Several important presentations from the HPTN 052 study were presented at IAS 2015.
Although the international HPTN 052 study made headline news at the IAS conference in 2011 after reporting benefits of antiretroviral treatment (ART) to reduce the risk of HIV transmission, long-term follow-up meant that final results again produced more headlines at IAS 2015.
HPTN 052 randomised the HIV positive partner in 1763 serodifferent couples at sites in Africa (54%), Asia (34%) and South America (16%) to either immediate ART (at a CD4 count between 350 to 550 cells/mm3) or deferred ART (at CD4 count 250 cells/mm3). The primary endpoints were (i) linked HIV transmissions to the negative partners and (ii) clinical outcomes related to ART in the positive partner.
In April 2011, the study DSMB recommended stopping the randomisation to offer all positive participants ART, due to significantly lower rates of linked transmissions in the immediate vs the deferred ART arm (n=1 vs 27; 96% reduction, p<0.001). The single transmission occurred early after starting ART before viral load was likely to be suppressed.1
At IAS 2015, Myron Cohen from University of North Carolina at Chapel Hill presented results from >9800 patient years of follow-up collected until May 2015, together with combined overall results.3
Retention was higher for the positive partners with 87% still in the study, compared to <70% of the negative partners, reflecting changes in relationship status.
Although all positive participants were offered ART in April 2011 and 70% had started within 6 months, a small percentage continued to decline ART (16%, 7% and 3% after 1, 2 and 3 years respectively, with only 2% still not on ART when the study finally closed in May 2015.
During the last four years, an additional 9 linked transmissions occurred, 2 vs 7 in the early vs deferred groups respectively (at rates of 0.08 vs 0.29 per 100 years of follow-up; with a rate ratio 0.28 and 72% reduction in the early ART group).
As would be expected from the study design, the numbers of unlinked transmissions was similar between arms, with 14 vs 12 in the combined 2015 analysis.
Only 1/9 transmissions occurred before starting ART, with 4/9 occurring very early after ART was started and 4/9 occurring after the positive partner had virological failure on ART.
The presentation concluded that no HIV transmissions occurred over the whole study period from HIV positive partners who were on ART with undetectable viral load.
Susan Eshelman from Johns Hopkins University presented details on the phylogenetic analysis, which were used to confirm the linkage of within-partner transmission in HPTN 052, as a late breaker oral abstract in the same session.4
Other important results from HPTN 052 -- about participants who experienced viral failure that therefore also impacted the efficacy of TasP for both partners in the study -- was only available in a poster rather an oral presentation.5
Of concern, the analysis presented at IAS 2015 is only for the participants in the early treatment arm whose treatment failed by May 2011 during the blinded phase of the study.
In this group, viral failure occurred in 93/832 (11%) of participants in the early ART up to May 2011, with an annual incidence 5.6% (95%CI: 4.6 to 6.9%).
Cumulative rates of viral suppression at 1, 3, 6, and 12 months were 46%, 78%, 89%, and 93%, respectively. In multivariate analysis, higher viral load at ART initiation (HR 0.87; 95%CI: 0.84 to 0.91, p<0.0001) and younger age, (<25 vs 25-39; HR=1.31 [95%CI: 1.06-1.62]; p=0.012) were independently associated with longer time to viral suppression.
Lack of viral suppression by 3 months (and 6 months) was significantly associated with time to ART failure (HR 9.34; 95%CI: 6.14 to 14.2) and risk of subsequent treatment failure (HR 8.99; 95%CI: 5.63 to 14.3), both p<0.0001.
Limited data on drug resistance in HPTN 052, again only until April 2011 and in the participants whose treatment failed in the early ART group, were presented in a second poster. Genotypic resistance results were available from 85/93 (89%) of these participants whose treatment failed.6
Resistance was found retrospectively in baseline samples of 7/85 patients (8%): NRTI n=1, NNRTI n=3 and dual NRTI+NNRTI n=3). In samples at time of virological failure, 35/85 (35%) had resistance, including 27 (32%) with new resistance to one or more drugs: NRTI n=4; NNRTI n=4; NRTI+NNRTI n=19. No protease mutations were detected. Only higher viral load at baseline (per unit log increase) was associated with new resistance at failure (OR 1.62; 95%CI: 1.16 to 2.25, p=0.005).
Finding no linked transmissions with a further four years of follow up is clearly important and impressive.
However, it is unclear why the extremely limited data on viral failure has been held back for so long. It is also unclear why this aspect of the study was not included with the main results given that response to ART is a co-primary endpoint.
The risk of early failure is particularly important for people in countries with limited treatment choices.
This might still be good news for TasP though if people start ART earlier in infection.
The START study reported 97-98% viral suppression at 12 months. The significantly lower baseline viral load in START perhaps explains the lower rate of viral failure compared to HPTN 052.7
Unless stated otherwise, references are to the Programme and Abstracts of the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015), 19-22 July 2015, Vancouver.
- Cohen MS et al. Prevention of HIV-1 infection with early initiation of antiretroviral therapy. NEJM, August 2011; 365:6.
- Grinsztejn B et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis. 2014; 14: 281-290.
- Cohen MS et al. Final results of the HPTN 052 randomized controlled trial: antiretroviral therapy prevents HIV transmission. IAS 2015, 19-22 July 2015, Vancouver. MOAC0101LB.
- Eshleman SH et al. Treatment as prevention: characterisation of partner infections in the HIV Prevention Trials Network 052 trial. IAS 2015, 19-22 July 2015, Vancouver. MOAC0106LB.
- Fogel J et al. Identification of factors associated with viral suppression and treatment failure when antiretroviral therapy is used for HIV prevention: results from the HIV prevention trials network (HPTN) 052 trial. IAS 2015, 19-22 July 2015, Vancouver. Poster abstract MOPEC417.
- Sabin D et al. Analysis of HIV drug resistance in adults receiving early antiretroviral treatment for HIV prevention: results from the HIV prevention trials network (HPTN) 052 trial. IAS 2015, 19-22 July 2015, Vancouver. Poster abstract TUPEB285. (no PDF available)
- Lundgren J et al. Initiation of antiretroviral therapy in early asymptomatic infection. NEJM (20 July 2015). DOI: 10.1056/NEJMoa1506816.