Category Archives: 6.11. Monitoring

6.11. Monitoring

– Christian Hoffmann, Christian Noah –

Which parameters should be included in routine laboratory monitoring of HIV-positive patients? What results can be expected? This section deals with viral load, CD4 T cells, routine checks, and plasma levels. Resistance and tropism tests are the subject of a separate chapter (see HIV Resistance Testing). For the tests to be performed on initial presentation see The New Patient.

Viral Load

Viral load is the amount of HIV RNA in the blood. Alongside the CD4 T cell count, viral load has become the most important surrogate marker for HIV infection (Hughes 1997, Mellors 1997, Lyles 2000, Ghani 2001, Phillips 2004). It provides information on how high the risk is for disease progression and whether antiretroviral therapy is indicated; it is the critical value in determining the success of therapy. Viral load assays measure the amount of HIV RNA (viral genetic material), which correlates directly with the number of virions. The units are viral copies/ml (or genome equivalents). This is reported either as a direct whole number or as a logarithmic number. A change of one or more logs refers to the change in viral load by one or more decimal powers. Many labs provide both values, the number and the log. There is no standardized international unit/ml as in used in hepatitis B or C.

Number of copies Log10
10 1.0
50 1.7
100 2.0
500 2.7
1000 3.0
10,000 4.0
50,000 4.7
100,000 5.0
1,000,000 6.0

Assessment

The higher the viral load, the higher the risk of decrease in CD4 T cells, with subsequent disease progression or occurrence of AIDS-related illnesses (Mellors 1997, Lyles 2000, Phillips 2004). A viral load above 100,000 copies/ml (sometimes even above 50,000 copies/ml) is considered to be high; a value below 10,000 copies/ml (sometimes below 5000 copies/ml), low. However, these thresholds are not absolute and only provide points of reference.

The effects of plasma viremia on immune status can vary greatly between individuals. There are some patients whose CD4 T cells remain stable for relatively long periods despite having a high viral load, while others experience a rapid drop, although the viral load is relatively low. Even in the so-called elite controllers in which the viral load is undetectable without ART a slow but constant drop in the CD4 cells can be observed (Stellbrink 2008).

Viral load is probably lower in women than in men. In a meta-analysis, the difference was 41% or 0.23 logs (95% CI 0.16-0.31 logs) (Napravnik 2002). The reason for this phenomenon remains unclear and whether it should have an impact on the indication for treatment is still the subject of debate.

Methods

Three methods or assays are currently used to measure viral load: Reverse Transcription-Polymerase Chain Reaction (RT-PCR); branched-chain DNA (bDNA); and, occasionally, Nucleic Acid Sequence-Based Amplification (NASBA). These three methods differ both in levels of detection and in the linear range within which measurement is reliable or reproducible (see Table 11.1). In the case of PCR and NASBA, the viral RNA is transformed in several enzymatic steps and then amplified to measurable amounts. Detection occurs after binding of marked DNA fragments. bDNA does not require an enzymatic step; signal amplification occurs via binding of branched DNA fragments to viral RNA.

The market for assay systems is very dynamic. New assay systems will become available, existing ones further developed. Siemens, for example, offers an RT-PCR in addition to bDNA technology. Roche concentrates on RT-PCR and is working on additional functions such as “dual-target detection” for more successful results. This means that not one section of the viral RNA, like before, but two sections can be duplicated at the same time. If duplication fails in one section on account of the high variability of the HIV genome (the result in this case would be incorrect negative), it will be duplicated in the second section. Besides already established manufacturers, newer companies such as Qiagen are trying to gain market share. Experience will show whether their testing systems are reliable or not.

Recent further developments also concern a reduction below detection level which is at 20 copies/ml in the most sensitive tests. Clinical relevance of a viral load below 50 copies/ml is questionable due to lack of data. It should be noted that a higher sensitivity can lead to insecurity in patients and clinicians and to more frequent control tests.

Although intra-assay variability is fairly good for all three methods, methodological variations should be carefully considered. Differences of less than 0.5 logs are not considered significant. A decrease from 4.3 to 3.9 logs, for example (corresponding to a decrease from approximately 20,000 to 8,000 viral copies/ml) does not necessarily signify a drop in viral load. The same holds for increases in viral load. Changes of up to threefold can therefore be irrelevant. Patients should be made aware of this.

Considerable differences exist between the methods (Coste 1996) and to change from one method to another is therefore generally not advisable. The results obtained by bDNA are usually lower than the PCR by a factor of 2. Different subtypes are also detected with varying success according to the method employed (Parekh 1999). One should be particularly cautious in patients from Africa and Asia with non-B subtypes in whom the viral load at first presentation can be unexpectedly low. In such cases, use of a different assay may actually be indicated. However, newer versions with improved primers are probably superior in measuring even unusual HIV subtypes with adequate sensitivity.

All assays have a linear dynamic range, outside of which precise numbers are not so reliable. The following rule applies: use one method, one laboratory. The laboratory should be experienced and routinely perform a sufficiently large number of tests. Measurement should take place as soon as possible after blood withdrawal, and correct collection and shipping of centrifuged plasma is also important (contact the laboratory ahead of time on these issues).

Tabelle 11.1. Methods of measurement.
Company

Test

Technology

Detection limit (co-pies/ml)

Linear Range (copies/ml)

Roche Diagnostics

COBAS TaqMan HIV-1 Test; v2.0

RT-PCR

20

20–10,000,000

Siemens Healthcare Diagnostics

Versant HIV-1 RNA 1.0 Assay (kPCR)

RT-PCR

37

37–11,000,000

Abbott Molecular

Abbott RealTime HIV-1

RT-PCR

40

40–10,000,000

Siemens Healthcare Diagnostics

Versant HIV-1 RNA 3.0 Assay (bDNA)

bDNA

65

50–500,000

Biomérieux

NucliSENS EasyQ HIV v. 2.0

NASBA

250

25–7,900,000

Influencing factors

Apart from methodological variability a host of other factors may influence levels of viral load including vaccinations and concurrent infections. During active OIs viral load is often high. One study showed a 5- to 160-fold elevated viral load during active tuberculosis (Goletti 1996). Viral load can also increase significantly during syphilis and declines after successful treatment (Buchacz 2004, Kofoed 2006, Palacios 2007). In a large retrospective study, 26% of transient viremia in patients on ART were caused by intercurrent infections (Easterbrook 2002). In these situations, determining the viral load does not make much sense.

Following immunizations, for instance for influenza (O’Brien 1995) or pneumococcus (Farber 1996), the viral load may be transiently elevated (Kolber 2002). As the peak occurs one to three weeks after immunization, routine measurements of viral load should be avoided within four weeks of immunization. It should be noted that not every increase is indicative of virologic treatment failure and resistance. Slight transient increases in viral load, or blips, are usually of no consequence, as numerous studies in the last few years have shown (see chapter on Goals and Principles of Therapy). The possibility of mixing up samples always has to be considered. Unusually implausible results should be double-checked with the laboratory, and if no cause is found there, they need to be monitored – people make mistakes. Should there be any doubt on an individual result; the lab should be asked to repeat the measurement from the same blood sample.

Viral kinetics on ART

The introduction of viral load measurement in 1996-1997 fundamentally changed HIV therapy. The breakthrough studies by David Ho and his group showed that HIV infection has significant in vivo dynamics (Ho 1995, Perelson 1996). The changes in viral load on antiretroviral therapy clearly reflect the dynamics of the process of viral production and elimination. The concentration of HIV-1 in plasma is usually reduced by 99% as early as two weeks after the initiation of ART (Perelson 1997). In one large cohort, the viral load in 84% of patients was already below 1000 copies/ml after four weeks. The decrease in viral load follows biphasic kinetics. In the first phase, i.e., within the first three to six weeks, an extremely rapid drop occurs, followed by a longer phase during which the viral load gradually decreases further (Wu 1999).

The higher the viral load at initiation of therapy, the longer it takes to drop below the level of detection. In one study, the range was between 15 days with a baseline viral load of 1000 and 113 days with a baseline of 1 million viral copies/ml (Rizzardi 2000). The following figure shows a typical biphasic decrease in viral load after initial high levels.

Numerous studies have focused on whether durable treatment success can be predicted early (Thiabaut 2000, Demeter 2001, Kitchen 2001, Lepri 2001). In a study on 124 patients, a decrease of less than 0.72 logs after one week was predictive of virologic treatment failure in more than 99% of patients (Polis 2001). According to another prospective study, it is possible to predict virologic response at 48 weeks even after 7 days (Haubrich 2007). However, this has little clinical relevance, and in our opinion it is pointless to start measurement of viral load only one or two weeks after initiation of therapy.

 

Figure 1: Typical biphasic decrease in viral load on ART. Viral load was initially very high, and reached a level below 50 copies/ml only at week 32. Note the temporary increase at week 24, which is possibly due to methodological variability. ART was not changed.

We recommend to measure viral load every four weeks until it has dropped to below detection of 20-50 copies/ml. Once that is achieved, measurement every three to four months is enough. Eventually, longer intervals are possible (Chaiwarith 2010). In case of rebound, closer monitoring becomes necessary. Within the first 4 weeks of therapy initiation the viral load should be reduced by a factor of 100, after 3-4 months (6 months if viral load was high) it should be below the level of detection.

Viral load can also be measured fairly reliably in body fluids other than blood or plasma (for example cerebrospinal, vaginal or seminal fluid). However, such tests are usually performed for scientific purposes and are not officially licensed for other reasons.

Practical tips for dealing with viral load (see chapter Goals and Principles of Therapy)

  • Use only one assay, if possible.
  • Use only one experienced laboratory, if possible, no home-brewed assays.
  • Watch for assay variability (up to half a log) and explain this to the patient.
  • Monitor viral load every four weeks with new ART until the viral load is below the level of detection (50 copies/ml).
  • Then measure viral load sparingly – on successful ART every three months may be sufficient.
  • Not on ART, measurement every three months is usually sufficient.
  • Do not measure shortly after vaccinations or with concurrent infections.
  • Implausible results should be rechecked after 2-4 weeks.
  • Consider differences between subtypes (in some cases it may be useful to use another method).

CD4 T cells

CD4 T cells are T lymphocytes that express the CD4 receptor on their surface. This lymphocyte subpopulation is also referred to as T helper cells. Alongside viral load, measurement of the CD4 T cell level is the most important parameter or surrogate marker in HIV medicine. It allows for a reliable estimate of the individual risk of developing AIDS. All HIV-positive patients should have a CD4 T cell measurement every six months. Two reference values are generally accepted: above 400-500 CD4 T cells/µl, severe AIDS-related diseases are very rare; below 200 CD4 T cells/µl, the risk of AIDS-related morbidity increases significantly with increased duration of immunosuppression. Most AIDS-related illnesses occur below 100 CD4 T cells/µl.

Several points should be considered when measuring CD4 T cells (usually by flow cytometry). Blood samples should be processed within 18 hours. The lower normal values are between 400 and 500 cells/µl, depending on the laboratory. Samples should always be sent to the same (experienced) laboratory. The same applies for viral load as for CD4 T cells: the higher the level, the greater the variability. Differences of 50-100 cells/µl are not unusual. In one study, the 95% confidence intervals with a real value of 500 cells/µl were between 297 and 841 cells/µl. At 200 CD4 T cells/µl, the 95% confidence interval was between 118 and 337 cells/µl (Hoover 1993).

Measurement of CD4 T cells should only be repeated in the case of highly implausible values. As long as the viral load remains below the level of detection, there is no need to be concerned even with decreases in CD4 T cells. In such cases, the relative values (CD4 percentages) and the CD4/CD8 ratio (ratio of CD4 to CD8 T cells) should be referred to; these are usually more robust and less prone to fluctuation. As a general point of reference, with values above 500 CD4 T cells/µl, fluctuations of more than 29% are to be expected, with less than 200 CD4 T cells/µl fluctuations of less than 14%. Individual laboratories may define the normal ranges for the relative values and the ratio differently. If there are considerable discrepancies between absolute and relative CD4 T cells, any decisions involving treatment should be carefully considered – if in doubt, it is better to check the values again. The remaining differential blood count should also be scrutinized carefully – is leucopenia or leukocytosis present?

Clinicians sometimes forget that the result of the CD4 T cell count is of existential importance for the patient. To go to the doctor and discuss the test results can involve a great deal of stress for many patients. Insensitively informing the patient of a supposedly bad result can lead to further negative results. From the start, patients must be informed about the possible physiological and method-related variability of laboratory tests. In the case of unexpectedly good results, every effort should be made to contain euphoria. In the long run, this saves time and discussions, and the patient is spared unnecessary ups and downs. We do not consider it advisable for non-physician personnel (without extensive HIV experience) to inform patients of results.

 

Figure 2: Slow decline of the absolute and relative (dashed line) CD4 T cells/µl over almost ten years in a treatment-naïve patient. Note the variations in the absolute numbers.

Once CD4 T cell counts within the normal range are reached in addition to adequate viral suppression, measurements every six months should suffice, in our opinion. The probability of CD4 T cells dropping to values below 350/µl is extremely low in such cases (Phillips 2003). Patients who might sometimes insist on more frequent monitoring of immune status can be assured that there are usually no detrimental changes in the CD4 T cell count as long as HIV remains suppressed.

Influencing factors

Several other factors can influence CD4 T cell counts apart from laboratory-related variables. These include concurrent infections, leucopenia of varying etiology and steroids or other immunosuppressive therapies. Extreme exertion, surgical procedures or pregnancy can also lead to lower values. Even diurnal variation occurs; CD4 T cells are lower at noon, and highest in the evening around 8 p.m. (Malone 1990). Psychological stress seems to play a negligible role, even though patients often assume the contrary.

Kinetics of CD4 T cells on ART

Similarly to viral load, a biphasic increase in CD4 T cells occurs following the initiation of ART (Renaud 1999, Le Moing 2002), with a rapid increase within the first three to four months and a much slower rise thereafter. In a study of almost 1000 patients, the CD4 T cell count increased by 21/µl per month during the first three months. In the following 21 months, this rate was only 5.5 CD4 T cells/µl per month (Le Moing 2002). The initial rapid increase in CD4 T cells is probably due to redistribution, which is followed by the new production of naïve T cells (Pakker 1998). Diminished apoptosis may also play a role (Roger 2002).

It is still being debated whether the immune system steadily continues its recovery even after a long period of viral suppression, or whether a plateau is reached after three to four years beyond which there is less improvement (Smith 2004, Viard 2004).

Several factors can influence the extent of immune reconstitution during ART. The degree of viral suppression is crucial – the lower the viral load, the more pronounced the effect (Le Moin  2002). The absolute increase is higher if CD4 T cell counts were high at the start of ART (Kaufmann 2000). Naïve T cells still present at initiation of therapy are a particularly important factor for long-term immune reconstitution (Notermans 1999).

Age is also important (Grabar 2004). The larger the thymus and the more active the process of thymopoiesis, the more significant the rise in CD4 T cells is likely to be (Kolte 2002); due to age-related degeneration of the thymus, CD4 T cells in older patients do not increase as much as those in younger ones (Viard 2001). However, we have seen both 20 year-old patients with very poor CD4 T cell count recovery and 60 year-old patients with very good, above average increases in CD4 T cells. The regenerative capacity of the human immune system seems to vary considerably, and no method to date has been capable of reliably predicting this capacity.

It is possible that some antiretroviral therapies such as ddI+tenofovir are associated with less immune reconstitution than others. In addition, current studies evaluate if immune reconstitution is better during treatment with CCR5 antagonists. Immunosuppressive concurrent medications should also be considered (see chapter on Goals and Principles of Therapy).

Practical tips for dealing with CD4 T cells

  • As with viral load: use only one (experienced) laboratory.
  • The higher the values, the greater the variability (consider numerous factors) – compare the relative (percentage) values and CD4/CD8 ratio with previous results.
  • Do not disconcert the patient when there are apparent decreases – if viral suppression is sufficient, the drop is usually not HIV-related. Only highly implausible results should be repeated.
  • If the viral load is below the level of detection, three-monthly measurements of CD4 T cells are sufficient.
  • In the presence of good viral suppression and normal CD4 T cells, CD4 T cells (not viral load) may also be checked less frequently.
  • CD4 count and viral load should be discussed with the physician. Do not leave patients alone with their results.

Beyond the measurement of the CD4 T cell count and lymphocyte subpopulations, a number of other assays allow detailed testing of the qualitative or functional capacity of the immune system, for example in response to specific antigens (Telenti 2002). These often cumbersome methods are not currently necessary for routine diagnostics and their use remains questionable. However, they could one day help to better describe individual immune status and, for example, identify those patients who are at risk of developing opportunistic infections despite good CD4 cell counts.

Routine checks – What else should be monitored?

Besides the CD4 T cell count and viral load several other parameters should be monitored in the HIV-positive patient. The following recommendations apply to clinically asymptomatic patients with normal results on routine laboratory evaluation, who have been on stable treatment for several months or who are not taking antiretroviral therapy. Of course, if treatment is started or changed or if the patient develops complaints more frequent monitoring is required. Depending on the problem additional tests may be necessary.

A complete physical examination should be performed regularly, and this often leads to the discovery of important findings such as Kaposi lesions or mycoses (thrush). The lower the CD4 T cells, the more frequently patients should be examined.

In patients with less than 200 CD4 T cells/µl, we usually perform fundoscopies every three to six months to exclude CMV retinitis. Close cooperation with an HIV-experienced ophthalmologist is essential. The better the CD4 T cells, the less often fundoscopies are necessary – in our opinion when CD4 counts have normalized these can be stopped completely. In contrast, regular gynecological examinations with PAP smears are recommended regardless of CD4 count. Many experts now also recommend rectal examination (including proctoscopy) for the early detection of precancerous lesions and anal cancer.

However, such guidelines or recommendations can be interpreted very differently. In our opinion in cases of good immune status unless there is a specific suspicion routine X-rays, ultrasound examinations (exception: patients with chronic hepatitis, as hepatocellular carcinoma is not rare in such cases), multiple serologies or lactate measurements are not necessary. An annual ECG is only indicated in our view in patients with a specific risk profile (see chapter on HIV and Cardiac Disease). The tuberculin test (the Mendel-Mantoux skin test with 5 IE once a year) should only be repeated if it is negative initially.

Table 11.2. Minimal evaluations per year in stable asymptomatic patients.
 

Patient on ART

per year

Untreated

per year

Blood count, LDH, ALT, AST, creatinine, bilirubin, AP, lipase, GGT, glucose

4-6 x

2-4 x

Viral load

4 x

2-4 x

CD4 T cells

2-4 x

2-4 x

Lipids

1-2 x

1 x

Physical examination, urine status

2-4 x

1-2 x

Gynecological examination

1 x

1 x

Funduscopy if CD4 T cells <200/µl

1-2 x

4 x

With regard to the growing age of the HIV population, it is essential not to forget cancer screening. In many countries, for example, colonoscopy is recommended for early detection of colorectal cancer for every individual older than 50-55 years (colonoscopy should be performed every 10 years). For further information see WHO website, http://www.who.int/cancer/detection/en/

Therapeutic Drug Monitoring (TDM)

Plasma levels of many antiretroviral drugs may vary considerably for diverse reasons (e.g., compliance, metabolism, absorption). Measurement of drug concentrations in serum or plasma is also referred to as therapeutic drug monitoring (TDM).

Sufficient plasma levels are essential for success of virologic treatment (Acosta 2000). In the VIRADAPT Study adequate PI concentrations were even more crucial than knowledge of resistance mutations (Durant 2000). The importance of sufficient plasma levels has also been shown for NNRTIs (Marzolini 2001, Veldkamp 2001). This information however dates to the early years of ART.

Whether TDM still improves virologic response today, is not clearly validated (Kredo 2009). Only a few large randomized studies exist that have provided data regarding this question (Review: Liu 2010). One of the few randomized studies could only show a trend to virologic (Best 2007). TDM remained without any effect in another study with patients receiving boosted PIs (Demeter 2009).

On the other hand, very high plasma levels correlate with a higher rate of side effects. Reported renal problems with indinavir (Dielemann 1999), gastrointestinal disturbances with ritonavir (Gatti 1999), hepatotoxicity with nevirapine (Gonzalez 2002) or CNS problems with efavirenz (Marzolini 2001) were all associated with high plasma levels. For this reason, TDM will remain a tool for therapy observation: not every interaction between antiretroviral drugs or with concomitant drugs has been investigated.

Measurement of plasma levels may currently be reasonable in the following situations (German-Austrian ART guidelines):

  • Complex drug combinations including boosted PIs
  • Patients with very high or low body weight
  • Side effects
  • Treatment failure (resistance?)
  • Suspected absorption or adherence problems
  • Severe liver or renal diseases
  • Art with children, pregnancy
  • Once daily regimen
  • Use of new drugs (unknown interactions)

Several problems associated with TDM limit its broader use. The measurement of NRTIs, for example, is not possible since they are converted to the active metabolites only intracellularly. Intracellular measurements are difficult and are not available in routine clinical practice. There is no valid data available for new antiretroviral agents such as T-20, raltegravir or maraviroc.

Measuring NNRTIs or PIs may therefore currently determine levels of only one component of a failing combination. Further problems include not only viral strains with different levels of resistance, different inhibitory concentrations, variable protein binding, and time-dependent variability of plasma levels, but also methodological problems with the assays, as well as the lack of clearly defined limits. Many uncertainties thus remain in the assessment of therapeutic drug plasma levels. Until data from randomized studies is available, proving the clinical value of TDM, both the measurement and interpretation of results should be left to specialized centers.

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