New Perspectives in HIV Treatment Interruption: The SMART Study

Lawrence Siegel, MD, MPH and Wafaa El-Sadr, MD, MPH

Based on a presentation at PRN by Wafaa El-Sadr, MD, MPH

Lawrence Siegel, MD, MPH Clinical Fellow Division of International
Medicine & Infectious Diseases, Weill Medical College of Cornell
University New York, New York

Wafaa El-Sadr, MD, MPH Professor of Clinical Medicine and
Epidemiology, Mailman School of Public Health, Chief of the Division
of Infectious Diseases, Harlem Hospital Center New York, New York

The advent of highly active antiretroviral therapy in the mid 1990s resulted in a dramatic increase in survival of HIV patients, especially among those with advanced disease,” Dr. Wafaa El-Sadr said in beginning her February 2006 PRN lecture. Follow-up studies, she explained, demonstrated the durability of this effect, with decreasing HIV-associated morbidity and mortality during the late 1990s and early 2000s.  She also acknowledged, however, that while combination antiretroviral treatment has changed the face of the HIV epidemic and enabled physicians to provide truly effective therapy, several issues and limitations of these regimens have emerged.

The most significant limitation has been the necessity and challenge of continued daily adherence to the medications.  “Taking these medications day in, day out is difficult for patients,” she said. The frequently cited study of antiretroviral adherence, conducted by Dr. Sharon Mannheimer and her colleagues, demonstrated that after eight months of therapy, only 60% of patients reported 100% adherence (Mannheimer, 2002). Extrapolating these data implies worsening of compliance over years of therapy, resulting in drug resistance and subsequent elimination of treatment options.

Metabolic effects are another concern with HIV treatment.  More alarming is evidence of increased myocardial infarction rates among patients on antiretroviral therapy.  An important study on this subject was the DAD study (Data Collection on Adverse Events of Anti-HIV Drugs), which found an increased risk of coronary artery disease in people on all types of antiretroviral therapy (Law, 2003).The DAD study also found that some of the risk was lowered upon discontinuation of anti-HIV drugs. Additional metabolic and general side effects of antiretroviral therapy include cardiovascular complications, lipoatrophy, peripheral neuropathy, and accelerated liver disease (Julg, 2006).

Rates of severe therapy-related adverse events are also worrisome.  In a cross-protocol study, rates of grade 4 adverse events associated with antiretroviral treatment were shown to be higher than that of AIDS events or deaths (Reisler, 2003). “While we see a dramatic decrease in the development of AIDS as well as associated deaths, there has been an increase in the development of adverse events of avariety of organ systems,” noted Dr. El-Sadr.

The high cost of medications also continues to be an issue.  Although programs exist in New York State and New York City for financial support for treatment, many parts of the United States and most other parts of the world do not have such programs established.  The continued inability to eradicate or cure HIV gives the prospect of lifelong drug treatment enormous monetary implications.

Rationale and Strategies for Treatment InterruptionTop of page

“There is a need for strategies that can optimize the use of available antiretroviral drugs in order to maximize the benefits while minimizing the risks,” Dr. El-Sadr explained.  Treatment interruption is one way to optimize antiretroviral therapy. However, while interruption of antiviral therapy carries clear benefits, its safety and efficacy have yet to be established.

Two main strategies for treatment interruption have been studied: time-defined and CD4+ cell-guided.  Time-defined strategies involve predetermined treatment interruption, such as medication breaks on weekends and one-month-on/one-month-off scheduling, in an effort to improve quality of life, promote adherence, decrease antiretroviral exposure, and minimize the development of resistance.  The CD4+ cell-guided strategy, used in the National Institutes of Health’s Strategies for Management of Antiretroviral Therapy (SMART) study, utilizes CD4+ cell counts to determine the starting and stopping point of intermittent therapy (IT).  In other words, antiretroviral treatment is started when the CD4+ cell count falls below a certain threshold, stopped when it increases above a certain level, restarted when the CD4+ cell count again falls below the threshold, and so on.  

The potential risks and benefits of continuous therapy (CT) are familiar to most practitioners. Potential benefits include maximal suppression of HIV-RNA, consistent CD4+ cell count gains, and a decreased risk of HIV transmission.  The potential risks of CT include higher rates of drug side effects, more difficult adherence, and potentially more drug resistance resulting in fewer drug options secondary to higher antiretroviral therapy exposure.   

Conversely, the potential benefits of IT include fewer side effects, better adherence, and improved quality of life.  The risks include possible increase in the development of resistance, lasting damage to the immune system, and an increase in the risk of HIV transmission due to non-suppression of viral load.

Studies Assessing Treatment InterruptionTop of page

Several studies, reported around the time of SMART, have investigated both CD4+ cell- and time-guided IT strategies. The Staccato trial randomized 430 patients to CT or IT (Ananworanich, 2006). Patients in the IT group started therapy when their CD4+ counts dropped below 350 cells/mm3 and then stopped therapy once their CD4+ counts increased above 350 cells/mm3. Interestingly, this small study showed 5.8% of the  IT patients experienced acute retroviral syndrome. Minor manifestations of HIV infection, such as candidiasis and thrombocytopenia, were more common in the IT group, while adverse events, including diarrhea and neuropathy, were more common in the CT group.  Ten patients (2.3%) had resistance mutations; there were no differences between groups. There was a 62% savings in antiretroviral therapy costs (Julg, 2006).

The Window-ANRS 106 trial randomly assigned 403 patients with undetectable viral loads and CD4+ counts greater than or equal to 450 cells/mm3 while on antiretroviral therapy to receive either CT or IT in eight-week off /on cycles (Marchou, 2006). The primary endpoint of CD4+ counts less than 300 cells/mm3 was reached by 3.6% in the IT group, compared with 1.5% in the CT group. At week 96, the proportion of patients with CD4+ counts greater than 450 cells/mm3 and viral loads of 400 copies/mL or less was  75% vs. 92% and 81% vs. 90%, IT or CT, respectively. The IT arm, the investigators concluded, appeared safe and without excess resistance, while reducing antiretroviral exposure by 48.5%.

The ANRS 1269 Trivican trial randomized 326 patients on antiretrovirals therapy with CD4+ counts greater than 350 cells/mm3 and undetectable viral loads to CT or one of two IT strategies: CD4+ cell-count-guided (stopping at 350 cell/mm3 and restarting at 250 cells/mm3) or time-guided (two-months-off, four-months-on) (Danel, 2006). At an interim point, the CD4+ cell-guided arm was terminated prematurely due to safety concerns. The results demonstrated a two-fold higher serious morbidity rate in the CD4+ cell-guided group, compared with the CT group, with recommendations for future studies to utilize higher CD4 count thresholds.

The ISS PART trial randomized 273 subjects to one of five different time-guided IT schedules (one to three months off therapy, followed by three months on treatment) or CT, with the primary endpoint being the proportion of patients with CD4+ counts greater than 500 cells/mm3 after 24 months (Palmisano, 2006). Significantly more patients in the CT group reached the primary endpoint (86.5% vs. 69.1%; P=.0075), with similar rates of virological failure. 

The SMART study is the largest IT trial to date. The study was a two-armed treatment comparison of CT to CD4+ cell-guided IT. The goal of the CT arm was to use antiretroviral therapy,irrespective of the CD4+ cell count, to achieve and maintain undetectable viral loads. The goal of the IT arm was to defer therapy until the CD4+ count was below 250 cells/mm3, continue treatment until the CD4+ count increased above 350 cells/mm3, with subsequent stops and restarts using these CD4+ cell count cutoffs. 

Patients entering the study were required to have a current CD4 count of greater than 350 cells/mm3 (CD4+ count nadir was permitted to be lower). They were randomized 1:1, in an open-label fashion, to either CT or IT. The SMART investigators hoped to enroll 6,000 patients and to accumulate approximately eight years of follow-up data. The primary endpoints were progression to AIDS or death, survival, serious complications (e.g., cardiovascular, renal, and hepatic), serious disease progression events (e.g., disseminated MAC, toxoplasmosis, cryptococcosis, Kaposi’s sarcoma), and grade 4 events. Additional comparisons involved adherence, side effects, metabolic complications, quality of life, drug resistance, and cost. 

The study was halted on January 11, 2006, due to safety concerns. At that time, 5,472 patients were enrolled and included in an intent-to-treat analysis. In an effort to obtain a comprehensive understanding of the primary outcome, several substudies were conducted to assess various outcome measures, including quality of life, risk behavior, body composition and metabolic parameters, neurological complications, and anal dysplasia.

The study represents a true international effort with participants from 33 countries and 318 sites. The majority of the participants were from North America and the United States with additional participation through sites in Europe, Africa, Asia, and South America. 

Baseline characteristics of the study groups include a median age of 46 years: 27% were women and 30% were black.  The median follow-up time was 14 months, with 2% lost to follow up. The median CD4+ count at entry was approximately 598 cells/mm3, with median nadirs of approximately 251 cells/mm3. Seventy-one percent had viral loads less than 400 copies/mL, 24% had prior clinical AIDS, and 4.7% were antiretroviral naïve (El-Sadr, 2006).

Results of the SMART study demonstrated statistically significant differences in clinical disease progression including death between the two groups .  There were 117 events per 100 person-years of follow up in the IT group, compared with 47 events per 100 person-years of follow up in the CT group.  This translated into a relative risk of clinical disease progression of 2.5 for the IT arm (P<.0001). Kaplan-Meier curves demonstrated slow and consistent accumulation of events in both arms over time, but with the IT group showing higher event rates starting four months after randomization (El-Sadr, 2006). 

The component breakdown of the primary endpoint shows that the relative risk favors the CT group with respect to survival and disease progression. Surprisingly, despite greater exposure to antiretroviral therapy, severe cardiovascular, hepatic, and renal complications were unexpectedly lower in the CT group, with a cumulative relative risk of 1.5. When the primary endpoint of HIV disease progression or death was further subdivided by race and sex, the CT group still maintained a clear advantage over the IT arm (El-Sadr, 2006).

The investigators also subdivided the outcomes by baseline CD4+ cell counts and viral loads, and demonstrated the same advantage to the viral suppression (CT) arm.  There were particular safety concerns regarding the group of patients with low CD4+ nadirs.  However, the data demonstrated that these patients were no more likely to experience disease progression or death when compared with patients with higher CD4+ nadirs. In fact, all groups of CD4+ nadirs favored the CT group equally.  With respect to viral loads at study entry, patients with viral loads less than 400 copies/mL had many more events in the IT arm, while those with detectable HIV-RNA levels did equally well in both arms (El-Sadr, 2006). 

The results of the SMART study showed that IT compared with CT, was associated with increased risks of HIV disease progression or death, serious HIV disease progression, and severe complications  “A very consistent finding,” Dr. El-Sadr noted. ”These results were not affected by gender, race, baseline CD4+ cell count, or nadir CD4+ cell count. Moreover, the risk was three-fold higher for patients on antiretroviral therapy with baseline viral loads below 400 copies/mL.” 

“Episodic use of antiretroviral therapy based on CD4+ cell counts, as utilized in the SMART study design, is inferior to continuous antiretroviral therapy for the management of antiretroviral-experienced patients,” Dr. El-Sadr said in her concluding remarks  She added that an insufficient number of antiretroviral-naïve patients (5%) were included to make a conclusion about the use of IT in this patient population.   

In contrast to many other IT studies that measured only viral load and CD4+ counts, the SMART study is particularly powerful because a broad range of clinical endpoints were examined. It is therefore crucial to look at all-cause mortality, not just HIV-related deaths, since there might be excess death not obviously attributable to HIV in the modern-day treatment era.  Although results of SMART were discouraging, Dr. El-Sadr stated, “We should continue to investigate strategies to get the most from the drugs for the longest period of time.”

ReferencesTop of page

Ananworanich J, Gayet-Ageron A, Le Braz M, et al. CD4- guided scheduled treatment interruptions compared to with continuous therapy for patients infected with HIV-1: results of the Staccato randomized trial. Lancet. 2006;368:459-465.

Danel C, Moh R, Sorho S, et al. The CD4-guided strategy arm stopped in a randomized structured treatment interruption trial in West-African adults: ANRS 1269 Trivican Trial. 13th Conference on Retroviruses and Opportunistic Infections, Denver, Colorado. February 5-8, 2006. Abstract 105LB.

El-Sadr W. Inferior clinical outcomes with episodic CD4-guided antiretroviral therapy aimed at drug conservation (DC) in SMART study: consistency of finding in all patient subgroups. 16th International AIDS Conference, Toronto, Canada. August 13-18, 2006. Abstract WEAB0204.

Julg B, Goebel FD. Treatment interruption in HIV therapy: a SMART strategy? Infection. 2006;34:186-188.

Law M, Friis-Moller N, Weber R, et al. Modelling the 3-year risk of myocardial infarction among participants in the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study. HIV Med. 2003;4:1-10.

Mannheimer S, Friedland G, Matts J, et al. The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials. Clin Infect Dis. 2002;34:1115-1121.

Marchou B, Tangre P, Charreau I, et al. Structured treatment interruptions in HIV- infected patients with high CD4 cell counts and virologic suppression: results of a prospective, randomized, open-label trial (Window – ANRS 106). 13th Conference on Retroviruses and Opportunistic Infections, Denver, Colorado. February 5-8, 2006. Abstract 104.

Palmisano L, Giuliano M, Bucciardini R, et al.  Final results of a randomized, controlled trial structured treatment interruptions vs continuous HAART in chronic HIV-infected subjects with persistent suppression of viral replication. 13th Conference on Retroviruses and Opportunistic Infections, Denver, Colorado. February 5-8, 2006. Abstract 103.

Reisler RB, Han C, Burman WJ, Tedaldi EM, Neaton JD. Grade 4 Events Are as Important as AIDS Events in the Era of HAART J Acquir Immune Defic Syndr. 2003;34:379–386.

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