Switching HIV Treatment in Adults Based on CD4 Count Versus Viral Load Monitoring: A Randomized, Non-Inferiority Trial in Thailand

: Using a randomized controlled trial, Marc Lallemant and colleagues ask if a CD4-based monitoring and treatment switching strategy provides a similar clinical outcome compared to the standard viral load-based strategy for adults with HIV 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/mm3) 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.gov NCT00162682 Background: About 34 million people (most of them living in low-and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV infection leads to the destruction of immune system cells (including CD4 cells, a type of white blood cell), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (HAART)—combined drugs regimens that suppress viral replication and allow restoration of the immune system—became available. For people living in affluent countries, HIV/AIDS became a chronic condition but, because HAART was expensive, HIV/AIDS remained a fatal illness for people living in resource-limited countries. In 2003, the international community declared HIV/AIDS a global health emergency and, in 2006, it set the target of achieving universal global access to HAART by 2010. By the end of 2011, 8 million of the estimated 14.8 million people in need of HAART in low- and middle-income countries were receiving treatment. Why Was This Study Done?: At the time this trial was conceived, national and international recommendations were that HIV-positive individuals should start HAART when their CD4 count fell below 200 cells/mm3 and should have their CD4 count regularly monitored to optimize HAART. In 2013, the World Health Organization (WHO) recommendations were updated to promote expanded eligibility for HAART with a CD4 of 500 cells/mm3 or less for adults, adolescents, and older children although priority is given to individuals with CD4 count of 350 cells/mm3 or less. Because HIV often becomes resistant to first-line antiretroviral drugs, WHO also recommends that viral load—the amount of virus in the blood—should be monitored so that suspected treatment failures can be confirmed and patients switched to second-line drugs in a timely manner. This monitoring and switching strategy is widely used in resource-rich settings, but is still very difficult to implement for low- and middle-income countries where resources for monitoring are limited and access to costly second-line drugs is restricted. In this randomized non-inferiority trial, the researchers compare the performance of a CD4-based treatment monitoring and switching strategy with the standard viral load-based strategy among HIV-positive adults in Thailand. In a randomized trial, individuals are assigned different interventions by the play of chance and followed up to compare the effects of these interventions; a non-inferiority trial investigates whether one treatment is not worse than another. What Did the Researchers Do and Find?: The researchers assigned about 700 HIV-positive adults who were beginning HAART for the first time to have their CD4 count (CD4 arm) or their CD4 count and viral load (VL arm) determined every 3 months. Participants were switched to a second-line therapy if their CD4 count declined by more than 30% from their peak CD4 count (CD4 arm) or if a viral load of more than 400 copies/ml was recorded (VL arm). The 3-year cumulative risk of clinical failure (defined as death, a new AIDS-defining event, or a CD4 count of less than 50 cells/mm3) was 8% in the VL arm and 7.4% in the CD4 arm. This difference in clinical failure risk met the researchers' predefined criterion for non-inferiority. The probability of a treatment switch was similar in the two arms, but the average time from treatment initiation to treatment switch and the average duration of a high viral load after treatment switch were both longer in the CD4 arm than in the VL arm. Finally, the future-drug-option score, a measure of viral drug resistance profiles, was similar in the two arms at the time of treatment switch. What Do These Findings Mean?: These findings suggest that, in Thailand, a CD4 switching strategy is non-inferior in terms of clinical outcomes among HIV-positive adults 3 years after beginning HAART when compared to the recommended viral load-based switching strategy and that there is no difference between the strategies in terms of viral suppression and immune restoration after 3-years follow-up. Importantly, however, even though patients in the CD4 arm spent longer with a high viral load than patients in the VL arm, the emergence of HIV mutants resistant to antiretroviral drugs was similar in the two arms. Although these findings provide no information about the long-term outcomes of the two monitoring strategies and may not be generalizable to routine care settings, they nevertheless provide reassurance that using CD4 counts alone to monitor HAART in HIV treatment programs in resource-limited settings is an appropriate strategy to use as viral load measurement becomes more affordable and feasible in these settings. Additional Information: Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001494.