Structured interruptions of highly active antiretroviral therapy in cycles of 4 weeks off/12 weeks on therapy in children having a chronically undetectable viral load cause progressively smaller viral rebounds

Article Outline

• Summary
• Introduction
• Materials and methods
  • Patient sample
  • Experimental design
  • Treatment safety and adherence
  • Statistical analysis
• Results
  • General characteristics of the patients
  • Viral response
  • Immune response
  • Evaluation of clinical response and treatment adherence
• Discussion
• Ethical approval
• Conflict of interest
• Acknowledgements
• References
• Copyright

Summary 

Objectives

To evaluate the viral, immune and clinical impact of a structured treatment interruption (STI) program of highly active antiretroviral therapy (HAART) in three cycles of 4 weeks off/12 weeks on therapy in a cohort of children with HIV infection under chronic viral control.

Methods

Using a single-group time series experimentation design and following informed consent, the HAART of children with HIV and a chronically undetectable viral load (VL) was discontinued for 4 weeks and then restarted and continued for 12 weeks for a total of three cycles. The VL, CD4+/CD8+ lymphocytes, and clinical status were evaluated at the end of each STI and at 6 and 12 weeks after HAART was resumed.

Results

Four children with a median age of 10.3 years (range 6.5–11.2 years) were included in the study. Their clinical immune categories were: A1 (n=2), A2 (n=1), and B3 (n=1). Treatment of all four patients was with zidovudine (AZT)+lamivudine (3TC)+ritonavir (RTV). At the end of the first STI, VL was a median 214000 copies/ml (range 27400–616000), corresponding to 5.3 log₁₀ (range 4.4–5.8). At the end of the second STI, VL was a median 72400 copies/ml (range 17800–126000) or 4.7 log₁₀ (range 4.2–5.1), which corresponds to a rebound 0.6 log₁₀ lower than the first. At the end of the third STI, VL was a median 28200 copies/ml (range 5370–140000) or 4.45 log₁₀ (range 3.7–5.1), a rebound 0.85 log₁₀ lower than the first. All rebounds were followed by a decrease in the VL to undetectable levels during the treatment periods. CD8+ T lymphocyte counts increased during viral rebounds and an initial decrease in CD4+ T lymphocyte counts was followed by a tendency to increase even exceeding CD8+ T cell counts. Only one event of transitory severe immunosuppression occurred. There were no symptoms related to the HIV infection.

Conclusions

The STI of HAART in cycles of 4 weeks off/12 weeks on therapy in children with chronically undetectable VL can cause progressively lower viral rebounds followed by a decrease to undetectable levels, with a low risk of severe immunosuppression and without the occurrence of symptoms related to HIV.

Keywords: Structured treatment interruptions, Highly active antiretroviral therapy (HAART), Acquired immunodeficiency syndrome (AIDS)

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Introduction 

The use of highly active antiretroviral therapy (HAART) has increased the survival of HIV-infected children and has improved their quality of life.^[1], ^[2] However, due to the fact that it is a lifetime treatment, it faces limitations related to costs, toxicity, and treatment adherence, which accumulate as time goes by.^[1], ^[3], ^[4], ^[5], ^[6], ^[7] Patients who interrupt HAART without medical indications experience a rapid viral load (VL) rebound followed by depletion of CD4+ lymphocytes.^[8], ^[9], ^[10], ^[11] In contrast, during structured treatment interruptions (STI) of HAART, controlled increases in viral replication could promote the development of a specific immune response against HIV, which in turn could cause a delay in the VL rebound, with a greater delay with each interruption.^[9], ^[12] This strategy could contribute to reducing the chronic toxicity of antiretroviral drugs, decreasing treatment costs and improving patient quality of life. Information available on STI of HAART in pediatric patients is scarce and that which refers to adult patients remains controversial.^[12], ^[13], ^[14], ^[15], ^[16], ^[17] The objective of this study was to evaluate the viral, immune, and clinical impact of an STI program of HAART in three cycles of 4 weeks off/12 weeks on therapy in a cohort of children with HIV infection under chronic viral control.

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Materials and methods 

Patient sample 

The sample included HIV-1-infected children with VL under the detection limit (<400copies/ml) by HAART, without immunosuppression (according to the 1994 Centers for Disease Control and Prevention (CDC) classification¹⁸), and who had been asymptomatic at least during the previous 12 months. Exclusion criteria were: (1) failure to complete 30% or more of the evaluations during the follow-up (they had to complete at least 14 of the 20 scheduled measurements) and (2) voluntary withdrawal from the study due to a decision by the parents, the person legally responsible for the patient's welfare, or the patient themselves, as applicable. Written informed consent was obtained from the parents or the person legally responsible for the patient. The study was approved by the institutional research and ethics review board of the Hospital de Especialidades No. 25.

Experimental design 

A case series of four children was evaluated through a single-group time series design with multiple treatment and withdrawal periods. The HAART of each child was interrupted for 4 weeks, followed by 12 weeks on HAART, until three interruption/restart cycles (4 weeks off/12 weeks on therapy) were completed. The drugs used for each patient remained identical during the study. Response was evaluated by measuring VL, CD4+ and CD8+ lymphocyte counts, and the clinical status of each patient at baseline, at the end of each interruption period, and at 6 and 12 weeks after restarting HAART. VL was measured by RT-PCR using the Cobas Amplicor HIV-1 Monitor test, version 1.5 (Roche Diagnostics, Branchburg, NJ, USA), which has a detection limit of 400copies/ml. T lymphocyte subpopulations were measured by standard flow cytometric methods, classifying the degree of immunodeficiency by age according to the 1994 CDC classification.¹⁸

Treatment safety and adherence 

Toxicity related to HAART was evaluated at each follow-up appointment, both clinically and by means of complete blood counts and routine biochemical values (including serum liver enzymes, amylase, lipase, lipids and cholesterol). Adherence to HAART was evaluated for each patient during outpatient appointments by the following means: (1) offering information, before entering into the study and during follow-up, to the parents or the persons legally responsible for the patient, and to the patient when appropriate, on the importance of HAART and of adhering to it as planned, as well as information on the potential risks of interrupting it without medical indications; (2) guided questioning of the parents, the persons responsible for administrating treatment, or the patient, about maintaining treatment as it was established; (3) asking the parents or guardians to fill out self-administration cards specially designed to optimize follow-up and to avoid involuntary forgetfulness; and (4) counting the remaining medication, comparing it to what should have been consumed by the patient.

Statistical analysis 

Median, ranges and quartiles 25 and 75 were used to describe the main results. The differences in VL and T lymphocyte counts over time, during HAART interruptions, and during periods on HAART, were evaluated through a visual graphic analysis and the Friedman analysis of variance for repeated measures. Analysis was carried out using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA). A p-value of <0.05 was considered to be significant.¹⁹

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Results 

General characteristics of the patients 

Between April and May 2004, four children were eligible and included in the study, three females and one male, with a median age of 10.3 years (range 6.5–11.2 years). All four patients acquired the HIV infection perinatally. The clinical immune categories were: A1 (n=2), A2 (n=1), and B3 (n=1). The four patients were receiving the zidovudine (AZT)+lamivudine (3TC)+ritonavir (RTV) HAART regimen at the recommended pediatric dosages.^[1], ^[3] Full-dose RTV as the only protease inhibitor was still recommended for the initial HAART regimen in children in Mexico when this study began.^[3], ^[5], ^[20] One of the patients had previously received two regimens, the latter based on indinavir (IDV)+AZT+3TC. The IDV was changed to RTV due to drug toxicity (Table 1).

Table 1. Baseline characteristics of four HIV-1-infected children included in a structured treatment interruption program (STI) of HAART in cycles of 4 weeks off/12 weeks on therapy.

	Patient 1	Patient 2	Patient 3	Patient 4
Age (years)	6.5	11.2	7.3	8.4
Sex	Female	Female	Female	Male
Previous ART (months)	–	AZT+ddC (28)	–	–
		IDV+AZT+3TC (61)
HAART regimena (months)	RTV+AZT+3TC (53)	RTV+AZT+3TC (8)	RTV+AZT+3TC (36)	RTV+AZT+3TC (29)
Viral load	<400 copies/ml (<2.6 log10/ml)	<400 copies/ml (<2.6 log10/ml)	<400 copies/ml (<2.6 log10/ml)	<400 copies/ml (<2.6 log10/ml)
Clinical immune categoryb	A2	A1	B3	A1

ART, antiretroviral treatment; HAART, highly active antiretroviral therapy; AZT, zidovudine; ddI, didanosine; IDV, indinavir; 3TC, lamivudine; RTV, ritonavir.

Viral response 

All four children had a VL under the detection limit at least during the 12 months before enrollment. At the end of the first period of 4 weeks of HAART interruption, the viral rebound was a median 214 000copies/ml (range 27 400–616 000) or 5.3 log₁₀ (range 4.4–5.8). VL fell under the detection limit at 6 weeks after resuming HAART and remained that way at the 12-week measurement. Because this first viral rebound was higher than we expected but VL decreased to undetectable levels after resuming treatment, we requested authorization to continue with the next interruption/resumption cycles from the ethics review board of the Hospital de Especialidades No. 25. Researchers expected VL rebounds to be no more than 4 log₁₀ at the end of each HAART interruption period of 4 weeks.^[17], ^[21] The ethics review board decided to approve continuing the trial on the basis of the reduction of VL to undetectable levels after resuming HAART. With the second interruption, VL increased to a median 72 400copies/ml (range 17 800–126 000) or 4.7 log₁₀ (range 4.2–5.1), which corresponds to a rebound 0.6 log₁₀ lower than the first (p=0.068). At the end of the third interruption, the VL rebound was a median 28 200 copies/ml (range 5370–140 000) or 4.45 log₁₀ (3.7–5.1), a rebound 0.85 log₁₀ lower than the first (p=0.050). All rebounds were followed by a decrease in the VL to undetectable levels during periods on HAART, except in the case of a female child who had a VL of 9530copies/ml (3.98 log₁₀) 12 weeks after the third restart, which coincided with an upper respiratory tract infection; this infection was probably viral but had an undetermined etiology. Six weeks later, the VL became undetectable in this patient (Table 2 and Figure 1).

Table 2. Viral load and T lymphocytes of four HIV-1 infected children included in a structured treatment interruption program of HAART in cycles of 4 weeks off/12 weeks on therapy

	Time of follow-up
	Months		Weeks
			↓			↓			↓
	−12	−6	0	4	10	16	20	26	32	36	42	48
	HAART			STIa	HAART		STIa	HAART		STIa	HAART
Patient 1
VL	<400	<400	<400	616 000	<400	<400	17 800	<400	<400	25 100	<400	9530
VL log10	<2.6	<2.6	<2.6	5.79	<2.6	<2.6	4.25	<2.6	<2.6	4.4	<2.6	3.98
CD4+ %	33.3	51	44	18	ND	32.2	22	ND	21	26	35	36
Absolute CD4+	829	927	858	648	ND	711	585	ND	673	485	534	692
Absolute CD8+	815	838	1029	2865	ND	963	1975	ND	2387	1280	958	1124
Patient 2
VL	<400	<400	<400	27 400	<400	<400	19 800	<400	<400	5370	ND	<400
VL log10	<2.6	<2.6	<2.6	4.44	<2.6	<2.6	4.3	<2.6	<2.6	3.73	ND	<2.6
CD4+ %	41.9	39.9	34.7	34	ND	25.2	ND	43	49	47	52	ND
Absolute CD4+	1199	1435	553	1445	ND	685	ND	1567	1729	1388	2004	ND
Absolute CD8+	746	1032	511	2559	ND	635	ND	1818	1585	1434	1681	ND
Patient 3
VL	<400	<400	<400	269 000	<400	<400	126 000	<400	ND	31 300	ND	<400
VL log10	<2.6	<2.6	<2.6	5.43	<2.6	<2.6	5.1	<2.6	ND	4.5	ND	<2.6
CD4+ %	30.4	33.8	40	14	ND	34.3	16	38	ND	24	ND	35
Absolute CD4+	890	546	1215	308	ND	763	493	766	ND	623	ND	489
Absolute CD8+	1121	670	1619	1846	ND	871	2370	1166	ND	1775	ND	814
Patient 4
VL	<400	<400	<400	159 000	<400	<400	125 000	<400	ND	140 000	ND	<400
VL log10	<2.6	<2.6	<2.6	5.2	<2.6	<2.6	5.1	<2.6	ND	5.15	ND	<2.6
CD4+ %	42.5	36.2	47	22	ND	36.9	33	39	ND	27	ND	25
Absolute CD4+	1186	415	1168	887	ND	1115	895	796	ND	677	ND	572
Absolute CD8+	1159	511	1197	2896	ND	1117	1689	1125	ND	1960	ND	1483

HAART, highly active antiretroviral therapy; STI, structured treatment interruption; VL, viral load; ND, not determined.

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• Figure 1. 

  Viral load as the number of copies of viral RNA/ml (filled squares) and the log₁₀ of that number (empty circles) of four HIV-1 infected children in a structured treatment interruption program (STI) in cycles of 4 weeks off/12 weeks on HAART. X_n are the 4-week treatment interruption periods. Values correspond to median and quartiles 25 and 75.

Immune response 

Important increases in the CD8+ T lymphocyte counts were observed during the treatment interruption periods, which coincided with the virological rebounds. This response was accompanied by an initial decrease in the CD4+ T lymphocyte counts, which conditioned an inversion in the CD4+/CD8+ lymphocyte ratio. After the second interruption period, the CD4+ T cell counts demonstrated a tendency to increase, and even to exceed CD8+ T cell counts (Table 2 and Figure 2). According to the absolute CD4+ T cell counts, only one patient had moderate immunosuppression (308–493cells/μl) at the end of the two first interruption periods and no child developed severe suppression during follow-up. On the other hand, according to CD4+ percentages, six events of moderate immunosuppression occurred, five of them during viral rebounds, and although all children experienced some decline in CD4+ percentages during follow-up, only one event of severe immune suppression (CD4+ below 15%) occurred. Thus, the nadir usually occurred during viral rebounds, and was 18% for patient 1, 25% for patient 2, 14% and 16% for patient 3, and 22% for patient 4 (Table 2).

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• Figure 2. 

  CD4+ percentage (filled triangles), and CD4+ (empty squares) and CD8+ (empty circles) absolute T lymphocyte counts of four HIV-1 infected children in a structured treatment interruption program (STI) in cycles of 4 weeks off/12 weeks on HAART. X_n are the 4-week treatment interruption periods. Values correspond to median.

Evaluation of clinical response and treatment adherence 

There was no symptomatology related to both HIV infection and adverse events related to HAART. At the end of the first interruption cycle patient 1 presented an upper respiratory tract infection with rhinorrhea, coughing, pharyngeal hyperemia, and cervical adenomegalies. These symptoms were considered to have been caused by a viral infection, but the etiology was not determined. Two more patients had acute upper respiratory tract infections of undetermined etiology, including the patient whose viral load rebounded at week 48 of follow-up coinciding with one of these events (patient 1). There were no other symptoms during the follow-up. Children gained weight and height during follow-up. The median weight at the beginning of the first interruption period was 27.1kg (range 19.2–37.2) and at week 48 of follow-up was 31.25kg (range 24–40.1) (p=0.068). The median height at the beginning of the first interruption period was 129cm (range 113–146) and at week 48 of follow-up was 132cm (range 121–154) (p=0.066). We did not detect any problems related to treatment adherence.

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Discussion 

Although HAART has increased the survival of HIV-infected patients, its high cost, the toxicity conditioned by its chronic use, and failures in adherence that accumulate as time passes are important limitations to its effectiveness in the long term.^[1], ^[5], ^[6], ^[7], ^[22], ^[23] STI of HAART can reduce the impact of these three HAART limitations.^[8], ^[9], ^[10], ^[11], ^[12], ^[13], ^[14], ^[15], ^[16], ^[17] It has been suggested that STI of HAART may facilitate long term treatment, since they can result in an increase in individual tolerance by reducing the toxicity associated with the chronic use of antiretrovirals, reducing the treatment burden, reducing costs, improving adherence, and improving the quality of life of the patient without risking the efficacy of the treatment.^[7], ^[9], ^[10], ^[12], ^[17] Although in recent years abundant information has been published on STI of HAART, most of this information involves adult patients and remains controversial.^[8], ^[9], ^[10], ^[12], ^[16], ^[22], ^[23], ^[24], ^[25], ^[26], ^[27], ^[28], ^[29] Thus, although the SMART study showed that CD4+ guided episodic antiretroviral therapy in adult patients increases the risk of opportunistic diseases and death as a consequence of lowering CD4+ counts and increasing viral load, a number of STI issues remain unresolved, such as whether STI may be appropriate in circumstances other than those used in the SMART study.^[23], ^[24] In the present study, the viral, immunological and clinical impact of a HAART STI program was evaluated in three cycles of 4 weeks off and 12 weeks on therapy in a cohort of four children with HIV infection under chronic virological control.

The duration of the off/on HAART cycles in the present study was chosen due to the fact that the prospective studies carried out in adults have used STI periods as long as 3 months or as short as 2 weeks.^[6], ^[9], ^[10], ^[11] In addition, a non-structured HAART interruption study for intercurrent problems in patients with controlled chronic infection and undetectable viral load showed that interruptions of no longer than 4 weeks appear to be safe,⁷ and a recent prospective study evaluating pediatric patients also demonstrated that interruption periods of 4 weeks appear to be safe.¹⁷

Progressively smaller viral rebounds at the end of the two following interruption periods could suggest that temporary exposure to HIV induces the development of a specific immune response,^[7], ^[9], ^[10] and that if this tendency continues during a longer follow-up, it could eventually delay the rebound occurrence and, therefore, patients could go without treatment for longer periods of time. Results of some studies in adults submitted to STI in the acute phase of HIV disease have reported an increase in the viral control of the infection due to a quantitative increase in the specific immune response determined by T cells, which has suggested the possibility of auto-immunization. However, results have not been consistent from one study to another.^[8], ^[9], ^[10], ^[12], ^[14], ^[15] A prospective pediatric study that included eight children submitted to progressively longer antiretroviral treatment interruptions demonstrated significant increases in HIV-specific immune responses and reductions in viral RNA levels in children subjected to more than 10 STI cycles.¹⁷ In contrast, in the PENTA 11 trial that included 109 children with chronic HIV infection from nine countries, 56 were randomized to undergo one or two CD4+ guided STI over 48 weeks. Although reductions in CD4+ counts were greater in STI children, just four of them had a CD4+ end-point (<15% and for those ≥7 year-old <200cells/mm³) vs. one in continuous therapy. However, after 72 follow-up weeks, 94% in continuous therapy vs. 81% in STI were suppressed at <400 copies of RNA/ml.³⁰

In the present study, all the viral rebounds were followed by a decrease in the VL to undetectable levels during the treatment periods in the four patients, with only one exception. This finding suggests that the transitory viral rebounds do not induce the selection of quasi-species resistant to antiretrovirals. This risk is higher when there is viral replication in the presence of sub-therapeutic levels of such drugs, as occurs when there is failure in the adherence to treatment.^[1], ^[8], ^[9], ^[13] Although we did not search for mutations related to antiretroviral resistance, the results obtained suggest that the risk of developing resistance and of secondary loss of viral control is low since, except for the first hours of the interruption periods, there was no viral replication in the presence of the circulating drug.^[9], ^[10], ^[13] Studies of structured and non-structured interruptions of HAART in adult patients have reported mutations related to antiretroviral resistance ranging between 0.75% and 45%.^[9], ^[10], ^[24] The VL of the children in the present study would not have fallen to undetectable levels in such a consistent manner if selection of quasi-species with these types of mutations had occurred. However, in this study it is possible that resistance had occurred, particularly the mutation M184V conferring resistance to 3TC, and as has been suggested by others it is also possible that M184V could have resulted in a less fit virus, which might explain the progressively lower viral rebounds.^[31], ^[32] The only exception with regard to the absence of detectable VL during periods on HAART was a female child in the final measurement. During sample collection for this determination, the child presented upper respiratory tract infection symptoms. Although no studies were done to determine the etiology of these symptoms, it was very probable that they had a viral etiology. Although this patient's VL became undetectable at the next measurement, it has been shown that such events induce transitory increases in viral replication which recede once the intercurrent infectious process resolves.^[33], ^[34]

The progressive reduction in magnitude of the viral rebounds we found could be attributed to assay and biological variations in HIV RNA levels. Although most of this variability results from biologic variation and can be as much as 3-fold (0.5 log₁₀) for adult patients, changes greater than 0.5 log₁₀ (3-fold) should be considered to reflect a biologically and clinically significant change in children older than 2 years.^[1], ^[33], ^[34], ^[35], ^[36] The median of the reductions in the rebound magnitudes was higher than the 0.5 log₁₀ attributed to this biological variation, above all the magnitude of the third rebound with respect to the first (0.8 log₁₀). These reductions also allowed the viral load at the end of the third rebound to be established at least at the logarithm immediately below that of the first rebound, and to always return to undetectable levels once treatment was reinitiated. Thus, it is very unlikely that the reduction in the magnitude of the rebounds observed was due exclusively to biological variability of HIV RNA levels.^[35], ^[36]

Significant increases in CD8+ T lymphocyte counts observed in most treatment interruption periods, which coincided with the viral rebounds, suggest the development of a vigorous T cytotoxic response secondary to the viral stimulus, as has been demonstrated in some previous studies.^[8], ^[9], ^[17], ^[27] However, this finding has not been consistent in the different studies.^[8], ^[9], ^[10], ^[12], ^[14], ^[15], ^[16] In the present study, this vigorous CD8+ T response was accompanied by an initial decline in the CD4+ T lymphocyte counts and percentages. In spite of this, the progressive increases in the CD4+ T lymphocytes after the second interruption period, even exceeding the CD8+ T lymphocyte counts, suggest that the risk of loss of control of the immune response with the final development of secondary clinical events is low. On the other hand, the progressively smaller virological rebounds seem to support one of the possible benefits of the HAART STI, an increase in the specific immune response. By suspending HAART, limited and temporary replication of the autologous virus would allow induction of a specific immune response against the HIV. If HAART interruption/reinitiation cycles are applied in a continuous manner, a delay in the VL rebound could be produced, which could increase with each interruption.^[9], ^[10], ^[12], ^[17] Nevertheless, the decreases in CD4+ percentages observed in the short term follow-up in the present study may raise concerns about the possibility of the development of more immune problems if patients are submitted to more cycling in a longer follow-up. Borkowsky et al. demonstrated the development of an HIV-specific immune response with progressive reductions of viral load in children who were submitted to more than 10 progressively longer antiretroviral treatment interruptions.¹⁷ Although immune responses were not further characterized in the present study, rendering us unable to determine whether the changes observed are HIV-specific responses suppressing viral replication or whether they just represent non-specific immune activation, our results could suggest that the development of an HIV-specific immune response restricting viral replication is possible earlier and using a more simple schedule than that used by Borkowsky et al. In addition, because only one event of severe immunosuppression occurred, which was transitory, early on during the follow-up and with no symptoms, the results obtained seem to suggest that the STI of HAART applied to children in the conditions tested in this study are immunologically safe.

With the exception of one patient, no symptoms related to the HIV infection occurred in the children. Although studies in adults submitted to HAART STI have shown contrasting results,^[10], ^[15], ^[27], ^[28], ^[37] the results of the present study suggest that the risk of developing acute and opportunistic clinical events is low with this HAART STI program for children with a controlled chronic infection.

Although the number of patients in this study was small, the consistency of the results obtained suggests that a HAART STI program such as that evaluated in this study in children with chronically undetectable VL causes progressively lower virological rebounds. These results also suggest that such rebounds are followed by a drop of VL to undetectable levels and by the development of a vigorous CD8+ T response with an initial decline in the T helper response, which is followed by progressive increases in the same. All this suggests that temporary and repeated exposure to the autologous HIV may induce the development of a specific immune response. In addition, because no serious clinical events related to HIV occurred and despite the immune events we detected, these results also seem to suggest that this STI program could be safe from the clinical and immunological point of view. However, evaluation of larger cohorts over longer periods of time, including different antiretroviral regimens, and, above all, controlled clinical trials, are needed before definitive conclusions about the benefits and safety of STI of HAART in children may be drawn.

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Ethical approval 

This study was approved by the institutional research and ethics review board of the Hospital de Especialidades No. 25, Instituto Mexicano del Seguro Social, Monterrey, Mexico.

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Conflict of interest 

No conflict of interest to declare.

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Acknowledgements 

This study was supported by grants 2005/1/I/071 from the Instituto Mexicano del Seguro Social and 44519 from the Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico.

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