Patients receiving ART may eventually reach a point where they experience treatment failure: clinical worsening despite receiving ART. Treatment failure generally occurs as a result of inadequate levels of ART in a patient’s bloodstream,¹⁰ usually due to poor treatment adherence or drug malabsorption. The low levels of ART allow the HIV virus to replicate and select for mutations that confer drug resistance.¹¹ Once mutations in the virus have conferred resistance to an ART drug, viral replication will recur and, over time, CD4 cells will once again start to be destroyed, resulting in worsening immune suppression. Detection of virologic replication while on ART is thus the gold standard for determining treatment failure. Treatment failure may also be considered based on clinical features such as weight loss, fever, adenopathy, or the onset of a new OI. Immunologic criteria may also be used to evaluate treatment failure: the WHO has established a 50 percent decrease in CD4 count from the peak count registered, or a drop below the pre-ART baseline, as reasonable criteria.

Assessing the patient’s adherence to the prescribed ART regimen is the first and most important step in evaluating possible treatment failure.¹² The next step is to carefully rule out other possible causes of clinical worsening, including immune reconstitution syndrome (see Section 3.9.7) or the presence of OIs (particularly extrapulmonary TB) or chronic diarrhea, which may result in malabsorption of ART.

The most sensitive test to determine whether or not ART is resulting in suppression of viral replication is a viral load assay. When such assays are available, viral load should be measured every three to six months during treatment.¹³ An increase in viral load of greater than 1 log while the patient is on ART is suggestive of treatment failure.

In practical terms, however, because surveillance of viral load is not available in most resource-poor settings,¹⁴ evaluation of treatment failure must start with both a thorough history and a physical examination to assess for signs of clinical progression of disease.¹⁵ If a patient experiences clinical progression when ART and CD4 monitoring are not available, and new or refractory OIs and immune reconstitution syndrome have been rigorously ruled out, it is reasonable to assume treatment failure and consider a change in ART. Protocol 3.2 outlines an algorithmic approach to assessing the clinical and immunologic response of patients receiving ART.