Important note: Information in this article was accurate in March 2000. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, March 2000
Mike Youle, M.B. ChB.
Director, HIV Clinical Research, Centre for HIV Medicine,
Centre for HIV Medicine, Royal Free Hospital,
London NW3 2QG
Infection with HIV results in progressive immunodeficiency in the majority of individuals over a varying length of time, eventually leading to clinical disease and AIDS. The speed of deterioration in any patient is a complex interaction between the activity of the virus, the response of the immune system and the general health of the person. Although it is likely that genetic factors are important in determining the time-course of HIV disease, environmental issues such as exposure to infectious agents or antigen, nutritional status, lifestyle and concurrent illnesses all play their part. Combination antiretroviral chemotherapy has yielded clear morbidity and mortality benefits.[1] Where that therapy is accessible, the reversal of clinical illness and improvement in health has become a remarkable epidemiological success story. [2]
Opposing these benefits are increasing signs of long-term drug toxicity, including the new clinical syndromes of lipoatrophy and lipodystrophy.[3] Also, confidence that the drugs could eradicate HIV from the body has received a serious setback with the recognition that long-lived reservoirs of latently infected cells exist within the immune system.[4] A further setback occurred when research suggested that low-level viral replication continues even with the most aggressive available antiretroviral drug combinations.
In addition, the strain of taking complex regimens with dietary restrictions, although ameliorated by new and better formulated drugs, is significant and for some may be a cumulative problem[5]. The many studies assessing adherence/compliance/concordance generally have indicated that duration of treatment is a factor involved in the ability of an individual to take therapy as prescribed.
There appears to be an association between development of genotypic then phenotypic resistance to HIV and surrogate marker failure. Evolution of HIV resistance in patients on suboptimally suppressed regimens argues for changing to a new effective combination of drugs.[6] Unfortunately, many individuals have already been exposed to almost all available antiretrovirals, and cross-class resistance limits further opportunities for this group. But some patients have clearly done extremely well in terms of immune restoration, with reduced clinical events despite never achieving or maintaining viral suppression to undetectable levels. [7] The existence of such patients argues for caution in using up all options quickly before CD4+ cell decline and therapeutic failure have occurred.
In other therapeutic areas - oncology, rheumatology and infectious diseases, for instance - intermittent or cyclical therapy is a standard of care for managing the use of some effective but highly toxic treatments. This approach is also clearly logical for symptomatic interventions or for relapsing and remitting conditions, such as Crohn's disease. In such conditions as asthma, different agents are utilized for acute and chronic phases.
There have always been people with HIV who have interrupted their therapy. Treatment interruptions have occurred because of drug toxicity, intercurrent illness, boredom with treatment, chaotic life style, uncertainty over therapeutic advice and many other reasons - not least the vagaries of reporting by the scientific and popular press. When the Concorde study was published [8] and showed a negative result, many patients on AZT ceased therapy and remained untreated for a prolonged period before starting a new regimen. In the early years of antiretroviral treatment, forced treatment interruptions were commonplace when toxicity occurred, as no new drugs were then available. Now that there are more licensed drugs, this is less likely to be necessary. Patients usually can change from regimen to regimen without needing to stop treatment, at least initially.
Many patients still wish to stop therapy temporarily (or permanently), and it is the unplanned treatment interruption (UTI) that currently dominates the field. Often patients will announce that they have stopped their drugs for a particular social or medical reason - or no particular reason whatever - when they next attend clinic. Others find it difficult to discuss this with their physicians, who often remain unaware that treatment had ceased many months before. Short UTIs occur when pills are left at home, forgetfulness occurs or life becomes just too complex.
One issue that may be important immediately after treatment interruption is the differential half-life of drugs, which may vary between body compartments. For instance, the half-life in plasma of nevirapine and efavirenz is greater than 48 hours whereas many other drugs clear from the body at much quicker rates. Stopping a combination regimen containing one of these longer-lived drugs could result in a period of effective monotherapy, leading to the development of resistance to the agent. In addition, the issue of recurrent early side effects such as rash, or the potential increase in risk of hypersensitivity, should raise concerns over repeated reintroduction to some drugs. Nevertheless, since treatment interruptions have been and are a common phenomenon, it is time they were evaluated scientifically.
There are as yet no long-term trial data on interruption of treatment, although some small studies have commenced. The new area of interest investigated by these pilot studies is the concept of structured treatment interruptions, or STIs, formerly known as "pulsed therapy" or "drug holidays."
Overheard in a London clinic:
"Drug holiday? I thought that was two weeks in Ibiza."
True more than we'd like to think.
Rather than spontaneously stopping, the basic idea is to plan a break in treatment and then monitor the patient. Therapy could be restarted at some predefined point in the future, for example after a certain period of time or when a certain viral load or CD4+ cell count threshold is reached.
There are several specific but significantly different scenarios in which treatment interruptions may be relevant to HIV disease. These are discussed below. The individual approaches have varying aims and objectives. It is vital that goals be clear, since the potential risk to the individual of interrupting therapy is likely to be greater in those whose virus is currently well suppressed. Treatment interruption at present is ill-advised outside the setting of carefully established studies, although an individual may choose to interrupt therapy and be monitored intensively thereafter. Recent data presented here are from the 7th Conference on Retroviruses and Opportunistic Infections, which took place in San Francisco, January 30 to February 2, 2000.
The first area of STI research is in people whose HIV was first treated during primary infection syndrome, before seroconversion has occurred. This theory proposes that if treatment commences during this period, normal immune responses may be protected. Of particular concern are the anti-HIV cellular responses: the CD4+ T-helper cells and the CD8+ cytotoxic lymphocytes (CTLs) that they stimulate. This cellular immune defense, which has been associated with the climax of the primary infection syndrome and the beginning of a period of partial control of HIV, usually begins to decline during the subsequent years. A series of STIs in patients treated soon after contracting HIV, it is hoped, might act as a periodic autologous vaccine to further stimulate cellular responses while drug therapy keeps HIV under control.
Altfeld and colleagues from Massachusetts General Hospital in Boston [9] followed 15 acutely infected ndividuals identified before seroconversion and treated with immediate HAART. After more than one year of HAART, seven of 15 individuals underwent an STI. HIV viral loads and CD4+ T-helper cell counts were measured weekly, and the population of HIV-targeting CTLs assayed. Mean baseline viral load at diagnosis was 13.8 million. Viral loads became undetectable in all patients after a median 10 weeks (range 4-19) on HAART and remained undetectable during HAART treatment. Low-magnitude CTL responses against one to four epitopes (the assay-detected products of the env, gag, nef and pol genes) were seen in 10 of 15 trial participants at diagnosis and persisted at lower frequencies during HAART.
In the seven STI patients, virus rebounded within one to eight weeks (levels not given), and HAART was reintroduced. CTL responses were boosted in all STI patients, who gained a median of two newly recognized epitopes (range zero to three) and increased their responses to those previously recognized. Three of the people who had a second or third STI exhibited additional CTL responses. These three also had low final viral loads before retreatment - 5,000-8,000 copies/mL - after an initial peak in viremia.
The researchers noted, "CTL responses are detectable during acute HIV-1 infection prior to seroconversion, but are narrowly defined at a few epitopes. These responses persist at lower levels during HAART. It appeared that STIs resulted in a persistent augmentation of the frequency and breadth of CTL responses in these subjects, which can be further boosted by additional controlled interruptions."
A group from Buenos Aires and Vancouver followed 18 patients treated during PHI with d4T, ddI, and nevirapine with or without hydroxyurea (HU). [10] Patients were offered an STI when 48 weeks of treatment were completed. Treatment was to resume after 30 days if viral rebound occurred. After 48 weeks of HAART, 83% had viral loads below 500 copies/mL, and 67% had less than 50. Eight patients (five on HU) interrupted therapy after a median 57 weeks (range 53-75). All eight had viral rebounds, with HIV levels first peaking and then subsiding. Viral loads remained above 5,000 copies/mL after 21 days. HU did not significantly affect the kinetics of rebound. All patients' viral loads returned to below 50 copies/mL when treatment resumed.
Jin and associates at the Aaron Diamond Research Center in New York treated four individuals with AZT/3TC/indinavir within 100 days (median 60) after they were infected. [11] Median baseline RNA was 57,500 copies/mL. HAART suppressed viral load below 50 in all persons. As an alternative to a series of STIs, patients were vaccinated with ALVAC 1452/rgp160, a vaccine consisting of canarypox virus engineered to produce HIV proteins. The vaccine also included additional gp160 HIV envelope protein. The vaccine was administered four times (at days 0, 30, 90 and 180).
After 1,162 days of HAART and one week following their final vaccination, these four patients chose to stop therapy. Delayed viral rebound was observed in two of the four individuals. For these two, viral loads became detectable at 68 and 85 days post-vaccination. The initial virus doubling times were 4.5 and 3.2 days respectively, compared with 1.5 days in previously studied individuals who stopped HAART. The other two patients experienced rapid viral rebound (doubling times of 1.4 days) and detectable virus within 13 and 23 days. The late rebounders had significant increases in CTLs to more than one viral antigen following vaccination. The two rapid rebounders either had no measurable CTL response to vaccination or a monospecific response to a single gag epitope.
Prior to the 7th Retrovirus Conference, several groups of investigators reported interrupted antiretroviral therapy for short periods in small numbers of individuals (fewer than 20) who had previously suppressed HIV to below levels of detection for prolonged periods of time by currently available ultrasensitive assays (plasma HIV RNA below 20-50 copies/mL). [12]-16 The first study[12] came from Christine Katlama's Groupe Hosp. Pitié-Salpêtrière, Paris, France and showed rebound of viremia after approximately a week when treatment (AZT/3TC/indinavir) ceased. The study followed ten patients with baseline CD4+ counts of 414 cells/mm3 and a viral load that had decreased to below 1,000 copies/mL. After a four-week STI, viral loads varied from 14% below pretreatment levels to 386% above the starting value. All viral loads fell to below 200 copies/mL on reintroduction of the same treatment.
Two Spanish studies also showed the ability to completely resuppress viral activity when therapy was reintroduced after rebound to baseline levels had occurred. 13,14 As with all the studies so far, there appeared to be variability in time to rebound, and some patients experienced an overshoot in viremia to above pretreatment levels. This was associated with CD4+ cell decline. Rebound also occurred in all compartments studied, including tonsillar tissue. In the latter study, two persons evinced no rebound after one month off treatment, five returned to baseline after 10 to 15 days and the other five were back to baseline by 18 to 21 days.
Richard Davey in the NoHRT study [15] at the National Institute of Allergy and Infectious Diseases examined the effect of stopping in 18 individuals, some of whom had been in an interleukin-2 study and who had viral load below 500 copies/mL for greater than two years. Some of the study participants had undetectable HIV levels in cerebrospinal fluid and lymph nodes as well as in latently infected CD4+ cells. Even so, there was a rapid rebound of virus in the same fashion as other studies in which the duration of viral suppression was shorter. The NoHRT study suggests that length of time undetectable may not influence rebound on stopping. Whether baseline viral load and immune function are a predictor of response to STI is as yet uncertain. In a subset of the NoHRT study, the median difference between pretreatment viral burden and that after STI was +0.45 log copies/mL (a 2.8-fold increase). There was a median of 5.9 years between the two measures, which might indicate that treatment delays the trend for viral burden to increase.[16]
Garcia and colleagues at the 7th Retrovirus Conference reported on ten chronically infected patients undertaking STIs after 52 weeks of d4T, 3TC and ritonavir or indinavir. [17]The ten had sustained viral load under 20 copies for more than 32 weeks. The report described the results of three STIs, each separated by six months of the same triple HAART combination. Viral rebound occurred in all cases, with a mean doubling time of 2, 2.9 and 3.2 days after start of the first, second and third STI, respectively.
Drug-resistance mutations were not detected after any of the STIs. During the second STI, four of nine patients (44.4%) had viral loads that rebounded to levels similar to those before treatment and then dropped spontaneously by -0.8 to -2.09 logs (84% to 99%). These four patients developed strong and broad CTL and CD4+ cell responses to HIV-1 antigens. A third, more prolonged STI lasted until trial participants reached a viral load equilibrium, or setpoint. Four of nine ended up with viral loads that were –0.6 to -1.5 logs (75% to 97%) lower than their pretreatment levels. Again, there was a correlation between reduced viral load and the development of cellular immune responses against HIV.
The researchers commented that STIs " may induce effective specific cytotoxic and CD4+ lymphocyte proliferative immune responses against HIV-1 antigens associated with a spontaneous drop in plasma viral load in chronic HIV infection."
Carcelain and colleagues from the Hosp. Pitié-Salpêtrière assessed HIV-specific T- cell responses and HIV control after three or four 7- to 21-day treatment interruptions.[18] The study involved three individuals whose viral load had stayed below 20 copies and whose CD4 count had risen above 400 cells/mm3 for at least two years on HAART. They measured viral loads, HIV p24 antigen-specific CD4+ cell proliferation, interferon (IFN)-gamma production, CD8+ cell responses and T-cell activation. Five control patients whose virus rebounded during the first six months of HAART were also studied.
Before treatment interruption, there were no significant CD4+ and weak CD8+ cell responses to HIV. In patient 1, three seven-day interruptions did not induce viral rebound or CD4+ cell stimulation. In patient 2, Th-1 responses (the type of CD4+ T-helper cell response that produces CTL-stimulating cytokines) increased only at the first rebound. In patient 3, Th-1 responses occurred at each interruption but were transient. The investigators inferred that rebounding HIV suppressed the CD4+ T-helper response. HIV-specific CD8+ cell frequencies did not increase.
Papasavvas and colleagues from the Wistar Institute in Philadelphia measured anti-HIV cellular (CD4+ and CD8+) immune responses in five chronically infected individuals who had maintained viral suppression on HAART and subsequently went on an STI and compared them with five untreated controls. [19] The STI group experienced significant increases in anti-HIV CD4+ cell responses against p24 and gp160 (HIV core and envelope antigens, respectively). These preceded significant increases in IFN-gamma-secreting CD8+ T-cell responses against viral envelope antigens. The augmentations in immune response depended on the length of the STI and waned when therapy resumed.
After a median 46-day STI, three persons restarted HAART, achieved 98.86% reductions in plasma viremia by 21 days and maintained or further increased their cell-mediated anti-HIV responses. The remaining two trial participants continued off therapy while maintaining high cell-mediated responses and viral loads below 1,080 copies.
Renslow Sherer and colleagues from Chicago identified 13 HIV-infected individuals who maintained a viral load below 500 copies/mL for at least 90 days after stopping antiretroviral therapy (median 2.5 years, range 3 months to 5.6 years). [20] There were no striking features of the prescribed antiretroviral regimens, which consisted of double nucleosides only. Only two patients had received intermittent therapy, and two were treated during primary HIV infection (PHI). All remained HIV antibody-positive. Pretherapy viral loads (available for seven of the patients) were very low (ranging from below 500 to 9,000 copies/mL). Three of ten patients were heterozygous for the protective deletion in the CCR5 chemokine receptor gene. Another two had clade A HIV. These observations suggest that isolated cases of individuals with low or undetectable viral load after stopping therapy are not indications of an exceptional therapeutic effect.
Later in February, at the 2nd Frankfurt Symposium on the Clinical Implications of HIV Resistance, Dr. Richard Harrigan presented parallel results from a survey of the cohort from the BC Centre for Excellence in Vancouver, Canada. [21] His study compared pre- and post-therapy viral load in 238 individuals who stopped therapy for at least 90 days. It turned out that the final viral loads after stopping therapy were, on average, very close to the pretherapy equilibrium (setpoint) levels. On an individual basis, viral loads presented a normal (bell-curve) distribution about the pretreatment setpoint, with nearly everyone ending up within a log (from one-tenth to ten times) of that setpoint. The thirteen individuals that kept their viral loads below 400 copies/mL after stopping therapy all had very low setpoints to begin with. Their median pretreatment viral load was less than 1,500 copies/mL.
The researchers concluded that " on a population level, plasma viral load rebounds to pretherapy levels within 90 days of ceasing treatment. Maintenance of an undetectable viral load is associated with low pre-therapy levels."
Dr. Franco Lori and colleagues conducted a case-control study comparing nine individuals receiving just the nucleoside analog ddI with hydroxyurea (HU) with eight individuals on HAART.[22]The nine on ddI plus HU were part of the "PANDA" cohort. "Unlike HAART patients, PANDAs have low but detectable viremia and vigorous HIV-specific cellular immune responses," they noted. The PANDAs had all received ddI plus HU for over three years while maintaining a low but measurable viral load. They had previously undertaken a first treatment interruption of eight weeks. During the first six weeks of that STI, viral loads rose to nearly 20,000 then abruptly fell during the last two weeks.
The PANDAs and HAART controls interrupted therapy for eight weeks. The groups were matched according to the duration of previous treatment (longer than two years),and CD4+ and CD8+ cell count (an average of 549 cells/mm3 and 874 cells/mm3, respectively, for those on HAART while the PANDAs averaged 560 and 825 cells/mm3). Viremia before STI was significantly different – below 50 copies in six of eight on HAART (average viral load of 97 copies/mL), versus only one of nine among the PANDAs, who had an average viral load of 549 copies/mL. Failure during STI was defined as a viral load rise to above 10,000 copies or CD4 count fall to below 200 cells/mm3. Whatever the outcome, the treatment interruption was scheduled to end after eight weeks.
In contrast to the HAART plus HU trial described above [10], the group on hydroxyurea here showed a clear advantage over the others. Six of those on HAART had to restart therapy early - one at week 2 and four at week 6. None of the PANDA cohort was forced to return to treatment before the scheduled end of the eight-week STI. The PANDAs again at first experienced a viral load increase, to about 4,000 copies/mL at week 4. Their viral loads had decreased to pre-STI levels by week 8.
This study was the most successful example of STI presented at the 7th Conference on Retroviruses, but several caveats are in order. The first is the that PANDAs are a highly selected group. The original PANDA trial followed 40 volunteers on ddI plus hydroxyurea for six months. The present cohort consists of those who decided to remain on the ddI/HU combination rather than switch to other regimens, particularly those including protease inhibitors. The remaining volunteers may have, in some way, been more resistant to HIV than the others, though Dr. Lori says that there are no evident signs of this. Also, the PANDA cohort was on its second STI while the comparison HAART group was on its first. Dr. Lori concedes that at this point we do not know how many people will benefit from a ddI/HU regimen that includes STIs or how long that benefit will last. More rigorous controlled trials with lengthy follow-up are necessary.
Lidia Ruiz and colleagues from Barcelona assessed virologic and immunologic changes during an STI in chronically infected individuals who achieved long-lasting viral suppression (greater than two years) and a near normal CD4/CD8 ratio above 1. [23] The trial participants were randomized to stay on HAART (group 1, N=13) or interrupt therapy every three months until trial participants reached a viral load above 3,000 copies/mL or 30 days without drugs (group 2, N=12). Five members of group 2 also received two five-day courses of high dose IL-2 (3 MIU twice daily), which causes activation and proliferation in CD4+ cells. Viral rebound kinetics were measured every two days during the two STI periods in group 2 and every 3 months in group 1. Flow cytometry cell sorting and proliferation assays were carried out before and after the first STI. Genotypic resistance was tested after treatment resumed.
Two of 12 patients did not rebound after 30 days during the first STI. Only one maintained viral load below 20 during the second STI. Among the rest, viral load became detectable (above 20 copies/mL) after a median of 14 and 15 days during the first and second STIs. Viral load rose exponentially, with a mean doubling time of 1.6 and 2.2 days during the first and second STIs. The proportion of CD4+ and CD8+ cells did not change during STIs, but CD38+ expression, a measure of CD8+ cell activation, rose significantly in response to viral rebound. Four patients gained CD4+ cell responses to non-HIV recall antigens, and two of these developed HIV-specific responses to p24 core antigen during the first STI. The investigators found, though, that after two cycles, there were no sustained CD4+ cell responses to p24. An added benefit from IL-2 also was not apparent.
In a different approach to IL-2, Kendall Smith and colleagues from Cornell Hospital in New York selected nine chronically infected, "aviremic" individuals with normal circulating lymphocyte counts on HAART plus daily low-dose interleukin-2 (IL-2) therapy. [24] Upon cessation of HAART, but continuation of IL-2, plasma HIV became detectable in all individuals in ~19 days, then increased rapidly over two weeks (doubling time ~2.0 days) to a peak of ~350,000 (± 230,000) copies/mL. The virus concentration then decreased progressively over the next four weeks, stabilizing at ~26,000 (±8,000) copies/mL, or less than 10% of the peak concentration. This level was significantly lower than the mean viral load prior to HAART. CD4+ counts dropped by 24% compared to baseline just after the peak of viremia. CD8+ cells rose to 200% of baseline and remained high while viremia declined.
The largest prospective STI data set comes out of the Spanish Swiss Intermittent Treatment Trial (SITT). [25] Eligible patients were antiretroviral-naive before HAART, did not experience treatment failure during HAART, maintained viral load below 50 for at least six months, and were NNRTI-naive. The trial specifies four cycles of two weeks off therapy followed by eight weeks on. At week 40, treatment is suspended unless viral load rebounds to above 5,000. Measures of response include the amplitude of rebounds and the number of trial participants with viral loads below 5,000 and CD4+ counts above 400 cells/mm3 after four weeks without therapy.
Enrollment is continuing, with 108 of a projected 120 recruited so far. Pre-HAART median CD4+ count was 398 cells/mm3, with a viral load of 36,000. Median pretrial HAART duration was 24 months, with a median 21 months of viral loads below 50 copies/mL. Only 30% of the 96 volunteers who went through the first two-week STI had no detectable rebound. At the time of the 7th Retrovirus Conference presentation, 54 persons had stopped therapy a second time and 23 a third time. During these subsequent STIs, there had so far been no clear tendency for HIV rebounds to decrease in frequency or amplitude. There was some increase in HIV-specific responses by CD4+ T-helper cells, but no such trend yet for CD8+ cells.
Here, as in all other studies presented at the 7th Retrovirus Conference, reintroduction of the same therapy has resulted in a return of viral load to pre-STI levels after some months. But acquisition of mutant virus was detected in the period after a two-week STI in four out of ten patients in one previous study. [26] The impact of treatment interruption on selection for drug-resistant HIV is uncertain. The aim of these studies was to evaluate the viral dynamics and consequences of interrupting treatment, and a relationship did appear to exist between baseline immune status, as measured by CD4+ T-lymphocyte levels, with greater rebound in those individuals with fewer than 100 cells/mm3 prior to therapy.
Further work needs to be carried out to assess the value of recurrent interruptions in therapy on long-term outcomes, and to assess the potential for larger simple trials of cyclical or pulsed therapy. Several groups have suggested pulse therapy studies in recent years. These suggestions have been rejected by the pharmaceutical industry as lacking in scientific justification. Longer studies can proceed now that there is some pilot data supporting the immediate safety of this approach.
The third scenario in which the effects of treatment interruptions have been evaluated is in persons who were failing antiretroviral therapy with rising viral load on treatment.27,28 Here, the attempt has been to relieve the selective pressure exerted by the drugs. It is hoped that the mutant, drug-resistant HIV population in a person will then fade away, ceding its place to the fitter, faster-replicating wild-type virus.
In the 63-patient salvage therapy cohort at the Royal Free Centre (London), a treatment interruption was followed by treatment with hydroxyurea, efavirenz, two protease inhibitors (usually ritonavir and indinavir) and nucleoside analogs (usually ddI and 3TC). There was a median rise in CD4+ count of 120 cells/mm3 and a viral load drop of 3.08 logs (99.91%) after 28 weeks of this regimen; 62% of the cohort achieved a viral load below 50 copies/mL, and 82.5% were below 400 copies/mL. [28] The Frankfurt salvage therapy cohort[27] had lower rates of surrogate marker response to a similar "mega-HAART" therapy, but members of that group had greater prior exposure to antiretrovirals.
Although no controlled clinical data exist, these pilot studies both found that the majority of trial participants had favorable changes in their HIV drug-resistance patterns over the period of treatment interruption. Patients who had resistance assays performed on peripheral blood samples while on the failing drug regimens had a number of mutations associated with drug resistance in HIV reverse transcriptase and protease genes. These genetic changes were less detectable after a period off therapy as measured by both genotypic [27], [29] and phenotypic[27] assays.
Genotypic (using two different assays in separate laboratories) and phenotypic resistance assays were performed on samples from 18 members of the London cohort at two, four and eight weeks after introduction of the salvage regimen. [30],[31] In all three assays, before viral load fell below 50 copies/mL, there was a statistically significant reduction in the number of mutations found.
There appeared to be a relationship between the rise in viral load on stopping therapy and the decreases in detectable mutants. When salvage therapy with multiple antiretroviral agents (median of five drugs) was introduced into these patients, a significant proportion of individuals achieved suppression of HIV to below 50 copies/mL. This outcome was linked to length of time off therapy: For each month elapsed after stopping the failing regime, one was 15% more likely to suppress his or her HIV with the new salvage therapy.[28]
At the same time, significant drops occurred in CD4+ cell counts during the period off therapy - back to pretherapy levels in the majority of those studied with late-stage disease. This would suggest that careful monitoring should be performed during treatment interruptions and consideration given to prophylaxis against opportunistic infections at appropriate CD4+ cell counts.
Deeks and colleagues at San Francisco General Hospital conducted a prospective study of STIs among patients virologically failing protease inhibitor (PI)-based therapy. [32] Eligible patients had virologic failure for at least 12 months and a viral load above 2,500 copies/mL. Phenotypic resistance, viral load and CD4+ cell counts were measured weekly for 12 weeks and then every four weeks.
Eighteen patients stopped therapy (mean baseline CD4+ cell count of 254 mm3, baseline viral load of 39,800, and 56-fold median decrease in PI susceptibility). The median CD4 decrease was 94 cells/mm3 and the median viral load increase was +0.82 log (85%). Virus reverted to PI-susceptible in 16 of 18 cases (88.9%), with a mean time to reversion of 8.5 weeks (range 2-15). Greater PI resistance and higher viral load over baseline values were associated with delayed reversion. In seven of the patients with reversion to PI-susceptible HIV, nucleoside analog resistance persisted, though often at reduced levels.
Replicative fitness (relative to wild-type virus) increased from a median 22.3% to 67.1% after the switch to drug-sensitive HIV. But resistant virus identical to the original strain could still be cultured from four of eight patients' peripheral blood mononuclear cells when exposed to PIs 12 to 36 weeks after therapy stopped. Although these eight exhibited drug-susceptible HIV in phenotypic resistance assays, background drug-resistant HIV existed in at least half of them. What will happen when this cohort goes back on therapy remains to be seen.
Precedent exists in other viral diseases for reversion to wild type after treatment interruption [33],[34]) and for the successful reintroduction of the same antiviral therapy after a period of no therapy. [35] Presumably the selective pressure of the agents results both in the development of resistance due to ongoing viral replication and, after removal, to the reversion to native species. The presumption, by HIV researchers, but not by all virologists, that a rapid re-emergence of resistant HIV quasispecies would preclude a benefit from stopping and then restarting therapy is not borne out in the study of other viruses.
The current paradigm is that treatment of HIV must be continuous and for life. This is based on present knowledge of HIV dynamics under therapy.[36] The perception is that cessation of treatment would lead to immediate reversion to pretreatment clinical status and be detrimental to the patient. But modeling of viral kinetics suggests that to prevent emergence of resistance to HIV in the long term would require suppression of HIV to below 1 copy/mL. [37] This level of suppression is probably not achievable with current therapy options.
Structured treatment interruptions, intermittent treatment or pulsed therapy has distinct attractions for patients and healthcare providers, with potential for reduced toxicity, improved tolerance, greater adherence to dosing schedules, and lower cost. The ability to reuse drugs that previously ceased to work and to reduce overall exposure to antiretroviral agents is invaluable with a restricted palette of drugs. These first studies of interrupting HIV treatment appear to challenge the assumption that only harm would occur and to support the evidence that the virus is more forgiving than has been realized. [38]
Investigation of the changes in mutant viral strains at the clonal population level needs to be carried out in persons failing therapy to further delineate the potential for re-emergence of resistant strains. However, it is vital to tread prudently when patients have much to lose, such as when their viral burden is fully suppressed when on treatment. Therapeutic vaccination might be a safer alternative in this group. Good pilot studies and long-term planning will help. What is certain is that we cannot turn the clock back on treatment interruptions. They are already a fact of life.
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3. Carr A, et al. Diagnosis, prediction and natural course of HIV-1 protease inhibitor associated lipodystrophy, hyperlipidaemia and diabetes mellitus: a cohort study. Lancet 1999;353:2093-99.
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5. Walsh J. Adherence in clinical trials and clinical practice. Antiviral Therapy 1999; 4(supplement 3):49-54.
6. Martinez-Picardo J, et al. Selection of antiretroviral resistance in the latent reservoir of human immunodeficiency virus type-1 during successful therapy. (Abstract 238) 7th Conference on Retroviruses and Opportunistic Infections, San Francisco 2000.
7. Deeks S, et al. Delayed immunologic deterioration among patients who virologically fail protease inhibitor therapy. (Abstract 236) 7th Conference on Retroviruses and Opportunistic Infections, San Francisco 2000.
8. Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet. 1994 Apr 9;343(8902):871-81.
9. Altfield M, et al. Increase in breadth and frequency of CTL responses after structured therapy interruptions in individuals treated with HAART during acute HIV-1 infection. (Abstract 357) 7th Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
10. Zala C, et al. Viral load rebound upon discontinuation of d4T + ddI + NVP with or without hydroxyurea (HU) during primary HIV infection (PHI). (Abstract 558) 7th Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
11. Jin X, et al. Discontinuation of HAART after a course of therapeutic vaccination with ALVAC1452 and rgp160 may be associated with delayed viral rebound kinetics. (Abstract LB12) 7th Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
12. Neumann A, et al. HIV-rebound during interruption of highly antiretroviral therapy has no deleterious effect on reinitiated treatment. AIDS 1999; 13:677-83.
13. Garcia F, et al. Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS 1999; 13:F79-F86.
14. Ruiz L, et al. Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. (Abstract 1224) 7th European Conference on Clinical Aspects and Treatment of HIV Infection, Lisbon, 1999.
15. Davey R, et al. The NoHRT trial: a prospective study of cessation of HAART in HIV-infected patients after prolonged viral suppression. (Abstract 689) 39th ICAAC, San Francisco 1999.
16. Hatano H, et al. Plasma viral loads approximate pre-HAART levels after discontinuation of HAART. (Abstract 349) 7th Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
17. Garcia F, et al. Structured cyclic antiretroviral therapy interruption (STI) in chronic infection may induce immune responses against HIV-1 antigens associated with spontaneous drop in viral load. (Abstract LB11) 7th Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
18. Carcelain G, et al. Intermittent interruptions of antiretroviral therapy in chronically HIV-infected patients do not induce immune control of HIV. (Abstract 356) 7th Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
19. Papasavvas E, et al. Boosting of HIV-1-specific cellular immune responses in chronically infected persons after treatment interruption. (Abstract 353) 7th Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
20. Sherer R, et al. No detectable HIV RNA in thirteen individuals months after stopping antiretroviral therapy. (Abstract 351) 7th Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
21. Harrigan P, et al. Plasma HIV after therapy interruption. (Poster 39) 2nd Frankfurt Symposium on the Clinical Implications of HIV Drug Resistance. February 25-27, 2000.
22. Lori F, et al. Control of viremia after treatment interruption. (Abstract 352) Seventh Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
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24. Smith KA, et al. Cessation of HAART plus daily low-dose interleukin 2 to promote immunity to HIV. (Abstract 355) Seventh Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
25. Fagard C, et al. SITT: a prospective trial of strategic treatment interruptions. (Abstract 458) Seventh Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
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31. Devereux HL, et al. Reduction in detection of genotypic and phenotypic resistance on the initiation of an antiretroviral salvage regimen. (Poster 15) 2nd Frankfurt Symposium on the Clinical Implications of HIV Drug Resistance. February 25-27, 2000.
32. Deeks SG, et al. Virologic and immunologic evaluation of structured treatment interruptions (STI) in patients experiencing long-term virologic failure. (Abstract LB10) Seventh Conference on Retroviruses & Opportunistic Infections, San Francisco, 2000.
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34. Chayama K, et al. Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild-type after cessation of therapy. Hepatology 1998;27(6):1711-16.
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