Despite the previous findings, the first data from a large prospective study comparing monitoring strategies, the Home Based AIDS Care (HBAC) study, suggests that when it comes to preventing morbidity and mortality, CD4 monitoring of people on ART can perform quite well — at least for the first three years on treatment and when adherence is excellent. However, clinical monitoring alone was associated with an increased rate of new AIDS-defining events and a trend towards increased mortality when compared to either CD4 cell count or virological monitoring.
Although the fewest clinical events occurred in the virological monitoring arm, the difference when compared to CD4 monitoring did not reach statistical significance— possibly because there were so few poor outcomes in this cohort during the course of the study. In other words, in this study, CD4 cell count monitoring resulted in equivalent clinical outcomes out the three years of follow-up. However, routine viral load testing did add considerably to the expense of monitoring (see below).
HATIP has previously made reference to this study, because of the exceptionally high standard of care offered to its participants despite being located in an extremely remote and under-resourced setting. The HBAC programme offers comprehensive holistic family-based care in the rural Tororo and Busia Districts in eastern Uganda, which includes a basic preventive package of care (described here: http://www.aidsmap.com/cms1234609.asp) and intensive community-based support, including weekly home visits by trained lay workers with delivery of ART and TB medications and routine symptom and adherence assessments (see http://www.aidsmap.com/cms1234974.asp). With this model of care, clinical symptoms and adherence problems would probably be detected sooner than at facility-based clinics with quarterly or even less frequent clinical monitoring.
So Dr Mermin and colleagues conducted a randomised study evaluating whether the approach to monitoring would lead to differences in the clinical outcomes (severe morbidity, essentially new AIDS defining events, and mortality) in people on ART during three years of follow-up, as well as the cost-effectiveness of the different monitoring regimens.
- Arm A: quarterly viral loads, CD4 cell counts and clinical monitoring (through weekly home visits)
- Arm B: quarterly CD4 cell counts and clinical monitoring (through weekly home visits)
- Arm C: clinical monitoring alone, provided by weekly home visits (see the annex on HBAC symptom/illness screening)
The definition of virological failure in Arm A was somewhat flexible. A patient could be categorised as failing virologically if they had two consecutive detectable viral loads (over 500 copies/ml) after six months of therapy; but if the viral load was between 50 to 5000 copies/ml and the participant was clinically well, first-line therapy could be continued. If there were clinical events or a fall in CD4 cell counts, the bias was to continue the first-line regimen as long as their viral load was suppressed.
For Arm B, failure was defined as a persistently declining CD4 cell count measured on two separate occasions and/or clinical failure.
In Arm C, definitions for clinical failure included:
- Unintentional weight loss of greater than 10%
- Appearance of CDC Category C illness (see http://www.aidsmap.com/cms1031859.asp)
- Diarrhoea or fever for more than one month without correctable cause, and
- New or recurrent oral, oesophageal or vaginal candidiasis without a known cause
A clinical case conference, involving a multi-disciplinary team of physicians, nurses, pharmacists and counsellors, was held to report and discuss information regarding all deaths, hospitalizations, opportunistic illnesses, abnormal labs and decided whether changes in ART regimens were necessary. But in each arm, Dr Mermin stressed that, “the first response to an indication of treatment failure was adherence counselling and support.”
The study enrolled 1,116 ART-naive people with CD4 cell counts ≤ 250 cells or WHO clinical stage III or IV disease. A total of 1,094 people started the first-line regimen: stavudine/lamivudine (d4T/3TC) plus nevirapine (efavirenz was substituted for nevirapine in those with concomitant TB treatment). The second line regimen was lopinavir/ritonavir (Kaletra), didanosine (ddI) and tenofovir.
Baseline characteristics were well matched (the median age was 38, the CD4 cell count was between 127-131, and viral loads were over 200,000 copies/ml) with the exception of gender (67% of the participants in Arm C were women, compared to 75% in Arms B and C, p=0.01).
After a median follow-up of three years, there were:
- 126 deaths (11.2% of the total population), 47% of which occurred within the first three months of therapy
- 148 new AIDS-defining illnesses, 57% of which were in the first three months
- 61 (5.8%) of participants had two consecutive viral loads greater than 500 copies/ml after the first 6 months
- Only 28 (2.7%) of participants were ultimately switched to second line drugs.
In a Kaplan-Meier analysis of the time to an event of severe morbidity or mortality, the clinical monitoring arm had a significantly higher rate of morbid events and/or death than Arm A, whether using an intention-to-treat approach from the date of randomization (p = 0.02) or a per protocol approach starting three months after initiating ART (p=0.004). The per protocol analysis is particularly important because the first laboratory results after baseline were not drawn until three months after initiation of ART. In the per protocol analysis, the difference was also statistically significant in the comparison of Arm B to Arm C (p=0.034). There were no significant differences in time to death using the intent-to-treat or per protocol analysis.
After adjusting for age, gender, baseline CD4 cell count, viral load, body mass index and depressions scores, the rate of first severe morbidity or mortality advances was roughly one and a half times higher in Arm C than in either Arms A or B, in the intent-to-treat analysis (see Table below), and twice as high in the per protocol analysis. There was no significant difference between Arms A or B.
“Although we have not yet analysed the adherence data, in Arms A & B, participants with either viral load or CD4 cell count measurements that indicated failure were counselled and improved medication adherence and this may be the reason that viral loads improved without the need for a change to a second-line regimen,” said Dr Mermin. “However, in Arm C we did not detect drug failure as rapidly and people had elevated viral loads for a longer period of time.”
Dr Mermin noted research from the Western Cape in South Africa (previously reported in HATIP) by Dr Catherine Orrel and colleagues, which has recently been published in Antiviral Therapy. “Using a system of early detection of virological breakthrough leading to implementation of a targeted adherence strategy, 23 (53%) of 43 people with initial VL >1,000 copies/ml subsequently achieved full virological suppression,” wrote Orrel et al. They also stressed that the timing of failure detection was critical, because when the adherence intervention comes too late, it is less likely to result in viral suppression.
Of course, that study referred strictly to viral load, though the study by Basenero et al reported at IAS also found that adherence support offered on the basis of CD4 failure was able at least to stabilise CD4 cell counts in a large proportion of the ‘failing’ patients (at least temporarily). It’s not clear whether the improvement in viral load in Arm B could really be considered significant (though at least it didn’t get worse). But while CD4 cell counts and viral load might be increasingly discordant with time on ART, there is a chance that CD4 cell counts picked up participants who simply weren’t taking their medication at all (as opposed to those who were erratically adherent).
For example, CD4 cell counts can be sustained in people on incompletely suppressive for years, but studies have shown that people on incompletely suppressive ART regimens who stop treatment altogether suffer a rapid increase in viral load and a rapid fall in CD4 cell counts (Deeks).
Note, however, that in HBAC, the immunological definition of failure is simply two declining CD4 cell counts — criteria that could have a different sensitivity for early detection of virological failure. Perhaps, given common variations in CD4 cell counts, transient dips in CD4 cell counts prompted more adherence support.
“Our first effort was always adherence monitoring… so we first counselled people and then we re-assessed with the laboratory and clinical monitoring to see if they got better,” said Dr Mermin. “But for the arm with clinical monitoring only we couldn't wait — We would have to switch them. That’s maybe why we had a greater number of people [in the clinical monitoring arm] who were switched to second line regimens after an AIDS-defining illness.”
“Clinical criteria alone were poorly sensitive in detecting early failure, and poorly specific in restricting drug changes to those participants with an elevated viral load,” said Dr Mermin. “Clinical monitoring alone was associated with an increased rate of new AIDS-defining events and a trend towards increased mortality. This supports efforts to build laboratory capacity and provide laboratory monitoring.”
“But there was no benefit seen for adding quarterly viral load measurements to CD4 cell counts, supporting WHO guidelines and suggesting that priority should be given to a standing access to CD4 cell count measurements — at least in patients adhering well to ART,” added Dr Mermin.