As the prevalence of human immunodeficiency virus (HIV) continues to increase,^1,2 family physicians are encountering more patients at risk for this disease. It is imperative to diagnose patients as early as possible because advances in antiretroviral therapy are resulting in impressive extensions of life span and increased quality of life,^1–3 and because of the need to break the cycle of ongoing infections through preventive behavior changes.^4,5 Family physicians need to be current and comfortable in their approach to patients at risk for and those infected with HIV. The management of advanced acquired immunodeficiency syndrome (AIDS), opportunistic infections, and antiretroviral therapy is complex and requires additional training and expertise. However, the initial evaluation and preventive care of patients with HIV is straightforward^6,7 and within the scope of family physicians.

Issues For Patients Newly Diagnosed with HIV

PSYCHOSOCIAL STABILIZATION

As with any potentially life-threatening illness (especially HIV, which can be associated with social stigma), coping should be the first issue addressed.^4,8,9 Family physicians are trained in psychosocial and community medicine, and therefore are able to address patients’ safety; support systems; potential depression and suicide risk; family reactions such as blame and domestic violence; and potential impact on employment, finances, and health insurance resources. Knowledge of local legal regulations and community resources is important, and physicians should be prepared to provide appropriate referrals to counselors; social workers; financial and insurance assistance programs; and housing, drug treatment, and legal resources.

TRANSMISSION PREVENTION

Diagnosing a new case of HIV infection presents a unique opportunity to interrupt the cycle of HIV spread.^4,5 Despite physicians’ knowledge and education about HIV transmission, the annual number of new HIV infections has not declined over the past decade.^1,2,4,10 In 2002, there were more than 40,000 new HIV infections in the United States, one half of them occurring in people younger than 25 years. Among women, the majority of cases are attributable to heterosexual contact. Thus, enhanced effort in preventing HIV transmission, among infected and uninfected persons, is crucial.

The most important prevention approach is education and behavior modification. The Centers for Disease Control and Prevention’s (CDC’s) revised guidelines^4,11,12 on the prevention of HIV emphasize behavioral intervention strategies that focus on interpersonal prevention skills rather than just patient knowledge. Key points include screening patients with HIV for ongoing or recurring risk behaviors, discussing sexual activities and drug use, positively reinforcing incremental changes toward safer behavior, and addressing how to disclose HIV-seropositive status to a sex or drug partner.¹²

The safest sexual practices are abstinence followed by monogamy. For patients who are neither abstinent nor monogamous, the physician should convey the following infection prevention messages: consistent and correct condom use; sex only while sober; reduced numbers of sex partners; and less mucosal trauma. For patients who use intravenous drugs, physicians should recommend cessation of illicit drug use or, if this is unlikely, using bleached or new needles and not sharing needles.

Other approaches to the prevention of HIV transmission include interruption of maternal-child transmission through prenatal HIV testing and antiretroviral therapy for mother and newborn,^5,13 reduction of HIV sexual transmission through antiretroviral therapy to reduce viral concentration in genital secretions,¹⁴ and treatment of other sexually transmitted diseases (STDs) to mitigate the enhancement of HIV transmission that otherwise occurs in this context.¹⁵ Numerous studies^13–17 have reported decreased rates of sexual and perinatal transmission among persons with lower levels of plasma viremia, including those undergoing antiretroviral therapy.¹⁴ However, other studies^18–20 have documented an imperfect correlation between serum viremia and viral levels in sexual secretions, finding that an undetectable serum viral load does not guarantee the safety of unprotected sex.

The increased risk of HIV transmission due to elevated HIV viral concentrations in genital tract secretions during acute HIV infection²¹ and episodes of STDs underscores the importance of early HIV detection and screening and counseling for all STDs in the context of sexually transmitted infections or risk factors.²²

Prevention approaches that are highly attractive from a pandemic perspective are topical microbicides and HIV vaccination. Unfortunately, research to date has produced no viable candidates, relegating these modalities to future hopes. Lastly, although HIV is not casually transmitted, patients in the household setting should be advised to clean visible blood spills or soiled garments with a bleach solution and not to share toothbrushes or razors with anyone. No other specific precautions are necessary.

PARTNER NOTIFICATION AND CASE REPORTING

The goals of partner notification and HIV testing are to interrupt the cycle of repeated HIV exposure and to detect other cases of HIV infection to facilitate entry into medical care. Providers need to be familiar with local public health statutes concerning partner notification and patient confidentiality, because these vary among states. When providing testing of contacts, attention must be paid to the likely timing of potential exposures because seroconversion typically occurs subsequent (and consequent) to the initial period of acute infection viremia. Thus, during the first three months after HIV exposure, early detection may require testing of HIV RNA levels confirmed by repeat serologic testing.^4,6,7,9,23

The reporting of cases of HIV or AIDS is an important public health requirement, especially because in most states these figures determine the distribution of federal Ryan White AIDS CARE Act funds or Medicaid funds for the care of uninsured patients.^9,24 Information regarding requirements and procedures for reporting cases of HIV or AIDS can be obtained through local public health departments.

Baseline Medical Evaluations

The main goals of baseline evaluation are to: (1) assess the risk of HIV disease progression to determine the need for antiretroviral therapy; (2) assess the risk for opportunistic complications, to guide prevention education and prophylaxis; (3) evaluate current symptoms based on HIV stage; (4) screen for common infectious and noninfectious comorbidities related to HIV infection; and (5) target appropriate health maintenance interventions.

HISTORY AND PHYSICAL EXAMINATION

High-risk sexual activity and drug use increases the risk of HIV transmission and may have direct health risks for patients infected with HIV. It is recommended that physicians regularly ask their patients about such behaviors; published guidelines and questionnaires are available to guide physicians in having these discussions.^7,8,12 Physicians also should evaluate patients for the signs and symptoms of high-risk activities, such as manifestations of genital and systemic STDs.²²

Other important evaluations concern detection of HIV-related disease manifestations.^7,8 Common early manifestations include fever and sweats, weight loss, generalized lymphadenopathy, recurrent vaginal candidiasis, recurrent oral ulcers, onychomycosis, seborrhea, and shingles (Table 1^6,7,25). There are also many comorbid conditions common to patients with HIV that should be evaluated, such as tuberculosis and hepatitis B and C.

A more detailed review of HIV-related manifestations (including those that occur at more advanced stages of HIV disease) and the implications of antiretroviral therapy (e.g., drug interactions and effects on non-HIV-related conditions such as diabetes and hyperlipidemia) and other therapies (e.g., methadone, herbal remedies) is provided in the following sections and in referenced resources.^7,8,26–28

LABORATORY TESTS

When patients are first identified as HIV seropositive, there are numerous baseline laboratory evaluations that should be performed. As listed in Table 2,^7,8,25,26 the first category of tests is to assess patients’ risk for HIV disease progression and opportunistic complications as determined by CD4⁺ T-lymphocyte cell counts, which decline at a rate that is affected by plasma HIV RNA levels (viral load).^25,29 In addition, baseline is the best time to perform an HIV-1 genotype test to determine whether the patient is infected with a drug-resistant virus.²⁶

CD4⁺ T-lymphocyte cell counts are obtained by ordering a complete blood count, along with a CD4 and CD8 lymphocyte subset analysis. Table 1^6,7,25 lists the correlations between HIV disease stages, CD4⁺ cell counts, and common clinical manifestations associated with each stage.^25,30 Knowledge of a patient’s CD4⁺ T-lymphocyte levels can help focus the clinical evaluation of presenting symptoms. For example, a dry cough at high-normal CD4⁺ T-lymphocyte levels would be less consistent with AIDS-related Pneumocystis jiroveci pneumonia (formerly known as Pneumocystis carinii pneumonia) than if the same presentation were to occur at CD4⁺ T-lymphocyte cell count levels of less than 200 cells per mm³ (200 × 10⁹ per L).

A normal CD4⁺ cell count is roughly 1,000 cells per mm³ (1,000 × 10⁹ per L). Early symptoms may begin when CD4⁺ T-lymphocyte cell count levels drop below 500 cells per mm³ (500 × 10⁹ per L). AIDS-related opportunistic manifestations usually do not occur until CD4⁺ counts are below 200 cells per mm³, with a subset of more serious complications at CD4⁺ cell counts below 50 cells per mm³ (50 × 10⁹ per L). However, it is common for patients to remain asymptomatic (or unaware of mild symptoms) even with CD4⁺ cell counts below 200 cells per mm³. In addition, although CD4⁺ cell counts typically decline at a rate of 50 to 100 cells per year following infection, as many as 30 percent of patients may progress at faster or slower rates. Thus, whereas an initial CD4⁺ cell count of 700 to 800 cells per mm³ (700 to 800 × 10⁹ per L) might be reassuring of early or mild disease, T-lymphocyte cell counts should be reassessed every three to six months to monitor disease progression.

Tests approved by the U.S. Food and Drug Administration for HIV RNA include: the Amplicor HIV-1 Monitor test by Roche Diagnostics (PCR), the Versant branched-DNA (bDNA) assay distributed by Chiron Corp., and the NucliSens HIV-1 RNA nucleic acid amplification test by Organon Teknika. A repeat viral load test conducted one to two weeks after the initial test generally is recommended (unless waiting for the repeat test would delay intervention in a patient with advanced HIV) because of normal test variability (up to threefold differences) and to detect false elevations caused by recent illness or vaccination. Thereafter, serum viral load tests typically are monitored every four to six months.²⁶

The interpretations of plasma viral load and CD4⁺ tests are based on numerous studies^7,8,26–29 of the natural history of disease progression and the effectiveness of antiretroviral agents. In general, the higher the viral load, the more active and aggressive the HIV infection, resulting in a more rapid decline in CD4⁺ cell counts and quicker progression to AIDS or death. Regardless of viral load, the CD4⁺ level is the determining factor for a patient’s risk of opportunistic complications, although both are independent predictors of risk of AIDS.²⁹ Thus, low viral load levels (i.e., below 10,000 copies per mL or, ideally, undetectable at the ultra-sensitive level) or high CD4⁺ cell counts (i.e., above 200 cells per mm³ and, ideally, above 500 cells per mm³) are associated with a better prognosis and are the basis for and outcome goals of antiretroviral therapy.

INFECTION SCREENING TESTS

Patients infected with HIV often are coinfected with other pathogens related to the route of transmission or to psychosocial circumstances. Thus, broad-spectrum screening for these pathogens at baseline and periodically is an integral part of the care of patients with HIV.^7,8,22,25 Table 2^7,8,25,26 lists the relevant screening tests to consider. Table 3²⁵ lists the definitions of the CDC’s evidence ratings system.

The first screening category is for pathogens that are preventable through vaccination, namely hepatitis A and B. The second category is for infections to which patients may have repeated exposure through unsafe sexual practices or illicit drug use. These include syphilis, chlamydia, gonorrhea, and hepatitis C. Note that management of hepatitis B and C in patients with HIV is critically important because it can affect patient longevity (directly, by counteracting progressive liver disease; or indirectly, by protecting a patient’s liver against the side effects of antiretroviral medications).³¹ In patients who are immunodeficient, it is not uncommon for hepatitis C infections to be seronegative; therefore, it is important to check serum HCV RNA levels if serum alanine transaminase levels are elevated.

The third category is screening for recurrence of previous or newly acquired infections, such as Mycobacterium tuberculosis and human papillomavirus (HPV). Tuberculosis is intertwined with the AIDS epidemic, with each infection exacerbating and commonly coexisting with the other. The standard public health approach is to screen for coinfection whenever either infection is detected.

When screening for tuberculosis in patients with HIV, the tuberculin skin test generally is considered positive at an induration of at least 5 mm. In addition, routine chest radiograph examination often is needed for patients with a negative tuberculin skin test given the increased possibility of anergy, particularly at lower CD4⁺ cell counts (although anergy skin testing is not recommended by the CDC because of a lack of effectiveness).^25,32 Lastly, even in patients with HIV whose skin test and chest radiograph screening results are negative, prophylaxis may be indicated based solely on a history of high exposure risk.

HPV is more aggressive in patients with HIV and tends to be more prevalent, persistent, and recurrent, and progresses more rapidly to HPV-related dysplasia. Thus, increased vigilance in screening is indicated in patients with HIV, including cervical Papanicolaou (Pap) smears performed every six months for the first year and annually thereafter, if normal.

The fourth category of screening is for opportunistic infections unique to patients who are immunodeficient.²⁵ Infections in this category include cytomegalovirus, toxoplasmosis, and varicella zoster virus. For opportunistic infections, there are two relevant timing considerations in patients with HIV. First, baseline evaluations are needed for all patients, regardless of CD4⁺ cell count level, with education on how to limit pathogen exposure and thereby reduce the risk for subsequent reactivation of such infections. Second, all patients whose immunodeficiency is in the AIDS range (i.e., CD4⁺ cell count less than 200 cells per mm³) should be screened for previous pathogen exposure (e.g., toxoplasmosis), or current symptoms (e.g., fever and anemia of Mycobacterium avium intracellulare) because these will affect initiation of prophylaxis. In addition, baseline knowledge about previous occurrence of chickenpox or activities with high risk for cytomegalovirus exposure (e.g., men who have sex with men) also guide preventive interventions.

The outcome goal of screening for coinfections is not only to direct the provision of prophylactic therapies but to guide patients in ways of minimizing exposure to potential opportunistic pathogens. Table 4²⁵ lists the basic areas of patient education relevant to preventing infections associated with HIV.

TESTS FOR NONINFECTIOUS COMORBIDITIES

There are many laboratory abnormalities commonly seen in patients with HIV,^7,8 including: anemia (caused by chronic disease, malnutrition, or quiescent mycobacterium infection); thrombocytopenia (related to untreated HIV or to chronic liver disease); leukopenia and lymphopenia (reflective of immunosuppression); hypergammaglobulinemia (caused by overall dysregulation of the immune system); hypoalbuminemia (caused by malnutrition or liver disease); transaminitis (caused by viral hepatitis); and proteinuria (caused by HIV-associated nephropathy, most often in blacks). Patients who are diagnosed later in the course of their infection may also have complications related to HIV that may be initially detected through routine chemistry evaluations (e.g., lymphoma with an elevated lactate dehydrogenase, M. avium intracellulare complex with an elevated serum alkaline phosphatase).

Patients with HIV also have typical health care needs beyond conditions related to HIV.^7,8 These include the need for routine, age-appropriate health-maintenance screening for cardiovascular health and for cancer (e.g., breast, prostate, colorectal). In addition, as patients with HIV age they may become afflicted with obesity, hypertension, insulin resistance, diabetes, hyperlipidemia, or atherosclerotic disease. Any of these may be a consequence of the antiretroviral therapies or of aging itself. Thus, extra preventive focus at baseline is increasingly important for these patients.

Baseline Therapies

Initial therapy in patients newly diagnosed with HIV follows from the goals and results of baseline evaluation: (1) health maintenance interventions, (2) opportunistic infection prophylaxis, and (3) antiretroviral therapy.

HEALTH MAINTENANCE

One component of health maintenance in patients with HIV is routine vaccinations such as for tetanus and diphtheria.^7,8,25 However, there are several special considerations pertinent to these patients. First, live viral vaccinations (e.g., smallpox, oral polio vaccine) pose an actual risk of infection consequent to the vaccines and are therefore contraindicated in patients with HIV and their household contacts. Second, because of immunodeficiency, patients with HIV are in the high-risk group targeted to receive immunization against pneumococcus and influenza. However, patients initially vaccinated at low CD4⁺ cell count levels often have a blunted immune response to the pneumococcal vaccine and thus generally should be revaccinated when their CD4⁺ cell counts rise above 200 cells per mm³. In addition, vaccination against hepatitis A and B also is important for patients with HIV, with post-vaccination serology to assess immune response.

INSTITUTION OF OPPORTUNISTIC INFECTION PREVENTION

Table 5^2,6,7,25,27 lists the CDC’s recommended prophylaxis guidelines and their indications. The most important prophylaxis is for P. jiroveci pneumonia, because the incidence rate approaches 80 percent in the absence of prophylaxis at CD4⁺ cell count levels below 200 cells per mm³, and its preventability is above 90 percent. Even pending the results of baseline T-lymphocyte cell counts and viral load, the presence of oral thrush or herpes ulcers for more than four weeks indicates sufficient immunodeficiency to warrant P. jiroveci pneumonia prophylaxis, which may save the patient an unnecessary bout with the most common opportunistic infection related to HIV.

ANTIRETROVIRAL THERAPY

Even if patients are referred to an outside consultant, it is important for family physicians to be aware of the indications for initiation of antiretroviral therapy. The overall goal of antiretroviral therapy is to convert HIV infection into a chronic disease by suppressing viral replication to arrest or revert immunodeficiency progression and prevent opportunistic complications. With this goal in mind, therapy is desirable for patients who have or are near to having AIDS, based on symptomatology or CD4⁺ cell counts. In addition, there are some proponents of antiretroviral treatment during acute (primary) HIV infection for the purpose of limiting viral dissemination and disease progression²³; however, more recent studies³³ have shown that these benefits are lost after discontinuation of therapy, thus necessitating lifelong therapy after such early initiation.

Several guidelines^26–28 for antiretroviral therapy concur that treatment is indicated for patients who are symptomatic (e.g., have thrush, fevers, thrombocytopenia, or wasting); have AIDS (CD4⁺ cell counts of less than 200 cells per mm³ or AIDS-defining conditions); or who are pregnant (to prevent perinatal transmission). The controversy among the guidelines revolves around the appropriate CD4⁺ cell count or HIV RNA levels at which to initiate therapy in asymptomatic pre-AIDS patients. Depending upon the amount of “pre-AIDS buffer zone” desired, antiretroviral therapy can be initiated later, when CD4⁺ cell counts are nearing the AIDS level of 200 cells per mm³; or sooner, when CD4⁺ cell counts are below 350 cells per mm³ (350 × 10⁹ per L). The later therapy is initiated, the greater the risks of opportunistic complications, potential suboptimal immune restoration, and medication toxicity. Conversely, the earlier antiretroviral therapy is initiated, the longer the duration of therapy and the greater the risk of medication-related long-term side effects (e.g., lipodystrophy, hyperlipidemia, and insulin resistance)³⁴ and the development of viral-resistant mutations through imperfect medication adherence. Regardless of the disease stage or need for therapy, a patient’s readiness, willingness, and ability to adhere to therapy are key prerequisites for treatment success.²⁶

Antiretroviral therapy requires expertise to deal with these complex issues and to keep up with the changing treatment guidelines and new research data. Accordingly, treatment by “HIV experts” is the national standard. Although some family physicians have the additional training and experience necessary to become HIV experts, referral to HIV subspecialists often is necessary. Verification of provider expertise can be assessed in reference to national HIV-expert criteria.^35,36 General family physicians, however, still have an important role in the care of patients with HIV. Early diagnosis and counseling, ongoing prevention emphasis, screening and provision of continuity health maintenance, and reinforcement of the importance of medication adherence are all important contributions that family physicians can provide.