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. As the demographics of HIV infection evolve, both in the United States and around the world, it is clear that all dental 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 should be obtained by all dental professionals.
This course is designed for all dental professionals involved in the care of patients with HIV/AIDS.
NetCE is designated as an Approved PACE Program Provider by the Academy of General Dentistry. The formal continuing education programs of this program provider are accepted by AGD for Fellowship, Mastership, and membership maintenance credit. Approval does not imply acceptance by a state or provincial board of dentistry or AGD endorsement. The current term of approval extends from 10/1/2015 to 9/30/2021. Provider ID 217994. NetCE is an ADA CERP Recognized Provider. ADA CERP is a service of the American Dental Association to assist dental professionals in identifying quality providers of continuing dental education. ADA CERP does not approve or endorse individual courses or instructors, nor does it imply acceptance of credit hours by boards of dentistry. Concerns or complaints about a CE provider may be directed to the provider or to ADA CERP at www.ada.org/cerp. NetCE is a Registered Provider with the Dental Board of California. Provider Number RP3841. Completion of this course does not constitute authorization for the attendee to perform any services that he or she is not legally authorized to perform based on his or her license or permit type. NetCE is approved as a provider of continuing education by the Florida Board of Dentistry, Provider #50-2405.
NetCE designates this activity for 5 continuing education credits. AGD Subject Code 755. This course meets the Dental Board of California's requirements for 5 unit(s) of continuing education. Dental Board of California course #05-3841-16194.
In view of the already existing crisis in health care in the United States, the problems associated with providing the necessary care for persons with HIV infection or AIDS are significant. The purpose of this course is to address those problems in the discussion of epidemiology, organism characteristics, pathophysiology, transmission, clinical manifestations, complications, treatment advancements, prevention, ethical and legal aspects of care, and workplace concerns.
Upon completion of this course, you should be able to:
- Discuss the background and significance of the HIV/AIDS epidemic.
- Outline the viral pathogenesis and disease course of HIV.
- Utilize knowledge of HIV transmission and risk behaviors to effectively counsel patients who have the infection and others who are at risk of exposure.
- Describe the natural history, clinical characteristics, and stages of chronic HIV infection and disease progression.
- Identify and devise the appropriate antiretroviral treatment regimen and follow-up for a given patient, in consultation with an infectious disease specialist.
- Anticipate and assess the variations in the clinical presentation, treatment, and preventive aspects of HIV infection in women, children, and the elderly.
- Discuss effective and emerging approaches to HIV/AIDS prevention.
Jane C. Norman, RN, MSN, CNE, PhD, received her undergraduate education at the University of Tennessee, Knoxville campus. There she completed a double major in Sociology and English. She completed an Associate of Science in Nursing at the University of Tennessee, Nashville campus and began her nursing career at Vanderbilt University Medical Center. Jane received her Masters in Medical-Surgical Nursing from Vanderbilt University. In 1978, she took her first faculty position and served as program director for an associate degree program. In 1982, she received her PhD in Higher Education Administration from Peabody College of Vanderbilt University. In 1998, Dr. Norman took a position at Tennessee State University. There she has achieved tenure and full professor status. She is a member of Sigma Theta Tau National Nursing Honors Society. In 2005, she began her current position as Director of the Masters of Science in Nursing Program.
John M. Leonard, MD, Emeritus Professor of Medicine, Vanderbilt University School of Medicine. Dr. Leonard completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers, and then joined the Vanderbilt faculty in 1974. He has served as director of educational programs for the Department of Medicine and was the Residency Program Director from 1981 to 2003. Dr. Leonard's clinical experience includes an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.
Contributing faculty, Jane C. Norman, RN, MSN, CNE, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
William E. Frey, DDS, MS, FICD
The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.
Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.
It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.
- A BRIEF OVERVIEW OF HIV DISEASE
- HIV TESTING
- TRANSMISSION OF HIV
- NATURAL HISTORY AND CLASSIFICATION OF HIV INFECTION
- MANAGEMENT OF HIV INFECTION
- HIV INFECTION IN SPECIAL POPULATIONS
- AIDS PREVENTION
- CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS
- Works Cited
- Evidence-Based Practice Recommendations Citations
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#58901: HIV/AIDS: Epidemic Update
Despite scientific advances in our understanding of pathogenesis and transmission and expanded options for prevention and treatment, human immunodeficiency virus (HIV) remains a complex, challenging public health concern of epidemic proportion. In the United States, the prevalence of infection has increased substantially among young women and among the elderly in recent decades. The former has serious implications for maternal and child health; the latter presents new challenges for nurses and physicians who provide elder care. As yet, there is no cure or preventive vaccine; however, combination antiretroviral therapy controls HIV infection and permits individuals to lead relatively healthy, productive lives for decades.
The purpose of this course is to provide a basic, practical review and update of knowledge concerning HIV infection and acquired immune deficiency syndrome (AIDS), addressing the key issues that impact clinical and public health practice. Topics to be addressed include immunopathogenesis, modes of transmission, natural history and clinical staging, risk behavior assessment, prevention (including postexposure prophylaxis), diagnosis, management, and follow-up.
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.
Two human immunodeficiency viruses, HIV-1 and HIV-2, have been identified and both cause AIDS. Researchers in the United States 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, likely around 1908 . Genetic studies suggest that the lower monkeys first became infected with SIV 100,000 years ago .
HIV-2 is believed to be endemic in West Africa, though even areas with previously high rates (e.g., Senegal) are seeing HIV-2 being increasingly overtaken by HIV-1 . Several well-documented cases of HIV-2 infection have been reported in Europeans and among West Africans residing abroad. A total of 242 cases meeting the Centers for Disease Control and Prevention's (CDC's) definition of HIV-2 infection were reported between 1988 and 2010 in the United States, the majority of which were associated with immigration from, travel to, or a sexual partner from West Africa . Differences in the global spread are attributed to differences in transmissibility and duration of infectiousness .
According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), an estimated 35 million individuals worldwide were living with HIV/AIDS by the end of 2013, approximately 16 million of whom are women . Northern Africa and the Middle East have the fastest growing epidemic; since 2001, new HIV infections in this region have increased by 31% . In addition, rates in Eastern Europe (particularly the Russian Federation) and Asia began increasing in the late 2000s . It is important to note that despite increases in certain geographic areas and demographic groups, overall, the rate of new infections is declining. Africa is still the hardest hit area, with 71% of all HIV-infected persons living in sub-Saharan Africa in 2013 .
Beginning in 2003, the U.S. government has worked to fight the disease in Africa, partially through the implementation of the President's Emergency Plan for AIDS Relief (PEPFAR) . PEPFAR was reauthorized in 2008, with a total of $48 billion in funds over the following five years and expansion to address additional health issues, including malaria, tuberculosis, maternal health, and clean water . This was extended to 2018 with the PEPFAR Stewardship and Oversight Act of 2013 .
As of 2011, an estimated 1.2 million individuals 13 years of age or older were living with HIV/AIDS in the United States . The CDC estimates that approximately 14% of these individuals are unaware of their infection . When reviewing trends in HIV transmission, one should keep in mind that the widespread use of antiretroviral therapy has resulted in fewer deaths and longer survival.
As of 2014, the Centers for Disease Control and Prevention (CDC) report several trends in the HIV/AIDS epidemic :
By region, 50% reside in the South, 18% in the Northeast, 19% in the West, and 12% in the Midwest.
By race/ethnicity, 44% are black/African American, 27% white, 24% Hispanic, 2% Asian, and less than 1% are American Indian/Alaska Native or Hawaiian/Pacific Islander.
By sex, 81% of adults and adolescents living with HIV are male.
HIV, known formerly as human T cell lymphotropic virus (HTLV-III), is a member of the retrovirus group and as such carries a ribonucleic acid (RNA) genome and a reverse transcriptase enzyme (RNA-directed DNA polymerase) that enables the virus to replicate within infected host cells. Susceptibility in humans is determined by the binding affinity of virion envelope proteins for a specific cell surface receptor molecule (CD4+) found on tissue dendritic cells, macrophages, and CD4+ T lymphocytes. The pathogenesis of infection, and the subsequent perpetuation of the disease state, involves a complex set of interactions by which HIV is able to take advantage of cellular pathways while avoiding or neutralizing various components of the immune system [11,12].
The most common mode of HIV infection is sexual transmission across exposed mucosal epithelium. Dendritic cells and macrophages are found beneath the mucosal epithelium of the anogenital and cervicovaginal tracts, as well as within tonsillar and adenoidal tissue. Studies in primates demonstrate that after the virus penetrates the mucosal epithelium, infection is initiated within nearby dendritic cells and macrophages. Infected dendritic cells then fuse with CD4+ T lymphocytes and the infection extends to deeper tissue and, shortly thereafter, to regional lymph nodes . Within days, this proliferation of infected CD4+ T lymphocytes, combined with the migration of infected macrophages, leads to the appearance of viral RNA in the blood stream. This is followed by widespread secondary amplification of infection within the lymphoid tissue of the gastrointestinal tract, spleen, and bone marrow.
Once the virus enters the cell, it may replicate, induce cell fusion and propagation of infection, or lead to cell death . The defining characteristic of HIV disease is the immune deficiency state caused by ongoing viral replication and cell-to-cell transmission within lymphoid tissue. With chronicity of infection there is a progressive depletion of CD4 (helper-inducer) lymphocytes, the very T lymphocyte cohort whose function it is to direct other cells in the immune system, and to orchestrate the inactivation of virus antigen. The result is a depressed T lymphocyte functional capacity, characterized by depletion of helper T cells (T4), impaired killer T cell activity, and increased suppressor T cells (T8). In persons with intact lymphocyte immune systems, the normal number of CD4 T cells ranges from 600–1,200 cells/mcL, depending on the stage and duration of infection.
The clinical manifestations of HIV disease are determined by the stage of primary infection and the chronicity and degree of the resultant cellular immunodeficiency state. Acute, primary HIV infection may be asymptomatic, but most often it is manifest by a subacute viral syndrome of malaise and fatigue, fever, sore throat, rash, myalgia, headache, and lymphadenopathy—clinical features similar in many respects to that seen with Epstein-Barr virus mononucleosis, cytomegalovirus (CMV), and certain types of herpes simplex infections . A variety of atypical symptoms and signs may be seen, including aseptic meningitis syndrome, genital ulcers, and ulcerations involving the gingiva, palate, or buccal mucosa. The acute illness usually resolves in less than 14 days, but may follow a protracted course over many weeks .
Early in the chronic phase of HIV infection, when the CD4 lymphocyte population is only modestly depressed and declining slowly, patients are often asymptomatic or may exhibit generalized lymphadenopathy and recurrent oropharyngeal candidiasis (thrush). During this stage, a reservoir of HIV is established throughout the lymphoid tissue system, including the spleen. Gradually, wandering (infected) macrophages disseminate the virus to certain internal organs, notably the brain, kidney, and adrenal glands.
Chronic HIV disease follows a variable course but eventually leads to a variety of clinical manifestations, some of which are directly related to the impact of chronic infection on vital organs. Common syndromes include HIV encephalopathy and dementia, peripheral neuropathy, interstitial nephropathy, a variety of skin eruptions, and signs of adrenal insufficiency.
The late clinical manifestations of HIV disease are most frequently the result of acquired immunodeficiency syndrome (AIDS) that follows progressive depletion of CD4+ T lymphocytes to levels <200 cells/mcL. AIDS-defining illnesses include secondary, opportunistic infections and certain malignancies usually encountered only in clinical settings of severely impaired cellular immunity.
Opportunistic infections are very common in persons with undiagnosed or poorly treated chronic HIV infection and are of two types. The first type is infection newly acquired by exposure to micro-organisms normally nonpathogenic, or of low pathogenicity, for persons with a healthy immune system. Examples are Pneumocystis jiroveci, Cryptococcus neoformans, Histoplasma capsulatum, and atypical mycobacteria, all of which are commonly associated with inhalational exposures and transient colonization of the respiratory tract in healthy individuals. The second type is reactivation of latent infection acquired earlier in life, which typically remains dormant throughout life. Examples of this type are CMV, Toxoplasma gondii, Mycobacterium tuberculosis, and Histoplasma capsulatum. The advent of an opportunistic infection may serve as the herald sign of unrecognized, undiagnosed chronic HIV infection/AIDS.
Clinically, these infections tend to present in one of several distinct syndromes, with useful differential diagnosis considerations:
Pneumonia: Pneumocystis jiroveci pneumonia (PJP), Mycobacterium avium complex (MAC), cryptococcosis, histoplasmosis
Meningoencephalitis: Toxoplasmosis, cryptococcosis, tuberculosis
Gastrointestinal disease (diarrhea): Common bacterial dysentery, cryptosporidium, fungal and atypical mycobacterial infection
Fever of unknown origin (often with abdominal complaints, hepatosplenomegaly, and/or lymphadenopathy): CMV, MAC, tuberculosis, histoplasmosis
Late clinical manifestations related to HIV-induced malignancy include Kaposi sarcoma of the skin or respiratory tract and lymphoma presenting as lymphadenopathy, splenomegaly, or focal gastrointestinal disease.
Without satisfactory antiretroviral therapy, the usual patient with HIV/AIDS experiences a slow, inexorable wasting illness punctuated by periods of feverishness and diarrhea, becoming increasingly anorectic, malnourished, and lethargic. Late clinical signs include muscle wasting and weakness, anemia and thrombocytopenia, lymphadenopathy, pulmonary infiltrates, and neurologic abnormalities (such as dementia, peripheral neuropathy, and tremors). The median survival of patients with advanced HIV/AIDS (CD4 count <50 cells/mcL) is approximately 12 to 18 months. Patients succumb to complications of uncontrolled infection, malignancy, or critical organ failure (such as uremia or adrenal insufficiency).
There are several recommendations for HIV screening. The U.S. Preventive Services Task Force (USPSTF) and the Agency for Healthcare Research and Quality (AHRQ) recommend that all persons 15 to 65 years of age regardless of risk level have at least one test for HIV status and that all pregnant women be screened prior to childbirth [13,14]. In addition, younger and older individuals at increased risk (e.g., new sexual partners) should also be screened.
The initial testing for HIV generally consists of an FDA-approved, fourth-generation antigen/antibody combination immunoassay that detects HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen to identify both established and acute infections . If this test is reactive, repeat testing is recommended to differentiate HIV-1 antibodies from HIV-2 antibodies. If this second test is non-reactive, testing with an FDA-approved HIV-1 nucleic acid test is indicated . It is important to note that HIV-2 is not reliably identified by usual immunoblot antibody tests. Additional testing specific to HIV-2 should be considered if HIV-1 test results are atypical or inconsistent with clinical findings, especially for persons from West Africa .
Other available tests, including enzyme-linked immunosorbent assay, may be used if the preferred combination immunoassay is not available. The HIV-1 Western blot and HIV-1 immunofluorescence assay, previously recommended to make a laboratory diagnosis of HIV-1 infection, are no longer part of the recommended testing algorithm .
HIV is transmitted person-to-person across mucosal or cutaneous barriers by exposure to infected genital secretions or blood and blood products. The common modes of transmission are sexual intercourse, injection drug use, infusion of blood products, and perinatal transmission. The risk from whole blood, packed cell, and fresh frozen plasma is, at present, extremely low by virtue of more sensitive crossmatching and screening techniques.
On the basis of newly reported cases, the transmission categories are :
Male-to-male sexual contact (MSM)
Injecting drug users (IDUs)
MSM who inject drugs
Other (includes hemophilia, blood transfusion, and risk factor not reported or not identified)
The CDC has published 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 sexually transmitted infections (STIs); 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 [16,17].
HIV has been isolated from blood, seminal fluid, spermatozoa, pre-ejaculate, vaginal secretions, urine, cerebrospinal fluid, saliva, tears, and breast milk of infected individuals. No cases of HIV infection have been traced to saliva or tears (though traces of the virus are present in these fluids) . 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.
Posing the highest risk of infection is unprotected anal receptive intercourse, followed by unprotected vaginal intercourse and unprotected insertive anal intercourse (particularly for uncircumcised men) [19,20]. 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. Likewise, the partner is protected from infectious pre-ejaculate, semen, and penile 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. It is estimated that latex condom use reduces the risk of HIV transmission by approximately 70% to 80% [21,22,23]. Although abstinence from sexual contact is the sole way to absolutely prevent transmission, sexual activity in a mutually monogamous relationship in which neither partner is HIV-infected and no other risk factors are present is considered safe . However, men who identify publicly as heterosexual and generally have committed relationships with women, but who also engage in sexual activity with other men, may be a transmission bridge to heterosexual women . To better understand the actual extent of this behavior and its impact on HIV transmission, more research is necessary.
Numerous studies have demonstrated that oral sex can result in the transmission of HIV and other STIs. 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 STIs. Prevention includes the use of latex condoms, a natural rubber latex sheet, plastic food wrap, a cut open condom, or a dental dam, all of which serve as a physical barrier to transmission .
It has been estimated that a milliliter of HIV-infected human blood contains up to 10,000 copies of the virus. In comparison, a milliliter of blood infected with hepatitis B virus has 100 million to 1 billion infective organisms [26,27]. Even so, HIV is transmitted via blood, primarily through sharing of contaminated needles among IDUs and, rarely, 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 of a donor screening program of the nation's blood supply in 1985 and advances in the treatment of donated blood products, blood transfusion is now even safer; the current risk of transmission of HIV through this route is conservatively estimated to be between 1 in 1.5 million . It is possible that before blood screening implementation, more than 12,000 people were infected . A large percentage of persons with hemophilia acquired HIV in this manner. Donor screening, HIV testing, and heat treatment of the clotting factor have greatly reduced the risks.
Transmission of HIV among injecting drug users occurs primarily through contamination of injection paraphernalia with infected blood. The risk of sustaining HIV infection from a needle stick with infected blood is approximately 1 in 300 . Behavior such as needle sharing, "booting" the injection with blood, and performing frequent injections increases the risk. Crack 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 cocaine for sex. Sharing of equipment is common due to legal and financial restrictions and cultural norms, and some studies have linked higher levels of psychological distress (e.g., anxiety and depressive symptoms) with an increased risk for needle sharing . Secondary transmission occurs to children and sexual partners. Preventative strategies include medication-assisted drug treatment, onsite 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.
In the absence of prophylactic treatment, approximately 25% to 30% of children born to HIV-infected mothers will contract HIV infection; this increases to 50% with prolonged breastfeeding . HIV is transmitted to infants by transplacental spread from mother to fetus in utero, during parturition, or through breastfeeding after birth. Because infants have underdeveloped natural resistance systems, they are highly susceptible to many infections, including HIV. Transmission usually occurs during labor and delivery and the early breastfeeding stage .
Worldwide, perinatal transmission accounts for most HIV infections among children. In the United States, perinatal transmission has been markedly decreased, by more than 90%, since the mid-1990s . Studies have shown the beneficial effect of treating pregnant women and newborns with zidovudine (ZDV) to prevent transmission to the child, resulting in dramatic declines in the incidence of perinatally acquired HIV . Standard screening of all pregnant women is necessary to reduce transmission of HIV to infants.
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 transplanted 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. However, in 2007, four organ transplant recipients contracted HIV and hepatitis C from a single organ donor, and in 2009, HIV was transmitted by a living kidney donor [36,37]. These were the first cases of HIV infection resulting from transplantation since 1985. Though the donors were tested for HIV and hepatitis, the tests resulted in false negatives. As with blood transfusions, donors testing antibody seronegative may pass HIV infection on to recipients. The use of nucleic acid testing and reconsideration of the use of high-risk donors have both been recommended to ensure the safety of donor recipients .
Transmission due to occupational exposure of healthcare workers has occurred in needlestick accidents and blood splashes to the mucous membranes. Needlestick is the most common route. Thousands of healthcare personnel who were so exposed have been studied, and only 58 cases of well-documented infection have been reported in the United States (24 of which were nurses) . 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 have greatly reduced the exposure rate. Healthcare personnel should apply Universal Precautions, as discussed in the Occupational Safety and Health Administration (OSHA) Bloodborne Pathogens standard regulations, to all activities to avoid contact with human fluids.
The U.S. Public Health Service has developed recommendations for situations where healthcare personnel 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 postexposure prophylaxis (PEP) . Because most occupational HIV exposures do not result in the transmission of HIV, potential toxicity should 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.
It is recommended that PEP be started as soon as possible after the potential exposure and continue for four weeks . A regimen containing three (or more) antiretroviral drugs is now recommended routinely for all occupational exposures to HIV; the suggested regimen is emtricitabine, raltegravir, and tenofovir.
In 2005, the CDC published guidelines for the recommendation of PEP for nonoccupational exposures. This section is taken from Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States as reported in MMWR, January 21, 2005.
Accumulated data from animal and human clinical and observational studies demonstrate that antiretroviral therapy initiated as soon as possible within 48 to 72 hours of sexual, injection-drug use, and other substantial nonoccupational HIV exposure and continued for 28 days might reduce the likelihood of transmission. Because of these findings, the Department of Health and Human Services (DHHS) recommends the prompt initiation of nPEP with combination antiretroviral therapy (cART) when persons seek care within 72 hours after exposure, the source is known to be HIV infected, and the exposure event presents a substantial risk for transmission. When the HIV status of the source is not known and the patient seeks care within 72 hours after exposure, DHHS does not recommend for or against nPEP but encourages clinicians and patients to weigh the risks and benefits on a case-by-case basis. When the transmission risk is negligible or when patients seek care more than 72 hours after a substantial exposure, nPEP is not recommended; however, clinicians might consider prescribing nPEP for patients who seek care more than 72 hours after a substantial exposure if, in their judgment, the diminished potential benefit of nPEP outweighs the potential risk for adverse events from antiretroviral medications.
Clinical latency, sometimes referred to as the window period, is the time elapsed between acquisition of the virus and the body's immune response sufficient to generate detectable antibody. This latent period is longer for HIV than for most other viral pathogens and is variable among newly infected individuals.
As discussed, HIV infection is a protracted illness that passes through several stages and, if untreated, carries an 80% mortality rate at 10 years. Within 15 to 30 days after acquisition of HIV infection, the majority of patients (50% to 90% in reported series) develop an acute retroviral syndrome similar to infectious mononucleosis . 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 is self-limited, with an average duration of two to three weeks. Laboratory abnormalities include lymphopenia, atypical lymphocytosis, thrombocytopenia, and a decreased CD4 cell count. During this early phase of clinical illness, HIV antibody tests are often 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, coincident with seroconversion and the rise in CD8 cytotoxic T cells, the viral load decreases steadily, reaching a relatively stable level at about six months. At this juncture, the degree of viral load correlates with the subsequent pace of disease progression. Patients having the highest viral loads, exhibit the most rapid progression to AIDS. As a result of the ongoing, protracted infection of target lymphocytes, the CD4 count gradually declines over time in the absence of treatment, at the average annual rate of about 50 cells/mcL.
Approximately 10% to 20% of persons with newly acquired HIV are asymptomatic during the initial two months following acute infection. While initial routine laboratory studies are relatively normal, serologic and virologic studies are positive and these patients show the same host-virus dynamics, including gradual decline in CD4 count, as that seen in symptomatic patients.
The serologic diagnosis of HIV infection in an asymptomatic patient does not, in and of itself, establish how recently the patient became infected. The stage of infection may be estimated on the basis of careful history and physical examination, and a standard laboratory evaluation that includes complete blood counts, lymphocyte subsets or CD4 count, and viral load. The duration of this asymptomatic stage is variable depending on prevailing CD4 count and viral load and is amenable to treatment with cART.
In the months following acute infection, whether symptomatic or not, many patients have persistent, painless generalized lymphadenopathy (PGL) without other disease manifestations. PGL is defined as palpable lymph node enlargement of 1 cm or greater at two or more extrainguinal sites that persists for more than three months in the absence of a concurrent illness or explanation other than HIV infection. In some cases, lymphadenopathy regresses as HIV disease advances, probably because the architecture of the lymph node is gradually destroyed .
Chronic, asymptomatic HIV infection with ongoing low-level viral activity may last for many years before eventual progression to AIDS. Symptomatic illness can be expected to supervene as the CD4 count declines to a level less than 200 cells/mcL, as this correlates with severe immunodeficiency. The CDC defines late-stage HIV infection as AIDS on the basis of two criteria: CD4 count less than 200 cells/mcL or a characteristic AIDS-defining illness such as PJP, central nervous system (CNS) toxoplasmosis, or other opportunistic infections or tumors (Kaposi sarcoma). A variety of clinical syndromes may supervene at this juncture including dementia, peripheral neuropathy, wasting syndrome, and chronic diarrhea. In the United States, the most common AIDS-defining opportunistic diseases are: PJP, Kaposi sarcoma, candidiasis, cryptococcosis, cryptosporidiosis, CMV, atypical mycobacteriosis, systemic herpes, toxoplasmosis, and tuberculosis .
In the absence of effective therapy, the average survival is approximately 3.5 years after the patient's CD4 count has reached 200 cells/mcL and 1.5 years for the patient who has developed an AIDS-defining diagnosis. The natural history and the prognosis for the patient with chronic HIV infection have been dramatically altered by antiretroviral therapy, especially by the use of cART that followed the introduction of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) in 1996.
Primary care providers 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 cART and prophylaxis for opportunistic infections, HIV disease shares features of other multisystem, chronic diseases characterized by acute exacerbations and end-stage manifestations.
Primary care providers should conduct risk factor assessment of their patients and, when appropriate, screen for HIV infection with pretest and post-test counseling. 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. 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, and provide supportive counseling. Specialists should be consulted for patients intolerant of standard drugs, those in need of systemic chemotherapy, and those with complicated opportunistic infections. In some cases, a single specialist 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 may include:
Quantitative HIV RNA
Complete blood count (CBC)
Hepatitis serology and liver chemistry panel
Purified protein derivative (PPD) skin test to diagnose tuberculosis
Combination antiretroviral therapy, or cART, combines six major classes of agents: nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, PIs, fusion inhibitors (FIs), integrase strand transfer inhibitors (INSTIs), and chemokine (C-C motif) receptor 5 (CCR5) antagonists. Initiated in 1995 in the United States, antiretroviral therapy regimens have 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. Two types of combination regimens are recommended as initial therapy: INSTI-based regimens or a PI-based regimen. The goal of these regimens is to effectively reduce HIV-associated morbidity, prolong the duration and quality of survival, restore and preserve immunologic function, and prevent HIV transmission while also avoiding drug resistance . A significant proportion of patients starting cART are infected with drug-resistant strains of HIV, which may lead to suboptimal virologic responses. Therefore, pretreatment genotypic resistance testing should be used to guide selection of the most optimal initial regimen .
NRTIs, used singularly or in combination, can increase 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 NRTIs result in better viral suppression, more sustained CD4 counts and decreased emergence of resistance. Available NRTI agents include: abacavir (Ziagen, ABC); zidovudine (Retrovir, ZDV, AZT); didanosine (Videx, ddl); stavudine (Zerit, d4T); lamivudine (Epivir, 3TC); and emtricitabine (Emtriva, Coviracil, FTC) . Tenofovir (Viread, TDF) is often categorized as an NRTI but is actually a nucleotide reverse transcriptase inhibitor.
NNRTIs 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); nevirapine (Viramune, NVP); etravirine (Intelence); and rilpivirine (Edurant) .
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: indinavir (Crixivan, IDV); nelfinavir (Viracept, NFV); ritonavir (Norvir, RTV); saquinavir (Invirase, Fortovase, SQV); lopinavir/ritonavir (Kaletra); atazanavir (Reyataz, ATZ); tipranavir (Aptivus, TPV); darunavir (Prezista; DRV); and fosamprenavir (Lexiva, FPV) .
In 2003, the FDA approved the drug enfuvirtide (Fuzeon), the first new class of anti-HIV drug in seven years . Enfuvirtide, a fusion inhibitor, works by blocking the ability of HIV to infect healthy CD4 cells. When used in combination with other anti-HIV medications, enfuvirtide 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.
In 2007, maraviroc was approved by the FDA for patients with CCR5-tropic HIV-1 infection . Maraviroc is a CCR5 antagonist; it blocks replication of the virus by preventing it from entering noninfected CD4 cells via the predominant route of entry, the CCR5 co-receptor . This medication is intended for use in combination with other antiretroviral agents in treatment-experienced patients with evidence of viral replication and HIV-1 strains resistant to multiple agents . Because both fusion inhibitors and CCR5 antagonists block HIV from entering CD4 cells, they are sometimes grouped together under the category of entry inhibitors.
In 2007, the FDA approved raltegravir, the first agent in a class known as integrase strand transfer inhibitors, or INSTIs . A two additional integrase inhibitors, dolutegravir and elvitegravir, were approved by the FDA in 2013 and 2014 [43,45]. These agents act by preventing the viral DNA from inserting into the host DNA, effectively limiting infection of additional cells and decreasing viral load . INSTIs are approved for use in combination with other antiretrovirals in treatment-experienced and treatment-naïve patients with evidence of HIV replication.
In an effort to improve the efficacy of other antiretroviral medications in a cART regimen, a pharmacokinetic enhancer may also be included. The agents most commonly used for this purpose are ritonavir (a PI) and cobicistat. Both of these agents inhibit cytochrome P450 (CYP) 3A enzymes, prolonging the effects of other medications . However, they are not interchangeable; cobicistat is a more potent inhibitor of CYP . The use of pharmacokinetic enhancers increases systemic exposure of effective antiretroviral medications, allowing for less frequent dosing and a lower pill burden.
Patient compliance may be improved with therapies that combine more than one drug into a single pill, making it easier for patients to comply with their medication regimen. As of 2016, there were 11 combination medications available :
Atripla: Efavirenz, emtricitabine, and tenofovir
Combivir: Lamivudine and zidovudine
Complera: Emtricitabine, rilpivirine, and tenofovir
Epzicom: Abacavir and lamivudine
Evotaz: Atazanavir and cobicistat
Kaletra: Lopinavir and ritonavir
Prezcobix: Darunavir and cobicistat
Stribild: Elvitegravir, cobicistat, emtricitabine, and tenofovir
Triumeq: Abacavir, dolutegravir, and lamivudine
Trizivir: Abacavir, lamivudine, and zidovudine
Truvada: Emtricitabine and tenofovir
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 cART. Physicians and patients alike should be aware of the advantages, potential toxicities, and complexity of monitoring therapy. At the present time, the most active triple-drug regimen 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 cells/mcL, 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. Patients having a viral load in excess of 60,000 copies per milliliter have a relatively rapid course and average survival of a little more than four years. In contrast, those with less than 6,000 copies per milliliter have an average survival of more than 10 years. The CD4 count is also a prognostic factor, as counts less than 350 cells/mcL indicate severe damage to immune function and corresponding risk for opportunistic infection.
Antiretroviral therapy should be initiated immediately for all patients infected with HIV in order to reduce the risk of disease progression and limit transmission . There is growing evidence that early initiation of cART is effective in preventing clinical events (e.g., non-AIDS malignancies, infection, AIDS-defining illness) regardless of pre-treatment CD4 count [48,49]. Advances in the development of antiretroviral medications and combination tablets makes adherence to therapy more effective, more convenient, and better tolerated than regimens used in the past. Deferral of therapy may be considered in patients with high CD4 counts (e.g., more than 500 cells/mcL) if adherence will be very difficult or impossible, comorbidities complicate or prohibit antiviral therapy, or a patient is considered a long-term non-progressor .
For treatment-naïve patients, initial recommended therapy generally consists of two NRTIs in combination with a third active antiretroviral drug from one of three drug classes: an INSTI, an NNRTI, or a PI with a pharmacokinetic enhancer (cobicistat or ritonavir) . 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 the majority of patients after four to six months .
Depending on the CD4 count and other risk factors, asymptomatic patients may benefit from treatment to prevent opportunistic infections. In many cases, cART is useful in the prevention and treatment of these infections. Recommendations for antimicrobial prophylaxis of opportunistic infections are summarized in Table 1 according to guidelines provided by the CDC, the National Institutes of Health, and the Infectious Diseases Society of America (IDSA) . 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 patients whose serologic testing indicates susceptibility.
PROPHYLAXIS TO PREVENT FIRST EPISODE OF OPPORTUNISTIC DISEASE AMONG ADULTS AND ADOLESCENTS INFECTED WITH HIV
|Pneumocystis jiroveci pneumonia (PJP)||CD4 count <200 cells/mcL (AI); or oropharyngeal candidiasis (AII), or CD4 <14% (BII); or history of AIDS-defining illness (BII), or CD4 count >200 but <250 cells/mcL if monitoring CD4 cell count every three months is not possible (BII)||Trimethoprim-sulfamethoxazole (TMP-SMZ) 1 double-strength (DS) daily (AI), or TMP-SMX 1 single-strength (SS) daily (AI)||TMP-SMX 1 DS three times weekly (TIW) (BI); or dapsone 100 mg daily or 50 mg twice daily (BI); or dapsone 50 mg daily + pyrimethamine 50 mg + leucovorin 25 mg weekly (BI); or dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg weekly (BI); or aerosolized pentamidine 300 mg via Respirgard II nebulizer every month (BI); or atovaquone 1,500 mg daily (BI); or atovaquone 1,500 mg + pyrimethamine 25 mg + leucovorin 10 mg daily (CIII)|
|Toxoplasma gondii encephalitis||Toxoplasma immunoglobulin G (IgG)-positive patients with CD4 count <100 cells/mcL (AII). Seronegative patients receiving PJP prophylaxis not active against toxoplasmosis should have Toxoplasma serology retested if CD4 count decline to <100 cells/mcL (CIII). Prophylaxis should be initiated if seroconversion occurred (AII).||TMP-SMX 1 DS daily (AII)||TMP-SMX 1 DS TIW (BIII); or TMP-SMX 1 SS daily (BIII); or dapsone 50 mg daily + pyrimethamine 50 mg + leucovorin 25 mg weekly (BI); or dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg weekly (BI); or atovaquone 1,500 mg daily (CIII); or atovaquone 1,500 mg + pyrimethamine 25 mg + leucovorin 10 mg daily (CIII)|
|Latent Mycobacterium tuberculosis infection (LTBI)||A positive screening test for LTBI, with no evidence of active TB and no prior treatment for active TB or LTBI (AI); or close contact with a person with infectious TB, regardless of screening test results (AII)||Isoniazid (INH) 300 mg + pyridoxine 25 mg daily for nine months (AII); or INH 900 mg biweekly (by direct-observation therapy) + pyridoxine 25 mg daily for nine months (BII).||Rifampin 600 mg daily for four months (BIII); or rifabutin (dose adjusted based on concomitant ART) for four months (BIII). For drug-resistant TB, consult an expert or public health authorities (AII).|
|Disseminated Mycobacterium avium complex (MAC) disease||CD4 count <50 cells/mcL after ruling out active disseminated MAC disease based on clinical assessment (AI)||Azithromycin 1,200 mg once weekly (AI); or clarithromycin 500 mg twice daily (AI); or azithromycin 600 mg twice weekly (BIII)||Rifabutin 300 mg daily (dose adjusted based on concomitant ART) (BI); rule out active TB before starting|
|Streptococcus pneumoniae infection||Individuals who have not received any pneumococcal vaccine, regardless of CD4 count||13-valent pneumococcal conjugate vaccine (PCV13) 0.5 mL IM (AI), followed in eight weeks by PPV23 if CD4 count ≥ 200 cells/mcL||23-valent pneumococcal polysaccharide vaccine (PPV23) 0.5 mL IM (BII). For individuals who have previously received PPV23, one dose of PCV13 should be given at least one year after the last receipt of PPV23 (AII).|
|Re-vaccination is recommended for patients 19 to 64 years of age and ≥5 years since the first PPV23 dose; or ≥65 years of age and ≥5 years since the previous PPV23 dose.||PPV23 0.5 mL IM or SQ (BIII)||—|
|Influenza A and B virus infection||All HIV-infected patients (AIII)||Inactivated influenza vaccine annually (AIII)||Note: Live-attenuated influenza vaccine is contraindicated in HIV-infected patients (AIII).|
|Syphilis||Persons who have had sexual contact with a person who receives a diagnosis of primary, secondary, or early latent syphilis within 90 days preceding the diagnosis, even if serologic test results are negative (AIII), or who have had sexual contact with a person who receives a diagnosis of primary, secondary, or early latent syphilis >90 days before the diagnosis should be treated presumptively for early syphilis if serologic test results are not immediately available and the opportunity for follow-up is uncertain (AIII).||Benzathine penicillin G 2.4 million units IM for 1 dose (AII)||For penicillin-allergic patients: doxycycline 100 mg twice daily for 14 days (BII); or ceftriaxone 1 g IM or IV daily for 8–10 days (BII); or azithromycin 2 g for 1 dose (BII) (not recommended for MSM or pregnant women [AII])|
|Histoplasma capsulatum infection||CD4 count <150 cells/mcL and at high risk because of occupational exposure or living in a community with a hyperendemic rate of histoplasmosis (>10 cases/100 patient-years) (BI)||Itraconazole 200 mg daily (BI)||—|
|Coccidioidomycosis||A new positive IgM or IgG serologic test in patients who live in a disease-endemic area and with CD4 count <250 cells/mcL (BIII)||Fluconazole 400 mg daily (BIII)||—|
|Varicella-zoster virus (VZV) infection (pre-exposure)||Patients with CD4 counts ≥200 cells/mcL who have not been vaccinated, have no history of varicella or herpes zoster, or who are seronegative for VZV (CIII)||Primary varicella vaccination (Varivax), 2 doses (0.5 mL SQ each) administered three months apart (CIII).||VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent potential transmission of VZV to their HIV-infected contacts (BIII).|
|Varicella-zoster virus (VZV) infection (post-exposure)||Close contact with a person with chickenpox or herpes zoster and is susceptible (i.e., no history of vaccination or of either condition or known to be VZV seronegative) (AIII)||Varicella-zoster immune globulin (VariZIG) 125 IU IM per 10 kg (maximum: 625 IU), administered as soon as possible and within 10 days after exposure (AIII)||Acyclovir 800 mg five times per day for 5–7 days (BIII); or valacyclovir 1 g three times per day for 5–7 days (BIII)|
|Human papillomavirus (HPV) infection||Age 13 to 26 years (BIII)||HPV quadrivalent or 9-valent vaccine 0.5 mL IM at months 0,1–2, and 6 for men and women (BIII); or HPV bivalent vaccine 0.5 mL IM at months 0,1–2, and 6 for women (BIII)||—|
|Hepatitis A virus (HAV) infection||HAV-susceptible patients with chronic liver disease, or who are injection-drug users, or MSM (AII).||Hepatitis A vaccine 1 mL IM x 2 doses at 0 and 6–12 months (AII). IgG antibody response should be assessed 1 month after vaccination; non-responders should be revaccinated when CD4 count >200 cells/mcL (BIII).||For patients susceptible to both HAV and hepatitis B: combined HAV and HBV vaccine (Twinrix), 1 mL IM as a 3-dose (0, 1, and 6 months) or 4-dose (days 0, 7, 21 to 30, and 12 months) series (AII)|
|Hepatitis B virus (HBV) infection||Patients without chronic HBV or without immunity to HBV (i.e., anti-HBs <10 IU/mL) (AII); or patients with isolated anti-HBc and negative HBV DNA (BII). Early vaccination is recommended before CD4 count falls below 350 cells/mcL (AII). However, in patients with low CD4 cell counts, vaccination should not be deferred until CD4 count reaches >350 cells/mcL, because some patients with CD4 counts <200 cells/mcL do respond to vaccination (AII).||HBV vaccine IM (Engerix-B 20 mcg/mL or Recombivax HB 10 mcg/mL) at 0, 1, and 6 months (AII); HBV vaccine IM (Engerix-B 40 mcg/mL or Recombivax HB 20 mcg/mL), 0, 1, 2 and 6 months (BI); or combined HAV and HBV vaccine (Twinrix) 1 mL IM as a 3-dose (0, 1, and 6 months) or 4-dose (days 0, 7, 21 to 30, and 12 months) series (AII)||Some experts recommend vaccinating with 40-mcg doses of either HBV vaccine (CIII).|
|Vaccine non-responders: anti-HBs <10 IU/mL 1 month after vaccination series||Re-vaccinate with a second vaccine series (BIII)||HBV vaccine IM (Engerix-B 40 mcg/mL or Recombivax HB 20 mcg/mL), 0, 1, 2 and 6 months (BI)|
|Malaria||Travel to disease-endemic area||Recommendations are the same for HIV-infected and HIV-uninfected patients.||—|
|Penicillium marneffei||Patients with CD4 cell counts <100 cells/mcL who live or stay for a long period in rural areas in northern Thailand, Vietnam, or Southern China (BI)||Itraconazole 200 mg once daily (BI)||Fluconazole 400 mg once weekly (BII)|
|aAll medications are taken orally unless otherwise indicated.|
RECOMMENDATIONS RATING SCHEME
|Strength of Recommendation|
|Level of Evidence|
|I||One or more randomized trials with clinical outcomes and/or validated laboratory endpoints|
|II||One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes|
The CDC, the National Institutes of Health, and the IDSA have developed guidelines for the prevention of opportunistic infections among HIV-infected individuals . The report offers guidelines specific to each type of opportunistic infection and can be viewed at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
People dually infected with HIV and tuberculosis have a 20 to 30 times greater risk of developing active tuberculosis and becoming infectious compared to people not infected with HIV . However, cART significantly decreases the risk of conversion from latent to active disease, though patients with HIV remain at higher risk of TB disease than the general population . Among individuals in the United States with tuberculosis, an estimated 8.6% are coinfected with HIV .
In addition to the recommended prophylaxis to prevent first episode of opportunistic tuberculosis, guidelines for the treatment of HIV-related tuberculosis have been developed. These guidelines include call for directly observed therapy for all patients with HIV-related tuberculosis; prolonged treatment (up to nine months) for patients with a delayed clinical or bacteriological response to therapy or perhaps with cavitary disease on chest radiograph; and rifabutin-based regimens given at least three times a week for patients with tuberculosis and advanced HIV disease . Special considerations apply to children and pregnant women with HIV-related tuberculosis.
Healthcare professionals should be familiar with the guidelines to ensure the use of the most effective management strategies for patients with tuberculosis and HIV, while concurrently promoting optimal cART for these patients.
Women now make up nearly half of all AIDS cases worldwide and 20% in the United States [10,53]. The rate of HIV infection in women had been rising rapidly, but the proportion of new HIV diagnoses among women in 2014 (19%) represented a 21% decrease since 2008 [10,53]. In the last 30 years, the proportion of AIDS cases in women has more than doubled, from 8% in 1985 to 20% in 2014 [10,53]. In 1993, when the CDC expanded the case definition of AIDS, there was a 151% increase in the number of AIDS cases in women and a 105% increase in cases in men. More women were found to meet the AIDS case definition when the CD4+ T-lymphocyte count of <200 cells/mcL was added to the criteria. This may be evidence that the previous case definitions based on the clinical characteristics of men did not accurately reflect the clinical manifestations of HIV in women .
AIDS is the ninth leading cause of death in women 35 to 44 years of age in the United States, and it is the fourth leading cause of death in African American women in the same age group . Women of color have been disproportionately affected by HIV/AIDS, with black women accounting for 64% of new HIV diagnoses among women in the United States while representing only 13% of the female population . Women of color also tend to contract HIV at a younger age than their white counterparts.
The risk for acquisition of HIV and the factors that may affect seroconversion in heterosexual women are areas of research. It is clear that, in the absence of protective measures, women are much more likely to become infected with HIV through heterosexual sex (i.e., vaginal or anal receptive sex) than men. Although latex condoms are effective at preventing transmission of HIV when used correctly and consistently, some women may be afraid of the repercussions of insisting on condom use with their partners .
Many symptoms and signs of acute HIV infection and non-specific manifestations, such as fevers, weight loss, and fatigue, are the same for women and men. Because past research has either excluded women altogether or included only small cohorts of women, it has been difficult to determine gender differences in the clinical course of HIV disease. More recent research indicates that women with HIV initially present with lower viral loads but may be more likely than men to progress to AIDS, regardless of the viral load . cART appears to be more effective in preventing opportunistic infections and disease progression among women with HIV than among men, but it is also more likely to result in toxicities among women and men [58,59].
Gender-specific manifestations of HIV disease include irregular menstruation, recurrent vulvovaginal candidiasis, human papillomavirus (HPV)-related cervical dysplasia (abnormal, precancerous cell growth), and cervical cancer . HIV-infected women have a higher prevalence of HPV infection, a higher risk of progression from infection to disease, and an increased risk of invasive cervical cancer and other HPV-related cancers than non-infected women . Research indicates that cART does not significantly decrease the incidence of HPV-related cancers. As such, the American College of Obstetricians and Gynecologists recommends that women with HIV should have cervical cytology screening twice in the first year after diagnosis and annually thereafter .
Hormonal contraception also has an effect on the manifestations of HIV, the risk of acquisition/transmission, and treatment efficacy. An older study found that combined oral contraceptive use was associated with lower absolute CD4 cell count . Research focusing on HIV in women using hormonal contraceptive has indicated a slightly increased risk of acquisition and transmission, particularly with injectable methods of birth control [62,63]. There has been some evidence of an increased risk of HIV transmission to an uninfected male partner if the woman is using hormonal contraceptives . Hormonal birth control may interact with cART to create additional drug toxicities and treatment failures, and cART may reduce the effectiveness of some hormonal contraceptives .
Studies have shown that women with AIDS have a poorer prognosis than men (mainly attributed to socioeconomic factors), though the majority of research was completed in the pre-cART era. Researchers have speculated that poorer access to or use of healthcare resources (later diagnosis), domestic violence, homelessness, and lack of community support may contribute to the seemingly higher mortality rate for HIV-infected women .
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 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 to the woman .
Initiation of cART is recommended for pregnant women with HIV in all stages of pregnancy. Regardless of the stage of pregnancy or childbirth, if a woman is found to be HIV-positive, there are treatment options that should be explored .
Patients should be registered with the Antiretroviral Pregnancy Registry, which collects observational, nonexperimental data. The registry is sponsored by GlaxoSmithKline, in affiliation with the CDC and Kendle International, Inc. Women who have been treated with cART at any time during their pregnancies are eligible for registry enrollment. The telephone number for registration is (800) 258-4263, and the website is http://www.apregistry.com
In the United States today, the predominant route of infection with HIV in children is perinatal (from an infected pregnant woman to her fetus or infant) . Thus, the epidemic in children is closely linked to the epidemic in women.
Children with HIV/AIDS may have more than one infection at the same time or in succession (multiple opportunistic infections). Conditions associated with HIV infection in children are :
Serious bacterial infections, multiple or recurrent (only among children younger than six years of age)
Candidiasis (esophageal or pulmonary)
Invasive cervical cancer (only among adolescents and children six years of age or older)
Cryptosporidiosis or isosporiasis with diarrhea persisting longer than 1 month
Herpes simplex virus infection causing bronchitis, pneumonitis, or esophagitis or causing a mucocutaneous ulcer that persists for longer than 1 month
Disseminated or extrapulmonary histoplasmosis
Disseminated or extrapulmonary Mycobacterium tuberculosis
Disseminated Mycobacterium avium or kansasii
Progressive multifocal leukoencephalopathy
Recurrent Salmonella septicemia (nontyphoid)
Toxoplasmosis of the brain
As with adults, cART is believed to play a major role in slowing progression of HIV in children and adolescents. For treatment-naïve children younger than three years of age, the preferred regimen is ritonavir-boosted lopinavir with two NRTIs . The U.S. Department of Health and Human Services recommends that efavirenz or ritonavir-boosted lopinavir and two NRTIs be used in the treatment of children three to six years of age. The preferred PI-based regimen for children six years of age and older consists of either of the options outlined for children three to six years of age or atazanavir/low-dose ritonavir and two NRTIs .
Children receiving cART should be monitored for side effects, adherence, efficacy and toxicity. The U.S. Department of Health and Human Services recommends evaluating all pediatric patients within one to two weeks to monitor compliance, side effects, and response to treatment. Subsequently, a visit should be scheduled every three to four months . Strategies to improve adherence should focus on selecting an appropriate regimen, educating the family/caregiver, and consistent follow-up.
Approximately 16.5% of newly diagnosed cases of HIV in 2014 occurred in individuals 50 years of age or older; 24% of all persons living with HIV/AIDS are 50 years of age or older [10,68]. Until recently, there had been little attention given to this group. HIV/AIDS has traditionally been thought to be the disease of the young; therefore, in the past, prevention and education campaigns had not been targeted toward older adults. However, evidence points to the increasing number of infected older people and a need for change in prevention and education campaigns. Some older persons may have less knowledge about HIV and risk reduction strategies. Due to divorce or being widowed and the availability of medications to treat erectile dysfunction, increasing numbers of older people are becoming sexually active with multiple partners . For postmenopausal women, contraception is no longer a concern, and they are less likely to use a condom. Furthermore, vaginal drying and thinning associated with aging can result in small tears or cuts during sexual activity, which also raises the risk for infection with HIV/AIDS . Studies indicate that at-risk individuals in this age group are significantly less likely than younger at-risk adults to use condoms during sex . In addition, healthcare professionals are less likely to discuss sexual activity or take a sexual history if the patient is older than 50 years of age . The combination of these factors increases the risk for unprotected sex with new or multiple partners in this age group, thereby increasing their risk for AIDS. This increase should be considered when evaluating older patients.
Early possible signs of immunosuppression that are frequently overlooked or mistakenly attributed to aging include thrush and skin problems, especially seborrheic dermatitis and herpes zoster. When HIV is not recognized or treated, the most typical opportunistic infections are PJP and recurrent bacterial pneumonia, CMV, and Mycobacterium tuberculosis or Mycobacterium avium complex. PJP can present as 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 disease.
In 2012, the FDA approved the first medication for the prevention of sexually transmitted HIV infection, the combination drug Truvada (emtricitabine/tenofovir DF) . In conjunction with safer sex practices, Truvada has been found to be partially effective as pre-exposure prophylaxis in high-risk patients. The Chemoprophylaxis for HIV Prevention in Men study, also known as iPrEx, studied the effect of once daily Truvada in 2,499 HIV-seronegative men or transgender women who have sex with men compared to placebo . Researchers found that persons receiving Truvada experienced a 44% reduction in the incidence of HIV after a median of 1.2 years compared to placebo. Pre-exposure prophylaxis was most effective among participants at particularly high risk for HIV (i.e., self-reports of unprotected receptive anal intercourse).
In 2014, the CDC and the U.S. Department of Health and Human Services released clinical practice guidelines for pre-exposure prophylaxis for the prevention of HIV infection . This new guideline outlines indications for prophylaxis as one prevention option for HIV transmission. The most important first step in determining if an individual is a candidate for pre-exposure prophylaxis is a thorough history, including sexual and injection drug activities. All candidates will be adults without an acute or established HIV diagnosis. Pre-exposure prophylaxis is indicated for high-risk MSM, meaning those who have had any male sex partners in the past six months, are not in a monogamous partnership with a recently tested, HIV-negative man, and have one of the following :
Anal sex without condoms (receptive or insertive) in the past six months
Any STI diagnosed or reported in the past six months
An ongoing sexual relationship with an HIV-positive man
Prophylaxis is also recommended for high-risk heterosexual adults who have had sex with an opposite sex partner(s) in the past six months, are not in a monogamous partnership with a recently tested, HIV-negative partner, and one of the following :
Is a man who has sex with both women and men (behaviorally bisexual)
Infrequently uses condoms during sex with one or more partners of unknown HIV status who are known to be at substantial risk of HIV infection (IDU or bisexual male partner)
Is in an ongoing sexual relationship with an HIV-positive partner
IDUs are also considered candidates for pre-exposure prophylaxis if they meet certain criteria. The guideline states that persons who have injected drugs not prescribed by a clinician in past six months may be candidates for prophylaxis if they also are positive for one of the following factors :
Any sharing of injection or drug preparation equipment in the past six months
Been in a methadone, buprenorphine, or buprenorphine/naloxone treatment program in the past six months
Increased risk of sexual acquisition (based on the previously outlined criteria)
Only fixed-dose combination tenofovir and emtricitabine (Truvada) taken daily is approved for pre-exposure prophylaxis, and it is considered the recommended first-line option [70,72]. However, because tenofovir alone has been proven effective in trials with IDU and heterosexually active men and women, it is the alternative option for these populations . No other antiretroviral regimens should be used for pre-exposure prophylaxis.
All patients prescribed Truvada for pre-exposure prophylaxis must have a negative HIV test prior to initiating treatment and every three months thereafter. In addition, patients should be advised regarding possible side effects and the continued necessity for safe sex practices. Eligible patients should also be screened for hepatitis B and have a confirmed creatinine clearance of 60 mL per minute or greater .
Both preventive and therapeutic vaccines are being studied for use in the fight against HIV. Preventive vaccines are developed to protect individuals from contracting HIV, while the goal of therapeutic vaccines is to boost immune response to and better control existing HIV infection. Of course, the ultimate goal in vaccine research is a vaccine that will prevent infection; however, despite many trials, no vaccine effective in preventing HIV has been discovered.
Most progress on HIV vaccine development may be monitored through the International AIDS Vaccine Initiative (IAVI). The IAVI has three main objectives: accelerating the development of AIDS vaccines, establishing partnerships to expand the diversity and number of AIDS vaccine candidates, and building support for AIDS vaccine research and development .
Because HIV is spread predominantly through sexual transmission, the development of chemical and physical barriers that can be used intravaginally or intrarectally to inactivate HIV and other STI pathogens is critically important for controlling HIV infection.
Researchers are developing and testing new creams or gels (topical microbicides) that could be applied before intercourse to protect individuals against HIV and other sexually transmitted organisms . One of the most promising is 1% vaginal gel formulation of tenofovir, which showed a 54% decrease in the incidence of HIV infection in high adherers in one clinical trial . However, there are concerns regarding compliance with recommendations to ensure protection.
New topical microbicide candidates would ideally be non-irritating and inexpensive. In addition, they should be available in both spermicidal and non-spermicidal formulations so women do not have to put themselves at risk for acquiring HIV and other STIs in order to conceive a child.
Many adolescents engage in behaviors that put them at risk for HIV infection. According to the CDC, 46.8% of high school students have ever engaged in intercourse . Approximately 40.9% of currently sexually active high school students had not used a condom at last sexual intercourse; 1.7% had ever injected an illegal drug . Although 85.3% of adolescents report having received education on HIV prevention in school, the content of these discussions may not provide adequate information on the subject. Furthermore, the American Academy of Pediatrics determined that school-based education and intervention programs do not provide the necessary opportunities of confidential discussions or targeted counseling . Healthcare professionals have a unique opportunity to intervene in this population to provide accurate and complete information on HIV transmission and risk reduction.
For patients who are not proficient in English, it is important that education regarding the risks, prevention, and treatment of HIV be provided in language that they understand. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.
Although prevention and new medical interventions may reduce the pace of the epidemic, HIV will be a significant disease for many years both in the United States and the world. Education provides the opportunity to ensure that healthcare professionals have the information necessary to provide the best possible care for persons with HIV. Those who specialize in HIV care should identify ways to renew themselves through education, individual support, staff support, and variation of workload so that they can continue to contribute their valuable expertise to patients with HIV. With no easy cure in sight, healthcare professionals have the opportunity to work with patients to help them achieve and maintain their optimal level of health during the continuum of HIV disease.
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