Intermittent therapy for the treatment of chronic HIV infection

Introduction HAART has changed HIV infection from a life-threatening into a chronic condition, but the perspective of never ending HAART once it is started is daunting to many patients. As a cure for HIV infection is currently not in sight, many patients, who are looking to their physicians for advice on whether to stop HAART. New drugs and combinations with better safety and tolerability profiles have become available [1], but there will still be patients who experience toxicity [1–3]; therefore, being able to take a rest from HAART may be beneficial [3]. Worldwide, the cost of treating millions with HIV burdens fragile economies; intermittent treatment promises relief. Many scheduled treatment interruption (STI) studies have shown between 40 and 60% drug savings with STI [4–7]. For example, in Thailand, using the least expensive generic fixed dose combination of stavudine/lamivudine/nevirapine, which is US$27 per month, the yearly cost of treating 500 000 HIV-positive individuals would decrease from US$162 million to US$81 million if there is a 50% drug saving. Moreover, STI may provide the possibility that a potent and inexpensive drug such as stavudine may still be used without many side-effects, whereas continuous use would necessitate its replacement by a less toxic, but mostly more expensive, alternative. However, these potential benefits have to be weighed against the potential risks, which include the development of HIV-related illnesses, acute retroviral syndrome, thrombocytopenia, resistance and the transmission of HIV infection. Most individuals with HIV are diagnosed and treated during the chronic HIV infection phase. In those who have a good response to HAART and are able to maintain high CD4 cell counts and low viral loads (VL) for a period of time, STI have been explored with fixed time strategies (such as one week on–one week off, or 8 weeks on–8 weeks off) or with varying off times depending usually on the CD4 cell count. The goal here is to improve quality of life and HAART toxicity, and lower costs while maintaining patients' good health and a safe level of CD4 cells. Initial studies have been small and uncontrolled: later studies have enrolled several hundred patients and used a control group of continuously treated patients. On the whole, results have been quite encouraging [4,8–13], although a meta-analysis of STI studies published from January 1996 to March 2005 concluded that evidence to support STI was inconclusive [14]. In January 2006, the largest STI study that had recruited over 5000 patients, the Strategy for Management of Antiretroviral Therapy (SMART), showed that an STI strategy using CD4 cell counts as a guide led to an increase in HIV and non-HIV-related serious illnesses. As a result, recruitment was stopped prematurely [15]. In this article, we present the rationale for STI, review data on STI in chronic HIV infection, consider the effects of STI on the selection of resistance mutations, and finally provide a perspective on the future of STI. CD4 cell counts after stopping treatment CD4 cell counts decline when HAART is stopped. The most dramatic drop occurs within the first 4 weeks, with an average decline of 30 cells per week, followed by a more gradual drop of 3 cells per week (Fig. 1) [16]. The VL usually becomes detectable 7 days after stopping and peaks at approximately 4 weeks [9]. CD4 cell counts tend to drop faster in patients who have low pre-antiretroviral CD4 cell counts, high CD4 cell counts before stopping and high VL at the time of peak VL rebound [11,16,17].Fig. 1: Biphasic CD4 cell count decline after scheduled treatment interruption. The error bars show standard errors of the mean for scheduled treatment interruptions (STI) lasting 4 and 24 weeks. They have been deleted for STI lasting 8 and 12 weeks so as not to overload the figure. Data are from patients enrolled in the Staccato and the Swiss Spanish Intermittent Treatment Trial studies showing CD4 cell declines in patients who were able to stop HAART for different lengths of time until they reached the CD4 cell count of less than 350 cells/μl restart criteria. It shows that patients with lower baseline CD4 cell counts reached the CD4 cell count restart criteria (< 350 cells/μl) before week 24. Regardless of the STI time, the CD4 cell count dropped most dramatically during the first 4 weeks, after which a more gradual drop was seen [19].STI ≥ 24 weeks (112);STI 12 weeks (19);STI 8 weeks (43);STI 4 weeks (24).Scheduled treatment interruption studies in chronic HIV infection using CD4 cell counts as a guide Stopping and starting treatment based on the CD4 cell count makes sense as it is the best predictor of HIV disease progression. This is also a strategy that is tailored to each individual's immune status providing an opportunity for some to be off treatment for a long time, particularly those who have a high baseline CD4 cell count. The different randomized CD4 cell count-guided (referred to hereafter as CD4-guided) studies in VL-suppressed patients are summarized in Table 1. Because of space constraints, studies that are non-randomized or use non-standard HAART are not described [12,13,18–21].Table 1: Summary of randomized CD4 cell count-guided scheduled treatment interruption study results in virally suppressed chronic HIV-infected patients.Table 1: (Continued)The BASTA study randomly assigned 69 patients with CD4 cell counts greater than 800 cells/μl to either continuous or CD4 cell count-guided HAART with a CD4 cell count restart criteria of less than 400 cells/μl. They found that the CD4 arm was safe and most CD4 arm patients could stop for at least one year. After 64 weeks, 72% had CD4 cell counts greater than 400 cells/μl [11]. The Tibet study randomly assigned 201 patients with CD4 cell counts greater than 500 cells/μl and VL less than 50 copies/ml to CD4 cell count-guided HAART (stopping at CD4 cell counts ≥ 500 cells/μl and starting at CD4 cell counts < 350 cells/μl compared with continuous HAART). At 96 weeks, no one had AIDS-defining illness. The CD4 arm had more adverse events related to the antiretroviral syndrome after stopping treatment but had lower adverse events from antiretroviral drugs. The drug exposure was 68% less in the CD4-guided arm compared with the continuous arm [22]. The ACTG 5102 evaluated the use of IL-2 in combination with HAART to raise the CD4 cell count before stopping therapy. Almost all patients were able to stop for the 48-week duration and the HAART plus IL-2 arm had a higher CD4 cell count [23]. The HIV–NAT 001.4 study was a pilot study to Staccato but was performed in a different patient population: HIV–NAT 001.4 patients were dual nucleoside reverse transcriptase inhibitor (NRTI)-pretreated compared with patients newly treated with HAART in Staccato; nevertheless, the results were similar to those of Staccato [4]. Staccato evaluated a CD4 stop/start threshold of 350 cells/μl in 284 patients who had baseline CD4 cell counts greater than 350 cells/μl in comparison with 146 continuous HAART patients. After almost 2 years, there was no difference in AIDS or death [one death or 0.4 per 100 person-years (100PY) in the continuous versus one death or 0.2 per 100PY in the STI arms] and the VL responses to HAART retreatment were the same between the arms, with approximately 90% having VL of less than 50 copies/ml. The CD4 arm, however, had more minor HIV-related illnesses including oral and vaginal candidiasis (2.28/100PY in the CD4 versus 0.34/100PY in the continuous arms, P = 0.04). The CD4 arm had lower CD4 cell counts (median 374 cells/μl in the CD4 arm versus 601 cells/μl in the continuous arm), but the CD4 cell count rose rapidly after 12 weeks of HAART and there was a significant antiretroviral drug saving. In addition, the patients in the CD4 arm felt they had less lipodystrophy and the cholesterol level was lower, and more patients in the continuous arm had antiretroviral drug-related neuropathy and diarrhea [5]. Trivacan and SMART both enrolled patients with similar criteria as Staccato, baseline CD4 cell counts greater than 350 cells/μl and VL below the limits of detection (the latter for all patients in Trivacan and 72% in SMART), but the start/stop CD4 cell count criteria were different. Both of the studies stopped HAART at CD4 cell counts greater than 350 cells/μl and restarted at CD4 cell counts of less than 250 cells/μl, whereas in Staccato, treatment started again when the CD4 cell count declined below 350 cells/μl. In Trivacan and SMART, there was a significantly higher incidence of serious illnesses in the CD4-guided arm. In the Trivacan study, World Health Organization stage 3 and 4 illnesses were found in 17.6/100PY in the CD4 arm compared with 6.7/100PY in the continuous arm (P = 0.001). The most common serious illness was invasive bacteremia, which is not usually considered an HIV-related disease. Oral and vaginal candidiasis was also more common in the CD4 arm [7]. In the SMART study, the number of opportunistic infections (OI)/death events were 3.3/100PY in the STI arm compared with 1.3/100PY in the continuous arm (P < 0.0001). The excess risk of the CD4-guided arm was evident in all subcategories: death (1.5/100PY in CD4 arm versus 0.8/100PY in the continuous arm, P = 0.007), serious OI (0.4/100PY in the CD4 arm versus 0.1/100PY in the continuous arm, P = 0.01) and non-serious OI (1.7/100PY in the CD4 arm versus 0.5/100PY in the continuous arm, P < 0.001). The most common cause of death was cancer, and only 7% of death was due to OI. Esophageal candidiasis was the most common non-fatal OI in both arms. For non-OI events, major cardiovascular diseases and metabolic events were 1.8/100PY in the CD4 arm compared with 1.0/100PY in the continuous arm (P = 0.01) with events in the subgroups as follow: fatal or non-fatal cardiovascular diseases (1.3/100PY in the CD4 arm versus 0.8/100PY in the continuous arm, P = 0.06), fatal or non-fatal renal disease (0.2/100PY in the CD4 arm versus 0.1/100PY in the continuous arm, P = 0.05) and fatal or non-fatal liver disease (0.3/100PY in the CD4 arm versus 0.2/100PY in the continuous arm, P = 0.46). The grade 4 severe toxicities according to the Division of AIDS, National Institutes of Allergy and Infectious Diseases grading system were not different in the two arms (4.8/100PY in the CD4 arm versus 4.1/100PY in the continuous arm, P = 0.20; the SMART Study Group, in preparation). SMART patients had up to 4 years of follow-up, with a mean follow-up time of 16 months. Patients were able to stop for a long period: the median first period off HAART was 18 months (interquartile range 5.8–43.5 months). The hazard ratio of both OI/non-OI events appear to increase in the CD4 arm after 8 months in the study. Most patients stopped only once, with approximately 12 and 2% stopping two or three times. With the HAART re-initiation CD4 cell count criteria of less than 250 cells/μl, the time patients spent at CD4 cell counts below 200 cells/μl was only 3% of the total study time. The median CD4 cell count at re-initiation was 234 cells/μl. After HAART retreatment, the response was good, with a median time to VL suppression below 400 of 3.1 months and a CD4 cell increase of 164 cells by 8 months. On average, the CD4 arm had 206 less CD4 cells/μl than the continuous arm. The time on HAART was much less in the CD4 arm (33%) compared with the continuous arm (94%). In SMART, the following factors did not significantly affect the number of OI/non-OI CD4 cell duration of HAART and baseline antiretroviral status antiretroviral patients had a higher risk of events in both treatment the risk of events, CD4-guided to continuous As the of the continuous suppression arm was in those patients was at In the patients with the continuous and CD4-guided arms had similar is evidence for whether such treatment is continuously or The of SMART was based on the CD4 cell counts and VL are before and to the OI/non-OI As having a lower CD4 cell count and higher VL one at more risk of both OI and and non-OI for both the CD4 and continuous arms. who OI had a CD4 cell count at least cells lower than the group for both arms. The CD4 cell count before OI events to be lower than those before non-OI events in both arms. is is that the risk of both OI and non-OI events is higher in the CD4 arm than the continuous arm only when the CD4 cell counts 350 cells/μl. the the risk of OI and but not the non-OI in both arms to be when the VL is greater than 50 000 copies/ml. the risk of both OI and non-OI is higher in the CD4 arm compared with the continuous arm only when the VL is 400 copies/ml or less [15]. this all The SMART patient had a high baseline CD4 cell count (the median CD4 cell count in SMART was a CD4 cell count drop to below 250 cells/μl and exposure to high VL over a long stop time (median time off after the first interruption in SMART was 18 months). In the patient had lower CD4 cells at and the median time to starting treatment again was only 18 weeks. the OI and non-OI events while the patients are still off or they after HAART has been restarted during the CD4 cell increase and VL decline This may be similar to an immune syndrome in which the occurs when there is a decline in VL and a in the CD4 cell with an incidence of OI after starting HAART. However, immune syndrome occurs in patients who are more immune suppressed than those who in STI studies and of SMART data in are not in of this The results of SMART as shown in Table and in of the randomized ACTG HIV–NAT 001.4 and used a CD4 cell count restart threshold of cells/μl and did not serious and two studies and used a CD4 cell count restart threshold of 250 cells/μl and an increase in serious This that the CD4 cell count restart threshold is however, all the studies SMART did not have the to a difference in serious at this time, it is whether CD4 cell count stop/start at which the difference between an STI and continuous treatment strategies would be factors than the CD4 cell counts may be with SMART, Staccato enrolled patients with lower CD4 cell In the CD4 cell count-guided arm, HAART was restarted at 350 CD4 cells compared with 250 in STI were much in Staccato (median of 18 weeks compared with 18 months in study below used STI with a fixed of 8 weeks. Both Staccato and showed no excess in events in the STI arms. the of SMART to Staccato, 16 such events would have been in the CD4 arm, whereas only one was On the of these one may that the of treatment interruptions but not STI increase the risk of It will also be to whether a strategy that has the potential of drug costs and toxicity and quality of life be as a of the difference in the compared with continuous HAART in from SMART on the non-HIV-related illness such as cardiovascular in the CD4 arm and the CD4 in those who disease will in best to treatment interruption studies in chronic HIV infection using fixed time time to maintain a high CD4 cell count with a low risk of disease and to significant drug savings using a strategy that a patient could The different randomized studies in virally suppressed patients are shown in Table Summary of randomized fixed scheduled treatment interruption study results in virally suppressed chronic HIV-infected used a week off and showed that of patients were able to maintain their VL at less than 50 copies/ml at the of the week off for weeks. However, the HIV–NAT 001.4 and the Staccato study, both randomized studies one week on–one week off with continuous and CD4 cell count-guided showed of and to of that arm no significant resistance were found in patients who and when with continuous HAART using the same the VL was The study, to patients the off of enrolled 30 with CD4 200 and VL who were on different on on and on those had VL < 50 while or 2 of those in the arms had VL This may be due to the long life of level was at the of interruption fixed time strategy that had to be prematurely of an risk of resistance to and reverse transcriptase inhibitor used an 8 weeks weeks off After the of patients, of in the STI arm had resistance Most of the patients were treated with before HAART and may have had that to the resistance seen after STI at an 8 but with an off time of 4 weeks. The study enrolled with a CD4 cell count greater than 100 cells/μl, VL less than 200 copies/ml and CD4 cell count of cells/μl or greater for months or to showed no significant difference in and in the of patients with CD4 cell counts less than cells/μl at 96 in STI compared with in the continuous arms. The with VL of 400 copies/ml or less was lower in the STI compared with 90% in the continuous arm (P = but the incidence of and resistance were not different. was also a drug savings a study to whether interruptions before a long stop the time to a VL greater than 5000 copies/ml. the first patients either three fixed interruptions of 4 and weeks, followed by HAART for up to weeks until the VL was less than 50 copies/ml or continuous HAART for 40 weeks. In both stopped HAART. The time to a VL of greater than 5000 copies/ml was approximately one in both Treatment was more common in the continuous however, more resistance during VL rebound were in the interruption arm, but almost all patients their VL after the same also evaluated a fixed time strategy with STI of 2 and 3 each followed by 3 months of compared with continuous HAART. The median of CD4 cell to of follow-up was cells in the STI At 24 more than 90% in both arms had VL of less than 400 and time to as VL 400 copies/ml after 12 weeks of were not different. were found in of STI patients, to a risk of resistance at 24 months of were to be patients on their first without evidence of however, many had resistance in their baseline and In the study did not from a with lengths of STI. The of Therapy in is an randomized to HIV disease with antiretroviral in by two compared with plus and STI weeks weeks off) compared with continuous HAART. The has enrolled patients in and data of patients followed up to 40 weeks showed that the STI arm had more HIV-related disease compared with the continuous arm most of the events were which were and did not these were considered therefore, the STI arm patients continuous HAART as of March concluded that the 12 weeks weeks off strategy be in patients who have had a time before STI and had low CD4 cell counts and many illnesses before such as those who in the in scheduled treatment interruption studies After treatment is drug decrease at and have than study in showed that after a dose of the median time to an level was days to in and days in is with the which is common in it could take more than days for to be the of these drug HIV to the stage for the selection of a dose of to transmission of resistance This is the in most STI studies stopped between 3 and days before in an to the risk of resistance The selection of resistance is particularly if in before STI However, there is evidence that are during STI, and it that the risk may be with and with In the study by of the patients randomly assigned to the continuous arm but of of the 8 weeks off arm had This was treated with but the patients were at more risk as three of patients had two with and one with The two patients were on and had resistance to one with and one with It is to that most patients had a of antiretroviral treatment Table Data on resistance from scheduled treatment interruption the Swiss Spanish Intermittent Treatment Trial patients had of 2 weeks weeks and of the patients VL was 50 copies/ml after 8 weeks of retreatment had mutations, mostly In the Tibet study one CD4 arm patient and continuous arm patients had CD4 arm patients had performed on a viral rebound after and had the patients in the continuous arm, were and three had were mostly but many of the were newly In HIV–NAT 001.4 using there was no selection of major in the CD4 arm, many patients had a of treatment on Staccato had of 146 continuous arm and of 284 CD4 arm patients with at least one VL greater than 500 copies/ml after at least 12 weeks on HAART only one STI patient and three continuous treatment patients had mutations, mostly to resistance were in patients who at least two STI only had and almost all were to with patients also having or with patients who the risk of resistance was for (P = and for (P = more VL in the continuous arm of compared with the fixed interruption arm of In this 60% were on all the were patients had no VL but resistance were during the long three of in the continuous arm and of in the fixed interruption arm. were most as the patients were drug of 12 patients the same and viral a similar of in the STI compared with the continuous arms, but 40 of STI mutations, to a risk over 24 months. In the STI arm, baseline greater than copies/ml and during STI with the risk of Most patients had in at and this resistance selection after STI (P = 0.001). The use of also selection (P = results be with as resistance data on the continuous arm are In at the and of continuous and CD4 cell count-guided arms had resistance to at least one drug (P = The is and there is no at this time [7]. scheduled treatment interruption retroviral syndrome with high VL rebound during STI. In Staccato, acute retroviral syndrome was seen in with VL greater than 250 000 copies/ml in [5]. The acute HIV infection. Treatment is to HAART. also during STI of a of HAART the count. The risk of transmission during VL rebound is a major health HIV increase in a with CD4 cell counts is not it was in of almost 5000 HIV-infected Swiss individuals of HIV transmission during treatment interruption has been in a who stopped safe after the VL on and to have during an STI an HAART interruption be considered at a high risk of HIV during It is the of the to the of safe during treatment interruption. on the future of scheduled treatment interruption SMART many without at the present time. the most of these is to the between SMART and STI studies such as the of SMART to Staccato, between and events would have whereas one was The most between the two studies are the CD4 cell count at which treatment was started again cells/μl in SMART and 350 cells/μl in the of time on HAART before the study months in SMART and months in the of interruption months in SMART and 18 weeks in and the of the patients (median years in SMART and years in It is but from that these particularly the duration of treatment and of interruption and the lower CD4 cell count threshold for HAART in SMART, to the The SMART study was and with results that show that STI increase the risk of AIDS-defining OI and the benefits in of cardiovascular and were not it in a in the results of SMART have started never stop is the future for quality of life is to many patients may that their of is by time off and the one in risk of is Moreover, the to for drug toxicities will an in HIV is to STI will using higher CD4 cell count and stop criteria. the SMART however, it is that study with will be data on fixed STI with at least 8 weeks on HAART are and may provide an of a STI with a 50% in drug use and In the SMART study the of only after also that STI be