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Expert Analysis: Insights for International Clinicians on New Data From CROI 2020

Josep M. Llibre, MD, PhD
Laura Waters, FRCP, MD
Released: April 21, 2020

Outcomes With Rapid ART Start

Time to ART Initiation and Subsequent Loss to Care in Rwandan Cohort

Laura Waters, MD:
There is an ongoing debate among HIV clinicians regarding how quickly PWH should initiate ART. The WHO recommends that all individuals should initiate ART within 7 days of HIV diagnosis.[21] In my practice in London, we have moved toward rapid or same-day ART initiation. The question remains: Does starting ART on the same day of an HIV diagnosis lead to better outcomes than waiting for 7 days or even longer?

The next 2 reports that we discuss offer data implying that we should not necessarily be trying to start all patients on ART on the same day as diagnosis. 

Rwanda Cohort: Study Design and Time to ART Initiation

Laura Waters, MD:
The first report was a retrospective cohort study that examined the relationship between time to ART initiation and loss to care among individuals newly diagnosed with HIV in Rwanda. Ross and colleagues[22] analyzed data drawn from 1712 PWH aged 15 years or older who had at least 15 months of follow-up after their HIV diagnosis, which had to occur after July 1, 2016. These individuals were part of a large prospective cohort of more than 36,000 PWH across 10 health centers in Kigali, the capital of Rwanda. In this analysis, the investigators estimated the probability of being lost to care—defined as having more than 120 days since the last clinic visit, if the patient is not known to have transferred care or died—and used Cox proportional hazards regression to assess loss to care by time to ART initiation.

The study population was notable for being primarily female, with women comprising 50% to 72% of each group of patients categorized by time to ART initiation (same day, 1-7 days, 8-30 days, and > 30 days).

Rwanda Cohort: Earlier ART and Loss to Care

Laura Waters, MD:
Starting ART within 7 days of HIV diagnosis did not improve retention in care in the overall population.[22] In fact, the probability of loss to care was significantly improved if ART initiation was deferred for more than 7 days (P = .003 vs within 7 days). This overall result was driven by the minority of participants who did not have a CD4+ cell count available (P < .001), whereas there was no significant difference in loss to follow-up for the majority of participants who had a CD4+ cell count available (P = .74).

Rwanda Cohort Study: Probability of Loss to Care

Laura Waters, MD:
Indeed, among those with an available CD4+ cell count, there was a nonsignificant trend toward improved care retention with earlier ART initiation. The adjusted HR for being lost to care among those who deferred ART by more than 7 days was 1.4 (95% CI: 0.65-1.99)—translating to a 40% higher risk of being lost to follow-up in this subgroup. However, the CIs were wide and spanned 1.0 for that HR.

I was struck by the finding that those who did not have a CD4+ cell count available were significantly more likely to be lost to follow-up if they started ART quickly. I am uncertain what explains that observation, although the investigators suggested that missing the CD4+ cell count may be a surrogate for less support by the health center or decreased patient engagement in care.

Rwanda Cohort Study: Clinical Implications

Laura Waters, MD:
The main takeaway from this retrospective study was that starting ART quickly after HIV diagnosis was not associated with any overall benefit to retention in care.[22] Furthermore, in PWH who did not have a CD4+ cell count available, the loss to follow-up may be greater when they quickly initiate ART.

Josep M. Llibre, MD, PhD:
As an HIV clinician practicing in Spain, I have observed that sometimes when you start ART on the first visit, you risk losing the patient to follow-up because you have not yet built a relationship of trust with the patient.

Laura Waters, MD:
In London, where I practice, same-day ART has become the gold standard by default. Many of my newly diagnosed patients are motivated to promptly start ART because they want to bring the virus under control. Although clinicians should support our patients’ treatment goals, we should be honest about the data on outcomes associated with early vs deferred ART initiation. I would discuss how there is somewhat limited evidence of the benefit of same-day ART in high resource regions of the world,[23-29] as well as no substantial evidence of harm when the patient defers ART to take several days to a couple of weeks to adjust to the HIV diagnosis. In fact, this deferment affords us time to obtain the full set of baseline tests.

Demographics by ART Initiation Timing Among Cohort in Thailand

Laura Waters, MD:
Investigators in Thailand also evaluated the associations between timing of ART initiation and loss to follow-up, along with assessments of virologic suppression and safety outcomes. Seekaew and colleagues[30] analyzed these outcomes in 3888 clinically eligible patients diagnosed with HIV at 10 healthcare facilities implementing same-day ART between July 2017 and July 2019 in Thailand. After being diagnosed with HIV and deemed eligible for ART, all patients initiated treatment with EFV/FTC/TDF. Participants were categorized by the length of time between engaging in care and initiating ART (same day, 2-7 days, 8-14 days, 15-21 days, and more than 21 days). The investigators compared the demographics and outcomes among these categories and also performed multivariable logistic regressions to identify factors significantly associated with loss to follow-up, virologic suppression, and safety events.

Of the 3888 participants in this analysis, the vast majority initiated ART on the same day as diagnosis (n = 3053).[30] In contrast to the Rwanda study, most participants in this Thailand study were male (76.1% to 85.1%). There were no significant differences between the ART initiation groups by sex (P = .126), but there were some small but statistically differences in age and education achievement (both P ≤ .001). Overall, the groups were fairly similar.

Thailand Study: Timing of ART Initiation by Baseline CD4+ Cell Count

Josep M. Llibre, MD, PhD:
I was somewhat surprised that when the investigators analyzed the timing of ART initiation by baseline CD4+ cell count, there was no trend toward PWH with very low CD4+ cell counts (ie, ≤ 50 cells/mm3) being treated earlier. Indeed, among the approximately 9% of patients who initiated ART at 8 days or more after HIV diagnosis, most had low CD4+ cell counts. Is there an explanation for that observation?

Laura Waters, MD:
I would assume that these individuals with very low CD4+ cell counts also presented with opportunistic infections. There are recommendations to defer ART in cases with suspected cerebral pathology (eg, cryptococcal meningitis), for example.[31]

Thailand Study: Retention in Care

Laura Waters, MD:
Looking at retention in care at Month 3, the investigators observed that the proportion of those lost to follow-up was lowest at 1.1% in the participants who had the longest duration from HIV diagnosis to ART initiation (> 21 days).[30] Among those who started ART on the same day as diagnosis, 4.9% were lost to follow-up. However, this was a nonsignificant trend (P = .409).

Regarding retention in care at Month 12, the differences in loss to follow-up had attenuated and were similar across the groups at this time point (P = .913). The proportion of those lost to follow-up was 4.8% among patients who initiated ART more than 21 days after diagnosis and 3.7% among those who started ART on the same day.

Overall, there was no significant difference in the proportion of patients achieving virologic suppression (defined as HIV-1 RNA < 50 copies/mL after being on ART for ≥ 6 months) between those who started ART on the same day vs those who deferred ART after diagnosis (P = .054).[30]

There was also no significant difference between groups in the rates of any clinical adverse event and death (P = .685 and .895, respectively).

Thailand Study: Factors Associated With Loss to Follow-up and Clinical Adverse Events in Multivariable Regression

Laura Waters, MD:
When the investigators assessed potential risk factors, they observed that transgender women had significantly greater odds of being lost to follow-up (adjusted odds ratio [OR]: 1.70; 95% CI: 1.03-2.80; P < .05).

Although no factor was significantly associated with the viral suppression or likelihood of death, the investigators again found that transgender women had significantly greater odds of experiencing any clinical AE (adjusted OR: 1.52; 95% CI: 1.07-2.17; P < .05).

Thailand Study: Clinical Implications

Laura Waters, MD:
To summarize, in this study, early retention rates trended higher for those who deferred ART initiation, whereas later retention rates were similar regardless of whether ART was initiated the same day or deferred.[30] The virologic and safety data indicate that same-day ART was not superior to waiting to initiate ART.

Josep M. Llibre, MD, PhD:
It seems that we are faced with a clinical conundrum: Because we now have ART regimens that can be given to nearly anyone without baseline testing, we do not have a medical reason to delay ART initiation. On the other hand, the evidence suggests that for most PWH, in whom an HIV diagnosis does not represent an emergency, the patient will gain no benefit from starting immediately compared with starting after several days or even 1 week.

Laura Waters, MD:
I agree. My experience has been that some PWH who have started ART on the same day have had a rocky course, and it is challenging to predict who will have difficulty adjusting to a new HIV diagnosis.

From the clinician's perspective, so many developments in HIV care have been so positive—from the normalization of life expectancy, to undetectable = untransmissble (U=U), to the availability of single-tablet regimens and ART regimens that can be started without baseline testing—that we can forget that HIV infection is still a lifelong condition with a major effect on our patients’ lives.

I have had young patients who switched ART regimens several times in the first 6 months after diagnosis due to symptoms that they attributed to medication adverse event, but which I sometimes suspected might have been more related to their very understandable anxieties as they were adapting to their HIV diagnosis.

So although same-day ART initiation is a strategy that would work for many PWH, clinicians need to bear in mind that there are cases where it may be better to wait a little longer before initiating ART.

A limitation of both studies that we just discussed is that the analyses only captured data through approximately 1 year. We need longer-term data on adherence, retention in care, and patient-reported outcomes, including treatment satisfaction metrics, for those who started ART on the same day vs those who took more time to consider their options and adjust to their diagnosis.

Before we move on, I want to highlight a key finding from the Thailand study indicating that transgender women were more at risk for being lost to follow-up as well as developing adverse events. These findings complement the observations that transgender women are at high risk of acquiring HIV and emphasize that we need to provide better support for this at-risk population.[32]

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