HIV Drug Resistance in Adults Receiving Early vs. Delayed Antiretroviral Therapy

HPTN 052

Philip J. Palumbo, BA; Jessica M. Fogel, PhD; Sarah E. Hudelson, BS; Ethan A. Wilson, MS; Stephen Hart, PhD; Laura Hovind, MS; Estelle Piwowar-Manning, BS, MT (ASCP); Carole Wallis, PhD; Maria A. Papathanasopoulos, PhD; Mariza G. Morgado, PhD; Shanmugam Saravanan, PhD; Srikanth Tripathy, MD; Joseph J. Eron, MD; Joel E. Gallant, MD, MPH; Marybeth McCauley, MPH; Theresa Gamble, PhD; Mina C. Hosseinipour, MD, MPH; Nagalingeswaran Kumarasamy, MBBS, PhD; James G. Hakim, MD; Jose H. Pilotto, MD, PhD; Johnstone Kumwenda, FRCP; Victor Akelo, MBChB, MPH; Sheela V. Godbole, MD, PGDEPI; Breno R. Santos, MD; Beatriz Grinsztejn, MD, PhD; Ravindre Panchia, MBBCh, BSc; Suwat Chariyalertsak, MD, DrPH; Joseph Makhema, MD, ChB, FRCP; Sharlaa Badal-Faesen, MBBCh; Ying Q. Chen, PhD; Myron S. Cohen, MD; Susan H. Eshleman, MD, PhD

Disclosures

J Acquir Immune Defic Syndr. 2018;77(5):484-491. 

In This Article

Abstract and Introduction

Abstract

Introduction: We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005–2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350–550 cells/mm3 (early ART arm) or <250 cells/mm3 (delayed ART arm). In May 2011, interim study results showed benefit of early ART, and all participants were offered ART regardless of CD4 cell count; the study ended in 2015.

Methods: Virologic failure was defined as 2 consecutive viral loads >1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure.

Results: HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure.

Conclusions: In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.

Introduction

Initiation of antiretroviral therapy (ART) at higher CD4 cell counts decreases HIV transmission[1,2] and improves outcomes and quality of life for those on treatment.[3–7] Although there are clear individual and public health benefits to early ART initiation, emergence of HIV drug resistance remains a concern in both HIV prevention and treatment settings. Drug-resistant HIV may emerge during treatment and can be transmitted to others, limiting future treatment options. HIV drug resistance is frequently observed at the time of ART failure.[8–12] Several factors have been associated with drug resistance at failure, including the presence of resistance before treatment, previous exposure to antiretroviral (ARV) drugs, higher baseline viral load, lower baseline CD4 cell count (<50 cells/mm3), low adherence to ART, younger age in women, and having no education/schooling.[13–15] Some studies suggest that individuals who initiate ART at higher CD4 cell counts (>350 cells/mm3) may be less likely to have drug resistance at failure.[13,16,17]

The multinational HIV Prevention Trials Network (HPTN) 052 study evaluated the impact of early ART on HIV transmission in serodiscordant couples.[1,2] HIV-infected index participants were enrolled with CD4 cell counts of 350–550 cells/mm3 (enrollment period 2005–2010). Couples were randomized to 1 of 2 study arms. In the early ART arm, index participants started ART at study enrollment. In the delayed ART arm, index participants started ART once their CD4 cell count dropped below 250 cells/mm[3] or they developed an AIDS-defining illness.[1,2] In May 2011, interim study results revealed that early ART initiation prevented 96% of HIV transmissions and offered health benefits to the index participant.[1] After release of the interim study results, all index participants not already on ART were offered ART regardless of CD4 cell count and were informed of the benefits of early ART. The study continued until May 2015. In the delayed ART arm, 96% of the index participants had initiated ART by the end of the study.[2] The overall reduction in HIV transmission in the early ART arm compared with the delayed ART arm was 93%.[2]

We previously analyzed virologic outcomes in the HPTN 052 study.[18,19] In the first phase of the study (by May 2011), participants in the delayed ART arm took longer to achieve viral suppression compared with those in the early ART arm.[18] Over the entire trial period, higher pre-ART viral load was associated with a longer time to viral suppression, but was not associated with increased risk of virologic failure.[19] In the first phase of the study, the frequency of HIV drug resistance at the time of virologic failure differed by study arm. That study included resistance data from only 8 participants from the delayed ART arm because most participants in the delayed ART arm did not start ART until after May 2011.[13] A preliminary comparison of drug resistance in the 2 study arms in that study found a higher rate of resistance in the delayed ART arm compared with the early ART arm [7/8 (87.5%) vs. 30/85 (35.3%), P = 0.006].[13]

In this report, we extended the analysis of HIV drug resistance in the HPTN 052 trial to include participants who failed ART at any time during the trial (through May 2015). This increased the number of participants analyzed in both study arms, which provided more power for identifying factors associated with emergence of resistance. Inclusion of participants from the entire trial period also allowed us to compare drug resistance among participants in the early ART arm to those in the delayed ART arm who started ART before vs. after release of the interim study results. These 2 groups started ART at different baseline CD4 cell counts and had different knowledge about the benefits of early ART.

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