Virologic and Immunologic Monitoring
Medical Care Criteria Committee, June 2016
Periodic laboratory tests are necessary to evaluate the response to ART and its potential related side effects. In the setting of ART failure, viral resistance assays should be used.
|HIV RNA AS MEASURE OF EFFECTIVE ART|
Regular monitoring of CD4 counts in patients with consistently undetectable HIV viral loads and CD4 counts >200 cells/mm3 offers little utility in clinical practice today. Clinicians rarely use this information to guide decision-making for clinically stable, virologically suppressed patients. Monitoring of HIV RNA levels to confirm appropriate response to treatment and durable viral suppression is the most accurate and meaningful measure of the effectiveness of ART .
Very few studies address the appropriate frequency of viral load monitoring. A recent retrospective study noted that the strongest predictor of virologic failure at 12 months was a missed or cancelled appointment rather than the interval of follow-up . However, this and other similar studies [3,4] have significant limitations, including their retrospective nature and short follow-up periods. Data indicate that the linked sexual transmission of HIV in sero-discordant couples in which the HIV infected partner maintains sustained viral suppression is negligible . Based on this information, persons with HIV may rely on their antiretroviral therapy as a strategy to prevent viral transmission to an uninfected partner. Studies do not indicate the appropriate interval for viral suppression monitoring for the purposes of ongoing transmission prevention. Until more definitive data are available, the decision to lengthen monitoring intervals for HIV RNA level should be individualized. Patients who are monitored at longer intervals should be carefully selected based on length of viral suppression, CD4 count, use of antiretroviral therapy for transmission prevention, and adherence to medical care, including visit attendance and retention in care.
Table 1 provides a guide for monitoring HIV RNA levels and CD4 counts.
|Table 1: Virologic and Immunologic Monitoring for Non-Pregnant Patients [a]|
|At Baseline||HIV RNA Levels (copies/mL)||CD4 Lymphocyte Count (cells/mm3)|
|Treatment Monitoring||HIV RNA Levels (copies/mL)||CD4 Lymphocyte Count (cells/mm3)|
Following (1) initiation of ART or (2) a change in ART regimen after virologic failure [b] with new resistance to prior ART
Following a change in ART to simplify treatment regimen or reduce toxicity for patients with suppressed virus
Patients on ART who achieve complete suppression [c]
Patients on previously suppressive ART with new HIV RNA [d] above the lower limit of detection using a highly sensitive assay [c]
Viral load ≥500 copies/mL:
Viral load <500 copies/mL:
Patients not on ART: According to NYSDOH recommendations, ART is recommended for all HIV-infected patients [g]
Plasma levels of viral RNA have been shown to correlate with clinical outcome, including overall mortality, and measurement of HIV RNA levels provides the most precise means of establishing whether a response to ART has occurred [8-12]. HIV RNA levels should be obtained from all patients at baseline [13-18].
For patients beginning ART, or those changing therapy as a result of virologic failure, HIV RNA should be measured at 4 weeks after initiation of therapy and should decrease by at least 1 log (10-fold) in the presence of effective therapy  (see Appendix: Interpretation of Viral Load). For patients who do not have background antiretroviral resistance, an undetectable viral load (<50 copies/mL) is usually achieved within 3 months. Patients with a baseline HIV viral load >100,000 copies/mL can be expected to achieve an undetectable viral load within 6 months of effective treatment.
An absent or incomplete response of viral load to ART should raise concerns about poor adherence to therapy and/or viral resistance [20,21].
Patients on previously suppressive ART with newly detectable HIV RNA levels of 50 to 500 copies/mL may be experiencing low-level transient viremia (“blip”) and not virologic failure. A blip by definition means that the viral load is again below the level of quantification on repeat testing performed promptly after a detectable result in someone previously suppressed. Persistent elevation, even at low levels, warrants further investigation. Acute concurrent illness and/or recent vaccination may cause this transient rise; however, studies have suggested that low-level transient viremia represents random biologic and statistical variation or false elevations of viral load resulting from laboratory processing [22,23]. Blips are not known to be associated with the development of resistance mutations or virologic failure and do not require a change in ART . Retesting should be performed within 4 weeks to differentiate low-level transient viremia (a blip) from sustained viremia and possible virologic failure. The risk of virologic rebound (breakthrough) increases when values are >500 copies/mL . However, ART should not be changed based on a single viral load elevation.
Advances in molecular detection technology have led to the development of HIV nucleic acid tests (NATs) that are highly sensitive and more reliable than earlier versions. Real-time polymerase chain reaction (PCR) technology has been widely adopted for HIV-1 RNA quantification, but new technologies are continually emerging and being adapted to viral detection and quantification. The currently available HIV-1 viral load tests that use real-time PCR technology offer larger dynamic range of quantification than early-version viral load tests. The lower and upper limits of quantification of the currently available FDA-approved HIV-1 viral load tests are shown in Table 2. Several different HIV viral load tests have been developed, and four are currently approved for use in the United States.
|Table 2: FDA-Approved Quantitative HIV-1 RNA Assays for Viral Load Monitoring|
Lower and Upper Limits of Quantification (LOQ)
Abbott RealTime HIV-1 (Abbott Laboratories)
Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, version 2.0 (Roche Diagnostics)
Cobas HIV-1 quantitative NAT for use on Cobas 6800/8800 systems (Roche Diagnostics)
Cobas TaqMan HIV-1 Test, v2.0 for use with the high pure system (Roche Diagnostics)
*This lower LOQ applies when 1.0 mL of plasma is used. When 0.5 mL and 0.2 mL of plasma are used, the lower LOQ is 75 copies/mL and 150 copies/mL, respectively.
All of the current FDA-approved viral load assays quantify the level of cell-free virus in an individual’s plasma and are approved for monitoring response to ART, tracking viral suppression, and detecting treatment failure. Successful ART should decrease viral load 1.5 to 2 logs (30- to 100-fold) within 6 weeks, with the viral load decreasing below the limit of detection within 6 months . Cohort studies strongly suggest that patients with viral loads <50 copies/mL have more sustained viral suppression than patients with viral loads between 50 and 400 copies/mL. Assays that can detect <50 copies/mL are recommended for determining prolonged viral suppression and for monitoring patients who are on ART.
CD4 lymphocyte count is used to evaluate immunologic staging, predict the risk of clinical progression, and make decisions regarding prophylaxis of opportunistic infections [25,26]. Low CD4 cell counts can be seen in other disease processes and should therefore not be used for diagnosis of HIV. Although, historically, CD4 cell count was used to establish a threshold for initiating ART, current guidelines in New York State recommend ART for all HIV-infected patients regardless of CD4 cell count. For patients who may not be ready to initiate ART, CD4 cell count can be used to guide discussions between patient and provider regarding the urgency of initiating ART.
Although CD4 counts should be obtained from patients at baseline [27-31], clinicians are unlikely to use CD4 counts to guide clinical decision-making in practice for virologically suppressed patients once their CD4 count remains above 200 cells/mm3. However, for persons infected with HIV-2 or HIV-1 variants that cannot be accurately quantified using viral load assays, CD4 count remains the most effective monitoring tool for progression of disease (see Human Immunodeficiency Virus Type-2).
Although a significant CD4 count increase often occurs among patients treated with effective ART, the absence of such an increase should not be interpreted as treatment failure if the viral load declines appropriately. ART regimens are generally not changed in patients with undetectable viral loads who experience immunologic failure, although patients should remain on appropriate prophylaxis for opportunistic infections based on CD4 count. Lack of correlation between viral load and CD4 cell response is particularly common among patients ≥50 years old [32,33] and patients with low initial CD4 cell counts (<100 cells/mm3) [27,34,35].
Absolute CD4 cell counts are calculated values that may fluctuate widely. The calculation is made by multiplying the total white blood cell count (in thousands) by the percentage of total lymphocytes and then by the percentage of CD4 lymphocytes. Therefore, any change in one of these three parameters will cause the absolute CD4 count to vary. CD4 percentage is a direct measurement and more reliable than the calculated absolute CD4 value, especially over time. A stable CD4 percentage, even in the setting of fluctuations in the absolute CD4 cell count, can reassure both the patient and the clinician that immunologic stability is present.
Some factors that can cause these fluctuations include sex, age, race, drugs (zidovudine, cephalosporins, cancer chemotherapy, nicotine, interferon, and corticosteroids), anti-lymphocyte antibodies, and splenectomy. Differences in reagents and equipment both within a laboratory and between laboratories may further contribute to variations in CD4 cell counts. There is also interlaboratory variation of normal range.
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- Lee PK, Kieffer TL, Siliciano RF, et al. HIV-1 viral load blips are of limited clinical significance. J Antimicrob Chemother 2006;57:803-805. [PubMed]
- DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. January 28, 2016. www.aidsinfo.nih.gov/
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Virologic and Immunologic Monitoring: Appendix: Interpretation of Viral Load
|Table 3: Interpretation of Viral Load|
|HIV -1 RNA Copy Number|
|Reduction with ART if Patient has 100,000 copies/mm3|
|Log Change||Percent Decrease||Fold Reduction||Resultant Copy Number|
HIV Resistance Assays
Medical Care Criteria Committee, June 2016
The interpretation of HIV resistance assays is one of the most challenging tasks clinicians encounter when caring for HIV-infected patients and is crucial for tailoring an effective therapeutic ART regimen. The replicative mechanisms of HIV lack proof-reading capacity, making them error-prone and subject to cumulative mutations (i.e., changes in its genetic sequence). This lack of replicative fidelity, coupled with the selective pressure of sub-therapeutic drug levels, can lead to the development of clinically significant (i.e., resistance-bearing) mutations.
The most commonly used ART drugs are targeted to inhibit the activity of three specific viral enzymes: the protease, reverse transcriptase (RT), and integrase. Mutations have been identified that interfere with the ability of one or more ART agents to inhibit viral protein activity, thus rendering the virus resistant to the drug(s). HIV resistance mutations and mechanisms for less commonly used ART drugs that target fusion and viral entry have also been identified.
New resistance mutations and the emerging clinical significance of these mutations frequently change. Several resources are available for more information on drug resistance mutations and resistance testing, including:
- Stanford University HIV Drug Resistance Database
- IAS-USA 2014 Update of the Drug Resistance Mutations in HIV-1
- HIV Resistance Response Database Initiative
- Los Alamos National Laboratory HIV Databases
- HIV French Resistance Database
- HIV InSite Links: HIV Resistance and Resistance Testing
Two methods are used to determine drug resistance for HIV: genotyping, which detects treatment-resistant genetic mutations; and phenotyping, which assesses the viral response to ART agents. Genotyping is the preferred test in most clinical situations.
In New York State, third-party reimbursement programs, including Medicaid, the New York State AIDS Drug Assistance Program (ADAP), and private insurers, often limit the number of resistance tests per year (within 12 months following date of first use). Medicaid Managed Care Plans (MMCPs) and private insurers may require prior authorization for these services and may limit the number of resistance tests performed annually, such as three tests per year, regardless of whether genotyping, phenotyping, or a combination of testing is obtained.
Providers should refer to their patient’s specific plan regarding frequency, annual limits, and whether prior authorization is required for any genotypic and phenotypic HIV resistance tests. Detailed information regarding Medicaid managed care-covered benefits for resistance testing, including current procedural terminology (CPT), codes is available at www.health.ny.gov/health_care/medicaid/program/update/2014/2014-03.htm#exp.
Investigational technologies, such as “single-copy” assays or “deep sequencing,” are under development; however, because they are not currently in use in clinical settings, these tests are not addressed here.
Genotypic resistance assays detect mutations known to be associated with therapeutic failure by directly sequencing the genomic coding region of the protein inhibited by the ART drug. The genomic mutations, which may include substitutions, insertions, or deletions in the viral protein’s coding region, are then compared with the known mutation(s) associated with the ART agent(s) clinical resistance profile.
Direct sequencing-based methods have been approved by the FDA, but the ViroSeq HIV-1 Genotyping System (Abbott Laboratories) is the only FDA-approved assay currently available. In addition, laboratory-developed (“in-house”) genotyping assays are available through several commercial laboratories (e.g., GenoSure MG, Monogram/LabCorp). Advances in genotyping assays continue to evolve. Testing for resistance to integrase strand transfer inhibitors and fusion inhibitors is now available and should be considered when resistance to these classes of drugs is a concern, such as when transmission of resistant virus is suspected or when a patient fails a regimen that includes one of these drugs.
In the RNA-based genotyping assays, the HIV-1 RNA is isolated from a plasma specimen and reverse-transcribed to produce complementary DNA (cDNA). Specific regions of the HIV genome are amplified by PCR and sequenced. This sequence is then compared with that of a drug-sensitive (“wild-type”) strain of HIV, and differences (mutations) present in the specimen sequence are noted. Computer software is generally used to perform this comparison and to predict whether resistance to specific drugs is likely to result from the particular combination of mutations detected in the virus. For most genotypic assays, this prediction is based on a set of rules derived from clinical observations, laboratory studies, and the advice of experts in the field. The actual prediction of resistance may vary from laboratory to laboratory for some combinations of mutations, depending on the interpretation algorithm used to define the rules.
Currently available RNA genotypic assays require a minimum viral load in the range of 500 to 2,000 copies/mL, depending on the assay, and generally require 2 weeks or less for results. DNA-based genotypic assays  are becoming commercially available, such as the GenoSure Archive (Monogram/LabCorp). These assays use next-generation sequencing technology and are designed to overcome the limitations that commonly used RNA genotypic assays encounter in the presence of low-level viremia. In traditional genotypic assays, identification of resistance mutations is often not possible when viral load levels are below the lower limit of detection of a given assay; the lower limit may range from 500 to 1,000 copies/mL across available assays.
In DNA-based genotypic assays, integrated proviral DNA is extracted from HIV-infected cells, rather than from the circulating HIV in the plasma. Once the proviral HIV cell-associated DNA is extracted, the DNA is PCR-amplified, sequenced, and analyzed in analogous fashion to the older genotype RNA methodologies. The coding sequences for reverse transcriptase-, protease-, and integrase-targeted inhibitors are matched, as with the RNA-resistance genotype assays, with known resistance-associated mutations. The results are usually reported as “sensitive,” “resistant,” or “resistance possible” for a given ART agent. Although the clinical efficacy of the DNA-based genotype assays has not been fully validated, this technology can provide information on “archived,” or noncirculating, viral resistance. It should not be assumed that all previous mutations will be detected. Although concordance across various studies using in-house, laboratory-developed tests was relatively high, the peripheral blood mononuclear cell (PBMC)-derived DNA assays often did not detect known previous mutations that had been documented with plasma-based RNA tests [3-5]; the results could vary by class, with the manufacturer’s own study showing lower concordance for protease mutations relative to those of reverse transcriptase in patients whose current viral load was undetectable . However, testing of archived proviral DNA may provide useful additional information when making decisions about switching ART regimens for those who are virologically suppressed or those with repeated low-level viremia, especially when historical data are unavailable . The commercial assay has not been validated for patients with viral loads >500 copies/mL, although some studies are investigating the assay’s performance at higher viral loads, when wild-type virus may have replaced drug-resistant variants typically detected by RNA-based assays . The results obtained from archived proviral DNA testing should be used to supplement all other available information regarding treatment and resistance history.
Neither the RNA- nor DNA-based resistance assays can detect mutations associated with currently available HIV entry inhibitors (see below).
An older, algorithmic resistance profile based on genomic sequencing “virtual phenotype” (VIRCO, vircoTYPE) ceased to be clinically available in the United States as of December 2013. It compared the results of a patient’s genotype and predicted potential drug sensitivities by comparing a patient’s genotypic mutational profile with a database of laboratory and genotypic (sequence) and phenotypic (drug sensitivity) data and samples.
Although still available, phenotypic assays generally do not add to the information provided by currently used genotypic assays. A phenotypic assay provides a direct measure of drug resistance and is analogous to antibiotic-susceptibility testing of bacteria. The currently available phenotypic assays use recombinant DNA methods to measure the ability of a patient’s virus to grow in the presence of a drug. Therefore, results from a phenotypic test include the net effect of any and all resistance mutations.
In the phenotypic assay, HIV RNA is isolated from plasma and converted into cDNA, and the relevant region is amplified by PCR. This amplified material is inserted into a recombinant virus system whereby the susceptibility to different drugs can be tested. The result from the phenotypic assay is a value that defines the concentration of the drug required to reduce growth of the virus by 50% (IC50). The IC50 of the patient’s virus is compared with the IC50 of a drug-sensitive (wild-type) reference virus, and the fold change is defined. If the IC50 of a person’s virus is greater than that of the reference virus for a particular drug, then the person’s virus has decreased sensitivity to the drug. The relative fold change helps determine whether the drug should still be included in the ART regimen or whether it should be removed entirely. Monogram Biosciences offers phenotypic resistance testing through clinical laboratories with the PhenoSense assay. Phenotypic assays have a minimum viral load requirement of 500 to 1,000 copies/mL and generally require 3 to 5 weeks for results. Phenotypic assays are more technically complex, labor-intensive, and expensive than genotypic assays.
Technical Limitations of Genotypic and Phenotypic Assays
In addition to the minimum viral load requirements needed for amplification (generally at least 500 to 1,000 copies/mL) in genotypic or phenotypic RNA-based resistance assays, all resistance assays, including the DNA-based genotype, are limited by sampling bias. Unlike acute infection, where infection is often established by a single progenitor virion  (see Diagnosis and Management of Acute HIV Infection), in established HIV infection, HIV exists as a virus population comprising multiple genomic variants. Genotypic and phenotypic resistance assays are each more likely to detect the common viral variants and fail to identify the minor variants. Similarly, standard genotypic and phenotypic resistance testing performed on plasma specimens will not detect noncirculating, or archived, resistant virus (i.e., virus resistant to ART agents from previous regimens). If therapy is stopped altogether, the selective pressure from the ART agents suppressing the noncirculating virus is removed and a pan-sensitive or wild-type HIV population over time will begin to resurface and dominate the circulating virus population. When this occurs, the RNA-based genotypic and phenotypic resistance assays may fail to detect the ART-resistant virus, despite being present either as archived virus or at low levels. Although a DNA-based assay may have utility in these circumstances, clinical data are insufficient to recommend for or against its use in the patient care setting. For these reasons, all copies of the patient’s previous genotype and/or phenotype resistance testing, along with the ART medication history, should be retained, and the information should be combined and used in constructing a subsequent ART regimen. Once resistance develops, it can be expected to persist indefinitely to that specific drug in archived form.
Another, more subtle, limitation is related to the level at which a virus is sensitive to a given ART agent. This “cutoff” may vary across assays, even when the same viral sample is used. Consultation with an experienced provider for interpretation of results is crucial.
Co-Receptor Tropism Assay
Co-receptor tropism analysis determines which cellular co-receptor (CCR5 or CXCR4) is used by the HIV-infected individual’s dominant viral population to gain access to host cells. The majority of acutely or recently infected individuals, including perinatally infected children, have a CCR5-tropic virus.
Because CCR5-tropic virus predominates early in HIV infection, whereas CXCR4-tropic virus is often present in late-stage disease, the CCR5 variant may be preferentially transmitted compared with CXCR4 variants. In chronically HIV-infected individuals, a population of mixed CCR5- and CXCR4-tropic viruses, as well as dual-tropic viruses, may also be detected. The tropism of these viral populations is often referred to as dual/mixed or D/M HIV.
In the United States, most co-receptor tropism testing involves phenotypic assays. However, genotypic assays, which predict tropism based on algorithmic analysis of viral V3 sequencing binding site [10, 11], are also available.
Although phenotypic testing can determine a viral population containing both tropisms, it is not sufficiently sensitive to differentiate between mixed and dual tropism. The Trofile (Monogram Biosciences) co-receptor tropism assay is an RNA-based test that permits phenotypic identification of CCR5, CXCR4 co-receptor, or dual/mixed-tropic (CXCR4/CCR5-utilizing) HIV-1 and should be used prior to the initiation of a receptor antagonist.
Another commercially available recombinant phenotypic assay for assessing HIV chemokine co-receptor tropism is the Phenoscript assay (Eurofins VIRalliance). In this assay, a 900-bp portion containing the patient’s V1-V3 envelope virus is amplified and inserted into a HIV-1 vector lacking the corresponding V1-V3 section. The fully complemented HIV-1 is then able to produce virus that can be used to infect cell lines with either CCR5 or CXCR4 on their surfaces with a colorimetric readout. The results are reported in a similar manner as the Trofile (i.e., CCR5-trophic, CXCR4-trophic, or dual/mixed tropic). This assay has not been validated in a clinical trial setting or against the Trofile assay.
Two DNA-based tropism assays are also available. The HIV-1 Coreceptor Tropism, Proviral DNA (Quest Diagnostics) uses population sequencing of the HIV envelope V3 loop to detect the presence of CXCR4-tropic HIV-1 . The Trofile DNA (Monogram Biosciences) uses the complete gp160 coding region to distinguish whether the HIV-1 population uses CCR5, CXCR4, or both (i.e., dual/mixed tropism) to gain entry into the cell. Unlike HIV-1 RNA-based assays, both the Trofile DNA and HIV-1 Coreceptor Tropism can detect virus in the setting of undetectable HIV-1 viral load levels and should be used when HIV RNA is beneath the lower limit recommended for RNA-based tropism assays (<1,000 copies/mL).
Resistance to the class of CCR5 co-receptor antagonists develops by two unrelated mechanisms. First, the patient’s viral population shifts its co-receptor usage (i.e., uses CXCR4 exclusively or uses both CCR5 and CXCR4 receptors to gain entry into the cell). The current assays are not sufficiently sensitive to discriminate between mixed- or dual-tropic populations. The second method by which resistance to a CCR5 receptor antagonist may develop is by the virus mutating and binding to the CCR5 receptor with the drug antagonist still in place. This second method can be discerned by a flattening of the IC90curves in a phenotypic assay or potentially by genotypic analysis. Analysis by phenotypic assay is the preferred method for this purpose because genotypic data are more complex.
Replicative capacity information may be provided as an adjunct to phenotypic or combination genotypic-phenotypic resistance assays. The relative replicative capacity of the virus from the patient is calculated as the ratio of the patient-derived sequences to wild-type sequences. A ratio of less than 1 reflects a reduced replicative capacity as compared with that of the wild-type control. The full clinical value of this adjunctive information remains under investigation, and it has no clear clinical value at this time.
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- Banks L, Gholamin S, White E, et al. Comparing peripheral blood mononuclear cell DNA and circulating plasma viral RNA pol genotypes of subtype C HIV-1. J AIDS Clin Res 2012;3:141-147. [PubMed]
- Delaugerre C, Braun J, Charreau I, et al. Comparison of resistance mutation patterns in historical plasma HIV RNA genotypes with those in current proviral HIV DNA genotypes among extensively treated patients with suppressed replication. HIV Med 2012;13:517-525. [PubMed]
- Lübke N, Di Cristanziano V, Sierra S, et al. Proviral DNA as a target for HIV-1 resistance analysis. Intervirology 2015;58:184-189. [PubMed]
- Toma J, Tan Y, Cai S, et al. Drug resistance profiles derived from HIV-1 DNA in ARV suppressed patients correlate with historical resistance profiles obtained from HIV-1 plasma RNA. ICAAC 2015, September 17-21, 2015, San Diego. http://www.natap.org/2015/ICAAC/ICAAC_10.htm
- Booth CL, McCormick A, Garcia-Diaz A, et al. Feasibility of testing and detection of HIV-1 drug resistance in pro-viral DNA. BMC Infect Dis 2014;14(Suppl 4)14:O25. http://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-14-S4-O25
- Derache A, Shin HS, Balamane M, et al. HIV drug resistance mutations in proviral DNA from a community treatment program. PLoS One2015;10:e0117430. [PubMed]
- Cohen MS, Shaw GM, McMichael AJ, et al. Acute HIV-1 infection. N Engl J Med 2011;364:1943-1954. [PubMed]
- Vandekerckhove L, Verhofstede C, Vandenbroucke I, et al. Direct comparison with 454 pyrosequencing validates V3-loop based genotyping in patients eligible for Maraviroc initiation. ICAAC, September 15, 2009, San Francisco, CA. Abstract.
- McGovern RA, Thielen A, Mo T, et al. Population-based V3 genotypic tropism assay: A retrospective analysis using screening samples from the A4001029 and MOTIVATE studies. AIDS 2010;24:2517-2525. [PubMed]
- Baumann R, Hamdan H, Schwab D. Performance of an HIV-1 co-receptor tropism assay utilizing replicate V3 loop sequencing and heteroduplex analysis with capillary electrophoresis. Presented at the 18th International HIV Drug Resistance Workshop, June 9-12, 2009, Ft. Myers, FL. Antivir Ther 2009;14:A132. Abstract.
Laboratory Monitoring of ART Side Effects
Medical Care Criteria Committee, March 2006 (unless noted otherwise noted)
This section describes monitoring of the following ART side effects: bone marrow suppression, pancreatitis, lactic acidosis/hepatic steatosis, hepatotoxicity, and renal toxicity. (See Table 14: Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects, in the DHHS guidelines for a table of common and/or severe adverse effects associated with ART).
Bone Marrow Suppression
Bone marrow suppression is most often associated with zidovudine therapy. Significant drug-induced cytopenias become more common in the later stages of symptomatic HIV infection but occasionally develop abruptly in patients at earlier stages.
The incidence of pancreatitis is higher in patients infected with HIV and may be associated with opportunistic infections as well as ART. Didanosine has been the agent most often associated with this complication; however, cases of pancreatitis also have been reported with other antiretroviral agents since the advent of triple combination therapy. Tenofovir increases the levels of didanosine, thereby increasing the theoretical risk of pancreatitis. Thus, when these antiretroviral medications are used in combination, the dose of didanosine should be reduced.
Pancreatitis should be considered in any patient receiving ART who presents with signs or symptoms of pancreatitis (e.g., abdominal pain, persistent nausea, and vomiting), and serum amylase and lipase should be obtained in this setting. Significant hypertriglyceridemia (>500 mg/dL) is associated with an increased risk of pancreatitis, particularly in patients with other risk factors for pancreatitis (e.g., alcohol or didanosine use). Other causes linked to pancreatitis in the general population should be included in the differential diagnosis.
Hyperamylasemia of non-pancreatic (e.g., parotid) origin may occur in HIV-infected patients. Serum lipase levels should be obtained to delineate the source of the increased amylase. Asymptomatic patients with modest elevations in amylase and lipase levels (<3-fold) may be monitored closely without change in therapy.
Lactic Acidosis/Hepatic Steatosis
The syndrome of lactic acidosis/hepatic steatosis is rare but associated with a high mortality rate and has been most often associated with the use of NRTIs. Groups at higher risk for this complication include African Americans, obese patients, female patients, and patients with chronic hepatitis C virus (HCV). The syndrome is marked by constitutional complaints, such as abdominal pain, anorexia, nausea/vomiting, hyperventilation, and/or myalgias associated with elevations in serum lactate levels and decreased serum bicarbonate levels. Blood sampling for venous lactate levels should avoid the use of prolonged tourniquetting, and samples should be transported on ice and processed promptly. Lactic acidosis is believed to manifest only at lactate levels >5 mmol/L with an accompanying decreased bicarbonate level.
Patients taking NRTIs who present with constitutional symptoms should be evaluated for lactic acidosis, including lactate (arterial or venous) and bicarbonate level, arterial blood gas determination, serum amylase and lipase, and serum liver enzymes. In conjunction with the evaluation, ART should be discontinued. If the evaluation does not support the diagnosis of lactic acidosis, ART may be restarted.
Patients with mildly elevated lactate levels (2.1 to 5.0 mmol/L) and a normal bicarbonate level are usually asymptomatic. The clinical significance of mildly elevated lactate levels is still unknown. In the absence of decreased bicarbonate levels, lactic acidosis is uncommon.
Use of Nevirapine
All antiretroviral agents have the potential to cause abnormalities in liver function, especially in patients with preexisting liver disease. Serum liver enzyme levels should be obtained at baseline and every 3 to 4 months in patients receiving ART. More frequent monitoring may be necessary for patients with preexisting liver disease or serum liver enzyme abnormalities. The use of full-dose ritonavir (600 mg twice daily) has been associated with worsening transaminases in patients with preexisting liver disease and should be avoided. Patients who develop serum liver enzyme abnormalities greater than five times the upper limit of normal should be promptly assessed. Any potentially hepatotoxic medication, including all antiretroviral agents, should be discontinued.
A higher incidence of significant hepatotoxicity associated with nevirapine therapy has recently been reported, especially in women with CD4 counts >250 cells/mm3, men with CD4 counts >400 cells/mm3, and in the setting of HCV coinfection. The greatest risk of severe and potentially fatal hepatotoxicity occurs in the first 6 weeks of treatment; however, the FDA and the manufacturer strongly recommend intensive monitoring during the first 18 weeks of nevirapine therapy, with discontinuation of the drug if moderate or severe abnormalities occur. In the absence of definitive clinical evidence, monitoring serum liver enzymes every 2 weeks for the first month of nevirapine therapy, then monthly for the first 12 weeks, and every 1 to 3 months thereafter is a reasonable approach, given the potential severity of adverse events. It is essential that the 14-day lead-in period be strictly followed. In some cases, the hepatic injury progresses even after discontinuation of nevirapine. In the setting of hepatotoxicity related to nevirapine, the patient should not be re-challenged with nevirapine.
Some clinicians would avoid using efavirenz after severe nevirapine-related hepatotoxicity (LFTs >5x ULN) with or without Grade 4 rash (Stevens-Johnson syndrome); however, there is no clear evidence to support an association between nevirapine-related hepatotoxicity and efavirenz-related hepatotoxicity . For mild to moderate nevirapine-related hepatotoxicity (LFTs >3-5 x ULN), switching to efavirenz after complete resolution of hepatotoxicity is an option if there are no other contraindications to efavirenz. Contraindications to efavirenz include known adverse reactions to efavirenz, first-trimester pregnancy, or strong likelihood of becoming pregnant.
For pregnant women with nevirapine-related hepatotoxicity, the clinician should switch the regimen to 2 NRTIs + PI. Efavirenz should only be considered after the first 8 weeks of pregnancy if there are no other options and the benefits outweigh the risks. For additional information, see the DHHS Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.
In the setting of severe nevirapine-related hepatotoxicity, all antiretroviral agents and any other possible offending agents should be discontinued. The risk of severe hepatotoxicity outweighs the risk of possible emergence of resistance.
For all HIV-infected patients receiving ART:
For patients receiving tenofovir:
For patients receiving indinavir:
HIV infection has been associated with several renal complications that may lead to renal insufficiency or failure [2, 3]. Renal impairment necessitates dose adjustment or discontinuation of many antiretroviral agents.
Clinicians should routinely obtain urinalysis and serum creatinine levels as well as calculate glomerular filtration rates (GFR) to assess renal function. When calculating GFR, the clinician should consistently use the same method. GFR can be calculated by using one of the following equations:
- Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) Calculator: Estimates GFR based on age, race, and serum creatinine.
- Modification of Diet in Renal Disease (MDRD) Calculator: Estimates GFR based on age, sex, height, serum creatinine, serum albumin, and serum blood urea nitrogen (BUN).
- Cockroft-Gault Calculator: Calculates creatinine clearance based on serum creatinine, age, weight, and sex.
Tenofovir is excreted by glomerular filtration and tubular secretion. Renal impairment has been reported in patients receiving tenofovir [3, 4]. The extent of this toxicity is unclear. Additional risk factors include low body weight, older age, use of boosted regimens, hypertension, diabetes, and use of other nephrotoxic drugs. Hypophosphatemia may be an early indicator of renal failure. Clinicians may want to use a lower threshold for dose adjustment in patients receiving tenofovir. Clinicians should discontinue tenofovir when patients present with symptoms suggestive of Fanconi syndrome, such as declining renal function with associated metabolic acidosis, hypophosphatemia, hypokalemia, glycosuria, and uricosuria. The decision to rechallenge with tenofovir should be made on a case-by-case basis.
Indinavir (especially when used with ritonavir) and agents used to prevent and/or treat opportunistic infections may cause hematuria, pyuria, or crystalluria. Patients receiving indinavir should be counseled to drink at least 48 ounces of fluid per day. Clinicians should consider urinalysis every 3 to 4 months for patients receiving indinavir-containing regimens.
For additional information regarding renal assessment and management of kidney disease in HIV-infected patients, see Kidney Disease in HIV-Infected Patients.
- Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: Role of hepatitis C and B infections. Hepatology 2002;35;182-189. [PubMed] The greatest risk of NNRTI-associated severe hepatotoxicity was observed in patients taking NVP, those with hepatitis B or C co-infection, and those co-administered PIs.
- Miro JM, Cofan F, Trullas JC, et al. Renal dysfunction in the setting of HIV/AIDS. Curr HIV/AIDS Rep 2012;9:187-199. [PubMed] HIV-infected individuals commonly experience renal complications and have a high prevalence of risk factors, including HIV infection itself, that contribute to the development of kidney disease.
- Zaidan M, Lescure FX, Brochériou I, et al. Tubulointerstitial nephropathies in HIV-infected patients over the past 15 years: A clinico-pathological study. Clin J Am Soc Nephrol 2013;8:930-938. [PubMed] Drug toxicity, infection, and syndromes associated with immunosuppression in the setting of HIV demonstrate the importance of monitoring kidney function HIV-infected patients.
- Laprise C, Baril JG, Dufresne S, et al. Association between tenofovir exposure and reduced kidney function in a cohort of HIV-positive patients: Results from 10 years of follow-up. Clin Infect Dis 2013;56:567-575. [PubMed] Tenofovir exposure significantly increased the risk of kidney dysfunction, but the loss in estimated glomerular filtration rate due to TDF was relatively mild over the long term.
Monitoring for ART-Associated Allergic Reactions
Medical Care Criteria Committee, June 2010
|Table 4: Antiretroviral Drugs Typically Associated with Allergic Reactions|
|ARV Drug (usual timing of symptoms)||Most Frequent Symptoms||Action|
|Abacavir* (first 4-6 weeks after initiation)||Hypersensitivity reaction: Fever, headache, gastrointestinal symptoms, malaise, arthralgias, myalgias, and respiratory problems. Skin involvement, with rash and pruritus may be mild or absent.||
|Delavirdine (first 4 weeks after initiation)||Mild to moderate cutaneous allergy||
|Efavirenz (first 4 weeks after initiation)||Mild to moderate cutaneous allergy||
|Enfuvirtide||In the phase 3 trials of enfuvirtide, three cases of probable hypersensitivity were identified. These included, either individually or in combination: rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated LFTs.||—|
|Etravirine (generally occurs in the 2nd week of treatment; infrequent after week 4)||
Severe reaction: Cutaneous, involving the mucocutaneous surfaces (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme)
Mild reaction: mild skin rash
| Severe reaction:
Mild reaction: Manage with antihistamines and close monitoring
|Fosamprenavir, tipranavir, and darunavir||Mild to moderate cutaneous allergy||
|Nevirapine (first 2 to 18 weeks after initiation)||
Severe reaction: Cutaneous, involving the mucocutaneous surfaces (Stevens-Johnson syndrome), often accompanied by fever and severe hepatitis
Mild reaction: mild skin rash
| Severe reaction:
|Raltegravir||Rashes, including severe skin rashes and cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported||Discontinue if rash is accompanied by constitutional symptoms (i.e., fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema)|
|*HLA-B*5701 is a pharmacogenetic test (HLA-B*5701) used to identify patients who are predisposed to abacavir hypersensitivity. Clinicians should perform HLA-B*5701 testing before initiating abacavir-based therapy.|
Many medications pose the risk of causing various types of allergic reactions, typically presenting as maculopapular rash, with or without fever. Occasionally, a more severe hypersensitivity reaction occurs, consisting of rash and fever, with a combination of other symptoms, such as headache, arthralgias, hepatitis, eosinophilia, and GI or respiratory symptoms. The hypersensitivity reaction usually occurs within 2 to 6 weeks after the drug is started.
Although trimethoprim/sulfamethoxazole is the drug most frequently implicated in common allergic reactions in HIV-infected patients, abacavir, darunavir, tipranavir, fosamprenavir, all of the NNRTIs (nevirapine, delavirdine, efavirenz, etravirine), and enfuvirtide (less commonly) have been associated with a hypersensitivity reaction or syndrome (see Table 4). These reactions are for the most part idiosyncratic and unanticipated. The reactions to darunavir, fosamprenavir, tipranavir (all have a sulfa moiety), delavirdine, and efavirenz are generally mild to moderate cutaneous allergy (drug rash). Patients may rarely develop severe mucous membrane involvement with systemic toxicity. Occasionally, patients will only have a fever. Clinicians should discuss the possibility of these reactions with patients initiating ART because they are most commonly seen in the first 4 weeks of treatment; clinicians should educate patients about the symptoms of hypersensitivity.
Systemic antihistamines may be useful in treating mild cases while patients continue to receive the offending drug. The offending drug should be discontinued when there is a moderate to severe skin reaction, mucous membrane involvement, systemic toxicity, or fever.
Individuals with human leukocyte Ag (HLA)-B*5701, HLA-DR7, and HLA-DQ3 have a genetic predisposition to development of abacavir hypersensitivity. HLA-B*5701 testing is the most thoroughly documented method for assessing for abacavir hypersensitivity and should be determined prior to treatment with this agent [1, 2]. Unlike virus-specific tests (HIV genotype, phenotype, co-receptor tropism assays), HLA genotyping is necessary only once during an individual’s lifetime, because it will not change over time.
Hypersensitivity to abacavir occurred in as many as 5% of patients before routine HLA-B*5701 testing was recommended. The reaction usually occurs within the first 10 to 14 days of therapy and rarely occurs after the first 6 weeks. Fever, headache, GI symptoms, malaise, arthralgias, myalgias, and respiratory problems are the most frequent manifestations of the abacavir hypersensitivity reaction. Skin involvement, with rash and pruritus, may be mild or absent. HLA-B*5701 is a pharmacogenetic test (HLA-B*5701) used to identify patients who are predisposed to abacavir hypersensitivity. Clinicians should perform HLA-B*5701 testing before initiating abacavir-based therapy.
Prompt discontinuation of abacavir when a hypersensitivity reaction is suspected is necessary because symptoms will worsen over time. Once abacavir has been discontinued because of a possible or definite hypersensitivity reaction, abacavir should never be administered again. Re-challenge may result in an anaphylactic reaction with associated hypotension or death.
Nevirapine, an NNRTI, has been associated with severe hypersensitivity reactions in the first 2 to 12 weeks of use. Graduated dosing of nevirapine at initiation with 200 mg daily for the first 2 weeks followed by 200 mg twice daily thereafter has reduced the incidence of hypersensitivity reactions. Systemic antihistamines or corticosteroids given at the time of nevirapine initiation have not been proven useful. Such reactions manifest as severe cutaneous reaction involving the mucocutaneous surfaces (Stevens-Johnson syndrome), often with accompanying fever and severe hepatitis. Deaths associated with these reactions have been reported. Patients who develop mild rashes without systemic toxicity may be managed with antihistamines and close monitoring. The nevirapine dose should not be escalated to twice daily until the rash has resolved. However, those with moderate to severe cutaneous toxicity should discontinue nevirapine promptly and should not be re-challenged with this drug. Because of potential cross-reactivity, use of an alternate NNRTI should be avoided in patients who have a severe reaction to nevirapine; however, the incidence of etravirine rash is not high in patients with a history of NNRTI rash.
Etravirine, an NNRTI, has been associated with hypersensitivity reaction. Up to 10% of patients in clinical trials reported rashes. Most reported mild to moderate rashes. Grade 3 and 4 rashes reported in 1.3% of patients, and up to 2.2% of patients required etravirine discontinuation. Rashes generally occur in the second week of treatment and are infrequent after week 4. Etravirine should be discontinued for severe rash or if rash is accompanied by fever, hepatitis, and other systemic symptoms.
In the phase 3 trials of enfuvirtide, three cases of probable hypersensitivity to the drug were identified. These have included, either individually or in combination, rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver enzymes.
- Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse transcriptase inhibitor abacavir. Lancet 2002;359:727-732. [PubMed]
- Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet2002;359:1121-1122. [PubMed]
|ALL RECOMMENDATIONS: MONITORING OF PATIENTS ON ART|
Virologic and Immunologic Monitoring (June 2016)
HIV Resistance Assays (June 2016)
Laboratory Monitoring of HIV Side Effects
Monitoring for ART-Associated Allergic Reactions (June 2010)