HIV and AIDS Part 3

Acute Infection

Diagnosis

Clinical Features

After acquiring HIV, infected persons may develop a nonspecific influenzalike or mononucleosis-like illness. The exact proportion of persons with acute HIV infection whose illness reflects primary HIV infection is difficult to ascertain, but estimates range from 40% to 90%.75 The most common route for HIV inoculation is via the genital mucosa; after genital inoculation, HIV initially infects Langerhans cells, fuses with local CD4+ T cells, and then infiltrates deeper tissues. Within 48 to 72 hours after inoculation, HIV can spread to adjacent inguinal lymph nodes; systemic dissemination and viremia typically develop after about 7 days after initial infection (range, 4 to 11 days).76 Once viremia develops, HIV extensively seeds lymphoid organs and the central nervous system. During this acute phase of infection, levels of HIV in the genital tract are apparently very high, and the person is likely to be highly infectious.

If a person with primary HIV infection develops a significant clinical illness, it typically begins from 7 to 14 days after the acquisition of the virus. In one study that followed persons considered to be at high risk for HIV, of 23 persons who became infected with HIV, 87% developed an acute HIV illness; of those who developed acute illness, 95% sought medical care, but only 25% were diagnosed as having acute HIV.22 The correct diagnosis is often missed because of the nonspecific nature of the clinical illness—acute HIV infection may resemble influenza, mononucle-osis, secondary syphilis, and more common viral illnesses.


Differing patterns of HIV-1 RNA and CD4+ T cell levels correlate with different patterns of HIV disease progression. During acute HIV infection, plasma RNA levels rise sharply until the cytotoxic T cell (CTL) response to HIV develops; RNA levels then fall and stabilize at the viral set point. (a) Typical progression is marked by the death of many CD4+ T cells, a fair HIV-CTL response, and fair HIV control. (b) Long-term nonprogression is marked by some CD4+ T cell death, a good HIV-CTL response, and good HIV control. (c) Rapid progression is characterized by considerable CD4+ T cell death, a poor HIV-CTL response, and poor HIV control.

Figure 9 Differing patterns of HIV-1 RNA and CD4+ T cell levels correlate with different patterns of HIV disease progression. During acute HIV infection, plasma RNA levels rise sharply until the cytotoxic T cell (CTL) response to HIV develops; RNA levels then fall and stabilize at the viral set point. (a) Typical progression is marked by the death of many CD4+ T cells, a fair HIV-CTL response, and fair HIV control. (b) Long-term nonprogression is marked by some CD4+ T cell death, a good HIV-CTL response, and good HIV control. (c) Rapid progression is characterized by considerable CD4+ T cell death, a poor HIV-CTL response, and poor HIV control.

The most common signs and symptoms are fever (seen in 80% to 90% of patients), fatigue (70% to 90%), rash (40% to 80%), headache (32% to 70%), lymphadenopathy (40% to 70%), pharyngitis (50% to 70%), and myalgias or arthralgias (50% to 70%).75 Although the clinical illness caused by acute HIV infection is often nonspecific, clinical findings of a morbilliform rash, acute menin-goencephalitis, or mucocutaneous ulcerations may be particularly useful in making the diagnosis. Acute HIV illness typically persists for less than 14 days, but some patients have had illnesses that have extended for longer than 10 weeks.22 Disease progression is generally more rapid in patients with severe and prolonged symptoms.

Laboratory Studies

Routine laboratory studies are generally nonspecific but may show varying degrees of lymphopenia or thrombocytopenia. Results of the standard recombinant enzyme-linked immunoas-say (ELISA) are generally negative at the time a patient presents with acute HIV infection; these tests do not typically show a positive result until 22 to 27 days after HIV infection.77 Although the plasma p24 antigen test is the only currently licensed test for diagnosing acute HIV infection, the HIV RNA assay yields positive results 3 to 5 days earlier than the p24 antigen test. The combination of a strongly positive HIV RNA test result and a negative HIV antibody test result confirms the laboratory diagnosis of acute HIV infection. Almost all persons with acute HIV infection have HIV RNA levels that exceed 50,000 copies/ml, and most have levels that exceed 300,000 copies/ml.75 Persons presenting weeks or months after their acute HIV illness are likely to have significantly lower levels. A low-level positive result on the HIV RNA assay (i.e., a result of less than 10,000 copies/ml) in a person suspected of being recently infected should be viewed with great caution, as it may represent a false positive result. In this situation, if the p24 antigen test or a repeat HIV RNA test demonstrating a substantial rise cannot be obtained, the HIV serologic test should be repeated 4 to 6 weeks after the clinical illness has resolved.75,78,79

Implications of Early Diagnosis

Making a diagnosis of acute HIV is important for several reasons. First, persons with acute HIV are highly infectious and are more likely to transmit HIV. Second, after this initial illness, a very long interval may occur before the infected person develops HIV-related or AIDS-related symptoms, and as a result, the infection may go undiagnosed for years. Third, and most compelling, treatment of persons with acute HIV infection may present a unique opportunity to preserve HIV-di-rected CD4+ T cells that are preferentially destroyed during acute infection. The preservation of these HIV-directed CD4+ T cells may enable the development of robust CD8+ T cell-mediated CTL responses that effect tight immune control of HIV. This could theoretically alter the natural course of the infection and delay disease progression even if antiretroviral therapy is withdrawn.

Treatment

At present, there are limited data on the treatment of patients with acute HIV infection. In the only randomized, placebo-controlled trial that has been performed, patients recently infected with HIV received either zidovudine or placebo. After 6 months, those who received zidovudine experienced a mean increase in their CD4+ T cell count of 173 cells/^l; those receiving placebo had a mean increase of 6 cells/^l.80

Several observational studies have demonstrated that treatment of early or acute HIV infection helps preserve HIV-direct-ed CD4+ and CD8+ T cells.81-84 However, there are only limited data to suggest that these favorable immunologic profiles translate into long-term clinical benefits. In one study, opportunistic and nonopportunistic infections and progression to AIDS occurred less frequently in 20 patients with early HIV infection who received treatment than in 47 largely untreated historical control patients.85 A large, randomized, placebo-controlled study has not been performed, however.

The 2004 Department of Health and Human Services (DHHS) guidelines note that certain authorities endorse treatment of acute HIV infection on the basis of the theoretical rationale and limited but supportive clinical trial data. In addition, these guidelines recommend considering therapy for patients who underwent seroconversion within the previous 6 months.86 However, several questions remain unanswered: (1) How early after infection does treatment have to be initiated? (2) What is the optimal therapeutic regimen? and (3) When and how should HIV therapy be stopped?

Structured Treatment Interruption

One promising strategy for the treatment of primary infection has been the use of structured treatment interruptions. This is a process of scheduled starting and stopping of antiretroviral medications that is intended to enhance CTL responses and thus provide better immunologic control of HIV. The interest in structured treatment interruptions arose from studies that showed the importance of CTL responses in controlling HIV87 and the observation that CTL responses became very weak in persons who achieved long-term control of HIV with antiretro-viral therapy.88 The goal of structured treatment interruptions is to intermittently expose the immune system to HIV-1 antigen in an attempt to upregulate HIV-specific CTL activity, thus leading to better immunologic control of HIV [see Figure 10].

Clinical interest in structured treatment interruption was sparked by a case report of a single patient, known as the Berlin patient, who received early aggressive antiretroviral therapy and then experienced several treatment interruptions; the Berlin patient achieved excellent control of HIV when not receiving an-tiretroviral therapy and showed excellent HIV-specific CTL re-sponses.

Conceptual diagram of structured treatment interruption. Medications are started and stopped on several cycles. HIV RNA levels are measured in copies per milliliter. (Rx—therapy)

Figure 10 Conceptual diagram of structured treatment interruption. Medications are started and stopped on several cycles. HIV RNA levels are measured in copies per milliliter. (Rx—therapy)

A subsequent report showed initially promising results with structured treatment interruption in a carefully selected group of eight patients identified and treated during acute HIV infection. All eight received antiretroviral therapy for longer than 1 year, and all had HIV RNA levels that were consistently lower than 50 copies/ml.90 With structured treatment interruptions, five of the eight patients were eventually able to maintain HIV RNA levels below 500 copies/ml without treatment. However, expansion of the group to 14 patients with longer follow-up yielded less encouraging results: by intention-to-treat analysis, control of HIV was maintained in only three of the 14 patients without antiretroviral therapy after 2 years.91 The concept of structured treatment interruptions needs to be evaluated in larger, prospective, randomized studies before it can be recommended.

Chronic (Established) Infection

Initial evaluation

The initial evaluation of a patient with HIV who is establishing routine care should include a thorough health history, physical examination, disease screens, vaccinations, and extensive laboratory studies. This initial evaluation process usually requires multiple visits. In the first visit, the health history is obtained, a complete physical examination is performed, and appropriate laboratory studies are ordered. During follow-up visits, which are conducted several weeks after the first, pertinent laboratory data are reviewed; the patient’s disease stage and prognosis are discussed; necessary vaccinations are administered; the need for prophylaxis against opportunistic infection is reviewed; and, if appropriate, antiretroviral therapy is discussed.

Medical History

Particular aspects of the HIV-related medical history that should be emphasized are the risk factors for HIV infection, the approximate date of acquisition of HIV, results of the first HIV test that indicated the patient had HIV, a history of an acute se-roconversion illness, prior CD4+ T cell and HIV RNA studies, prior HIV-related illnesses, prior and current antiretroviral therapy, and history of other infectious diseases, such as syphilis or hepatitis. Obtaining information regarding the patient’s past and current sexual activity and drug use provides insight into both the original acquisition of HIV and current behaviors that may place contacts at risk for HIV infection. In addition to obtaining a complete medical history, it is important to assess the patient’s social and psychiatric situation, because social and psychiatric issues can have a critical impact on the patient’s adherence to antiretroviral therapy.

Laboratory Studies

The recommended laboratory studies that should be performed at the initial office visit are listed [see Table 2].92

Overview of management

Prevention Strategies

Recommendations regarding the incorporation of HIV prevention strategies into the care of HIV-infected patients have been developed by the CDC, the Health Resources and Services Administration, the National Institutes of Health, and the HIV

Table 2 Laboratory Studies for the Initial Routine Evaluation of an HIV-Infected Adult

Test

Comment

HIV antibody test

Need to firmly establish diagnosis; this test can be omitted if HIV RNA test is convincing

CD4+ T cell count

Critical for staging disease and determining need for antiretroviral therapy

HIV RNA level

Critical for predicting progression of disease and determining need for antiretroviral therapy

Complete blood count

Hematologic problems are more common in HIV-infected persons; baseline value is useful because the number of medications used has effects on marrow

Serum chemistries

Useful to have routine serum chemistries as a baseline

Liver function tests

Useful to have as a baseline, considering potential hepatotoxicity of some antiretro-viral medications; useful in patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

Cholesterol panel

Useful as baseline; significant alterations in lipids can occur with antiretroviral therapy

Serologic testing for syphilis

Important with known higher rates of syphilis among HIV-infected persons

Toxoplasma IgG antibody

Useful in determining whether patient is at risk for developing toxoplasmosis; if negative, patient can receive counseling on preventing acquisition of T. gondii

Hepatitis A, B, or C antibody; hepatitis B antigen

Useful for identifying patients coinfected with HIV and either HBV or HCV; useful for identifying patients who are seronega-tive for hepatitis A virus or HBV and who should therefore receive vaccination; if HCV antibody is positive, testing should be performed to determine whether patient has a positive HCV viral load

Cytomegalovirus serology

IgG levels useful for determining past exposure and risk of reactivation

Urinalysis

Useful as a baseline screen

Purified protein derivative

Considered positive if a 5 mm induration; controls are no longer recommended

Chest x-ray

Useful as a baseline; some specialists obtain a chest x-ray only in patients with a history of pulmonary disease

Medical Association of the Infectious Diseases Society of America. 93 These recommendations are made with the understanding that prevention strategies directed toward persons with known HIV infection can reduce the transmission of HIV and may be particularly effective because they are targeted to a specific group of persons rather than the entire at-risk population. The recommendations include the following: (1) screening patients for risky behaviors, (2) discussing behaviors that are associated with HIV transmission, (3) reinforcing practices that reduce HIV transmission, (4) referring patients with substance abuse problems to appropriate programs, (5) facilitating partner notification and HIV counseling and testing, and (6) regular testing for and treatment of sexually transmitted diseases. These recommendations are particularly important when caring for acutely infected persons, given the high viral loads and high infectivity associated with primary infection.

Vaccination

Asymptomatic HIV-infected patients who have a CD4+ T cell count greater than 500 cells/^l generally produce good antibody responses to vaccines. Responses are frequently poor in patients with lower CD4+ T cell counts, particularly those with AIDS. Persons with more advanced immune suppression may respond better to vaccines administered after immune reconsti-tution through antiretroviral therapy. Preliminary studies raised concerns that vaccines given to HIV-infected persons could cause significant increases in HIV RNA levels. Further study has shown that although some patients do have a mild to moderate increase in HIV RNA levels after immunization, these increases generally are transient and do not have permanent adverse consequences. Nevertheless, concerns remain regarding the use of live-virus vaccine in HIV-infected patients, particularly those with advanced immune suppression. Vaccines for HIV-infected adults are listed [see Table 3].

Routine Follow-up

How often a patient should return for routine follow-up visits depends on the immune status, the clinical status, concomitant medical problems, and whether or not the patient is receiving antiretroviral therapy. In general, patients should have visits at least every 3 months for monitoring of CD4+ T cell counts, HIV RNA levels, and clinical status. More frequent visits are often needed in patients with significant ongoing HIV-related problems or ongoing concomitant medical problems and in those who have recently begun antiretroviral therapy. Visits every 6 months would be appropriate for patients whose disease will probably not progress in the interim, who have a CD4+ T cell count greater than 500 cells/ ^l, and whose HIV RNA level is less than 10,000 copies/ml.

Antiretroviral Therapy

Before starting antiretroviral therapy, the physician must give careful consideration to the patient’s social and medical conditions. In general, the patient should be both interested in and able to take antiretroviral medications consistently. Active social problems (e.g., ongoing drug use, homelessness, or unstable emotional states) can be major barriers to successful anti-retroviral therapy. In addition, if a patient has an active severe medical problem, every attempt should be made to defer anti-retroviral therapy until that problem is stabilized. Medical indications for antiretroviral therapy are based on the patient’s clinical status, the CD4+ T cell count, and the HIV RNA level [see Principles for Antiretroviral Therapy, below]. There is a wide array of possible antiretroviral drug combinations; in choosing a specific regimen, the clinician should take into account the dosing schedule, possible adverse effects, and underlying patient preferences.

Agents Currently, four different classes of medications, comprising a total of 20 drugs, target HIV: (1) nucleoside reverse transcriptase inhibitors (NRTIs)—abacavir, didanosine, emtri-citabine, lamivudine, stavudine, tenofovir disoproxil fumarate (tenofovir-DF), zalcitabine, and zidovudine; (2) nonnucleoside reverse transcriptase inhibitors (NNRTIs)—delavirdine, efavi-renz, and nevirapine; (3) protease inhibitors—atazanavir, fosam-prenavir, indinavir, lopinavir plus ritonavir, nelfinavir, ritonavir,and saquinavir; and (4) fusion inhibitors—enfuvirtide [see Figure 11 and Table 4].

Table 3 Vaccinations for HIV-Infected Adults

Vaccine

Comment

Haemophilus

influenzae type B vaccine

Not generally recommended for adults

Hepatitis A virus

vaccine (Havrix, VAQTA)

Recommended for men who have sex with men, injection-drug users, and persons with chronic liver disease; dosage is 1.0 ml given intramuscularly and repeated 6-12 mo later

Hepatitis B virus (HBV) vaccine (Recombivax HB, Engerix-B)

Recommended; regimen for vaccination is 10-20 ^g of recombinant HBV vaccine given in the deltoid muscle at 0, 1, and 6 mo; responses are often suboptimal, particularly in those with more advanced immune suppression

Influenza virus vaccine

Recommended; the dosage is 0.5 ml I.M. and should be administered during the period from late October through late December; the goal is to prevent influenza and secondary bacterial pneumonias

Mumps, measles, and rubella vaccine

Recommended, with exceptions; the dosage is 0.5 ml S.C.; patients with severe immunodeficiency should not receive this live vaccine; this vaccine is generally recommended for persons born after 1956 who do not have a documented history of measles or measles vaccination and persons who received the killed vaccine (1963 to 1967) and do not have a documented history of measles or live measles vaccination

Pneumococcal vaccine (polysaccharide 23-valent vaccine)

Recommended if CD4+ T cell count is > 200 cells/ ^l; the dosage is 0.5 ml I.M. repeated every 5 years; consider repeating vaccine if CD4+ T cell count was less than 200 cells/ ^l but has increased to greater than 200 cells/^l; there are insufficient data in HIV-infected persons to recommend conjugated 7-valent vaccine

Polio vaccine

Recommended; inactivated vaccine only; live oral polio vaccine is contraindicated in HIV-infected patients; patients who have not been immunized should receive inactivated polio vaccine (trivalent killed poliovirus), 0.5 ml S.C. at 0, 1, and 6 mo

Tetanus-diphtheria toxoid

Recommended; patients previously immunized should receive a booster every 10 years; those never immunized should receive primary vaccination, 0.5 ml I.M. at 0, 1, and 6 mo

Varicella vaccine

Insufficient data to recommend for adults

The NRTIs—also known as nucleoside analogues (or nucleotide analogues, in the case of tenofovir-DF)— structurally resemble the human nucleosides that HIV uses to make viral DNA. The HIV reverse transcriptase enzyme can mistakenly incorporate the synthetic nucleoside analogue into the elongating strand of viral DNA during the reverse transcrip-tase process; once incorporated into viral DNA, the nucleoside analogues act as chain terminators because they lack the 3′ hy-droxyl group required for chain elongation. The NNRTIs do not act as chain terminators; rather, they directly inhibit the proper functioning of the reverse transcriptase enzyme. The HIV protease inhibitors selectively bind to HIV protease and prevent this enzyme from performing its normal function of cleaving viral polyprotein precursors into individual functional proteins. Successful inhibition of HIV protease causes the formation of deformed HIV particles that generally do not replicate. The fusion inhibitor enfuvirtide represents the newest class of antiretroviral agents. It works by binding to the gp41 envelope protein of HIV to prevent it from mediating fusion of the viral and cell membranes.

Dosing schedules Practical considerations have led to the increasing use of antiretroviral regimens that have infrequent dosing schedules, minimal meal restrictions, and the least possible adverse effects. Most of the NRTIs can be taken twice daily without regard to food consumption; the exceptions are zal-citabine, which is taken three times daily, and didanosine, which is taken a half hour before a meal or 1 hour after a meal. Although the new enteric-coated didanosine capsule is taken once daily, it should not be taken with meals. Alcohol significantly increases the plasma levels of abacavir. The NNRTIs can be taken without regard to food consumption, with the caveat that efavirenz should not be taken after a meal high in fats, because this will increase the plasma level of efavirenz by approximately 50%. Dosing schedules and food restrictions are more complicated with the protease inhibitors. Atazanavir, nelfinavir, saquin-avir, and ritonavir should be taken with food; fosam-prenavir can be taken with or without meals. Indinavir should be taken 1 hour before or 2 hours after a meal, or it can be taken with a low-fat meal.

Combination therapy Increasingly, pharmacologic boosting of protease inhibitor levels is being used to simplify the dosing schedule, decrease the pill burden, and improve the efficacy of several of the protease inhibitors. Most often, this technique has involved the use of low-dose ritonavir in combination with another protease inhibitor, also at a reduced dosage. Ritonavir significantly increases the trough level of the other protease inhibitor, usually without causing a major increase in the peak levels [see Figure 12 and Table 5]. Long-term data from studies on the combination of ritonavir and saquinavir have shown this combination to be highly effective.94 The fixed combination of ritonavir and lopinavir (Kaletra) is highly effective and is preferred by many providers. Ritonavir is now also commonly used with atazanavir, fosamprenavir, or indinavir to boost the blood level of coadministered drug, simplify the dosing schedule, and reduce the pill burden. Two other fixed combinations are now available: emtricitabine and tenofovir-DF (Truvada) and aba-cavir and lamivudine (Epzicom).

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