Intermittent HIV treatment dosing may be a response to the funding crisis, but adolescent study raises concerns

Intermittent HIV treatment schedules – such as weekends off treatment – may not be inferior to continuous treatment in adults with well-controlled HIV, but they are not suitable for adolescents with HIV in Africa who receive one or two viral load tests each year, studies presented this week at the 13th International AIDS Society Conference on HIV Science (IAS 2025), in Kigali show.

Intermittent treatment for people with suppressed viral load has been proposed as a way of mitigating the impact of severe funding cuts on antiretroviral drug supplies. A UNAIDS survey of 56 countries affected by US funding cuts found that almost half (46%) had experienced supply chain disruption and 14% had less than six months stock of at least one antiretroviral drug.

Although any interruption in treatment carries a risk of viral rebound if drug levels fall too low, short interruptions of two or three days per week are less likely to lead to viral rebound as drug levels may remain sufficient to suppress HIV during the off-treatment period. Intermittent treatment schedules are not recommended in any national or international guidelines.

Several intermittent treatment strategies have been tested in clinical trials that were designed with a view to relieving the long-term pressure of adherence experienced by some people living with HIV.

As the studies were each relatively small, Dr Cassandra Fairhead of the Royal Free Hospital, London, and researchers in France, Indonesia, South Africa, Spain and the United Kingdom carried out a systematic review and pooled analysis of studies of intermittent antiretroviral treatment, to look at the impact of the strategy on viral suppression and drug resistance.

The systematic review identified eight randomised trials that compared continuous treatment to intermittent treatment taken on at least three days per week. The eight studies consisted of four that evaluated 5 days on, 2 days off treatment; one study of treatment on alternate days; one study of 4 days on, 3 days off treatment; and two studies of 3 days on, 4 days off treatment. Four studies employed an NNRTI-based regimen, two studies employed bictegravir, emtricitabine and tenofovir alafenamide, and one study evaluated any three-drug antiretroviral regimen.

Study participants were virologically suppressed at baseline. All studies excluded pregnant women, and all but one excluded people with hepatitis B.

The pooled analysis evaluated virologic suppression and the development of drug resistance in the 1346 participants in the studies. The analysis found no difference in virologic suppression between intermittent and daily treatment; 3% of participants assigned to each treatment strategy experienced viral rebound above 50 copies/ml.

Intent-to-treat analysis of each of the eight studies showed no significant difference in viral suppression below 50 copies/ml at week 48 between intermittent and continuous treatment, and no significant difference in rates of viral suppression between study arms in four studies which used highly sensitive viral load tests with thresholds of 20 copies, 5 copies, 2 copies or 1 copy/ml.

Only one study found a difference in adherence rates between study arms, favouring intermittent treatment.

Three studies evaluated treatment-emergent resistance; pooled analysis showed that the rates of emergence were similar for intermittent and continuous treatment (1.9% vs 2.1%).

But in settings with less frequent viral load monitoring or resistance testing, switching after treatment failure may be less rapid, leading to higher rates of viral rebound and resistance. Studies of intermittent treatment which use the viral load and treatment protocols employed in low- and middle-income countries are urgently warranted, Dr Fairhead concluded.

Intermittent treatment in adolescents

However, the 96-week results of the BREATHER Plus study showed that for one group who often experience adherence difficulties, intermittent treatment is inferior to daily treatment. BREATHER Plus randomised adolescents to continue their existing regimen of tenofovir disoproxil, lamivudine and dolutegravir (TLD) or switch to taking TLD 5 days on treatment, 2 days off.

The study recruited 470 participants with no history of treatment failure in Kenya, South Africa, Uganda and Zimbabwe, with a median age of 16.5 years. Ninety-seven per cent had acquired HIV through vertical transmission and participants had been on antiretroviral therapy for a median of 11.8 years, including a median of 2.5 years on dolutegravir.

The primary outcome of the study was confirmed viral rebound (two consecutive viral loads above 50 copies/ml by week 96). Viral load was measured at intervals recommended in national guidelines (6-12 months). The study used two tests of non-inferiority: a standard 95% confidence interval and a “smooth away from expected (SAFE)” non-inferiority margin, in which the confidence interval and non-inferiority margin changed according to the number of viral rebounds in the continuous treatment arm.

Ten per cent of participants in the continuous treatment arm and 5% in the intermittent treatment arm experienced viral rebound during the study, a risk difference of 5.1% (95% CI 0.5, 9.9) (p=0.034) – a significantly higher rate of viral rebound in the intermittent treatment arm. Kaplan-Meier analysis showed that adolescents receiving intermittent treatment were more than twice as likely to experience viral rebound after 96 weeks compared to those on continuous treatment (hazard ratio 2.1, 95% CI 1.0-4.4). Age or treatment site did not affect the risk of viral rebound.

A total of 33 participants experienced viral rebound. Eight of 11 in the continuous arm and 19 of 23 in the intermittent arm resuppressed, including eight of the 14 who remained on intermittent treatment.

During the study, 20 participants on intermittent treatment switched to continuous treatment (six due to viral rebound, 13 due to pregnancy or wanting to conceive, and one by choice).

Resistance test results were available for 12 of 23 people with viral rebound in the intermittent arm and six of 11 in the continuous arm by week 96. Three people in the intermittent arm had developed major NNRTI mutations; in the continuous arm, one participant developed low-level dolutegravir and high-level lamivudine resistance and two developed NNRTI resistance. The patterns of resistance found after viral rebound in participants taking dolutegravir-based treatment suggest that some had resuppressed viral load on previous treatment after viral rebound, or that previous treatment histories had not been fully recorded prior to study enrolment.

An adherence sub-study using electronic pill bottles in 210 participants found that tablets were taken correctly on 92% of study days over 24 weeks in each arm.

The study investigators concluded that intermittent treatment cannot be recommended as a treatment strategy for adolescents with HIV taking TLD and receiving viral load tests every six to 12 months.