Short Cycle,Intermittent Therapy: A Valuable Option in Selected,Virologically Suppressed People Living with HIV

Recommended antiretroviral therapy consisting of two nucleoside analogues and a third agent (integrase inhibitor, nonnucleoside reverse-transcriptase inhibitor, or boosted protease inhibitor) that must be taken every day (7 days/week) and continued lifelong, with a risk of reduced adherence and long-term toxicity. In recent years, different strategies have been studied to reduce the exposure of people living with HIV (PLWH) to antiretroviral drugs and to improve their adherence and quality of life, while maintaining safety and virological suppression.

In particular, the “intermittent” or “short-cycle” therapy (SCT) has received considerable attention. This strategy allows PLWH to take their antiretroviral drugs at standard doses and in combination for a limited number of consecutive days (generally 4 or 5 days) per week and interrupt the treatment during the weekend (Friday to Sunday or Saturday to Sunday).

The first study to investigate SCT was the “five-days-on, two-days-off” study, published in 2007, where investigators tested the strategy in adults treated with different antiretroviral regimens (largely including efavirenz), obtaining a 89.6% virologic suppression at week 48. ¹

Further evidence in support of SCT was provided by the “BREaks in Adolescent and child THerapy using Efavirenz and two nRtis” (BREATHER) study, a multicentric, randomized, controlled, open-label phase 2/3 trial, that demonstrated the noninferiority of a 5-days-per-week SCT compared to standard 7-days-per-week schemes in 199 adolescents taking efavirenz-based ART. ² This study, with an extended follow-up of 144 weeks, demonstrated that SCT improved patients' tolerability and quality of life, and reduced the cost of ART, without exposing the patients to increased risks for their health. ^{3 –5}

The rationale behind the choice of efavirenz-based ART in the BREATHER study was the long half-life of the drug (40–91 h), which allowed maintenance of viral suppression during the week-end break. ² Following this trial, Jacques Leibowitch and colleagues in France tested shorter cycles of treatment in two studies, which were effective in selected patients. ^6,7 In particular, in the “Intermittent, in careful short cycles, antiretrovirals may retain efficacy” (ICCARRE) study, 100% virological suppression was reported in all patients on a 4-days-on/3-days-off scheme. ⁷ The use in some cases, as third agent, of a protease inhibitor, which has fairly short half-life, suggested that factors other than half-life played a role in maintaining virological suppression during the “off” period.

Six other studies have focused on a 4-days-on/3-days-off antiretroviral strategy. ^{8 –13} In 2009, Rudy and coworkers reported that viral rebounds occurred in 12 of 32 adolescents followed for 48 weeks ⁸ ; these somehow disappointing results were attributed both to the short half-life of protease inhibitors and to the fact that the adolescents had a long history of antiretroviral treatments, and a few of them had many resistance mutations. ⁸ The French ANRS 162-4D trial, published in 2018, found that antiretroviral maintenance therapy 4 days a week was effective for 48 weeks in 96/100 patients ⁹ ; treatment included PI/r in 29 cases and non nucleoside reverse transcriptase inhibitor in the remaining 71. ⁹

In these 100 patients, total HIV DNA did not change after switch to short-cycle strategy over a follow-up of 48 months, and the patients' level of satisfaction for intermittent antiretroviral therapy was very high. ⁹ In a cohort study of 73 patients in France, Calin and colleagues focused exclusively on patients on integrase inhibitor-based combinations (in particular, 36 patients were on bictegravir); the virological efficacy rate (HIV RNA <50 copies/mL) at 48 weeks was 100% on a 4/5-days-a-week treatment. ¹⁰

A small, more recent study in Italy including 26 PLWH on virological suppression for over 12 months showed that a dual regimen of a single tablet of lamivudine/dolutegravir maintained HIV RNA below 20 copies/mL for a median of 14 months. ¹¹ Interestingly, these results were obtained even though pharmacokinetic analysis showed that in 60% of the samples, Ctrough of dolutegravir 60–72 h after the last dose was below the in vitro protein-adjusted 90% inhibitory concentration for wild-type virus (64 ng/mL). ¹¹

Similar results were obtained in another small observational Italian study on 4-days-on/3-days-off treatment of a cohort of 30 PLWH on a rilpivirine-containing regimen. ¹² At week 48, all patients were virologically suppressed, even though the rilpivirine concentration was below the efficacy threshold in 71.3% of the tested samples. ¹² The results of the latter two studies suggest that patient characteristics rather than drug pharmacokinetics play a role in maintaining virological suppression.

Finally, the ANRS 170 QUATUOR, a randomized, open-label, multicentric, noninferiority trial demonstrated the noninferiority of the 4-days-on/3-days-off strategy in a large cohort of HIV-infected suppressed patients on different ART regimens over 96-weeks follow-up period. ¹³ This trial, registered in 2017 and with the preliminary results presented at IAS 2019, ¹⁴ has shown the noninferiority of a 4/7 SCT in a cohort of 636 patients, with a treatment success rate of 96% at 48 weeks of follow-up and a similar rate at week 96 for participants in the intermittent treatment group. ¹³ Immunological parameters (CD4 cell count, CD8 cell count, CD4/CD8 ratio), inflammatory biomarkers and total HIV DNA concentrations in peripheral blood mononuclear cells did not differ between the two groups. ¹³ Importantly, ART costs were 43% lower with the SCT in respect of continuous daily treatment. ¹³ The study also found a correlation between a nadir CD4 cell count below 250/μL and a higher risk of virological failure of intermittent therapy versus continuous daily therapy, ¹³ strengthening the possibility ¹⁵ of a direct correlation between low nadir CD4 lymphocyte count and high HIV reservoir size, the latter being closely linked to the time of viral rebound after treatment interruption. ¹⁶ In the group on SCT, more than half of participants reported an improvement in daily life satisfaction versus only 7% of the patients in the group on continuous antiretroviral regimen. ¹³ Two other observational studies have confirmed the efficacy and safety of this strategy. ^17,18 Sellem and colleagues showed the virological efficacy of bictegravir/emtricitabine/tenofovir alafenamide administered 5 or 4 days per week in a cohort of 85 persons living with HIV; viral suppression was maintained at week 48. ¹⁷ Palich and colleagues found that doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) given 5 or 4 days per week maintained viral suppression in 43 PLWH on stable virological suppression, with a median follow-up of 78 weeks. ¹⁸

Recently, the ANRS 170 Quatour study group showed that SCT is effective in controlling genital HIV shedding, as shown by semen HIV RNA levels in 78 participants in the 4 days/week maintenance strategy study. ¹⁹ These results are consistent with those of a small Italian case series of seven patients with suppressed HIV infection on SCT. ²⁰

Overall, the studies published so far have indicated the safety of a short-cycle strategy, showing low rate of virological failure and low emergence of drug resistance mutations, even though in the ANRS 170 QUATUOR, the risk of emerging resistance mutations was higher in the group on 4 days a week antiretroviral maintenance therapy. ¹³

As third agent, either a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor or an integrase inhibitor were used in the trials mentioned. High rate of virological failure happened only in the intermittents, en cycle courts, les anti retroviraux resten efficaces study in the 3-days-on/4-off-treatment strategy, when raltegravir was used at a dose of 400 mg once a day instead of the standard dose. ⁷

A reasonable explanation for the success of a SCT strategy was well described by Leibowitch et al. in the ICCARRE project. ⁷ HIV rebound is observed after an eclipse phase of 1–7 days or even more following the interruption of an effective therapy, and this is particularly clear in PLWH with a long history of virological suppression, who have a reduced viral load, and whose lymphoid system is less activated and less favorable for HIV replication. In these conditions, lower concentrations of antiretroviral drugs are effective in controlling viral replication. A 2010 study showed that the longer the viral suppression, the higher was the number of missed drug doses allowed without virological failure ensuing. ²¹ The proposed explanation was that lower levels of drug exposure are sufficient to prevent virological failure because the overall viral burden declines over time. ²¹

The use of long-acting antiretroviral regimens will not be suitable for all PLWH for various reasons (previous virological failure with drugs of the same class, side effects, logistic difficulties, and costs). We think that SCTs could represent a feasible and valuable option for antiretroviral treatment optimization in selected individuals, as suggested in a 2017 document of a group of French experts on treatment optimization of suppressed persons living with HIV. ²² This strategy could also be inserted in official guidelines.

Finally, short cycle, intermittent therapy could be more widely used also in low- and middle-income countries; a study done over a decade ago in Uganda showed that 5-days-on/2-days-off intermittent treatment was at least as effective as continuous therapy, ²³ and the cost-effectiveness compared with continuous therapy has been demonstrated and is determined by lower antiretroviral costs. ⁵