Current Diagnosis & Treatment in Infectious Diseases

Section III - Special Patient Populations

23. Patients with Aids

Dani-Margot Zavasky MD

Julie L. Gerberding MD, MPH

Merle A. Sande MD

Essentials of Diagnosis

  • Predisposing factors include sexual activity with an infected person, injection drug use, blood product transfusion, especially between 1978 and 1985, perinatal exposure to an infected mother, and percutaneous occupational exposure.
  • Key signs and symptoms include systemic illness with fevers, night sweats, weight loss, diarrhea, lymphadenopathy, depressed immunity as evidenced by opportunistic infections, and unusual malignancies such as Kaposi's sarcoma and lymphomas.
  • Laboratory findings of antibody to human immunodeficiency virus (HIV)-1, 23–1 confirmed with Western blot, viral genome by polymerase chain reaction or branched DNA assay, HIV p24 antigen, and lymphopenia, especially depressed CD4 cell count. (See Tables 23-1,23-2)

General Considerations

When the first clusters of cases of Pneumocystis carinii pneumonia and Kaposi's sarcoma were identified in 1981, it was not known that this was just a prologue to one of the most significant pandemics in the history of mankind and that, < 20 years later, 50 million people would be affected. Our knowledge of the disease started with the dramatic growth in the number of cases of unusual opportunistic infections in patients without prior inherited immunodeficiency disorders. Acquired immunodeficiency syndrome (AIDS) entered the medical and colloquial vocabulary. Not until 1983 was the offending agent identified as a virus. Known initially as lymphadenopathy-associated virus, then human T-cell lymphotropic virus type III, and AIDS-associated retrovirus, the microorganism acquired its current name, human immunodeficiency virus (HIV), in 1986. See Chapter 40 for a discussion of the virology of HIV and other retroviruses.

  1. Epidemiology.Retrospective examination of sera collected for studies of the genetics of hematologic diseases indicate that HIV was already present in sub-Saharan Africa in the 1950s and in the United States by the late 1970s. In 1985, a related but distinct virus, HIV-2, was also found to be endemic in parts of West Africa and to cause AIDS. To date, this virus has been relatively restricted geographically, although it has been imported into the Western Hemisphere.

AIDS has been now reported in more than 150 countries. The United Nations estimates that as of December 2000, 58 million people have been infected with HIV. 22 million people have already died, of which 3 million died in 2000. As we are entering the third decade of AIDS history, the epidemic continues to spread rapidly through several continents. A total of 16,000 persons are infected per day worldwide, including 1600 children < 15 years of age. Women constitute over 40% of the adult cases. About 7000 people die from complications of HIV infection every day. Most infected persons live in either sub-Saharan Africa (> 70%) or South/Southeast Asia (> 20%).

In recent years, the epidemic has been particularly explosive in South/Southeast Asia and Central and Eastern Europe. The predominant mode of transmission appears to be heterosexual contact in Asia and injection drug use in Europe. Increasing syphilis incidence in Central/Eastern Europe signifies an increase in sexually transmitted diseases (STDs) of all kinds, including HIV, in this part of the world. There were 700,000 HIV infected patients by the end of 2000 compared with just 420,000 at the end of 1999.

In the United States, 920,000 AIDS cases and 460,000 deaths from AIDS were reported through December 2000. The total number of infected individuals in the United States probably exceeds 1 million; 45,000 of which became infected in 2000. The epidemiology of HIV infection is changing in the United States as the pandemic evolves. In 1992, 50% of all cases occurred in gay men and 25% in intravenous drug users, whereas 15% were derived from heterosexual contacts. Currently, the greatest increase in viral spread is occurring in the heterosexual population, similar to that observed in sub-Saharan Africa. The trends also confirm increase of infection in blacks and Hispanics, with blacks constituting ~41% of all adult cases. Also, women now account for 23% of all adult cases in the United States. The epidemic appears to affect predominantly women of color, particularly black women of African descent living in the southeastern part of the United States, in small rural communities (as opposed to the large cities, where HIV transmission in this same population occurred in the 1980s). Cases of AIDS in Hispanic women of Puerto Rican ancestry also predominate in the Northeast, especially in the states of Connecticut, New York, and New Jersey. However, in the Southwest and the West, Hispanic women of mostly Mexican and Central American descent have the same infection rate as white women. The facilitators of transmission in this heterosexual population again appear to be multiple sexual partners and the exchange of sex for money and drugs, especially crack cocaine.

In 1997, HIV/AIDS dropped from the first to the second leading cause of death in young adults in the United States. In 2000 it wasn't even one of the top 10 causes of death in young adults. The death rate in black men is fourfold that in white men and is also higher in black women than white men. Improved medical management of HIV disease resulted in an overall 23% decrease in AIDS deaths, especially among homosexual men, beginning in 1996. Also, between 1992 and 1995, perinatal AIDS cases decreased by 27% as a result of the widespread use of maternal and infant antiretroviral prophylaxis with zidovudine (AZT).

  1. Pathogenesis.HIV is transmitted between humans in at least three ways: sexually, perinatally, and by exposure to contaminated body fluids, especially blood. The virus has been demonstrated in particularly high titers in semen and cervical secretions, and a majority of infections result from sexual contact. Infection is facilitated by breaks in epithelial surfaces, which provide direct access to the underlying tissues or bloodstream. The relative fragility of the rectal mucosa together with a large number of sexual contacts probably contributed to the predominance of the disease among male homosexuals in the initial stages of the epidemic. Heterosexual transmission accounts for an increasing proportion of new cases in the western world but has always been the dominant mode of transmission in the developing countries. Sexual transmission appears to be more efficient from men to women. The risk of perinatal transmission from an infected mother to her child has been estimated at 20–30%.

Testing of donor blood and the use of recombinant or specially treated coagulation factors have now virtually eliminated blood products transfusion as a source of infection in developed countries. Transmission of infection by blood is now largely associated with the sharing of needles and syringes by injection drug users. In some areas of the world, the seroprevalence of HIV infection among injection drug users has been as high as 70%. Transmission of infection to health care workers is rare but occurs after 0.3% of exposures to blood during needle punctures.

Transmission of HIV does not occur through a casual (nonsexual) contact with infected individuals or through insect vectors. The virus has been detected in saliva, tears, urine, and breast milk, but with the exception of breast milk, these fluids are not sources of infection.

PREDICTORS OF DISEASE PROGRESSION

The course of HIV disease is dictated by the severity of the individual's immune deficiency and the resulting complications. The recent impact of highly active antiretroviral therapy (HAART) on the slowing progression of HIV infection has been dramatic; however, therapy is complicated and expensive, thus not available to the vast majority of patients worldwide that would benefit.

The determinants of progression of the HIV disease have been under intense scrutiny by the research community. Results of prior studies emphasized the role of high viral load, presence of particularly virulent strains (eg, those that produce syncytium formation in culture) and low T-lymphocyte function as predictors of rapid disease progression. Recently, several coreceptors for HIV have been identified. The two most important of these are CCR5 and CXCR4. Individuals homozygous for a deletion in the CCR5 gene are resistant to infection regardless of multiple exposures to the virus. Some infected persons who are heterozygous for this deletion have been noted to have a prolonged AIDS-free survival. In current clinical practice, however, two main markers are used to monitor disease progression and to evaluate the need for and response to treatment: CD4 lymphocyte count and viral load.

CD4 Lymphocyte Count (Immunologic Monitor)

CD4 lymphocytes are the major cellular target for HIV. Both absolute CD4 counts and the rate of decline have prognostic predictive value and are used to determine the need for antiretroviral therapy and for opportunistic infection prophylaxis. CD4 counts do not accurately indicate viral load per se, but they predict the short-term risks for progression to AIDS-related illness.

Quantitative HIV RNA (See Table 23-2) (Virologic Monitor)

The quantitative titer of circulating HIV RNA (viral load) is the single best predictor of long-term progression and response to treatment. Viral load is used to assess the steady-state concentration of HIV, the response to treatment, and, most likely, tissue HIV RNA production.

Two main methods are generally used to measure viral load: reverse transcriptase-polymerase chain reaction (RT-PCR) and branched-chain DNA (bDNA) amplification. (See Table 23-2) By 2001, three commercial assays based on these methods or modifications of these methods were used to measure viral load: Amplicor HIV Monitor (RT-PCR, lower limit of detection = 400 viral copies/mL), Quantiplex HIV assay (bDNA, lower limit of detection = 500 copies/mL), and Nuclisens (lower limit of detection = 40 copies/mL). Assays with even more sensitivity such as Amplicor Ultrasensitive (lower limit of detection = 20 copies/mL) and Quantiplex HIV 3.0 (lower limit of detection = 50 copies/mL) are currently undergoing clinical evaluation. To optimize interpretation, two measurements of viral load should be obtained on two separate occasions in the same laboratory using the same assay. When possible, viral load testing should be delayed until 4 weeks after intercurrent infections are treated, acute illnesses have resolved, and following an immunization.

Current guidelines for viral load testing suggest that the pretreatment measurement be obtained to evaluate the patient's prognosis and that tests be repeated every 3–4 months until treatment is started. Once treatment is initiated, a measurement should be obtained 4–8 weeks later to determine whether the expected initial therapeutic response (0.5–0.75 log reduction in titer) has been achieved. Another measurement should be made 3–4 months later to determine whether HIV replication is fully suppressed (below the level of detection). If not, then adherence should be assessed and treatment modifications considered. Once the patient is on a stable antiviral regimen, viral load tests should be obtained every 3–4 months to monitor ongoing virologic response.

CLINICAL SYNDROMES

HIV infection can produce a huge array of clinical syndromes. In general, these syndromes correlate with the duration of illness and severity of immunosuppression. The major clinical syndromes and their treatment are described in Box 23-1. The following sections describe the most common symptoms associated with HIV infection at various stages of infection.

  1. CONSTITUTIONAL SYMPTOMS

Fever (with or without night sweats) is common in patients infected with HIV, especially in the setting of advanced disease. The absolute CD4 cell count can help to guide the evaluation and differential diagnosis.

  1. Early Disease (CD4 > 500).Etiology similar to that in immunocompetent patients except for more common bacterial pneumonia and tuberculosis. Acute HIV infection is also associated with fever.
  2. Midstage Disease (CD4 200–500).Particular attention should be given to the possibility of disseminated tuberculosis. In sexually active adults, STDs and anorectal infections often go unrecognized as sources of fever.
  3. Late Disease (CD4 75–200).When fever accompanies an accelerated catabolic state with weight loss and anorexia, the presence of an opportunistic infection or malignancy (mainly lymphoma), signifying the onset of AIDS should be suspected. Systemic symptoms with fever also predominate over pulmonary complaints in early PCP. Common etiologies of fever at this stage of HIV disease are also disseminated tuberculosis, nonthyphoid Salmonellabacteremia, bartonellosis, and fungal diseases including histoplasmosis, coccidioidomycosis, and cryptococcosis.
  4. Advanced Disease (CD4 ≤ 75).Even though diseases as outlined in late-stage disease can also occur at this stage, disseminated mycobacterium avium complex and systemic cytomegalovirus (CMV) infections are common.
  5. CENTRAL NERVOUS SYSTEM (CNS)

Altered Mental Status

Changes in mentation involve cognitive dysfunction, decreased level of consciousness, and delirium and psychosis. Altered mental status can be caused by both infectious and noninfectious disorders. Differential diagnosis, again, is influenced by the known degree of immunosuppression, that is, the stage of HIV disease. Most infections occur in patients with CD4 counts < 200.

The mainstay of evaluation includes history (especially of substance abuse), neurological examination, neuroimaging (computer tomography or MRI), cerebrospinal fluid examination, and thorough review of medications. Altered mental status at any CD4 count can be caused by bacterial meningitis, neurosyphilis, as well as by noninfectious etiologies such as metabolic disorders, seizures, or trauma. Recreational drug use and prescription medication toxicity are other possibilities.

  1. Late Disease (CD4 75–200).At this stage of the HIV disease, patients can be afflicted with cryptococcal meningitis, herpes virus family (CMV, HSV, and VZV) encephalitis, and Toxoplasmaencephalitis. Patients are also vulnerable to HIV-associated dementia (AIDS dementia complex) and primary CNS lymphoma, which can be the result of Epstein-Barr virus-associated transformation of infected cells.
  2. Advanced Disease (CD4 < 75).Disorders typical for late disease as well as progressive multifocal leukoencephalopathy are caused by a human polyomavirus known as JC virus. Primary CNS lymphoma and advanced AIDS dementia complex are more common at this stage.

BOX 23-1 Clinical Syndromes, Opportunistic Infections, and Neoplasms Caused by HIV

Syndrome & Cause

Clinical Presentation

Laboratory Correlates

Treatment and Prophylaxis

Early Disease (CD4 > 500) Acute Retroviral Syndrome (HIV)

· Fever

· Andenophathy

· Pharyngitis

· Rash

· Myalgia/arthralgia

· Diarrhea

· Headache

· Nausea/emesis

· Hepatosplenomegaly

· Neuropathy

· Encephalopathy

· Thrombocytopenia

· Lymphopenia, then atypical lymphocytosis

· Transaminitis

· High-level HIV viremia

Usually resolves in 1-2 weeks; may benefit from antiretroviral therapy

Aseptic meningitis (HIV)

· Headache

· Photophobia

· Fever

· CSF: lymphocytic pleocytosis; mild, modest increase in protein

Immune Thrombocytopenic Purpura (ITP)

· Easy bruising

· Epistaxis

· Splenomegely

· Thrombocytopenia; no evidence of production defect on bone marrow aspiration

Have benefitted from antiretrovirals, especially AZT +/- prednisone. Options for refractory cases: IVIG, Danazol, alpha-interferon, splenectomy

Midstage Disease (CD4 200-500) Mycobacterium tuberculosis (TB)

Classic reactivation pulmonary disease with higher CD4 counts; cough, fever, weight loss, upper lobes infiltrate, pulmonary cavities. Atypical presentation with lower CD4 with hilar adenopathy, diffuse pulmonary infiltrates without cavitation, pleural effusions, or extrapulmonary disease (blood, lymph nodes, CNS, genitourinary tract, pleura).

CXR; sputum: AFB smear and culture; bronchoscopy if sputum is negative; blood cultures for AFB positive in 40%; pleural or lymph node biopsy

· Four-drug regimen: isoniazid, rifampin, pyrazinemide, ethanbutol.

· Same treatment principles as in HIV-negative population.

· MDR-TB treatment individualized.

· Purified protein derivative (PPD) of 5 mm or greater should be prophylaxed with isoniazid.

Kaposi's Sarcoma (HHV-S)

· Mucocutaneous palpable, firm, nontender nodules or ecchymosis-like lesions; violaceous, brown or black.

· Oral lesions common.

· Visceral disease: GI with bleeding, perforation, and obstruction; pulmonary with dyspnea cough, bronchospasm.

· Lesions may become painful.

· Edema formation.

Biopsy recommended; visceral disease visualized during bronchoscopy or endoscopy.

· Local therapy for cosmetic reasons: radiotherapy, cryotherapy, retinoic acid, intralesonal vinblastine.

· Systemic chemotherapy with, most commonly, doxorubicin, bleomycin, vincristine (ABV), or liposomal doxorubicin, or daunorubicin as a single agent.

· Marked reduction incidence with HAART.

Pneumococcal Disease (Streptococcus pneumoniae)

· Sinusitis or pneumonia with productive cough, fever, pleuritic chest pain; evidence of consolidation or effusion on physical exam.

· Meningitis bacteremia common.

CXR with lobar; positive sputum; or BAL; positive blood culture, pleural fluid or CSF.

· Ceftriaxone 2 g IV daily consolidation (each 12 h for meningitis), or cefotaxime, or others, depending on susceptibility.

· Pneumococcal vaccine recommended for all HIV-positive patients.

Thrush (oral Candidiasis)

· Pseudomembranous form with white plaques that can be wiped off leaving erythematous or bleeding base.

· Erythematous form with smooth, red patches.

KOH prep of the scraping and culture.

· Fluconazole, 200 mg first dose, then 100 mg PO per day for 14 d. Clotrimazole troches 10 mg PO 5×/day or Nystatin sol. or tab 3-5 ×/day for 5 days.

Headache

Headache may pose a challenging diagnostic dilemma. Besides a vast array of opportunistic CNS infections and malignancies, it can result from muscle tension, or a systemic illness without a direct affliction of intracranial structures. Headache can be induced by a medication frequently used for treatment of HIV disease, for example, AZT, or by migraine not related to HIV infection. At any stage of the HIV disease, patients are more susceptible to bacterial meningitis or sinusitis as well as to neurosyphilis. Other opportunistic infections tend to occur at specific levels of immunosuppression.

  1. Early Disease (CD4 > 500).Aseptic meningitis probably caused by HIV itself can accompany acute seroconversion in the early stage of HIV disease.
  2. Midstage Disease (CD4 200–500).Aseptic meningitis syndrome is even more common than in earlier stages and can assume a form of chronic meningitis.
  3. Late Disease (CD4 75–200).Many disorders mentioned above that can alter mental status also cause headache. These include cryptococcal meningitis and Toxoplasmaencephalitis.
  4. Advanced Disease (CD4 < 75).Both progressive multifocal leukoencephalopathy and primary CNS lymphoma are more frequent.
  5. GASTROINTESTINAL SYMPTOMS

Dysphagia

Swallowing difficulty (dysphagia) is frequently accompanied by pain (odynophagia). Patients complain about the sensation of food sticking. Appropriate diagnosis and treatment are important not only to alleviate the discomfort but also to prevent weight loss and malnutrition. At any stage of HIV disease, patients can develop reflux esophagitis. However, esophageal complaints and disorders are more typical for late to advanced disease.

  1. Midstage Disease (CD4 200–500).Early thrush (oral mucosal candidiasis) can occur with some esophageal discomfort. In that setting, PCP prophylaxis is indicated irrespective of the CD4 count.
  2. Late Disease (CD4 75–200).Most common cause is Candidaesophageal mucosal infection with frequent concomitant oral lesions. HSV type 1 or 2 can induce mucosal ulceration.
  3. Advanced Disease (CD4 < 75).Same as late disease, but CMV and aphthous ulcers are more frequently encountered.

Diarrhea

Diarrhea is a commonly encountered clinical problem in HIV-infected patients and may be caused by HIV itself. Symptoms range from frequent loose stools to fulminant diarrhea, producing profound weight loss, malabsorption, and intravascular fluid depletion. A thorough evaluation is warranted because virtually any gastrointestinal pathogen may be found.

Both small bowel and colon can be affected, causing enteritis or colitis, respectively. Symptoms of enteritis include profuse, watery diarrhea often with symptoms of bloating, nausea, and periumbilical cramping. Volume depletion and malabsorption may be marked. Colitis presents with fever, lower abdominal pain, tenesmus, and passage of frequent, small volume stools with mucus and sometimes blood. Characteristics of symptoms can guide the choice of initial diagnostic procedure but are unreliable to predict the most likely pathogen. CD4 cell count can, again, be useful in outlining differential diagnosis.

At any CD4 cell count, the following agents should be considered: Clostridium difficile; Salmonella, Campylobacter, Shigella, and Cyclospora spp.; Entamoeba histolytica; Giardia lamblia; Isospora belli; enteroviruses; and Strongyloides stercoralis. Most of the antiretroviral drugs also cause diarrhea.

  1. Late Disease (CD4 75–200).Cryptosporidium parvumand Microsporidium spp. should also be considered in addition to those listed above.
  2. Advanced Disease (CD4 < 75).Mycobacterium aviumcomplex and CMV should be included in the differential diagnosis.
  3. RESPIRATORY SYMPTOMS (DYSPNEA/COUGH)

The differential diagnosis of lower respiratory symptoms is extensive and largely depends on the stage of HIV disease with consideration to current PCP prophylaxis, history of travel, or area of residence. Tuberculosis can occur with various clinical signs, depending on the degree of immunosuppression and should be considered in every HIV patient regardless of CD4 count. Appropriate isolation precautions should be undertaken according to clinical suspicion. Irrespective of CD4 counts, typical bacterial causes of pneumonia should also be considered, especially Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae.

  1. Late Disease (CD4 75–200).PCP should always be considered, particularly in the setting of a lack of appropriate prophylaxis. Fungal pneumonias with Coccidioides immitis, Cryptococcus neoformans, or Histoplasma capsulatum are also possible. Kaposi's sarcoma is also known to cause pulmonary lesions, especially with worsening immunodeficiency.
  1. Advanced Disease (CD4 < 75).Besides the above etiologies, Pseudomonas aeuruginosaand Aspergillus species can be encountered, especially with neutropenia or repeated hospital exposure. Non-Hodgkin's lymphoma can also affect lungs. Isolation of CMV and Mycobacterium avium complex is common, but they rarely cause symptomatic pulmonary disease.
  2. CUTANEOUS LESIONS

Various dermatologic diseases are extremely common in HIV infection, affecting ~90% of patients. Some of the conditions occur in immunocompetent individuals but are more severe and resistant to therapy in HIV-infected persons. Other skin conditions are unique to HIV disease and tend to follow the degree of immunosuppression. Patients with HIV disease tend also to have a preponderance for drug sensitivity reactions compared with an HIV-negative population.

  1. Early Disease (CD4 > 500).Primary HIV infection may be associated with rash. Lesions associated with STDs (eg, genital HSV or genital warts) can be seen. Staphylococcal folliculitis, impetigo, ecthyma, hidradenitis, and cellulitis are the most common bacterial skin infections. Kaposi's sarcoma lesions can also occur at this stage.
  2. Midstage Disease (CD4 200–500).Mucocutaneous candidiasis, oral hairy leukoplekia, herpes zoster, psoriasis, seborrheic dermatitis, and atopic dermatitis become evident.
  3. Late Disease (CD4 75–200).Skin infections occurring earlier in the HIV course become more chronic (HSV, for instance) and refractory to therapy. Opportunistic fungal infections (eg, cryptococcosis or histoplasmosis) can present as skin lesions. Eosinophilic folliculitis associated with pruritus tends to affect patients with worsening immunosuppression.
  4. Advanced Disease (CD4 < 75).Very unusual skin lesions can occur that warrant biopsy to establish a diagnosis. Bacillary angiomatosis and Molluscum contagiosumcan develop, signifying a profound immunosuppression.

Treatment

In the past 2 years, tremendous progress has been made in treatment of HIV infection. New combination treatment regimens can suppress virus replication below the level of detection in many individuals. However, cure is still not possible.

Antiretroviral treatment guidelines are undergoing rapid evolution, but some consensus about general principles has been achieved. First, the major goal of treatment is to suppress viremia and prevent immunosuppression. To reduce the risk that drug-resistant isolates will emerge, therapy should be implemented only when the patient is ready to adhere to a treatment regimen. Treatment is recommended for all patients with symptomatic HIV infection (eg, AIDS, thrush, and fever of unknown origin). For asymptomatic patients, the decision is more complex. Potential benefits of starting therapy in these patients include the following:

  • Earlier control of HIV replication.
  • Decreased opportunity for mutations to occur.
  • Decreased total body viral burden.
  • Prevention of immunosuppression.
  • Delay in progression to AIDS.

However, these potential benefits must be weighted against treatment risks:

  • Reduced quality of life due to drug toxicity and the inconvenience of treatment.
  • Earlier development of drug resistance.
  • Limitations in future drug options.
  • Unknown long-term treatment toxicity.

Most experts believe that treatment should be offered to asymptomatic patients when immunosuppression has developed (ie, CD4 < 350) or when viral load is high (ie, > 30,000 copies/mL with bDNA assay or 55,000 copies/mL with RT-PCR), especially if the patient desires treatment and is likely to adhere to it. (See Table 23-3)

Monotherapy is no longer recommended for HIV treatment. A combination of three antiviral drugs, to fully suppress plasma HIV below the level of detection, is now recommended. Antiviral drugs are grouped into three categories: (See Table 23-4)

  • Nucleoside reverse transcriptase inhibitors (NRTI): nucleoside analogs that inhibit HIV reverse transcriptase (RT), interfering with formation of DNA.
  • Nonnucleoside reverse transcriptase inhibitors (NNRTI): inhibit RT by a different mechanism than NRTI.
  • Protease inhibitors (PI): prevent cleavage of viral proteins precursors interfering in viral maturation and assembly.

Table 23-4 lists the drugs that were approved for HIV treatment by 1998. Adherence, side effects, and drug-drug interaction should be considered when choosing a regimen. All medications are started at the same time at the full dose (although dose escalations are needed for ritonavir, nevirapine, and ritonavir in combination with saquinavir).

Table 23-1. Laboratory tests commonly used in the diagnosis of infection with HIV-1.

Test

Primary Purpose(s)

Sensitivity %

Specificity %

HIV-1 antibody tests
A. Detection of antibody in serum or plasma
   1. Enzyme-linked Immunosorbent Assay (ELISA) followed by Western blot for confirmation. Current ELISA assay detects antibodies to both HIV-1 and HIV-2.

 

 

For all high-risk groups (Table 1); antibody becomes positive approx. 3 wks. post-disease acquisition in majority; 6 mos. after infection, 95% pts antibody-positive.

99.9

99.9

Western blot:

1. No antibodies (bands) detected = negative

2. Antibody (bands) to Gp41 and Gp 120/160 or either of latter plus p24= positive

3. Any other pattern of positive = indeterminate. Proceed to plasma viral load testing.

2. Rapid detection method:
Examples: Single use diagnostic system (SUDS)

Results available in 30 minutes or less When quick answer needed, e.g., test blood of source pt in occupational exposure. Pts who may not comply with return visit: ER, STD clinics

99.9

99.6

3. Home test kits, e.g., Home Access Express.
NOTE: Other kits sold on internet unreliable.

Encourage individuals at risk to determine their antibody status. Convenient. Anonymity maintained.

100

99.95

B. Detection of HIV-1 antibody in other body fluids

   

1. Antibody in oral mucosal transudate (OraSure)

Major advantage is avoidance of need for a needlestick. Easy to use; collected by health care worker

99.9

99.9

2. Antibody in urine (Sentinel or Calypte): HIV-1 Urine ELISA

Rapid—results in 2.5 hrs. Like rapid tests, could be used on source blood if occupational exposure or in ERs, STD clinics

99.7

94

Table 23-2. Detection and measurement of HIV-1.

Test

Current Use

% Positive

Detection/measurement of HIV
A. HIV-1 p24 antigen (Assumes acid pretreatment to dissociate immune complexes)

· Diagnosis of acute HIV syndrome (antibody not detectable for ≥2 months)

· Used to screen all donated blood

% positive depends on method/ stage of disease, eg, in acute retroviral syn.: 100%; if CD4 200–500, 45–70%; if CD4 < 200, 75–100%

B. Measurement of plasma “viral burdens”Due to assay differences, use same assay repeatedly for a given patient. REsults with RT-PCR consistently 2-fold or more greater than bDNA
For given assay, need change of ≥ 0.5 log10for significant change

• Current methods:
(1) Couples reverse transcription (RT) to a DNA PCR amplification (RT-PCR) (Roche)
NOTE: Ideally collect with EDTA & separate plasma within 6 hrs.


>98

(2) Amplification of RNA of HIV; a nucleic acid sequence-based amplification (NASBA) (Organon Teknika)

>98

(3) Identification of HIVRNA then signal amplification by DNA branched-chain technique (referred to as bDNA) (Chiron-Bayer)

>98

Table 23-3. Timing of antiretroviral treatment.

When should antiretroviral treatment be started? The most important factor in answering this question is to determine if the patient is ready to comply with the difficult regimens since lack of compliance guarantees failure of the treatment and facilitates the emergence of resistant subpopulations of virus, making it more difficult to treat the patient later. It also creates the potential for spread of resistant viruses to others. Studies indicate that about 1/3 of patients are totally adherent, 1/3 partially adherent and 1/3 almost totally nonadherent to prescribed treatment. Two important factors affect adherence: (1) the number of pills and (2) ease of administration of the regimen (qd better than bid, which is better than tid). Mixing medications with different frequency and food restrictions makes total adherence nearly impossible. In one study of 88 pts, virologic failure occurred in 22% of pts who were adherent for >95% of doses and in 61% of those with 80% to 94.5% adherence. Every effort should be made to come to an agreement or contract with the patients as to what he/she is capable of or willing to comply with prior to initiating treatment. Frequent follow-up with advice and encouragement to the patient is important to help maintain compliance and to detect noncompliance. In 2001, a shift to a more conservative (later initiation of treatment was supported, based on saving drugs as long as possible from developing resistance and on minimizing long-term drug toxicity without sacrificing efficacy.
An exception to late therapy is the acute retroviral (HIV) syndrome: Most authorities would treat immediately with HAART in an attempt to rapidly control viral proliferation, establish a lower viral set-point, and preserve the immunologic response (virus-specific cytotoxic T-cells and CD4 helper cells) against HIV.

Ranges of CD4 Cell Count and Viral Load Levels for Therapy Initiation

CD4 + Cells, ×106/L

<5,000

Plasma HIV RNA Level, copies/mL 5,000–30,000 DNA (55,000 PCR)

>30,000 βDNA (>55,000 PCR)

>350

Consider therapy

Recommend therapy

Recommend therapy

<350

Defer therapy

Defer therapy

Recommend therapy

Note: Therapy is recommended in symptomatic patients.

Table 23-4. Quick reference guide to antiretrovirals

Inhibitor type

Generic

Brand

Dose

Comments and Common Side Effects

Nucleoside Analogs (NRTIs)

Zidovudine (AZT or ZDV)

Retrovir

300 mg twice daily

Initial nausea, headache, fatigue, anemia, neturopenia, neuropathy, myopathy

Lamivudine (3TC)

Epivir

150 mg twice daily

Generally well tolerated; active against HBV

AZT + 3TC

Combivir

1 tablet twice daily

Combination tablet containing 300 mg of AZT and 150 mg of 3TC

Didanosine (ddl)

Videx

200 mg twice daily or 400 mg once daily on empty stomach (>60 kg body weight) or 250 mg (orally, each day) (<60 kg body weight)

Clinical data supports twice-daily dosing as more effective. Peripheral neuropathy in 15%, pancreatitis; avoid alcohol. Contains antacid: ok to give tablets at same time as all NRTIs, nevirapine and efavirenz; delavirdine and indinavir must be taken at least 1 h prior to ddl: nelfinavir can be taken 1 h after ddl

Zalcitabine (ddC)

Hivid

0.375–0.75 mg 3 times daily

Peripheral neuropathy in 17–31% of trial participants; oral ulcers

Stavudine (d4T)

Zerit

40 mg twice daily (>60 kg body weight) 30 mg bid (for <60 kg)

Peripheral neuropathy (1–4% in early studies; 24% in expanded access patients with CD4+counts <50)

Abacavir (ABC)

Ziagen

300 mg twice daily

About 3%–5% hypersensitivity reaction: fever, malaise, possible rash, GI. Resolves within 2 days after discontinuation. DO NOT RECHALLENGE. Also: rash alone without hypersensitivity.

Protease Inhibitors (PIs)

Amprenavir

Agenerase

1200 mg (8 cap) twice daily

Rash (20%), diarrhea, nausea

Indinavir

Crixivan

800 mg (2 cap) every 8 h on empty stomach or with snack containing <2 g of fat.

Kidney stones in 6-8%: good hydration essential. Occasional nausea and GI upset.
Store in original container which contains dessicant; without this, IDV is stable for only about 3 days

Lopinavir

Kaletra

Coformulated lopinavir 400 mg + ritonavir, 100 mg 3 capsules twice daily with food

GI side effects common but mild. No significant food effect. Available in limited expanded access;

Nelfinavir

Viracept

1,250 mg (5 tab) twice daily with food

Diarrhea common; occasional nausea

Ritonavir

Norvir

600 mg (6 cap) twice daily; start with 300 mg twice daily and increase to full dose over 14 days

Nausea, diarrhea, numb lips for ≥5 weeks; occasional hepatitis. Store capsules in refrigerator. Stable at room temperature for ≤1 month. Used at lower dosages as pharmacokinetic enhancer of other protease inhibitors

Saquinavir soft gel cap

Fortovase

1,600 mg (8 cap) twice daily or 1,200 mg (6 cap) 3 times daily with fat-containing food (>28 g)

Soft gel formulation with improved absorption, essentially replacing previous hard gel formulation (Invirase). Long-term storage in refrigerator. Stable at room temperature for 3 months

 

Amprenaviir

Agenerase

1200 mg twice daily avoid high-fat meal

Skin rash in 28%; rarely severe in 1%; nausea, vomiting, and diarrhea common in 1/3; paresthesias and depression not uncommon

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Delavirdine

Rescriptor

400 mg (2 tab) 3 times daily

Transient rash. P450 3A4 inhibitor. 600-mg-twice-daily dosing being studied

Efavirenz

Sustiva

600 mg (3 cap) once daily at bedtime

Initial dizziness, insomnia, transient rash, P450 3A4 inducer; avoid clarithromycin

Nevirapine

Viramune

200 mg (1 tab) once daily for 2 weeks, then 200 mg twice daily or 400 mg once daily

Transient rash, hepatitis. P450 3A4 inducer. Once daily dosing recommendation basedon limited clinical data

Table 23-5. Summary of suggested initial treatment of HIV infection.1

Preferred

Alternative

Column A

Column B

Column A

Column B

Efavirenz
Indinavir ± ritonavir1
Ritonavir2 + saquinavir
Nevirapine

Stavudine + lamivudine
Stavudine + didanosine
Zidovudine + lamivudine
Zidovudine + didanosine

Abacavir
Amprenavir
Delavirdine
Lopinavir/ritonavir (Kaletra)
Nelfinavir + saquinavir
Ritonavir
Saquinavir SGC3

Didanosine + lamivudine

1Antiretroviral drug regimens are comprised of of one choice from column A and one from column B. Drugs are listed in alphabetical, not priority order.

2Increasingly, ritonavir is used in combination with other protease inhibitors because it lowers their metabolism (via P450 inhibition) and maintains high trough antiviral activity. This allows bid dosing while still preventing viral escape.
3Use of saquinavir hard-gel capsule is not recommended, except in combinatino with ritonavir.

 

Numerous clinical trials confirmed that antiretroviral combination therapy results in greater reductions of viral RNA copies, less frequent emergence of resistance, and a more sustained therapeutic response. Available data and clinical experience support using a combination of two NRTIs along with a PI as the most potent combination available (HAART). However, the choice of drugs has to be individualized based not only on the patient's virologic and immunologic response but also on the patient's tolerance of side effects, ease of use, potential drug-drug interactions, and cost. With growing numbers of new antiretrovirals, the recommendations about the best combination therapy continue to be modified. Alternatives to the two NRTI-one PI combination are indicated in Table 23-5).

For suggestions when initial treatment fails, See Table 23-6. Responses to failure.

Medical care should focus on providing comfort, preventing the opportunistic infections, and managing the new complexities of antiretroviral therapy. In the terminal stage of HIV disease, treatment of the virus itself along with opportunistic infections and especially the malignancies is often palliative and should be instituted after careful consideration of the potential complications of therapy. A thorough discussion of these facts with the patients will facilitate realistic treatment expectations. The use of life-support measures, including cardiopulmonary resuscitation and mechanical ventilation, should also be addressed as early as possible. The survival rate for AIDS patients with respiratory failure has actually improved in the past few years, and intensive care is certainly not contraindicated. However, the expected benefit from aggressive measures must be balanced against the overall quality of life in the face of progressive disease.

Prognosis

Throughout the course of HIV disease, there is an active viral replication and concomitant stimulation and destruction of the immune system, even during the clinically asymptomatic period. The rate of progression of the infection that eventually culminates in complete destruction of the CD4 lymphocytes is determined by a balance between the pathogen virulence factors and the host genetic make-up and immune defenses against HIV.

Prevention & Control

Vaccine against HIV is not yet available, and prevention of infection relies on controlling transmission of the virus. Control encompasses both prevention counseling and postexposure prophylaxis.

Assessment of risk factors as well as specific risk reduction information should be a part of routine primary care and a component of evaluation at the specific HIV testing centers and STD clinics. A supportive, nonjudgmental atmosphere, along with repeated, specific information targeting specific identified risk factors, is most effective.

Table 23-6. Responses to failure of treatment.

What is the appropriate treatment when the antiretroviral regimen fails? Failure may be due to many different reasons, and it is important to identify the cause. Most treatment failures are due to a patient's lack of compliance with the complicated triple-drug therapies. Patients may not recognize that they are being noncompliant or may be too embarrassed to admit it. The following actions and/or recommendations should be considered in the event of failure of the treatment:

· When the increase in viral RNAis likely due to a aptient's noncompliance to treatment, one may initially reinstitute the original regimen, especially if the patient stopped all drugs at once (it has been shown that after a year on treatment, when drugs are stopped simultaneously, the viral isolates will still be sensitive to all three drugs, and patients will again respond to reinitiation of the original treatment).

· When the increase in vrial RNAis likely due to the patient's erratic compliance with the treatment, or if the patient was compliant and still showed a rise in viral RNA, the virus may well be resistant to all drugs. In that event, a change in treatment is warranted, and, if possible, all drugs should be changed.

· When treatment failure cannot be shown to be due to either noncompliance or erratic compliance, drug malabsorption or a drug-drug interaction, both of which can decrease the effective plasma drug concentrations, should be considered. The use of plasma drug levels in cases where the cause of failure is not apparent may also be of value.

· Tests for detection of mutations that confer resistance (genotyping) and phenotypic tests for detection of resistance to antiretroviral drugs are now commercially available and are recommended for supporting the above clinical decisions regarding which drugs should be used next.

Injection drug users should be encouraged to join a drug rehabilitation program and offered evaluation for entry into methadone maintenance programs if available in the community. Short of discontinuation of drug injection, some behavioral modifications can reduce the risk of a potential HIV transmission; for example, using sterile equipment or cleaning drug paraphernalia, especially needles and syringes, with water and then bleach (for at least 30 seconds). Some communities also offer needle/syringe exchange programs. Eliminating needle sharing or reducing the number of sharing partners could further reduce the risk of transmission.

Promotion of safer sexual practices should be an essential part of prevention counseling. Such practices focus on implementation of consistent condom use and the reduction of the number of partners. Screening and treatment of STDs further contribute to reducing the risk of sexual transmission of HIV.

Counseling should also incorporate issues of contraception and a possibility of virus transmission from an infected mother to her baby. All pregnant HIV-infected individuals should receive antiviral treatment to prevent viral transmission to the baby.


Even though only AZT monotherapy was studied and proved to reduce the risk of HIV transmission to the neonate, a single drug antiviral regimen is no longer acceptable for treatment of the mother. Thus combination therapy should be used. Mothers should also be counseled about the potential risk of HIV transmission via breast milk, and alternative infant feeding should be initiated.

Prevention of occupational exposures should involve education and reinforcement of universal precautions and implementation of devices and safe disposal of contaminated materials that would minimize a possibility of exposure to infected body fluids. Postexposure prophylaxis with antiviral medications after an occupational high-risk exposure to contaminated body fluids has become widely accepted, and specific treatment protocols have been implemented by various health-care institutions. In general, postexposure prophylaxis should be initiated as soon as possible after a known or a potential exposure and should consist of a combination either of zidovudine and lamivudine or stavudine and didanosine. With either regimen, consideration should be given to the addition of a protease inhibitor (nelfinavir or indinavir) if exposure is especially risky (large volume/high titer) or if the source patient has a high viral load (> 50,000 copies/mL), has advanced AIDS, or has been previously treated with one or both nucleoside analogues in the recommended two-drug regimens. Triple therapy is the regimen preferred by most health-care providers.

Experience with occupational postexposure prophylaxis has led recently to considerations for expansion of prophylactic treatment of individuals with recent sexual exposure to HIV. The current proposed regimen is the same as for occupational exposure. Postexposure prophylaxis should only constitute a backup for failure of primary prevention measures. Counseling and implementation of risk reduction programs should always be the mainstay of prevention of HIV transmission.

REFERENCES

Carpenter CJ et al: Antiretroviral therapy for HIV infection in 1997. JAMA 1997;277:1962.

Centers for Disease Control: Update: trends in AIDS incidence–United States, 1996. MMWR 1997;46:861.

De Roda Husman AM et al: Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann Intern Med 1997;127:882.

Karon JM et al: Prevalence of HIV infection in the United States, 1984–1992. JAMA 1996;276:126.

Saag MS et al: HIV viral load markers in clinical practice. Nature Med 1996;2:625.

Sande MA, Volberding PA: The Medical Management of AIDS, 5th ed. WB Saunders, 1999.

Sande MA et al: The Stanford Guide to HIV/AIDS Therapy. 2001.

Vlahov D et al: Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users. JAMA 1998;279:35.

World Health Organization: HIV/AIDS. The global epidemic. Wkly Epidemiol Rec 1997;72:17.