Category Archives: 6.10. When to Stop ART?

6.10. When to Stop ART

A review of treatment interruption

– Christian Hoffmann –

Many treatment interruptions occur without the clinician’s knowledge. In the CASCADE cohort (8300 patients from Europe) the probability of treatment interruptions for at least several weeks was 16% (Touloumi 2006). Treatment interruptions are an important part of antiretroviral therapies whether as a clinician one approves of them or not. The following chapter provides an overview of the current knowledge in this area.

Viral load and CD4 T cells during treatment interruptions

Almost all patients who stop treatment experience a rebound in viral load within a few weeks, even patients in whom this has been undetectable for several years.  Viral load is usually detectable again within 10-20 days (Chun 1999, Davey 1999, Harrigan 1999). The viral load in compartments such as the CNS, as well as in semen and vaginal fluids, parallels that in the plasma (Garcia 1999) and is detectable in semen within only a few weeks (Ananworanich 2011). Patients should therefore be informed about the higher risk of transmitting HIV (Burman 2008). Some cases report infections during interruption (Bernasconi 2001). There may be an increased risk of maternofetal transmission, even if ART is interrupted in the first trimester (Galli 2009).

Frequently, an initial overshooting rebound is observed (De Jong 1997), and only after a few weeks does the viral load settle to its original, pre-treatment level (Hatano 2000). The rebounding virus evidently does not originate from latent reservoirs; other cell populations must exist from which this new virus is produced so quickly (Chun 2000, Ho 2000, Imamichi 2001).

Treatment interruptions can have serious immunological consequences. Often, CD4 T cell counts drop within a short time to pre-treatment levels. The ground that has been gained on ART is rapidly lost. The drop is bi-phasic, and the drop more pronounced in the first few months (Fagard 2005, Wit 2005, Skiest 2006). CD4 T cell losses vary greatly between patients but may reach 200 or 300/µl within a few weeks. The higher and faster the CD4 T cells increase on ART, the more rapid their decline (Tebas 2002). The CD4 nadir is also important. The lower it was and the older the patient, the more rapidly the count drops again (Maggiolo 2004, Molina 2006, Skiest 2006, Touloumi 2006). Probably there is also an association with high proviral DNA level at treatment interruption (Piketty 2010).

The loss of CD4 T cells during an interruption may not be regained as quickly. In a prospective study, we saw a significant disadvantage for patients undergoing treatment interruptions. After a follow up of 18 months, CD4 T cells were more than 120/µl less in these patients than in matched patients who had not interrupted treatment (Wolf 2005). This was also observed in the SMART study.

The risks: resistance, clinical problems, AIDS

Viral resistance always has to be anticipated whenever there is viral replication in the presence of suboptimal drug levels, and thereby resistant mutants gain a selective advantage over the wild-type virus. As a result, there are concerns that resistance could develop both during the washout phase of medication (increasing viral replication with insufficient plasma levels) and on re-initiation of treatment (continued replication despite sufficient plasma levels).

However, in the case of single treatment interruptions, the probability of this does not appear to be particularly high, as shown in 1999 by the small French COMET Study, one of the first studies on treatment interruption (Neumann 1999). But there is no certainty as to whether interruptions might not eventually lead to development of resistant isolates, which merely require more time until they are able to dominate. Mathematical models show that this risk – at least theoretically – is not low, especially if viral load rises to high levels (Dorman 2000, Bonhoeffer 2000).

The risk of resistance is probably higher for repeated treatment interruptions. In several studies, these have led particularly to NNRTI- or 3TC-resistance (Martinez-Picado 2002, Schweighardt 2002, Ruiz 2007). The risk seems particularly high for strategies involving stopping and starting at fixed intervals (see below). Table 10.1 describes the example of a patient who was clinically well and who interrupted treatment. It was probably the repeated stopping and starting of ART that ultimately led to resistance in this case.

Table 10.1. Example of the development of resistance due to repeated ART interruptions*.
Date ART/comments

CD4 T cells

Viral load

Jun 97 AZT+3TC+SQV

288

67,000

Oct 99 ART stopped, patient feeling well

540

<50

Dec 99 Diagnosis of autoimmune hyperthyroidism

400

63,000

Jan 00 AZT+3TC+NVP (+ carbimazole)

260

74,000

Feb 00 Diagnosis of anemia (Hb 7.3 g/dl)ART stopped again

347

1500

Mar 00 d4T+3TC+NVP (+ carbimazole)
Apr 00 Resistance mutations K103N, M184V

360

2400

*During the first treatment interruption the patient developed autoimmune hyperthyroidism, the treatment of which led to anemia after re-initiation of ART, so ART was interrupted again. As a result, resistance developed against NNRTIs and 3TC. Autoimmune phenomena in the context of treatment interruption as seen in this patient have not previously been described.

The sharp increase in viral load that may often occur can present as a retroviral syndrome. The symptoms are similar to acute HIV infection, with lymphadenopathy, fever, asthenia and malaise (Colven 2000, Zeller 2001). Thrombocytopenia occurs in 25% of cases, especially when low thrombocytes existed previously (Ananworanich 2003, Bouldouyre 2009). The blood count needs to be monitored, especially in patients with a history of thrombocytopenia.

Finally, attention should be paid to patients who are coinfected with hepatitis B. If the HBV treatment with 3TC, FTC or tenofovir is interrupted, HBV rebound can result in fulminant and life-threatening hepatitis (Sellier 2004, Dore 2010). It is therefore advisable to monitor these patients very carefully and read the liver enzymes at least every two weeks.

The risk of AIDS seems to be low for single interruptions provided the immune defect is only moderate. In the Swiss Cohort, the risk of progression was not increased (Taffe 2002). In 133 patients who interrupted treatment we observed no increased risk of AIDS after 24 months compared to 262 matched controls (Wolf 2005). However, almost all patients in this study were immunologically stable throughout. The risk is probably higher in patients with severe immunodeficiency (Deeks 2001, Lawrence 2003). The CPRC064 Study in which 270 patients with MDR virus and clear immunodeficiency (median 144 CD4 T cells/µl) were randomized before a salvage regimen either to a four-month treatment interruption or not was stopped because of high risk of progression. In comparison with the control group, a significantly higher progression to AIDS (17 versus 5) occurred in the group interrupting therapy. In a multivariate analysis, two factors were predictive for death or progression: treatment interruption and the CD4 T cell count at the time of interruption. The risk increased by 1.4 with every drop of 50 CD4 T cells. This study demonstrates that severely immunocompromised patients are particularly at risk of developing AIDS during treatment interruptions of several months. Treatment interruptions should be avoided in such patients. Newer data from the SMART Study, however, show that even with higher CD4 T cells treatment interruptions can lead to the development of AIDS (see below).

STI for immunologic reasons: no effects

Hardly any patient has become as famous as the acutely-infected man treated in a Berlin practice a few years ago who, with a viral load of approximately 80,000 copies/ml, began an ART regimen consisting of ddI, indinavir and hydroxyurea. The virus rapidly became undetectable. After several problems – and two short treatment interruptions – ART was completely stopped after 176 days. Surprisingly, even without drugs plasma viremia has remained below the level of detection for more than five years. Although virus was still detectable in lymph nodes, thus excluding eradication, the immune system in this case – referred to as the Berlin Patient (Lisziewicz 1999) – was obviously capable of durable control of infection. Why? Was it the early initiation of therapy, the hydroxyurea, or the treatment interruptions? No one knows the answer, even today. There may be a completely different explanation: it is possible that certain host factors in this patients that have not yet been elucidated could have influenced the course of disease – completely independently of ART, STI or hydroxyurea (Bloch 2006).

STIs have been extensively investigated in acutely-infected patients (see chapter on Acute HIV infection). The theory of “endogenous vaccination” seems plausible. Transient increases in viral load could strengthen HIV-specific immune responses, which decline with increasing viral suppression on ART.

In several pilot studies from 2000/2001 successive interruptions seemed to indeed prolong the time to viral rebound or decrease the rate of rebound and, in parallel, there were measurable improvements in HIV-specific CD4 or CD8 T cell immune responses (Haslett 2000, Garcia 2001, Lori 2000, Ortiz 1999, Papasavvas 2000, Ruiz 2000). However, almost none of these studies included more than 2-6 patients, and a control group was usually missing.

STIs were finally put to the test in the Spanish-Swiss SSITT Study (Oxenius 2002, Fagard 2003): 133 patients were monitored throughout four ten-week treatment cycles, each consisting of eight weeks ART and two weeks of treatment interruption. After this, ART was permanently interrupted. Treatment success – defined as a viral load below 5000 copies/ml without ART after 52 weeks – occurred in 21/99 patients. However, 5/21 patients had a low viral load even before the initiation of ART. Most importantly, none of the 32 patients with a pre-ART viral load above 60,000 copies/ml achieved a viral load of less than 5000 copies/ml. The viral load set point was lowered in only a few patients, usually those with low initial viral load, despite repeated STIs. In contrast to acute infection, improvement of HIV-specific immune response seems unlikely in the setting of chronic HIV infection. SSITT clearly showed that treatment interruptions on immunological grounds alone are not justified and are dangerous.

Approaches with immunomodulatory drugs such as hydroxyurea (Foli 2004), mycophenolate (Garcia 2004), steroids (Ulmer 2005) or IL-2 (Henry 2006, Kilby 2006, Angus 2008) took place to lengthen the period of STIs. These approaches, whose benefits anyway seemed questionable to this author, are still in the experimental phases and not justified outside studies. The same holds true for vaccination strategies (Harrer 2005, Jacobson 2006, Goujard 2007, Harrer 2008).

STI as a salvage strategy for MDR virus: no effects

In most patients with MDR virus, treatment interruption leads to a gradual shift back to wild-type and a loss of resistance. Resistance testing during treatment interruption is often of little use since mutations disappear from the blood as early as two weeks after treatment interruption (Devereux 1999). In modestly immunosuppressed patients, this shift is observed more frequently and faster. In more advanced stages of disease and with a longer duration of treatment, it lasts longer (Miller 2000, Izopet 2000), and sometimes after a longer interruption of therapy, no shift can be seen (Halfon 2005). When the shift is visible, PI mutations are the first to disappear, while NNRTI mutations are more protracted because they hardly affect viral fitness (Deeks 2001, Birk 2001). It is assumed that the wild-type merely dominates the resistant mutants. Special PCR methods can detect low quantities of resistant virus during STI (Izopet 2000) and when treatment is restarted resistance mutations rapidly re-dominate (Delaugerre 2001). Only a few cases have been described in which resistance mutations were apparently flushed out completely. There is one patient (Walter 2002) who was not able to attain sufficient viral suppression despite intensified ART, and who then interrupted treatment. During the following seven months of treatment interruption there was a gradual reversion to wild-type, and after re-starting ART (which, according to previous resistance testing, should have had no effect) the viral load was successfully suppressed for several years.

Can patients with MDR improve the effect of the salvage regimen if they have had a previous interruption of treatment? At least two studies have shown that the shift resulting from treatment interruptions can be beneficial for salvage strategies (Miller 2000, Katlama 2004). However, this data is in contrast to that of numerous other studies in which an increased risk of AIDS was occasionally seen during treatment interruptions (Lawrence 2003, Lawrence 2006, Ruiz 2003, Ghosn 2005, Beatty 2006, Benson 2006, Walmsley 2007, Holodny 2011). In view of the risk of AIDS and the lack of evidence regarding the benefits treatment interruptions are no longer justified.

STI for reduction of toxicity

Every antiretroviral therapy can cause side effects. Is it possible to reduce toxicity by treatment interruptions? Increased transaminases or lipid levels can drop quite rapidly after stopping treatment (Hatano 2000, Wolf 2005). However, it is not clear, whether this is relevant in reducing the risk of cardiovascular disease. In SMART (see below), the risk of cardiovascular and metabolic complications during STIs was actually higher. In contrast to other studies, no relevant improvement of lipids was observed (Lampe 2010). At present, it seems at least questionable that, through solitary or repeated interruptions, the cardiovascular risk profile can be improved.

What about lipodystrophy and mitochondrial toxicity? At least two studies have shown that, after a few months, mitochondrial DNA can regenerate itself following a treatment break (Cote 2002, Mussini 2005, Kim 2007). In contrast, another study showed no effect (Negredo 2006). Whether or not a clinically manifest lipodystrophy improves, remains to be seen. At least short treatment interruptions have not had any effect on morphological changes (Hatano 2000). A six-month ART interruption markedly improved adipose tissue function, although fat distribution did not visibly change (Kim 2007). Substudies from the SMART trial (see below), so far the largest, showed a moderate positive effect on peripheral fat, lipids and bone mineral density during CD4-guided treatment interruptions (Martinez 2010). Another subtrial showed more reduction of bone density on continued therapy than during interruption – however, numbers of a slightly reduced fracture risk during interruptions are still small (Grand 2009).

Conclusion: Although a treatment interruption is theoretically the solution to long-term toxicity on ART a convincing argument has not been provided by the data so far. Nevertheless, we will try to outline some relevant data. It is essential to distinguish between structured intermittent treatment with fixed intervals and interruptions that are individualized based on CD4 T cell count, in which case the interruption period depends on the patient’s immunological situation.

Structured Intermittent Treatment (SIT, Fixed Intervals): In the initial phase immediately following ART interruption the viral load usually remains low. Plasma viremia only reaches pre-treatment levels after about four, sometimes six weeks. The risk of developing resistance is presumably small at lower levels of viral replication (Bonhoeffer 2000). Does this indicate that ultra-short treatment interruptions could be utilized to reduce drug use, costs and long-term toxicity? In two NIH pilot studies on SIT in chronically infected patients ART was administered as seven days of treatment and seven days interruption (7-on-7-off). At 44-84 weeks, neither the viral load nor the proviral DNA increased (Dybul 2001+2004). CD4 T cells and HIV-specific immune responses remained unchanged suggesting that the immune system is probably unaffected by such ultra-short breaks in treatment. A significant reduction in lipid levels did, however, occur. Some patients experienced several blips (temporary increases in viral load) to above 100 copies/ml. It is impossible to predict whether this treatment strategy might result in a higher risk of resistance in the long term. There are still no larger studies, and it has become suspiciously quiet in this area. In addition, patients in the NIH studies were carefully selected, with good immune status and many years of viral suppression. This strategy is probably only applicable to a select group of patients. A three-armed study from Thailand showed a negative experience with the 7-on-7-off approach (Cardiello 2005). In this study, 19/36 patients experienced virologic treatment failure within a short period of time, and this treatment arm was consequently stopped prematurely. The main reason for this appears to lie in the fact that the majority of patients were NRTI-experienced. This means that if NRTIs are unstable, such on-off strategies are problematic.

ART only on weekdays? This approach was taken by the randomized FOTO Study (Five On, Two Off) in which TDF+FTC plus efavirenz was either given daily or from Monday to Friday and stopped at the weekends (i.e., sparing 28%). 60 patients were enrolled who showed an undetectable viral load for at least three months prior to the study. After 48 weeks, viral load increased in one patient despite low trough levels (Cohen 2007+2009).

In contrast, longer interruptions, over several weeks, with fixed intermittent treatment seem to be unfavorable. Results from a randomized NIH study with fixed intervals (each with one month of STI, two months of treatment) were disconcerting (Dybul 2003). The SIT arm contained significantly more patients with virologic treatment failure. Resistance mutations developed particularly against NNRTIs and 3TC, so that the study was stopped early. In the SSITT Study (2 weeks STI, 2 months ART) some resistance was seen (Yerli 2003), likewise in an Italian study (Palmisano 2007), but not in the French WINDOW Study (two months each of STI and therapy) (Marchou 2006). In the DART trial, the risk of AIDS was increased during the three months of treatment interruption (DART 2008).

CD4 T cell driven interruptions: Beside fixed intervals, whether short or long, there is another approach whereby interruptions are individualized based on CD4 T cell count. In other words, in patients with a good CD4 count, ART is interrupted until the CD4 count drops below some immunological cut-off and only then is it resumed. Over the last few years, many non-randomized studies with differing cut-off points and very heterogeneous patient populations came to the conclusion that this approach is safe and allows for a considerable reduction in drug exposure (Maggiolo 2004, Skiest 2004, Fernandez 2005, Mussini 2005). In the meantime, a few randomized studies compare such CD4-driven intervals with continuous administration of ART. The relevant data and results of these studies are given in Table 10.2.

It is clear that the results of these randomized studies differ considerably. While TIBET, Staccato or ACTG 5170 produced the verdict that CD4 T cell-driven interruptions are safe, two other studies, Trivacan and SMART came to other conclusions.

Table 10.2. Randomized studies of CD4 T cell guided structured treatment interruptions.
Source

n

CD4 BL

CD4 Restart

Clinical findings in the STI arms
TIBET, Ruiz 2005

201

>500
>6 Mo

<350
or VL >100,000

Some retroviral syndromes, some de novo NNRTI resistance, otherwise clinically safe (not a single AIDS case)
SMART, El Sadr 2006

5472

>350

<250

Morbidity and mortality risk low, but significantly raised. See Table 10.3.
Trivacan, Danel 2006

326

>350

<250

Morbidity significantly raised (double) due to invasive bacterial infections.
Staccato, Ananworanich 2006

430

>350

<350

Clinically safe (slightly more side effects in ART arm; more candidiasis in STI arm). No evidence of resistance.
ACTG 5170, Skiest 2006

167

>350

<250

In general safe, with risks only elevated when CD4 nadir was low.
LOTT, Maggiolo 2009

329

>700

<350

Clinically safe. More pneumonias but less cardiovascular events, no evidence of resistance.
FU=follow up; Mo=months; BL=baseline

In particular, the results of the SMART Study, which started in 2002, caused a sensation. In this, the largest randomized HIV study of all time, the cut-off levels for stopping ART were 350 cells/µl, and 250 cells/µl for re-initiating it. In the end, 318 centers in 53 countries recruited a total of 5472 patients. In 2006 an independent data safety monitoring board concluded that therapeutic interruptions result in an increased risk of AIDS – in the interruption arm, approximately twice as many AIDS illnesses were observed at follow-up, over an average of 18 months. This included severe opportunistic infections as well as malignant tumors. In fact, the overall risk was low, but so significantly elevated that the unusual and far-reaching decision was made to end the study.

In addition it was observed that cardiovascular incidents in the interruption arm did not become less frequent, but actually increased. The clinical incidents in SMART (http:/www.smart-trial.org/news.htm) are shown in the following table.

Table 10.3. Different events occurring in SMART, per 100 patient years (El Sadr 2006).
 

STI (n)

Control (n)

Odds ratio

Progression of disease or death

3.7 (120)

1.3 (47)

2.6 (1.9-3.7)*

Death

1.5 (55)

0.8 (30)

1.8 (1.2-2.9) *

Cardiovascular/renal/hepatic events

1.8 (65)

1.1 (39)

1.7 (1.1-2.5)*

Grade IV toxicity

5.0 (173)

4.2 (148)

1.2 (1.0-1.5)*

*Significant difference. **95% Confidence interval.

Quality of life did not improve in therapy interruptions – it even declined (Burman 2008). More recent studies showed that clinical and immunological disadvantages remained, even when ART was resumed (El Sadr 2008).

However, even after SMART, not all questions were answered. A striking fact was the high incidence of clinical occurrences compared to Staccato, a study involving 430 patients. As measured by the AIDS/mortality rates of ART, there should have been at least 17 cases in Staccato – instead there was not one. Moreover the significantly higher risk of an AIDS-defining malignancy during therapy interruption (Silverberg 2007) was questionable as the majority of the patients who developed KS or lymphoma in SMART had already suffered from AIDS illnesses before. Why were these patients enrolled in the SMART study?

Most of the deaths in the interruption group were not ascribed to AIDS (only 4 compared to 3 cases in the control group) but to cancer which is normally not associated with HIV infection (11 versus 5), and to cardiovascular incidents (7 versus 4). Cases of death of unknown cause were also more frequent in the interruption group (15 versus 3). One can only speculate about the increased cardiovascular, renal and hepatic incidents in the interruption group. How many patients interrupted therapy that should not have? How many patients with chronic hepatitis B experienced a HBV rebound during interruption, how many patients with previous HIVAN developed renal problems, how many patients decided to stop concomitant medications (statins) that led to a cardiovascular event? However, there are some newer studies that show an increase of inflammatory or coagulation parameters during therapy interruption (Kuller 2008, Calmy 2009). Cystatin C, a measure for renal function, also increases (Mocroft 2009).

Despite all these questions, the conclusion remains that it is difficult to find a reasonable argument for treatment interruption. Especially the argument that therapy interruptions improve quality of life is no longer acceptable. One can discuss higher values for initiation and interruptions, but there will certainly not be any second SMART with new starting/stopping values for some time.

Patients should always be encouraged to continue ART. Thanks to the new classes, the options have widened, enabling us to react to many side effects. If the patient, after discussion, still wishes to interrupt therapy the wish should be respected. The interruption will happen anyway with or without the doctor’s agreement. A monitored interruption is better than one done secretly behind the physician’s back. Under strict surveillance the risk for complications is rather low.

Practical tips for treatment interruptions

  • If there are no problems with ART, there is no reason to stop it.
  • To reverse resistance or for immunologic reasons, i.e., from a strategic point of view, STIs are not useful.
  • A positive effect on cardiovascular incidents or lipodystrophy has not been confirmed. From the SMART Study, this seems highly unlikely.
  • The patient’s wish for a break should be respected. The interruption will happen whether the clinician agrees or not. A supervised treatment interruption is always better than one undertaken without the awareness of the clinician.
  • Beforehand, information should be provided on possible clinical (retroviral syndrome, AIDS), immunologic (loss of CD4 T cells) and virologic (resistance) consequences.
  • Patients must be aware that the risk of infection increases – even after a longer suppression, viral load returns to initial levels after 4-6 weeks without ART.
  • Beware of HBV coinfection (danger of hepatitis flare-ups)
  • CD4 T cells (including percentage), viral load, and blood count (i.e., thrombocytes) should be monitored monthly during interruptions.
  • Risk of resistance is possibly higher with NNRTIs (choose robust regimens and stop NNRTIs several days earlier if possible – consider the half-life of the drugs).
  • Patients who started ART “too early” according to current standards can probably interrupt safely.
  • Resistance testing during treatment interruptions is not useful – it usually only measures the wild-type.
  • Start with ART again, but not too late.

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Filed under 6.10. When to Stop ART?, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy