Misdiagnosis of HIV treatment failure based on clinical and immunological criteria in Eastern and Central Kenya

In 2015, an estimated 1.5 million Kenyans were living with HIV, with 897,000 of them on antiretroviral therapy (ART) [1]. The number of HIV-infected Kenyans accessing ART is expected to rise due to increased early identification of HIV, roll out of the new ART guidelines [2], and increased adherence and retention in line with the UNAIDS 90–90-90 strategy, which has been adopted wholeheartedly by the Kenyan government. Whilst a majority of patients on ART are expected to achieve viral suppression within one year of treatment initiation [3, 4], 5–21% will experience treatment failure within 5 years of initiation [5‐7]. Timely identification of true treatment failure in patients on ART is vitally important as it informs optimization of the use of second-line regimens and protects against unnecessary switching of ART. The Kenya Ministry of Health (MOH) recommends the use of a combination of Tenofovir (TDF)/ Zidovudine (AZT)/Abacavir (ABC), Lamivudine (3TC) and Nevirapine (NVP)/ Efavirenz (EFV) as the first-line ART regimen, with Atazanavir (ATV), Lopinavir and Ritonavir (LPV/r) currently reserved for second-line use.

In Kenya, routine laboratory monitoring is part of the basic care package offered to people living with HIV (PLHIV), and includes tests to monitor the efficacy of ART on viral suppression (CD4 and viral load). Clinical failure is defined as occurrence of a new or recurrent WHO stage 3 or 4 disease after at least six months on ART (Table 1), while immunological failure refers to a CD4 count decrease by >30% from peak or failure of CD4 count to rise to >100 cells/mm³ after 12 months on ART [8]. Virological failure occurs when the repeat viral load remains persistently above 1000 copies/ml after three months of adherence counselling. The Kenyan Ministry of Health currently recommends the use of virological monitoring to identify treatment failure for patients on ART, with CD4 testing reserved for baseline investigation. The Ministry of Health has fully adopted routine viral load monitoring and disregarded the use of viral load for confirmatory testing in all health facilities offering HIV care and treatment in Kenya.

In this paper, we analyse viral load data collected from patients with suspected treatment failure based on clinical and immunological criteria between January 2013 and June 2014 from 11 APHIAPLUS KAMILI counties. We aim to demonstrate that a proportion of patients with clinical and immunological failure are virologically suppressed and yet may be misclassified as treatment failure.

Viral load data from 1859 patients in eight of the eleven counties supported by the project were analysed (Table 2). Three counties were excluded because they did not have care and treatment sites supported by the project, hence no data on viral load testing. The patient median age was 38 years (IQR 30–47 years), and majority were female (62%). The median viral load was 3317 copies/ml (0–47,547). The most common ART regimens used at the time of study were AZT/3TC/NVP (34%), TDF/3TC/NVP (26%), and TDF/3TC/EFV (23%). The median duration on ART was 4 years (IQR 2–6 years).

The most common indication by clinicians for requesting viral load testing was clinical failure (59%), followed by immunological failure (34%), and others (7%).

The proportion of patients with viral suppression was 39.5%, with 60.5% experiencing virological failure. There was no significant difference between the proportion of male patients who were virally suppressed (43.1%) and that of female patients (43.6%). Viral suppression was highest among patients aged above 61 years (55.4%) and lowest in those aged below 20 (23.9%) years.

Among the 799 patients who were reported as having clinical failure, 41.1% (n = 328) had confirmed viral suppression. Of the 463 patients reported as having immunological failure, 36.9% (n = 171) had confirmed viral suppression (Fig. 1). The combined number for both clinical and immunological failure was 1262. Of these, 499 (39.5%) had confirmed viral suppression and had been misclassified.

These results indicate that 41.1% of patients in the clinical failure group were misclassified as having treatment failure, compared to 36.9% patients in the immunological failure group. The difference in proportion of misclassified patients between the two groups was, however, not statistically significant (OR 0.84, CI 0.66–1.06). The sensitivity of clinical criteria in diagnosing true failure was 61% (CI 58%–65%) while immunological criteria had a low sensitivity of 38% (CI 35%–42%). The specificity of the clinical criteria was 34% (CI 30%–39%) while that of the immunological criteria was 66% (61%–70%) (Table 3).

At both bivariate and multivariate levels, increase in age of the patient was associated with reduced odds of virological failure (Table 4). Associations between virological failure and sex, ART regimen and duration on ART was not found to be statistically significant.

Viral load monitoring is routinely carried out in PLHIVs in most countries. In low income countries, viral load tests have been previously restricted to drug resistance studies and diagnosis of HIV-exposed infants, possibly due to inadequate resources. In Kenya, viral load testing is now recommended for monitoring of patients on ART, replacing CD4 testing, which has since been reserved for baseline screening to identify patients eligible for cryptococcal meningitis prophylaxis (CD4 < 100).

Our study presents data on discrepancies in classification of treatment failure based on clinical, immunological and virological criteria. Consequently, we demonstrate that the use of clinical and immunological criteria alone may result in misclassification of patients with viral suppression as treatment failure leading to unnecessary, untimely, and incorrect switching to second line regimens.

Our study adds to the literature from studies done elsewhere which also evaluated misclassification of treatment failure in patients on ART. In a prospective cohort study in Uganda, immunological criteria failed to identify all the genuine treatment failures and had a low sensitivity [9]. Studies in Kenya and Uganda by Moor et al. (2008), Kantor et al. (2009) and Mermin et al. (2011) were able to illustrate that virological monitoring is the most accurate way of identifying treatment failure as compared to clinical and/or immunological criteria [10-12]. These studies are important as the use of clinical and immunological criteria alone in treatment failure identification has been associated with increased resistance to HIV [13, 14].

In the course of treatment of PLHIVs, virological failure occurs early, followed by immunological and clinical failure. Therefore, there is need for timely and accurate treatment failure diagnosis based on viral load testing in order to avoid early or delayed switching of patients to second-line ART regimen. Switching early to second-line regimen increases the cost burden of HIV treatment and minimizes options for subsequent regimens, should they be required [11]. On the other hand, delayed switching to a second-line regimen has been associated with increased drug resistance, morbidity and mortality [15].

In this study, the age of the patient was associated with virological failure. Majority of patients who had virological failure fell within the age range of 20–40 years. This data is similar to that of a study conducted in Kenya by Hassan (2014) where young age was a significant predictor for virological failure and drug resistance [16]. Young HIV-infected patients constitute a special cohort experiencing challenges such as stigma, peer pressure, adherence and discrimination [17]. This, in turn, might affect adherence on ART, increasing their chances of virological (hence treatment) failure.

Patient viral load must necessarily be interpreted with caution - viral load is affected by inter-patient variation, laboratory errors, opportunistic infections, pre-ART viral load and the ART regimen [18, 19]. These factors can cause transient viral ‘blips’ which could be misinterpreted as virological failure. After such blips, viral load spontaneously drops to undetectable levels without change in ART regimen. It is possible that any of these factors may have influenced the findings reported in this paper.

Clinical and immunological criteria when applied without viral load testing are not sufficient to definitively identify treatment failure in a timely manner. There is need for accurate treatment failure diagnosis based on viral load to avoid early or delayed switching of patients to second-line ART, and the subsequent consequences of that untimely switching. This study recommends universal viral load testing for all HIV-infected individuals in line with Kenya’s ART guidelines. Findings from this study further strengthen policy and guidelines on viral load testing as the standard reliable test to be conducted prior to switching patients from first to second line ART regimens. A viral suppression survey with genotypic resistance is needed in the future to shed more light on treatment failure.