Trials of Strategic Treatment Interruptions in the Management of HIV Infection 

At the 13^th CROI in Denver, CO (February 5-8, 2006), researchers presented data from studies of CD4 cell-guided structured treatment interruptions (STIs). Two of the studies reviewed here show generally favorable outcomes for the use of STIs (ACTG 5170 and STACCATO), while results of two other trials --Trivacan and the SMART Study--demonstrate increased risk of disease progression and death with STI compared to the use of continuous antiretroviral therapy. The debate over the risks versus the benefits of STIs appears likely to continue.                    

Unless otherwise noted, all references are to the 13^th Conference on Retroviruses and Opportunistic Infections (13^th CROI). February 5-8, 2006. Denver, CO.

ACTG 5170 (Abstract 101)

In this multicenter study of 167 patients with a baseline median CD4 count of 833 cells/microliter, investigators evaluated the safety of treatment interruption and sought to identify parameters that would identify patients for whom treatment interruption was low risk [1].

At study entry, 136 subjects had viral load ≤400 copies/mL and nadir CD4 count of 436 cells/microliter and 3.9 years median antiretroviral therapy (ART).

96-week Results

Median time off therapy was 96 weeks.

17 participants had CD4 count >/= 250cells/microliter.

46 patients restarted ART.

5 patients died during the study, but all deaths were non HIV/AIDS-related.

Of 28 subjects, 24 with viral load ≤400 copies/mL at entry, and who restarted ART achieved a viral load of ≤400 copies/mL.

Low CD4 count nadir, lower entry CD4 count entry, and higher entry viral load predicted shorter time to primary endpoint at week 48 and 96.

The authors conclude, “ART interruption was generally safe in this cohort. Low nadir CD4 count is the best predictor of CD4 decline or clinical events following ART cessation.”

The STACCATO Trial (Abstract 102)

Although halting therapy may reduce costs, there is a concomitant risk of the development of drug resistance and an increase in immune suppression. The aim of this collaborative Swiss/Thai/Australian trial was to determine the risks vs benefits of stopping therapy [2].

430 patients with CD4+ counts > 350 cells/microliter and HIV RNA levels < 50 copies/mL were randomized to either discontinuation of therapy or to continuous treatment until the CD4+ count reached < 350 cells/microliter.

The median time on randomized treatment was 21.9 months. At the end of the study, both groups were again treated continuously for 12 to 24 weeks (mean=22 weeks).

352 Thai patients received 1600 mg of saquinavir (SQV) plus 100 mg of ritonavir (RTV) once daily with 2 NRTIs:  didanosine/stavudine (ddI/d4T) from 2002 until March 2003, and tenofovir/lamivudine (TDF/3TC) thereafter. In Swiss and Australian patients, the type of HAART used was defined by the treating physician.

Results

Probability of reinitiating treatment in STI was 53% at 6 months, 64% at 12 months, and 74% at 24 months.

Drug savings in STI, compared to continuous therapy, amounted to 61.2% during randomized treatment.

The percentage of patients with viral <50 copies was 91.8 % in continuous therapy, compared to 90.3% in STI after re-treatment at the end of the trial.

Median CD4 counts were 374 in STI (60.5% >350), and 601 in continuous therapy (96.2% >350).

After re-treatment, median CD4 counts rose in STI from 374 to 459 after 12 weeks, with 85.9% >350, compared with 96.9% in continuous therapy (p <0.01).

During STI, 17 patients (5.8%) had symptoms of acute retroviral syndrome. Diarrhea and neuropathy were more frequent in continuous therapy, whereas oral and vulvo-vaginal candidiasis and thrombocytopenia were more frequent in STI.

Resistance mutations occurred in 7 patients in the RT gene, and 3 in the P gene.

Based on these findings, the study authors write, “During 484 patient-years of STI, little evidence of treatment resistance emerged. Treatment-related adverse effects were more frequent in continuous therapy, but minor manifestations of HIV infection were more frequent in STI.”

The investigators noted no risk of increased progression to AIDS and no loss of response to antiretroviral therapy when restarted.

ANRS 1269 Trivacan Trial (Abstract 105LB)

326 patients were enrolled in this randomized STI trial among West-African adults [3]. Only data from the continuous therapy (n=110) and CD4-guided therapy (n=216) arms of the study were reported at the 13^th CROI.

The endpoints were either serious illness or death.

Results

The Data and Safety Monitoring Board halted the study due to extensive disease progression in the STI group.

Duration of therapy was 274 and 272 in the CT and CGT arms, respectively.

By October 31, 2005, overall median follow-up was 20 months, 4 patients were lost to follow-up, 5 patients were dead and 60 patients had experienced 84 serious morbidity events;

These events included oro-pharyngeal candidiasis (n=42), invasive bacterial events (n=24), and tuberculosis (n=16).

Median days in hospital were 38 and 68 in the CT and CGT arms, respectively.

Among the 286 patients who reached month 12 after randomization (CT 96, CGT 190), the median month 12 CD4 count was 546 cells/microliter in the CT arm and 333 cells/microliter in the CGT arm.

These results led the authors to conclude, “CGT led to a 2-fold higher serious morbidity rate than CT, mainly due to invasive bacterial diseases. Further structured treatment interruption trials assessing CGT strategies in sub-Saharan Africa should use higher CD4 thresholds for interruption/ introduction. Whether a fixed treatment-interruption strategy is appropriate in Côte d’Ivoire requires further follow-up.”

SMART Study (Strategies for Management of Anti-Retroviral Therapy) [Abstract 106LB]

The largest prospective HIV trial ever undertaken, the SMART Study was conducted by the CPCRA (Community Programs for Clinical Research on AIDS) [4]. This study enrolled almost 6000 patients from 318 sites in 33 countries who had CD4 >350 cells/microliter.

Patients were randomized to receive either (1) continuous HAART (the virologic suppression (VS) arm) OR (2) discontinuation of HAART when the CD4+ cell count was > 350 cells/microliter and resumption of HAART when the CD4+ cell count was < 250 cells/microliter (the drug-conservation (DC) arm).

The objective of the SMART trial was to determine a treatment strategy that maximizes benefits while minimizing risks through use of HAART to maintain CD4 above specific threshold.

The primary endpoint was HIV disease progression or death. On January 10, 2006, the Data and Safety Monitoring Board (DSMB) notified the team of increased HIV progression risk in the DC arm. Enrollment was stopped on January 11.

The authors conclude that the SMART trial showed “CD4-guided episodic ART use aimed at maintaining CD4 >250 cells/mm³ is associated with increased short-term risk of progression of HIV disease and death compared to continuous ART.”

In addition, the authors noted that the relative risk of disease progression or death (DC/VS) was greater in the first 2 years of follow-up compared to afterward.

03/07/06

References

1. D Skiest and others. Predictors of HIV Disease Progression in Patients Who Stop ART with CD4 Cell Counts >350 cells/mm³. 13^th CROI. February 5-8, 2006. Denver, CO. Abstract 101.

2. J Ananworanich and others. CD4 guided scheduled treatment interruption compared to continuous therapy: Results of the Staccato Trial. 13^th CROI. February 5-8, 2006; Denver, CO. Abstract 102.

3. C Daniel and others. The CD4 guided strategy arm stopped in a randomized structured treatment interruption trial in West African adults: ANRS 1269 Trivacan Trial. 13^th CROI. February 5-8, 2006; Denver, CO. Abstract 105LB.

4. W El-Sadr, J Neaton and (for the SMART Study investigators). Episodic CD4-guided use of antiretroviral therapy is inferior to continuous therapy: Results of the SMART study. 13^th CROI. February 5-8, 2006. Denver, CO. Abstract 106LB.