The goal of this lesson is to discuss the etiology and treatment of HIV infection and Acquired Immune Deficiency Syndrome (AIDS). The focus is directed toward providing information for pharmacists that can then be conveyed to patients and/or their caregivers regarding current therapeutic approaches and recommendations on caring for persons who are HIV-positive and those with AIDS.

At the conclusion of this lesson, the reader should be able to:

1. define AIDS in terms of HIV infection including incidence, epidemiology, pathogenesis and modes of transmission, and clinical presentation;
2. describe the biochemical and physiological bases for clinical presentation;
3. outline current recommendations for HIV counseling, testing, confidentiality of test results, referral, and testing of patients;
4. demonstrate an understanding of current protocols and procedures applicable to HIV counseling and testing, reporting, offering of HIV testing to pregnant women, and partner notification issues;
5. identify antiretroviral interventions to prevent and/or control HIV infection;
6. categorize drugs used in management of HIV infections by pharmacological class, identify their adverse reactions and other safety issues, and list advantages and disadvantages of each class; and,
7. select from a list appropriate information to convey to patients who are HIV-positive and/or their caregivers.

INTRODUCTION

A quarter century has passed since the first report appeared concerning a strange new disease. In June 1981 the Centers for Disease Control and Prevention (CDC) described five cases of Pneumocystis carinii pneumonia in previously healthy men living in the Los Angeles area who were immunodeficient.^1,2 In common was that all the men were practicing homosexuals. Over the next couple years, additional reports cited continued outbreaks of what appeared to be the same perplexing disease; however, the description of its victims expanded to include bisexual men, injecting drug users, heterosexual women who had sexual contact with infected men, children born to infected mothers, and recipients of blood products. Since the disease identified as Acquired Immune Deficiency Syndrome (AIDS) was first reported, an estimated 1,039,000-1,185,000 persons in the United States have acquired it, the highest number ever recorded in the country,³ with 40 million people world-wide living with HIV/AIDS.^4-6 HIV is now found in every country of the world.⁷ The World Health Organization (WHO) lists the HIV/AIDS pandemic at the top of its agenda.⁸ The pandemic remains a significant threat to the planet and a personal tragedy to those who are inflicted.⁹

The human immunodeficiency virus (HIV) is arguably the most studied virus in history. Since its identification as the causative agent of AIDS, HIV has been the focus of many thousands of research-based investigations and in-depth scientific inquiry.¹⁰ This monograph summarizes relevant information on HIV infection and AIDS and treatment guidelines for pharmacists to aid in patient counseling.

INCIDENCE AND PREVALENCE

The incidence of AIDS increased rapidly from its onset, peaked in the early 1990s, and then declined beginning in the mid-1990s.¹¹ From 1998, declines in both incidence and deaths leveled off.

Through the early 1980s, most AIDS patients were Caucasian. Cases among African Americans increased steadily so that by 1996, more new cases occurred in this group than any other racial/ethnic population. African Americans who make up approximately 12% of the U.S. population accounted for half of the HIV/AIDS cases diagnosed (Figure 1).^3,6 Black men who have sex with other men in the United States are more than twice as likely to be HIV positive as white and Latino homosexual men.¹² Cases among Asians/Pacific Islanders, American Indians/Alaska Natives, and Hispanics have increased also. Nearly two-thirds of persons diagnosed with HIV/AIDS are male (Figure 2).⁶ Approximately 83% of males and 76% of females with a diagnosis of HIV/AIDS are between ages 35 and 54 years.¹³

Figure 1. Race/ethnicity of persons (including children) who received a diagnosis of HIV/AIDS, 2003.¹⁵³

Note. Based on data from 33 areas with long-term, confidential name-based HIV reporting. Includes persons of unknown race or multiple races.

Figure 2. Sex of adults and adolescents who received a diagnosis of HIV/AIDS, 2003.¹⁵³

Note. Based on data from 33 areas with long-term, confidential name-based HIV reporting. 

In a recent survey involving 500 African Americans aged 15-44 years and living in the contiguous United States, one in seven said they believed that AIDS was created by the government to control the black population.¹⁴ One in three said they believed that HIV was produced in a government laboratory. Over half believed there was a cure for HIV/AIDS that was being withheld from the poor. Because of these perplexing beliefs identified by this study and others, there is a real risk that these conspiracy theories will frustrate efforts to halt the pandemic in African American communities.

Of the women diagnosed with HIV/AIDS in 2003, more than 70% were African American, and 62% of children born of HIV-infected mothers were African American.¹⁵ At present, women represent about half of all HIV/AIDS cases worldwide, and the virus is spreading fastest among female populations.¹⁶

In males, sexual activity with other men, and in females, heterosexual contact with infected males, have been the most common modes of exposure among persons with AIDS. These are followed by injecting drug use in both genders and heterosexual contact in males (Figure 3).^6,17 The incidence of AIDS increased steadily in all three of these risk categories through the mid-1990s.

Figure 3.  Exposure categories of adults and adolescents who received a diagnosis of HIV/AIDS, 2003¹⁵³

Note. Based on data from 33 areas with long-term, confidential name-based HIV reporting. 

The number of persons in the United States living with HIV continues to increase partly because of longer lifespan due to effective drug therapy.^6,18 The rates of decline in mortality have slowed somewhat, attributed to having reached the limits of therapy in extending survival, emergence of treatment-resistant viral strains, and delay in HIV testing. For AIDS to become maximally controlled, HIV-infected persons must be tested early in the progression of their disease and commit to strict adherence (ie, compliance, as discussed later) with chronic treatment strategies that will extend over their lifetimes. They must also adhere to a strict therapeutic protocol (eg, protected sex, etc.) to prevent acquisition or transmission of new infections.¹⁹ The CDC estimates that approximately 40,000 persons become infected with HIV each year in the United States,⁶ which includes over 300 infants each year who contract HIV because their mothers are infected.20 Nearly 25% of all infected persons are believed to be unaware of their infection.¹³

The Global Concern
People in certain other parts of the world are not as fortunate as those in the United States.^21-23 By the end of 2003 nearly 40 million people world-wide were infected with HIV (Table 1).^4,5 The pandemic is spreading globally at a rate of 14,000 new infections every day.⁵ Approximately 3 million people world-wide died from HIV/AIDS in 2003.^4,10

Over 90% of HIV-positive individuals infected with HIV live in developing countries. This disease prevalence trend will likely continue to rise in countries where poverty, poor health care systems, and limited resources speed the spread of HIV. WHO estimates that only about 400,000 of the infected persons in developing countries were receiving treatment in 2003. WHO also estimates that two-thirds of the new infections projected to occur by 2010 can be avoided if prevention strategies are increased substantially.⁸ Prevention remains the most effective strategy to combat HIV, especially prevention efforts that target high-risk groups, such as men who have sex with men, intravenous drug users, and sex workers and their clients.²⁴

An estimated 70% of the world's total of HIV-positive people (26 million out of 37.1 million) live in Sub-Saharan Africa, a region that contains only 11% of the world's population. Nine percent of all adults in Sub-Saharan Africa are HIV-positive compared to 0.6% of adults in the United States. More than 15 million Africans have died from AIDS since the beginning of the epidemic; 2.2 million AIDS deaths occurred there in 2001. The HIV/AIDS pandemic has thus reached catastrophic proportions in Sub-Saharan Africa.²⁵ In response, WHO launched an ambitious program in 2003, designated "3 by 5", in an attempt to treat at least 3 million infected people by the end of 2005.²⁶ Time will tell whether this goal will be achieved - by the end of 2005 - or even later.

Southern and eastern Africa have been the most severely affected regions with seven countries reporting an estimated adult HIV prevalence rate of 20% or greater. The HIV/AIDS epidemics in southern Africa came to light later than in the United States, but they have been more explosive. In Botswana for example, HIV prevalence among pregnant women in Francistown increased from 7% in 1991 to 44% in 2000.

In comparison, adult HIV prevalence in Asia is believed to be relatively low, exceeding 1% in only three countries: Burma, Cambodia, and Thailand. Prevalence in Thailand and Cambodia is declining or stabilizing at low levels. Of concern is a fear that the number currently reported for China and India, for example, countries that are first and second, respectively, in world population may be much higher. Slight increases in the percentage of HIV-positive citizens in these two countries could result in massive increases in the actual number of infected persons world-wide.

In Latin America and the Caribbean, HIV/AIDS epidemics vary from those that are concentrated among homosexual men (Peru and Mexico) or injecting drug users (Argentina and Uruguay), to others that are driven primarily by heterosexual transmission. The latter include the Bahamas, Haiti, Honduras, and Guyana, countries with the highest adult HIV prevalence levels in the area. Haiti, the poorest country in the Western Hemisphere, also bears the greatest AIDS burden in this part of the world.²²

EPIDEMIOLOGY OF HIV INFECTIONS

HIV is transmitted primarily by behaviors that encourage exchange of blood or body fluids containing the virus and/or HIV infected cells. The virus has been documented in blood products, semen, vaginal secretions, breast milk, tears, urine, cerebrospinal fluid, and saliva (Table 2).²⁷ Only HIV in blood, breast milk, vaginal fluids, and semen, however, has been noted to be a serious source of infection.

Transmission of the virus through casual sexual encounters is not highly efficient, so the risk of acquiring the infection from a single sexual event is relatively low (Table 3).²⁸ Transmission via sexual contact depends on the type and frequency of encounters and presence of risk factors such as unprotected sex. The incidence of HIV transmission in persons who do not use condoms or who use them incorrectly is increased significantly, compared with the incidence in persons who do practice protected sex. Different nonoccupational exposures are associated with varying levels of risk. The greatest per-act risk for HIV transmission is associated with blood transfusion, needle sharing by injection-drug users, receptive anal intercourse, and percutaneous needlestick injuries. Insertive anal intercourse, penile-vaginal exposures, and oral sex represent substantially less per-act risk.²⁸

Nearly all known acquisition of HIV through transfusion of blood or blood products occurred before screening of the nation's blood supply. Since HIV test kits were first introduced in the mid-1980s, the risk of infection from blood transfusion, blood components, or tissues has remained low, with approximately 1% of infections acquired by blood transfusions or use of contaminated blood products. Receiving a blood transfusion will probably always carry a small risk of contracting HIV because infected people may donate in an emergency setting during the early period before the presence of the virus can be detected.

Perinatal HIV Transmission
An estimated 120,000-160,000 women in the United States are HIV-positive; 80% are of childbearing age. Perinatal transmission can occur during pregnancy (intrauterine), labor and delivery (intrapartum), or after delivery through breast-feeding (postpartum). In bottle-fed infants, intrauterine transmission accounts for 25%-40% of infections with the remaining infections acquired during labor and delivery. Among breast-feeding women, approximately 20%-25% of perinatal infections are associated with intrauterine transmission, 60%-70% with intrapartum transmission or very early breast-feeding, and 10%-15% with later postpartum transmission through breast-feeding. In a clinical trial comparing formula-feeding with breast-feeding, approximately 44% of infants with HIV infection acquired HIV through breast-feeding. No link has been identified that correlates perinatal HIV transmission with maternal age, race/ethnicity, or previous history of delivering an HIV-positive child.²⁹

PATHOGENESIS AND CLINICAL PRESENTATION

Epidemiologic data have established that HIV-1 most likely evolved in a subspecies of the chimpanzee (Pan troglodytes) that live in central Africa.³⁰ The virus does not readily affect chimpanzees adversely. It is theorized that, in parts of Africa where nonhuman primates are kept as pets and/or butchered for food, this suggests likely routes of transmission.³¹ The virus mutated at some point in time and became able to infect humans. HIV-2 is similar genetically to HIV-1 and is endemic among another African primate. However, it is less prevalent and virulent than HIV-1.³² The earliest documented case of HIV infection in humans was identified in a sample of serum from the Democratic Republic of Congo that was collected and stored in 1959.³³ Based on the HIV-1 sequences obtained from this and other, more recent isolates, it has been estimated that the main group of HIV-1 strains diversified in humans in about 1931.³⁴ The year 1968 is estimated to be the date of origin of U.S. HIV subtype B.³⁵ The most recent common ancestors of HIV-2 subtypes have been dated to the 1940s.³⁶ The vast majority of HIV-infected individuals carry HIV-1, and most AIDS cases result from HIV-1 infection.³²

The HIV-1 virus mutates frequently so it is genetically diverse. HIV-1 is classified into two groups designated as group M (ie, major group) and group O (outlier group). Grouping is based upon differences in the sequencing of the viral envelope gene. Group M is subdivided into eight diverse subtypes, labeled A through H. The most common subtype in America and Europe is subtype B. The others are rare. Subtypes A, C, D and E are common to Africa and Asia.³⁷

HIV Infection and the Reservoir Concept
HIV-1 combines with CD4+ molecules on the cell surface of the host and then fuses with the cell membrane. HIV's baseline genetic material is RNA; the virus is uncoated as it enters the cell. Viral RNA, along with the enzyme reverse transcriptase, are released into the cell cytoplasm where the virus transcribes its own RNA into viral DNA. This DNA is then integrated into the host cell's human DNA by an enzyme known as integrase. At this point, the viral DNA serves as a template for replication of viral RNA along with synthesis of viral proteins and polypeptides. Viral components gather on the inner side of the host's cell membranes and bud off into new virus particles. During this process, the enzyme protease cleaves long polypeptides into their component enzymes and structural proteins to yield a mature virus particle.

Of great interest to medical scientists is discovery of at least four latent reservoirs for HIV-1 in resting CD4+ cells. The importance of this discovery to the lifespan of the infected individual and therapeutics to control the infection is that these reservoirs most likely provide a potential means for the virus to persist in an infected individual despite effective antiretroviral therapy.^38-41 They help explain why, at least at present, total elimination of the virus from patients has proven to be quite difficult to achieve.⁴²

Immune Defects
The hallmark of AIDS is a resultant deficiency within the immune system that exposes the individual to increased susceptibility to fatal opportunistic infections such as Pneumocystis carinii.⁴³ This occurs because of infection of CD4+ lymphocytes (ie, T-helper cells), the primary target of HIV.32,44 CD4+ T-lymphocytes aid B cells in manufacturing antibodies, stimulate T-cytotoxic cells (CD8+) to lyse virus-infected cells and tumor cells, and activate the body's macrophages to eliminate intracellular pathogens. Their destruction and/or inactivation compromise cell-mediated and humoral-immunity mechanisms. This in turn increases susceptibility to serious opportunistic infections with death as the common outcome.

HIV also infects CD4+ monocytes and macrophages.⁴⁵ These cells are not inactivated by HIV, but they serve as reservoirs for latent infections, and they are active in dissemination of the virus to other sites such as the brain, bone marrow, lungs, and lymphoid tissue. HIV has also been identified in brain microglia, bowel mucosal cells, liver endothelial cells, dermal fibroblasts, and Langerhans cells.

A number of factors modify the risk for HIV infection and disease progression (Table 4). Multiple sexual contacts and venereal disease that results in genital ulcers are primary risk factors. Host genetic differences apparently play a role since some individuals do not become infected despite multiple HIV exposures. Age at infection is an important consideration in that a person's immune response diminishes naturally with increasing age. The presence of other infectious microbials such as cytomegalovirus is an important factor. The strain of HIV may also play a role.

Clinical Presentation
Two surrogate markers are used routinely to assess indications for treatment and to monitor efficacy of drug therapy: CD4+ T-cell count and plasma HIV RNA.^17,46

CD4+ T-cell count.—The CD4+ T-cell count (CD4 count) is the primary clinical indicator of immunocompetence in HIV-infected patients. It is the most important consideration relevant to decisions regarding initiation of antiretroviral therapy. The most recent CD4+ T-cell count is the strongest predictor of subsequent disease progression and patient survival. A significant change between two tests is defined as a 30% change (ie, decrease) in the absolute count. Clinical AIDS is usually marked by a CD4+ T-cell count of <200 cells/mm³ in the blood.

Viral load.—Plasma HIV RNA (viral load) is a useful indicator in the decision to initiate therapy. Viral load is also a critical determinant for evaluating response to therapy. Analysis of 18 clinical trials enrolling over 5000 participants with viral load monitoring showed a statistically significant association between decreasing plasma viremia and improved clinical outcome. Thus, viral load assessment provides an objective marker for treatment response and may help predict clinical progression. The minimal change in viral load considered to be statistically significant is a three-fold or a 0.5 log10 copies/mL change (ie, increase).

Three distinct stages are recognized in the infection process. The first is the acute phase (also referred to as the diagnostic window or serological latency) that follows immediately after HIV infection. Viral nucleic acid and the HIV p24 antigen can be detected in the host serum but no host antibodies to HIV can be found. The host is therefore seronegative (ie, antibodies to HIV are not present). During this phase, HIV RNA levels in the blood peak at about 6 weeks following infection, then decline. The CD4+ T cell count declines rapidly during the 6 weeks postinfection then begins a slight increase.^47,48

An estimated 40%-90% of patients acutely infected with HIV will experience symptoms of acute retroviral syndrome (Table 5).^49,50 Acute HIV infection is often not recognized by primary care clinicians, however, because of the similarity of its symptoms to those of influenza, infectious mononucleosis, or other illnesses. Additionally, acute infection can occur asymptomatically.¹⁷

Antibodies to HIV can usually be detected about 6-8 weeks postinfection but may not be observed until 3 months postinfection.⁴⁷ Appearance of host antibodies is referred to as seroconversion. This marks the beginning of the second (ie, chronic) stage of infection. The host antibody response to the virus matures during this stage to result in increasing titres of antibody over the next several years. HIV RNA concentrations in the blood remain stable and the host CD4+ T cell count begins to fall steadily.⁴⁸

The third stage of HIV infection is marked by onset of clinical AIDS. This stage is distinguished by clinical symptoms associated with immunodeficiency that include the onset of opportunistic infections such as Pneumocystis carinii, as discussed earlier, and/or other bacterial, viral, or fungal infections.

HIV TESTING AND DIAGNOSIS

About half of individuals who report behavior that could transmit HIV have not been tested for HIV.⁵¹ Those who are HIV-infected may not be tested until late in their infection. Since medical treatment that lowers the HIV viral load should reduce the risk of transmission, early referral for treatment could prevent HIV transmission to others in the community while reducing the infected carrier's risk for HIV morbidity and mortality.⁵² Of an estimated 2 million tests for HIV in a cohort reported in the year 2000, approximately 18,000 outcomes were positive for HIV. Thirty-one percent of the newly detected HIV-positive individuals did not return to the clinics to learn their test results. Of 573 HIV-infected young homosexual men, 77% were unaware of their infection.

It is anticipated that most persons who learn they are HIV-positive will adopt behaviors to reduce the risk for transmitting the virus.⁵² A study of 1,363 HIV-infected men and women revealed that of 69% of persons who were sexually active during the previous 12 months, 78%-96% of them used a condom during recent anal or vaginal intercourse with a known HIV-negative partner. Fifty-two percent to 86% reported condom use with a partner of unknown serostatus.⁵³ The problem is, of course, that the term "most persons" who learn they are HIV-positive is not inclusive for "all persons".

Diagnostic tests for HIV reveal its presence by detecting host antibodies to HIV proteins or by directly sensing the whole virus or its various components (such as the HIV p24 antigen or HIV RNA).⁴⁷ The goal of testing is to detect HIV early following exposure.⁵⁴

Blood in some form (plasma, serum, or dried blood spots) is the preferred sample specimen for most HIV diagnostic tests. Serologic (ie, blood-based) tests also permit determination of HIV viral type (HIV-1 or HIV-2), viral subtype, viral load (as measured by viral RNA levels in the blood), HIV drug resistance, and how recently the viral infection was contracted. Blood specimens remain fairly stable and can be stored over long periods of time. Plasma and serum are usually refrigerated or frozen for prolonged storage, while dried blood spots remain stable at room temperature.⁵⁵

Blood specimens may be collected by venipuncture or finger pricks. These approaches are not always palatable to the test subject; as a result, several diagnostic tests (Table 6) have been developed that use saliva or urine as the test specimen. Urine and saliva collection also impose fewer biosafety concerns compared with blood collection. While comparable in sensitivity and specificity to blood tests, urine- or saliva-based HIV diagnostic tests are not suitable for additional analyses of HIV infection that serologic tests permit.⁵⁵

To date, FDA has not approved home-use HIV test kits that enable users to collect a sample at home, and evaluate their own HIV test results in a few minutes. The Federal Trade Commission has warned that some home-use HIV test kits (many of which are available on the Internet or through other "gray" commercial sources), give inaccurate results.⁵² These tests differ from FDA-approved kits which direct consumers to collect a sample in private, send it to a laboratory for testing, then telephone the laboratory for their HIV test result, counseling, and referral.

One approved test, the OraQuick HIV rapid test can identify HIV in <20 minutes, can be stored at room temperature, requires no elaborate equipment, and can be performed outside of clinical settings.⁵⁶ A rapid test that permits same-day results can increase the number of persons who receive test results, thus improving the chance for effective counseling and treatment. The sensitivity (ie, probability that the test result will be reactive if the specimen is a true positive) of OraQuick in clinical studies was 99.6%. Specificity (ie, probability that the test result will be nonreactive if the specimen is a true negative) is 100%. Both indicators are comparable to those of FDA-approved enzyme immunoassays (EIA) in widespread use. Since the prevalence of HIV is low in most US testing sites, the negative predictive value of screening (ie, the probability that the test will accurately predict the true infection status) with a single rapid test is high. Therefore, a negative result with a rapid HIV test requires no further testing and the patient tested can be counseled appropriately at the initial visit. Retesting is recommended for individuals who have a recent history (within 3 months) of known or possible exposure to HIV. In this instance, there might not have been sufficient time for detectable levels of antibodies to develop. As with any HIV screening test, a positive HIV test result still requires confirmation by either EIA or a Western blot assay.^12,56

EIA is the standard test used to screen for antibodies to HIV. Antibodies detected are usually of the immunoglobulin G (IgG) subtype.³⁷ To perform a typical indirect EIA, the patient's serum or plasma is incubated with an HIV antigen (usually p24, gp41 and/or gp120). If the patient is HIV-positive and has seroconverted, the anti-HIV antibodies in their blood will bind to the HIV antigen. The patient's antibody is later detected by an enzyme-labeled anti-human antibody or an enzyme-labeled antigen.47 There are several EIA assays that screen for infection with HIV-1 or HIV-2.

To minimize the risk of reporting false-positives, a confirmatory test should be conducted before release of a positive outcome of a screening test like the EIA.⁵⁷ The most commonly used test to confirm a positive EIA outcome is the Western blot. Most Western blot assays are designed to detect infection with group M, subtype B HIV-1. They are also effective for confirming infection with other HIV-1 group M subtypes because of cross reactivity to host antibody against these HIV subtypes. When used after seroconversion, the EIA/Western blot combination has a high sensitivity (ie, low rate of false-negative results) of 99.3%-99.7%, and a high specificity (ie, low rate of false-positives) of 99.7%.⁴⁷

CDC CLASSIFICATION

HIV infection represents a continuum of diseases. The classification is based on presence of anti-HIV antibodies plus three additional clinical and three laboratory categories (Table 7).⁵⁸

MANAGEMENT OF HIV INFECTION

Prevention
Since sexual relations with an infected person and injecting drug abuse are responsible for the greatest number of HIV infections in the United States, any program for preventing AIDS must include three strategic points:

  - Encourage people to limit the number of sexual contacts;
  - Promote the use of condoms; and,
  - Treat concurrent sexually transmitted diseases in people at risk for HIV.

Latex condoms plus spermicide afford the most effective means of prevention currently available. (Natural membrane or skin condoms do not block passage of viruses including HIV and should not be relied upon.) Only water-based lubricants should be used, since oil-based substances may weaken the latex membrane to reduce its barrier effectiveness. Diaphragms and cervical caps are ineffective barriers. The nonionic detergent, nonoxynol-9, is the only approved spermicide.^59,60 However, it may also increase a woman's risk for sexually transmitted infections, including HIV. Nonoxynol-9 does this, presumably, by inflicting minor damage to the epithelium in the genital tract, which then eases entry of HIV into the genital tissue.^61,62

The risk for male-to-female transmission is higher than in the reverse. A monogamous couple-both of whom are HIV-negative 6 months after their last unprotected intercourse-may continue without protection. A single protected coitus with an HIV-infected person is associated with a 15% risk of infection.

Persons in contact with HIV contaminated material should take extreme caution to avoid contamination. Basic infection control procedures include frequent hand washing, and wearing of gloves, mask, gown, and protective eyewear. Contaminated counters, tabletops and other hard surfaces should be washed thoroughly with diluted household bleach (1/4 cup bleach to 1 gallon water) to inactivate the virus.⁶³

The Search for an HIV Vaccine
Antiretroviral drug therapy