Medical Guidelines

Diagnosis

Serologic Screening for HIV

Image retrieved from US CDC, Electron microscopic image of HIV, seen as spheres atop white blood cells.

For twenty years, the accuracy of serologic screening has steadily improved with successive generations of assays. Thus, HIV diagnosis has become minimally burdensome for the health care practitioner.

• Both standard and rapid HIV testing are available. Though the specificity and sensitivity of both screening enzyme immunoassays (EIA) are considered excellent, both require confirmatory testing with western blot. EIA results appear as positive, negative and indeterminate. Both positive and indeterminate results require western blot for a) clarification or b) to rule out false positive.
• NEW 4th generation combination HIV antibody and antigen assays are also available. The advantage of these combination assays is their ability to detect HIV p24 antigen during acute infection when antibody formation may not yet be detected. This is the window period of acute infection.
• The accuracy of standard HIV serologic testing is very high (sensitivity and specificity >99%)
• Rapid HIV Testing: Rapid HIV testing allows for the practitioner to retrieve results at initial point of care. This is particularly useful for chaotic patients who seek sporadic care. The sensitivity and specificity of Rapid HIV testing is again >99%, but standard testing is required in follow up to establish a confirmed diagnosis of HIV. If Rapid antibody testing is negative, testing is considered complete. If there is suspicion of infection however, one can proceed to HIV p24 antigen testing or HIV RNA.

Note: Newly presenting patients who report history of HIV infection should be confirmed by serologic testing. Confirmation of diagnosis is important, as some reports of infection appear inaccurate.

Delayed Diagnosis

The US Center for Disease Control has estimated that early detection of HIV could prevent 32 000 cases of new HIV (in the United States) each year. This is a fifty percent reduction. According to a 2006 study published in the Lancet 40% of HIV positive patients receive testing and diagnosis within one year of an AIDS defining illness. Looking to the evidence of HIV natural history, this then implies that 40% of HIV diagnosis occurs at least seven years after initial infection.

A review of 1302 "late testers" (patients with an AIDS diagnosis within one year of first positive test) demonstrated that these patients had a total of 7988 encounters with the health care system from 1997 to 2005 without HIV testing, an average of 6.5 visits/patient. These encounters were viewed as "missed opportunities" since early detection contributes to both individual and population health.

A subsequent retrospective study of 44,491 HIV-infected patients from 13 US and Canadian clinical cohorts found that the median CD4 count at diagnosis increased from 256 cells/mm3 to 317 cells/mm3 during the period from 1997 to 2007; although the median CD4 cell count at presentation improved, it was still below the threshold at which treatment is currently recommended.

If the following present in your patient population, HIV should be suspected

• Thrush
• Unexplained weight loss or fevers
• Unexplained dementia
• Generalized lymphadenopathy
• Aseptic meningitis
• Peripheral neuropathy
• Herpes zoster (if disseminated or involves more than one non-adjacent dermatome)
• Oral hairy leukoplakia
• Opportunistic infections suggesting defective cell-mediated immunity
• Kaposi's sarcoma
• B cell lymphoma, in particular extranodal
• Unexplained cytopenias
• New onset seborrheic dermatitis

Clinical Evaluation

Careful clinical evaluation should be completed at the time of initial assessment of an HIV positive individual. This will include blood work, review of systems, full physical exam. Special attention should be paid towards the patients understanding of his/her illness, emotional state, social supports, and willingness to partake in treatment. Exploration of issues of transmission must be discussed at length, as knowledge is variable around the world. HIV case workers may be useful where available. Special attention should be paid to comorbidities. These effect choice of ART.

Treatment

Antiretroviral treatment (ART) of adult HIV infection

Antiretroviral therapy has dramatically changed the course of HIV since its introduction over two decades ago. Opportunistic infections and other AIDS defining illness have dramatically declined.

For detailed review of HIV primary care please refer to the following 2 most up-to-date resources:

1. 2011 Therapeutic Guidelines for Adults with HIV, Created by the BC Center for Excellence in HIV
2. 2009 Infectious Diseases Society of America HIV Primary Care Guidelines

When should I initiate ART in a newly diagnosed patient?

The decision to initiate antiretroviral therapy is complex. Guidelines have changed over the years, trending towards earlier therapy. Risks of toxicity, resistance, and patient burden should be openly discussed with each patient. Today, we know that viral suppression can restore and improve immune system function. Patients must adhere to life long therapy for maximum benefit, a task that is sometimes difficult to achieve in Canada's most affected populations: injection drug users, sex workers, Canada's aboriginal populations, refugees, and men who have sex with men.

Trends toward earlier treatment result from:

1. Increasing risks of viremia highlighted in the literature
2. Risk associated with ART decreasing over years
3. Pill burden decreasing with combination formulations

We now know that untreated viremia creates an uncontrolled inflammatory state affecting all organ systems. End organ damage is common and inevitable. We are learning that comorbid conditions are likely developing due to this chronic inflammatory state. Mortality from non-AIDS events now exceeds AIDS defining opportunistic diseases in individuals on ART.

Current Recommendations

Initiate ART regardless of CD4 count if:

• Rapid progression of disease, as indicated by high HIV-1 RNA and rapid CD4 cell count decline
• Age > or equal to 50 (higher risk of AIDS and non-AIDS related deaths)
• Pregnant (ART must be offered at least by second trimester, continue therapy after birth)
• Chronic HBV or HCV co-infection (Note: Screen for hepatitis in all HIV patients initially. If testing is negative, repeat as per clinical indication).
• HIV associated kidney disease (but avoid tenofovir, indinavir, atazanavir --> effects on kidney)
• Consider therapy in sero-discordant couples
• High cardiovascular risk patients
• Patients with diagnosed opportunistic infections
• Once initiated HIV therapy should be life long

What Should I Start?

• The initial regimen can be a daunting task for a family practitioner to initiate. This therapeutic choice will have longstanding consequences as it will shape future therapy options if treatment failure occurs. Resistance testing and predicted antiviral efficacy should define your initial regimen, along with the patient's willingness to tolerate pill burden and dosing frequency.
• Current recommendations include combination of 2 nRTIs and a third agent from another class.
• In general, fixed dose formulations and once daily regimens are preferred initially.
• For up to date recommendations please see Table 2a of the BC Center for Excellence 2011 Therapeutic Guidelines for Adults with HIV.

Monitoring

Effective treatment should suppress viral load to less than 50 copies/mL (PCR)

• Frequent HIV-1 RNA monitoring recommended during first year of ART to detect failure.
• 4 weeks after initiation test HIV-1 RNA , then q 4-8 weeks until suppression achieved, then q 3-4 months for first year.
• In a previously suppressed patient whose plasma HIV-1 RNA becomes detectable, repeat in 2-4 weeks.

What is considered viral failure?

• Viral failure is only diagnosed if plasma HIV-1 RNA is twice consecutively at > or equal to 250 copies/mL.
• If viral failure is confirmed, perform resistance testing.
• Perform CD4 cell counts with HIV-1 RNA monitoring, especially with counts less than 200 mu/ L. This is important in order to monitor the need for opportunistic infection prophylaxis.
• Studies show that patients who maintain stable ART for 1 year have a low chance of experiencing treatment failure in ensuing months.
• When viral replication is suppressed at least 6 months, move to q 6 month monitoring (if virology suppressed and CD4 counts > 350 mu/L)

If there is viral load rebound on 2 occasions, with tests 2-4 weeks apart what should I do?

Evaluate:

1. Drug interactions
2. Patient tolerability
3. Patient adherence

What are the implications of a viral load of 20-50 copies/mL?

This is still unknown.

When might I see detection artifacts?

Changes in assay methodology may result in detectable and sporadic viral load.

When do I complete genotypic testing?

• Strongly recommended for all treatment-naive patients with initial diagnoses, before starting ART.
• If there is defined treatment failure (plasma HIV-1 RNA >250 copies/mL), will be crucial in deciding next therapy.
• Genetic testing should be done while patient is still taking the failing therapy

When should I monitor for toxicity?

• Toxicity may occur q 2-8 weeks after initiation; monitor at this time, repeat once HIV viral load is stable, then q 6 months.
• Frequency of monitoring should depend on toxicity of the ART.
• Assess renal function before ART if tenofovir is used.

Comorbidities

HIV and Vitamin D

Vitamin D deficiency is common in the setting of HIV. The evidence is unclear regarding whether this is a viral effect or iatrogenic. Guidelines recommend supplementation.

CVS monitoring

• HIV patients are at higher risk of CVS pathology. Studies show that a chronic inflammatory state may lead to this relationship.
• CVS risks should be measured intermittently by the best available tools. Framingham is currently best, but likely underestimates risk in HIV population.

HIV and Kidney Injury

• Consider HIV associated nephropathy
• Consider HIV associated immune complex kidney disease
• Consider thrombotic microangiopathy
• Tenofovir is associated with a decrease in GFR & tubular dysfunction
• Indinavir and Atazanavir are associated with nephrolithiasis

References

Aberg, JA, Kaplan, JE, Libman, H, et al. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2009; 49:651.

Daar, ES, Little, S, Pitt, J, et al. Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network. Ann Intern Med 2001; 134:25.

Simon, V, Ho, DD, Abdool Karim, Q. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet 2006; 368:489.

Losina, E, Schackman, BR, Sadownik, SN, et al. Racial and sex disparities in life expectancy losses among HIV-infected persons in the united states: impact of risk behavior, late initiation, and early discontinuation of antiretroviral therapy. Clin Infect Dis 2009; 49:1570.

Althoff, KN, Gange, SJ, Klein, MB, et al. Late presentation for human immunodeficiency virus care in the United States and Canada. Clin Infect Dis 2010; 50:1512.

M Thompson, J Aberg, P Cahn, J Montaner, et al. Antiretroviral Treatment of Adult HIV Infection – 2010 Recommendations of the International AIDS Society – USA Panel. JAMA, July 21, 2010 – 304, (3) 321-333

Palella F, Armon C, Buchacz K, et al. CD4 at HAART initiation predicts long-term CD4 responses and mortality from AIDS and non-AIDS causes in the HIV outpatients study. In: 17^th Annual Canadian Conference on HIV/AIDS Research. San Francisco, CA: CrOI; 2010. Abstract 983.

Harrison KM, Song R, Zhang X. Life expectancy after HIV diagnosis based on national HIV surveillance data from 25 states, United States. J Acquir Immune Defic Syndr 2010;53(1): 124-130.

Lohse N, Hansen AB, Pederson G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 2007;146(2):87-95.

Reekie J, Mocroft A, Sambatakou H, et al; Euro-SIDA Study Group. Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure? AIDS 2008;22(17):2381-2390.

Mueller NJ, Fux CA, Ledergerber B, et al; Swiss HIV Cohort Study. High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. AIDS 2010; 24 (8): 1127-1134