Immediate ART has little impact on risk

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Starting antiretroviral therapy (ART) immediately rather waiting until a person’s CD4 count falls below 500 cells/µL has almost no impact on the person’s risk of developing antiretroviral resistance over the next seven years, The Body Pro reports according to a study. In this 51,000-person analysis, the impact of immediate ART on acquired drug resistance disappeared almost completely among people starting treatment in 2005 or later.

Antiretroviral guidelines in the US and throughout the world recommend ART immediately after HIV diagnosis, regardless of CD4 count. Research ties immediate ART to a lower risk of developing serious HIV-related and non-HIV-related conditions, as well as to lower HIV transmission risk. But concern persists that a longer overall duration of treatment resulting from immediate ART boosts a person’s chances of developing acquired antiretroviral resistance. To address this concern, researchers with the HIV-CAUSAL Collaboration in Europe and the US conducted this prospective analysis.

The study focused on routinely collected resistance data from six cohorts – one each in Greece, the Netherlands, Spain, and Switzerland, as well as two in the UK. Resistance study participants were at least 18 years old and had their viral load and CD4 count measured within three months of each other before they started ART. (No participants had an Aids-defining condition.)

The HIV-CAUSAL team compared emergence of resistant virus in three ART-initiation groups: (1) immediate ART (started within three months of baseline), (2) ART initiated within three months of reaching a CD4 count below 500 cells/µL, and (3) ART initiated within three months of reaching a CD4 count below 350 cells/µL or receiving an Aids diagnosis.

The primary outcome was acquired resistance to an antiretroviral up to seven years after follow-up began, using the Stanford University resistance database to assess resistance levels. To compare resistance rates with the three treatment strategies, the researchers used a regression model, the parametric g-formula, adjusted for fixed baseline variables and for time-varying confounders (CD4 count, viral load, Aids, resistance testing, and nonnucleoside antiretroviral class versus other classes).

Among the 50,981 eligible participants, 80% were men. The median baseline age was 35 years, and the median baseline CD4 count was 405 cells/µL. Almost three-quarters of participants, 71%, started follow-up after 2004. Of the 31,969 people (63%) who started ART, 3,207 (10%) did so with a CD4 count above 500 cells/µL. Among 22,161 participants (43%) tested for transmitted HIV drug resistance before starting ART and within 12 months of baseline, 6.1% had detectable resistant virus.

Overall risk of acquired resistance seven years after baseline was 2.7%. Seven-year estimated resistance risk did not differ significantly among any of the three ART groups: immediate ART (3.2%, 95% confidence interval [CI] 2.8 to 3.5), ART initiation below 500 cells/µL (3.1%, 95% CI 2.7% to 3.3%), and ART initiation below 350 cells/µL (2.8%, 95% CI 2.5% to 3.1%).

When the analysis was restricted to people with a baseline date between 2005 and 2015, estimated seven-year risk of acquired resistance varied hardly at all among the three groups: immediate ART (1.9%, 95% CI 1.8 to 2.5), initiation below 500 cells/µL (1.9%, 95% CI 1.7 to 2.4), and initiation below 350 cells/µL (1.8%, 95% CI 1.7 to 2.2). Seven-year acquired resistance estimates also virtually overlapped with an analysis restricted to people with a baseline CD4 count above 500 cells/µL: immediate ART (1.6%, 95% CI 1.2 to 2.3), initiation below 500 cells/µL (1.9%, 95% CI 1.4 to 2.4), and initiation below 350 cells/µL (1.6%, 95% CI 1.2 to 2.1). Results did not change substantially when researchers sequentially excluded each of the six cohorts from the analysis.

The investigators believe their findings indicate “it is unlikely that the clinical benefits of early ART initiation demonstrated by randomised trials and observational studies will be lessened by development of acquired drug resistance.” They note that starting ART immediately raised seven-year acquired resistance risk only 0.13% compared with starting ART at a CD4 count below 500 cells/µL, and by only 0.37% compared with starting ART below 350 cells/µL.

These minimal differences may be even smaller today, the authors add, because their study sample underrepresented treatment with newer protease inhibitors and integrase inhibitors associated with low resistance rates.

Objective: We estimated and compared the risk of clinically identified acquired drug resistance under i) immediate initiation (the currently recommended ART initiation strategy), ii) initiation with CD4 < 500, and iii) initiation with CD4 < 350 cells/mm3.

Design: Cohort study based on routinely collected data from the HIV-CAUSAL Collaboration.

Methods: For each individual, baseline was the earliest time when all eligibility criteria (ART-naïve, AIDS-free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g-formula to adjust for time-varying (CD4 count, HIV-RNA, AIDS, ART regimen and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics.

Results: In 50,981 eligible individuals, 10% had CD4 count>500 at baseline, and 63% initiated ART during follow-up. Of 2,672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% CI) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 < 500, and 2.8% (2.5,3.0) for initiation with CD4 < 350 cells/mm3. In analyses restricted to individuals with baseline in 2005–2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7,2.4) and 1.8% (1.7,2.2).

Conclusions: Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation.

Lodi Sara; Günthard, Huldrych F; Dunn, David; Garcia, Federico; Logan, Roger; Jose, Sophie; Bucher, Heiner C; Scherrer, Alexandra U; Schneider, Marie-Paule; Egger, Matthias; Glass, Tracy R; Reiss, Peter; van Sighem, Ard; Boender, T Sonia; Phillips, Andrew N; Porter, Kholoud; Hawkins, David; Moreno, Santiago; Monge, Susana; Paraskevis, Dimitrios; Simeon, Metallidis; Vourli, Georgia; Sabin, Caroline; Hernán, Miguel A

The Body Pro report
AIDS abstract

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