Starting treatment at lower CD4 cell counts increases risk of HIV drug resistance

Michael Carter
Published: 02 June 2009

Starting treatment at a CD4 cell count of 350 cells/mm3 or above does not increase the risk of developing resistance to antiretroviral drugs, a study published in the online edition of the Journal of Acquired Immune Deficiency Syndromes concludes.

The investigators, from the HIV Outpatient Study (HOPS) write that their findings “should be reassuring to clinicians and alleviate the concerns for accelerating acquisition of treatment-limiting resistance by starting highly active antiretroviral therapy (HAART) at CD4 cell counts of 350 cells/mm3 or above”.

HIV treatment guidelines in many parts of the world now recommend that HIV treatment should be started when a patient’s CD4 cell count is in the region of 350 cells/mm3. Starting treatment at this time, rather than waiting until a person’s CD4 cell count is lower, has been shown to lead to improved outcomes and a decreased risk of both HIV-related and non-HIV-related illnesses.

There are, however, concerns that due to the longer duration of treatment, starting treatment at higher CD4 cell counts could increase the risk of developing resistance to antiretroviral drugs, therefore limiting future treatment options.

Researchers from the prospective HOPS study therefore studied the frequency of drug resistance amongst patients whose viral load was suppressed following the initiation of antiretroviral therapy but subsequently rebounded.

Viral suppression was defined as a fall in viral load to below 1000 copies/ml, and rebound as an increase in viral load above this level. Patients were categorised according to their CD4 cell count at the time HIV treatment was initiated (0-199 cells/mm3; 200-349 cells/mm3; and above 350 cells/mm3). The investigators looked at the risk of developing resistance in the patients who had resistance tests performed after their viral load increased to see if CD4 cell count at the time antiretroviral therapy was started was significant.

A total of 760 patients were included in the investigators’ analysis. Data were collected until the end of September 2006.

A total of 683 individuals (90%) achieved viral suppression after starting HIV treatment. However, viral load subsequently increased in 243 of these patients. Resistance tests were performed on 78 (32%) of these patients.

CD4 cell count at the time HIV treatment was started did not affect the risk of viral load increasing. However, patients who started treatment with a CD4 cell count below 200 cells/mm3 experienced a rebound in their viral load within a median of eight months compared to a median of 21 months for patients who initiated HIV therapy with a CD4 cell count above 350 cells/mm3. This difference was significant (p = 0.026). The investigators emphasise that patients who started HIV treatment “at a higher CD4 cell count experienced the greatest durability of their initial highly active antiretroviral therapy (HAART) regimen”.

Resistance tests were significantly more likely to be performed after the virological failure of treatment on patients whose baseline CD4 cell count was below 200 cells/mm3 (p = 0.043).

Patients having resistance tests were more likely to be black, have an AIDS diagnosis and possess private health insurance (data not provided).

Resistance mutations were present in 50% of patients who started treatment with a CD4 cell count below 350 cells/mm3, compared to 22% of individuals who commenced HIV therapy with a CD4 cell count above this level. This difference was over borderline significance (p = 0.062).

Next the investigators looked at the relationship between resistance to specific classes of antiretroviral drug and CD4 cell count at the time HIV treatment was started. The first class of drugs to be analysed was nucleoside reverse transcriptase inhibitors (NRTIs). This showed that 48% of patients with a CD4 cell count below 200 cells/mm3 had resistance to this class of drugs, compared to 32% of individuals starting treatment with a CD4 cell count between 200 and 349 cells/mm3 and 11% of patients with a baseline CD4 cell count above 350 cells/mm3. These differences were significant (p = 0.005). A similar pattern was seen with NNRTI resistance (p = 0.04), and there was a trend for starting treatment with a lower CD4 cell count to be associated with subsequent development of resistance to protease inhibitors (p = 0.063).

“Among HOPS participants who achieved virologic suppression on their initial HAART regimen, and subsequently had virologic failure and underwent genotype testing, we observed a higher frequency of antiretroviral resistance mutations among patients who started HAART at lower CD4 cell counts compared with patients who started treatment at higher CD4 cell counts”, comment the investigators.

The investigators suggest that the factors explaining their findings may be biological, behavioural, or both. They note some limitations with their study, including a lack of information on treatment adherence and that only a minority of individuals experiencing virological failure had a resistance test.

“Data from our relatively small observational study suggest no gross evidence of harm in terms of increased risk of developing resistance mutations on first HAART regimen among patients initiating therapy at CD4 cell counts above 350 cells/mm3”, conclude the investigators.

Reference

Uy J et al. Initiation of HAART at higher CD4 cell counts is associated with a lower frequency of antiretroviral drug resistance mutations at virologic failure. J Acquir Immune Defic Syndr (online edition), 2009.