Switching HIV treatment in adults based on CD4 count versus viral load monitoring: a randomized, non-inferiority trial in Thailand.

BACKGROUND: Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand. METHODS AND FINDINGS: The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported. CONCLUSIONS: The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings. TRIAL REGISTRATION: ClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary

Characteristics of the patients at baseline, according to randomization arm.

a<p>There were eight protocol deviations reported related to inclusion criteria: One patient was not ARV naive, one woman was pregnant, one was chronically infected with hepatitis C, two had hemoglobin level <8.0 g/dl, two had absolute neutrophil count <1,000 cells/mm³, one had serum creatinine above 1.0× ULN.</p

Number of primary outcomes by arm.

a<p>Including nine cases followed by death.</p>b<p>Tuberculosis (8), cryptococcal meningitis (3), <i>P. jirovecii</i> pneumonia (2), systemic <i>P. marneffei</i> (2), disseminated <i>Mycobacterium avium intracellulare</i> (1), sepsis (2).</p>c<p>Tuberculosis (4), cryptococcal meningitis (4), <i>P. jirovecii</i> pneumonia (2), systemic <i>P. marneffei</i> (2), sepsis (3).</p>d<p>Sepsis (3), cerebrovascular accidents (2), heart failure (1), asthma attack (1), <i>P. jirovecii</i> pneumonia (1), hepatic failure (1), unknown cause (2).</p>e<p>Heart failure (3), cancer (2, 1 breast cancer, 1 liver cancer), suicide (2), renal failure (1), hepatic failure (1), pneumonia (1), sepsis (1).</p

Primary outcomes (clinical failure) at 3 y: death, new AIDS-defining events, or confirmed CD4 <50/mm³.

a<p>The 95% CI of the difference, −0.6% was −4.5% to 3.4%. The upper limit of this CI was below the pre-determined criterion for non-inferiority, 7.4%.</p

Serious adverse events by trial arm.

<p>Serious adverse events by trial arm.</p

Treatment switch to second-line, PI-based treatment.

a<p>Calculated starting in the middle of the time period between the last VL <400 copies/ml and first VL above.</p>b<p>Calculated starting in the middle of the time period between the last VL <50 copies/ml and first VL above.</p

Risk factors for clinical failure.

a<p>HR, hazard ratio.</p>b<p>Adjusted HR (AHR, Cox proportional analysis) adjusted for hemoglobin, CDC stage, CD4 count, VL, BMI, sex, and randomization arm.</p

Resistance mutations found at first ARV switch (VL arm).

<p>This table shows 18 patients randomized to the VL arm who reached switching criteria of >400 copies/ml. The last samples collected before switch were genotyped. One participant with extensive PI resistance in the pretreatment specimen is omitted from this table.</p>a<p>“Duration of replication before genotype” is defined as time from first detection of VL >400 copies/ml to genotyping. This may be shorter than the duration before ARV drug switching.</p>b<p>These two participants were not included in calculations related to ARV drug switches since, although they met VL criteria for switching during the study, they both switched after the end of the study (April 1, 2010).</p

Mean, 95% CI, median, and IQR of the Future Drug Options scores, by trial arm.

a<p>FDO calculated using the following ARV drugs: nevirapine, efavirenz, delavirdine, etravirine; abacavir, didanosine, emtricitabine/lamivudine, stavudine, tenofovir, zidovudine; nelfinavir, indinavir, ritonavir, lopinavir. saquinavir, atazanavir, fosamprenavir, darunavir, tipranavir.</p>b<p><i>p</i>-Value from Wilcoxon Mann-Whitney test.</p>c<p>FDO score 1: FDO-1 is calculated as the number of drug classes with one or more drug to which the virus was susceptible (NC) with extra credit (0.3) for full susceptibility in NRTI or PI classes.</p>d<p>FDO score 2: FDO-2 is calculated as NC + the number of drugs to which the virus was susceptible (ND) divided by the total number (19) of drugs available + 1, i.e., NC+(ND/20).</p

Resistance mutations found at first ARV switch (CD4 arm).

<p>This table includes all 16 participants in the CD4 arm who had VL >400 copies/ml at the time of switching.</p>a<p>Duration of replication before measurement of genotype may be shorter than duration before ARV drug switching.</p>b<p>These two participants both had Y181C mutations at baseline and were the only two of the participants switching to second-line regimens with major baseline NNRTI resistance mutations.</p