INTRODUCTION — Proper utilization of antiretroviral therapy (ART) requires ongoing patient monitoring to assess therapeutic response and to identify adverse events related to chronic administration of potentially toxic medications. Failure to respond to a recommended ART regimen is almost always a result of suboptimal adherence or viral resistance.
This topic will address laboratory monitoring during ART. Discussions related to the initiation and modification of ART are found elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "When to initiate antiretroviral therapy in persons with HIV" and "Overview of antiretroviral agents used to treat HIV".)
ADHERENCE — At each visit, patients should be interviewed regarding medication adherence in a nonjudgmental manner. Optimal adherence (ie, taking all medication doses at the time intervals prescribed) to an antiretroviral therapy (ART) regimen is important to help patients achieve and maintain virologic suppression. Adherence can vary over time and can be impacted by factors such as depression and substance use [1]. Strict adherence is most important when patients are initiating or changing an ART regimen.
To enhance adherence, patients should understand the link between adherence and drug resistance. In addition, it is useful to discuss medication schedules with patients to help them link pill-taking behaviors to other daily activities (eg, brushing teeth). If the patient admits to difficulties with adherence, potential barriers could involve the number and timing of doses, sizes of pills, food restrictions, and treatment-limiting side effects. The patient should also be advised to notify the provider if there is an anticipated problem with adherence, such as elective surgery, or a prolonged intercurrent illness. (See "Overview of antiretroviral agents used to treat HIV".)
Adherence can be difficult to assess. As an example, one study demonstrated that clinicians incorrectly predicted adherence in 41 percent of patients [2]. In addition, patients often exaggerate adherence to their provider. Pharmacy records are useful to help track compliance when refills are obtained from a single pharmacy source. Clinical trials have tried to assess whether directly observed therapy may improve virologic suppression rates. One meta-analysis of 12 studies suggested that such therapy seemed to offer no benefit over self-administered treatment [3]. However, directly observed therapy may be beneficial in patient subgroups that are at high risk for nonadherence, such as those who are homeless [4]. Other adherence interventions (eg, assessing serum drug concentrations, monitoring pill counts, or use of electronic drug monitoring devices) are not routinely recommended [5].
For patients who have achieved sustained viral suppression, current antiretroviral medications are less affected by changes in adherence than treatments used in the early years of combination ART. Present therapies are more potent, have a higher genetic barrier to resistance, and/or a long serum half-life. These advantages have allowed less stringent adherence with a lower risk of clinical consequences compared with some early antiretroviral medications. Despite this, patients should inform providers if doses are missed for more than a few days (eg, patient forgot to take pills on vacation) so that viral load testing can be performed.
Medication persistence — Medication persistence is defined as the duration of time from initiation to discontinuation of therapy. Whereas adherence measures "how often" patients take their medications, persistence measures "for how long" [6]. This concept of medication persistence is important since interruption of ART has significant consequences, not only in increased risk for opportunistic infections, but also for serious non-AIDS events [7], and transmission of HIV to others.
VISIT FREQUENCY — Patients who are started on ART should generally have follow-up within one to two weeks to ask patients about their understanding of the regimen, adverse effects, adherence, and prevention of transmission. Once patients are clinically stable on their ART regimen, visit frequency can decrease to every three to six months.
Measurements of height and weight for calculation of body mass index are advised at clinic visits; some clinics also incorporate measurements of waist circumference to detect early changes suggestive of HIV-associated lipodystrophy. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy".)
GENERAL LABORATORY MONITORING — The clinician should obtain several tests upon entry to care, before initiation of antiretroviral therapy (ART), and during ART. For more information, see table 3 of the United States Department of Health and Human Services (DHHS) Antiretroviral Guidelines for the Treatment of Adults and Adolescents [8], as well as the topic that discusses the initial evaluation of adults with HIV. (See "Initial evaluation of adults with HIV".)
For patients initiating antiretroviral therapy, the following laboratory tests should be obtained at baseline and then as indicated:
●Complete blood count with differential every three to six months when CD4 testing is required, and then yearly thereafter
●Basic chemistry, including blood urea nitrogen and creatinine, two to eight weeks following ART initiation and every six months thereafter
●Urinalysis every 12 months
●Alanine and aspartate aminotransferases and total bilirubin two to eight weeks following ART initiation and every three to six months thereafter
●Lipid and glucose (fasting glucose or hemoglobin A1C) levels should be obtained at baseline when starting ART, and every 12 months thereafter [8].
More frequent monitoring is warranted in patients who have abnormal results and may also be indicated depending upon the specific agent(s) that are used. As examples:
●Patients receiving tenofovir disoproxil fumarate should have a urinalysis obtained every six months since its use can be associated with kidney disease [8,9]. Tenofovir alafenamide is less likely to induce nephrotoxicity; however, the frequency of monitoring is unknown, and guidelines still recommend monitoring every six months [8].
●For patients receiving nevirapine, some experts recommend that liver function tests be performed at baseline and then at 2, 4, 8, and 12 weeks after initiation. If normal, they can be monitored every 3 months thereafter. Patients should also be instructed about the symptoms of clinical hepatitis, particularly if they have risk factors for hepatotoxicity, such as underlying chronic viral hepatitis. (See "Overview of antiretroviral agents used to treat HIV".)
●Hematologic monitoring is particularly important in patients taking zidovudine, which can cause bone marrow suppression [8].
If mild or moderate abnormalities are detected and persist, a change in the ART regimen may be required. As an example, patient’s renal function should be monitored using a creatinine-based estimated glomerular filtration rate; guideline recommendations suggest substituting an alternative agent for tenofovir disoproxil fumarate if a patient has a decline in their estimated glomerular filtration rate (eg, by >25 percent and to a level <60 mL/min/1.73m2) and there are no other explanations for the decline [10]. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)
Immune activation and inflammation are thought to play an important role in the pathogenesis of certain long-term consequences of HIV infection (eg, premature aging, non-AIDS defining cancers, cardiovascular disease). Markers of immune activation and inflammation are elevated with HIV infection and reduced, but in some patients not normalized, with antiretroviral therapy. However, despite the clinical significance of these abnormalities, routine testing for these markers is not recommended in clinical practice. (See "Pathogenesis and biomarkers of cardiovascular disease in patients with HIV".)
VIROLOGIC RESPONSE — Plasma HIV RNA should be measured in all patients at baseline and regularly during therapy since it is the most reliable indicator of response to antiretroviral therapy (ART) and is useful in predicting clinical progression [11,12]. The goal of therapy is viral load suppression below the limits of assay detection. The assays most commonly in use have lower limits of detection of between 20 and 40 copies/mL. (See "Techniques and interpretation of HIV-1 RNA quantitation".)
In adherent patients starting ART, the speed of the viral load decline depends primarily upon the agents used in the regimen. The most rapid declines occur with integrase strand transfer inhibitor-based regimens; non-nucleoside reverse transcriptase inhibitor-based therapies are intermediate, and protease inhibitor treatments the slowest. Despite these differences, the expectation is that the initial antiretroviral regimen will achieve substantial (2 log or more) viral load declines by weeks 2 to 4 of treatment, with anything less than this suggestive of poor adherence. The viral load should be near or below the level of detection by 8 to 24 weeks, regardless of prior treatment experience, with patients who start with the highest viral loads taking the longest to reach this threshold [8,13-18].
Acute illness and vaccinations can cause a transient increase in the viral load. Because of biologic variability, sequential HIV viral load measurements must exceed a threefold change or 0.5 log10 copies/mL to be considered significantly different [8]. Unanticipated results should be verified with a repeat test before making changes in antiretroviral therapy.
Virologic failure — The optimal goal of therapy is viral load suppression below the limits of assay detection. However, we consider a patient to have virologic failure if they do not achieve a viral load <200 copies/mL within 24 weeks of initiating ART or if they have a sustained recurrence of viremia to >200 copies/mL (ie, on two consecutive measurements) after initial viral suppression. This definition is consistent with the one used by the NIH AIDS Clinical Trials Group and the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents [8], and is based upon the following rationale:
●There is no definitive evidence that patients with single viral loads quantified as >20 copies/mL and <200 copies/mL using current assays are at increased risk for virologic failure.
●This definition eliminates most cases of transient viremia caused by release of virus without viral replication, or assay variability. (See 'Viral blips' below.)
There are two main causes for virologic failure: drug resistance and/or subtherapeutic drug levels. The latter is almost always due to problems adhering to the drug regimen, with less common causes being drug interactions or altered pharmacology due to host factors (eg, malabsorption). Thus, clinicians should thoroughly evaluate adherence in any patient who demonstrates a suboptimal early response to ART:
●Patients should be asked to describe how they are taking their ART regimen to detect errors in prescribing, dispensing, or patient comprehension.
●Patients should be asked how many doses they are missing in a non-judgmental manner. Patients will frequently overstate adherence and the following wording may be helpful in permitting patients to discuss adherence problems: "Taking pills every day can be difficult and some patients I care for have trouble taking every dose as prescribed. How much of the prescribed medication are you taking?"
●Pharmacy refill records are an excellent way to monitor patient adherence. Although rare individuals may evade this monitoring strategy by refilling their medications and discarding them, most non-adherent patients irregularly or never refill their medications.
Drug resistance testing should be performed in the setting of virologic failure even in patients who attest to excellent adherence. Drug resistance may be transmitted or acquired due to suboptimal treatment or inadequate adherence [14,16,19-23]. In addition, resistance mutations in patients with transmitted resistance may not be apparent with baseline testing if they are present in the minority pool. (See 'Drug resistance testing' below.)
Detailed discussions of the evaluation and management of patients with virologic failure are found elsewhere. (See "Evaluation of the treatment-experienced patient failing HIV therapy" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
Viral blips — Viral "blips" refer to an isolated low-level of detectable HIV RNA, typically 20 to 200 copies/mL, that occurs during long-term monitoring of patients on ART with a suppressed viral load (ie, HIV RNA below the limits of assay detection) [8,24]. We do not modify antiretroviral treatment for patients who have a "viral blip" unless the viral load is sustained at >200 copies/mL. Instead, if a blip is detected, we initiate a discussion with the patient regarding adherence, and repeat a viral load within four weeks.
Most viral blips are not clinically significant, and are thought to represent laboratory error or release of virions not related to active viral replication [25-27]. However, one study reported that patients with a viral rebound between 50 and 1000 copies/mL were at increased risk for virologic failure [28]. Data suggest there is a gradient of low-level viremia, which, at the higher ranges, may predict future treatment failure [29].
CD4 CELL COUNTS — CD4 cell counts correlate with the immune response. In patients who achieve and maintain viral suppression, immunologic improvement is progressive over many years [30]. Viral suppression is usually accompanied by an increase in CD4 count of ≥50 cells/microL at four to eight weeks, followed by slower incremental increases of 50 to 100 cells/microL per year [31]. The rate of increase in CD4 cells may be slower in older patients or in those with severe immunocompromise at baseline [32]. (See "HIV infection in older adults".)
CD4 cell counts may increase even in patients who cannot maintain viral suppression. These "discordant results" were seen most commonly in patients with extensive drug resistance to antiretroviral therapy (ART) when fewer drug classes were available [33]. Various hypotheses for this observed immunologic benefit in the face of ongoing viremia have been proposed, including decreased replication capacity of resistant strains, decreased immune activation, and preservation of non-syncytium-inducing strains [34]. However, this immunologic benefit was usually lost when the HIV RNA returned to the pre-treatment baseline [35]. With the current availability of a wide range of HIV treatments with activity against resistant viruses, most patients are able to achieve virologic suppression.
In contrast, other patients may obtain viral suppression without any significant improvement in absolute CD4 cell counts. Risk factors for this outcome include advanced age and low nadir CD4 count. This observation has also been noted in patients treated with the combination of didanosine and tenofovir disoproxil fumarate, which is no longer recommended.
The CD4 count can be affected by inter-laboratory variability, acute illness, medications that suppress the bone marrow, and diurnal variation. For these reasons, results that are unexpectedly different from prior ones should be confirmed with a repeat test. A significant difference between two test results is generally defined as a 30 percent change in the absolute CD4 count or a change in CD4 cell count percent by three percentage points [8]. (See "Techniques and interpretation of measurement of the CD4 cell count in people with HIV".)
FREQUENCY OF IMMUNOLOGIC AND VIROLOGIC MONITORING — Precise data are not available regarding the optimal frequency of virologic and immunologic monitoring after the initiation of ART. The time to achieve an undetectable viral load depends on the potency of the regimen, drug resistance, and the baseline viral load. Laboratory monitoring is done more frequently after the initiation or modification of ART; the interval can then be increased when viral suppression is achieved and sustained since virologic and immunologic failure is unlikely in patients with sustained virologic suppression and immunologic recovery [36,37].
Viral load monitoring — We recommend HIV RNA testing two weeks after initiation of ART and then at four to eight-week intervals until the level falls below the assay's limit of detection (<20 to 50 copies/mL by most commercial assays). Patients who have a suboptimal decrease in viral load, even after two weeks, could be confused about how to take their regimen and/or be non-adherent. Thus, providers should talk with such patients to ensure they are taking their medications properly (eg, dosing, avoiding drug interactions) and counsel them on adherence. Drug resistance testing should be performed on virus from patients who have not achieved HIV RNA suppression by 24 weeks, or earlier if there is an increase from a prior value. (See 'Virologic failure' above.)
Once viral suppression is attained, HIV RNA can be monitored every three to six months. Viral load testing can be performed every six months in patients whose viral load has been suppressed for more than two years and whose CD4 count remains above 300 cells/microL. More frequent testing should be resumed if a patient has a deterioration in their clinical status, such as an opportunistic infection, has a significant lapse in treatment for any reason, or if a patient has an undetectable viral load, but undergoes a change in regimen (eg, because of toxicity). For individuals changing their ART regimen, HIV RNA should be monitored within two to eight weeks after a change is made to be certain viral suppression has been maintained [8].
Recommendations of others — The DHHS and The International Antiviral Society-USA (IAS-USA) panels have issued guidelines for viral load monitoring. Their recommendations for the frequency of monitoring vary modestly, and are summarized as follows:
●The DHHS Panel recommends [8]:
•HIV load testing at two to eight weeks after initiating ART and then every four to eight weeks after that until the viral load falls below the assay’s limit of detection. The viral load can then be measured every three to four months. It is expected that viral suppression will occur 8 to 24 weeks after ART initiation.
•The interval for viral load monitoring may be extended to every six months for adherent patients who have suppressed viral loads (ie below the assays level of detection) for more than two years.
●The International Antiviral Society-USA (IAS-USA) expert panel recommends [13]:
•Measurement of plasma HIV RNA should be monitored within the first six weeks of starting ART and every three months after treatment is initiated until a non-detectable viral load is confirmed. The interval can then be extended to every three months.
•The interval for viral load monitoring can be extended to every six months in patients with dependable adherence once the viral load is suppressed for a year.
CD4 cell count monitoring — We obtain a CD4 cell count three months after initiating therapy, and subsequently every three to six months. This provides information regarding the need for continued prophylaxis to prevent opportunistic infections, especially in patients with CD4 cell counts <200 cells/microL.
We agree with guideline recommendations for less frequent measurements of the CD4 cell count in patients who have been on ART for at least two years if the CD4 cell count stabilizes at a level well above the threshold for opportunistic infection risk (eg, 300 cells/microL) and the viral load is consistently suppressed to undetectable levels [8,13]. In such patients we monitor the CD4 cell count every 12 months if the CD4 cell count is between 300 and 500 cells/microL. If the CD4 cell count is >500 cells/microL, CD4 cell count monitoring is optional. This use of less frequent CD4 cell count monitoring is supported by the following studies [37,38].
●A retrospective cohort study evaluated 832 patients with HIV and a viral load <200 copies/mL and a CD4 count of ≥200 cells/microL [37]. Individuals on ART with an HIV RNA <200 copies/mL and a CD4 count ≥300 cells/microL had a nearly 100 percent probability of maintaining a CD4 cell count ≥200 cells/microL over four years when non-HIV causes of CD4 lymphopenia were excluded.
●A prospective trial comparing different ART regimens analyzed data on 449 patients who had an HIV RNA <400 copies/ml and a CD4 cell count >200 cells/microL after 48 weeks of treatment [38]. These patients were followed for a total of 192 weeks, and only 5 (1 percent) had a reduction in their CD4 cell count to <200 cells/microL.
We recommend the resumption of more frequent monitoring (every three to six months) for the following individuals:
●Patients with an opportunistic infection
●Those undergoing immunosuppressive therapy
●Patients with a viral load >200 copies/mL and receiving ART
DRUG RESISTANCE TESTING — Drug resistance testing should be obtained in patients with evidence of virologic failure. These tests usually require a viral load >500 copies/mL. Resistance testing should ideally be performed while the patient is taking the failing regimen, or within a few weeks of discontinuing treatment; however this might not be possible in patients who are nonadherent to their regimen. The results should be evaluated by a clinician with expertise in interpretation, and then used to guide selection of a new regimen. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
In patients with virologic failure despite appropriate adherence, HIV resistance testing may detect archived mutations that were not found on baseline resistance testing but emerged during treatment [39]. In contrast, drug resistance testing may not detect all the viral mutations in patients who have virologic failure because of non-adherence, since drug-resistant virus may be out-competed by wild-type virus. This situation is most likely to occur when the patient has not taken his/her medications for more than four weeks when resistance testing is performed. However, many mutations do persist, and if found, are useful for selecting the next antiretroviral regimen. A more detailed discussion of how to evaluate a patient failing antiretroviral therapy is found elsewhere. (See "Evaluation of the treatment-experienced patient failing HIV therapy".)
THERAPEUTIC DRUG MONITORING — There are a myriad of factors that can affect serum drug levels, including liver disease, plasma protein binding and other factors. Marked inter-patient variation in drugs like protease inhibitors and non-nucleoside reverse transcriptase inhibitors, has led to interest in measuring serum drug concentrations to guide dosing. However, these assays are not standardized and there are conflicting data on clinical utility. These assays are not recommended at this time for routine use in clinical practice [13]. (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)
INDICATIONS FOR CHANGING THERAPY — Common indications for changing the antiretroviral regimen include:
●Virologic failure (see 'Virologic failure' above)
●Toxicity (see 'General laboratory monitoring' above)
●Intolerance
●Inconvenience or preference (eg, frequency of dosing, pill burden, or requirements for coadministration with food) (see 'Adherence' above)
Virologic failure should be confirmed with a second test before any treatment modification is considered. The evaluation and treatment of patients with virologic failure are discussed in detail separately. (See "Evaluation of the treatment-experienced patient failing HIV therapy" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in nonpregnant adults and adolescents".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: HIV/AIDS (The Basics)" and "Patient education: Tests to monitor HIV (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Proper utilization of antiretroviral therapy (ART) requires ongoing patient monitoring to assess therapeutic response and to identify adverse events related to chronic administration of potentially toxic medications. (See 'Introduction' above.)
●Patients should be interviewed regarding medication adherence at each clinic visit in a nonjudgmental manner. (See 'Adherence' above.)
●Patients who are started on ART should generally have follow-up within one to two weeks to ask patients about adverse effects, adherence, and prevention of transmission. Once patients are clinically stable on their ART regimen, visit frequency can decrease to every three to six months. (See 'Visit frequency' above.)
●Routine laboratory monitoring includes complete blood count with differential, blood urea nitrogen and creatinine, liver function tests, lipid and glucose levels, and urinalysis. Additional monitoring may be indicated depending upon the specific agent(s) that are used. (See 'General laboratory monitoring' above.)
●We do HIV RNA testing two weeks after the initiation of ART, and then every four to eight weeks until the level falls below the assay's limit of detection (below 20 to 50 copies/mL by most commercial assays). At that point, the viral load can be measured every three to six months to confirm ongoing viral suppression. (See 'Viral load monitoring' above.)
●A CD4 cell count should be obtained three months after initiating therapy, and subsequently every three to six months. (See 'CD4 cell count monitoring' above.)
●For patients who have suppressed viral loads for more than two years, viral load testing can be performed every six months and CD4 cell counts can be checked annually. If the CD4 cell count is >500 cells/microL, CD4 cell count monitoring is optional. However, more frequent HIV RNA monitoring should be resumed if there is a change in the patient’s clinical status or if there is a change in regimen. (See 'CD4 cell count monitoring' above and 'Viral load monitoring' above.)
●Virologic failure is defined either as primary failure to achieve a viral load <200 copies/mL or any sustained recurrence of viremia to >200 copies/mL after initial viral suppression. Virologic failure may be due to drug resistance or lack of adherence. (See 'Virologic failure' above.)
●Viral "blips" refer to an isolated low-level of detectable HIV RNA, typically 20 to 200 copies/mL, that occurs during long-term monitoring of patients on ART with a suppressed viral load (ie, HIV RNA below the limits of assay detection). Isolated viral blips do not appear to represent ongoing viral replication, unless low levels of viremia are sustained. (See 'Viral blips' above.)
●In patients with virologic failure, HIV resistance testing should be obtained. (See 'Drug resistance testing' above.)
●Therapeutic drug monitoring is not routinely recommended. (See 'Therapeutic drug monitoring' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge John G Bartlett, MD, who contributed to an earlier version of this topic review.
