment to decide about the appropriate duration of TB therapy
  • Occurrence and management of paradoxical reactions during TB treatment, when immune function is restored because of antiretroviral therapy
  • Use of 9 months of isoniazid daily or twice weekly for the treatment of M.tuberculosis infection
  • Short-course multidrug therapy for latent M.tuberculosis infection
  • Special considerations that apply to children and pregnant women with HIV-related TB

Healthcare professionals need to be familiar with these new guidelines to ensure the use of the most effective management strategies for TB patients infected with HIV, while concurrently promoting optimal antiretroviral therapy for these patients.

Dosing recommendations often change due to resistant strains and newly developed information: consult MMWR for current CDC recommendations. For more information, visit the CDC Division of TB Elimination website at http://www.cdc.gov/nchstp/tb and the MMWR website at http://www.cdc.gov/mmwr. Research findings have improved clinicians' understanding of how HIV affects the natural progression of TB and how TB affects the clinical course of HIV disease, and these findings support the recommendation for prevention, early recognition, and effective treatment for both diseases.

NEW MEDICATIONS

Fuzeon

In March 2003, the FDA approved the drug Fuzeon (enfuvirtide), the first new class of anti-HIV drug in seven years. Fuzeon, a fusion inhibitor, works by blocking the ability of HIV to infect healthy CD4 cells. When used in combination with other anti-HIV medications, Fuzeon can reduce the amount of HIV in the blood and increase the number of CD4 cells, slowing the progression of HIV in patients who have developed resistance to currently available medications. Fuzeon is administered as a twice-daily subcutaneous injection [43]. Manufacturers Roche and Trimeris, Inc. are finalizing a distribution plan to provide Fuzeon to patients and to ensure and uninterrupted supply to patients once they have begun therapy. The cost of the drug at approximately $20,400 a year, has caused some to speculate whether it would be affordable to the general public [44].

Reyataz

Reyataz (atazanavir sulfate), the first once-daily protease inhibitor, was approved by FDA for marketing clearance in June 2003. The FDA has granted manufacturers Bristol-Myers Squibb Company a six month priority review of the drug as data from phases II and III of clinical trials showed that Reyataz did not significantly increase total cholesterol and triglyceride levels, unlike many other protease inhibitors. Hyperbilirubinemia occurred in 15% to 24% of subjects taking the drug, but was shown to be reversible when the drug was discontinued. The recommended dose of Reyataz is two 200 mg capsules taken once a day with food in combination with other antiretroviral medications [45].

Emtriva

In July 2003, Gilead Sciences announced FDA marketing approval for Emtriva (emtricitabine), a new 200 mg capsule taken once a day. Emtriva is a nucleoside reverse transcriptase inhibitor and when used in combination with other anti-HIV therapies can help lower the viral load of HIV and increase the number of CD4 cells [46].

Viracept

The FDA has approved a new 625 mg formulation of Viracept (nelfinavir mesylate) a protease inhibitor, reducing the pill burden from five to two tablets twice a day. Manufacturer Agouron Pharmaceuticals, Inc. believes that the new dosage will result in greater patient compliance [47].