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February 2000

New York, NY

by Mark Harrington

At least 18 studies and speeches presented at the Seventh Retrovirus Conference included discussions related to treatment interruptions (TIs) and structured treatment interruptions (STIs) in various HIV infected populations — including primary HIV infection (three papers), chronic and virally suppressed (13 papers), and chronic and unsuppressed (two papers). Indeed, the conference ended with three late-breaker presentations focusing on STIs.

In an overview of recent data on metabolic toxicities associated with antiretroviral therapy, Bill Powderly of Washington University suggested that the unanswered question of when to start antiretroviral therapy and the unanswered questions about STI research (when to stop, and how; and when to restart) were in the spotlight due to the shifting treatment paradigm which has emerged in the four years since Vancouver, with the discovery of latently infected cell compartments, the diminution or disappearance of the eradication hypothesis, and the emergence of significant drug- related toxicities, adherence, resistance and cost issues.

Indeed, Powderly suggested that the only people for whom therapy is absolutely indicated are those with constitutional symptoms, opportunistic infections, or a CD4 count below 200. In those with earlier disease, intermittent therapy (pulsed HAART interspersed with STIs) may help prolong therapeutic efficacy. Perhaps viral load-based therapeutic goals should be supplemented or even replaced by CD4-based ones (keeping the CD4 count above a risk threshold; Powderly 2000). Donald Kotler commented that Powderly’s discussion of “these heretofore heretical propositions” was “a measure of our maturation in treating this disease” (Kotler 2000). Such discussions have certainly not been heretical among treatment activists in the past three years.

A few conclusions can be drawn from the STI research presented at the Retrovirus Conference. Most STI research is still uncontrolled, carried out for short periods of time in small patient groups. STIs appear safe in the short-term if patients receive frequent RNA and CD4 measurements and are retreated if necessary. Resumption of therapy appears to be successful if the patients were fully-suppressed before the STI, and the emergence of drug resistance has not observed in this population. However, the immunologic benefit of intermittent therapy remains undefined, and the clinical usefulness of HIV-specific CD4 and CD8 responses has yet to be demonstrated in this setting.

The usefulness of adjunctive approaches such as interleukin-2 (IL-2) or putative “therapeutic” vaccines such as ALVAC/gp120 has yet to be demonstrated clearly. Different teams reported divergent results (benefit or no benefit, immunologically) with IL-2 during or after HAART suppression; reports about HAART plus ALVAC/gp120 followed by an STI are too preliminary to yield any conclusions and, in any case, were no better than results shown for HAART followed by an STI with no vaccine.

In unsuppressed patients, the incidence of reversion to wild-type virus in plasma is at least as high as previously reported, but drug-resistant virus remains archived in mononuclear cells in at least half the cases observed. The clinical impact of reversion to wild-type in plasma or persistence of resistance in cells remains to be determined prospectively.

The most important conclusion is that further well-designed, prospective, and well-controlled studies of intermittent therapy and STIs need to be conducted across the spectrum of HIV disease.

A. Primary HIV Infection (PHI), Viral Load Suppressed

1. STI following HAART given during acute infection boosts and broadens anti-HIV CTL responses.

Altfield and colleagues from Mass General reported on fifteen acutely infected individuals who were identified before seroconversion and treated with immediate HAART. After over one year of HAART 7/13 individuals underwent an STI. HIV RNA, CD4, and cytotoxic T lymphocytes (CTLs) against env, gag, nef and RT, were measured weekly. Mean baseline viral load at diagnosis was 13.8 million; RNA became undetectable in all patients after a median 10 weeks (range 4-19) of HAART and remained undetectable during HAART treatment. Low magnitude CTL responses against one to four epitopes were seen in 10/15 subjects (66.7 ) at diagosis and persisted at lower frequencies during HAART. In the 7 STI patients, virus rebounded within 1-8 weeks [levels not given] and HAART was reintroduced. CTL responses were boosted in all STI patients, who gained a median of two new recognized epitopes and increased responses to previously recognized epitopes. Two people with no previous CTL responses gained them post-STI. In two people who had a second STI, additional CTL increases were seen. “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. STIs result in a persistent augmentation of the frequency and breadth of CTL responses in these subjects, which can be further boosted by additional controlled interruptions.” Of concern was an episode reported in the poster (but not the abstract) in which an individual simultaneously stopped HAART (for financial reasons and without telling the investigators) and received a flu shot; his viral load rebounded sky-high and he experienced the equivalent of a seroconversion syndrome. (Altfeld et al., abstract and poster 357)

Comment:This paper suggests the possibility of broadening anti-HIV cellular responses by using STIs after suppressive HAART during PHI and emphasizes the need for randomized studies of “when to start/when to stop” in the PHI population.

2. STI following 48 weeks of HAART + HU during PHI: rebound observed regardless of HU; rebound is blunted after 3 weeks; rechallenge is effective. 

Zala and colleagues from Buenos Aires and Vancouver followed 18 patients treated during PHI with d4T, ddI, nevirapine with or without HU. After 48 weeks of treatment, patients were offered an STI with rechallenge allowed after 30 days if viral rebound was confirmed. After 48 weeks of HAART, 83  hd viral load <500 and 67  hd <50. Eight patients (5 on HU) interrupted therapy after a median 57 weeks (range 53-75). All 8 rebounded to >5,000 copies after 21 days. “Plasma viral load peaked within three weeks and decreased thereafter by a median of 0.69 log.” HU did not significantly affect the kinetics of rebound. All patients responded to rechallenge (viral load <500) within a median of 4 weeks. One patient on ddI/d4T/NVP discontinued treatment due to grade 3 peripheral neuropathy at week 20 and his viral load remained <50 after 46 weeks off therapy. (Zala et al., abstract 558).

3. Two of 4 PHI patients treated with HAART, immunized with ALVAC/rgp160, and going on STI blunted viral rebound and may have broadened anti-HIV CTL responses.

Jin and colleagues at New York’s Diamond Center treated 4 individuals with AZT/3TC/indinavir within 100 days (median 60) after they were infected. Median baseline RNA was 4.76 log. HAART suppressed viral load <50 in all subjects. After 2.5 years of therapy, subjects were vaccinated four times with the prime-boost ALVAC 1452/rgp160. After 1,162 days of HAART and one week after their final vaccination, four patients chose to stop therapy. In two individuals (50%) delayed viral rebound was observed; RNA became detectable at 68 and 85 days post vaccination; initial virus doubling times were 4.5 and 3.2 days respectively. The other two patients (50%) experienced rapid viral rebound with detectable virus within 13 and 23 days; both had viral doubling times of 1.4 days — similar to previously reported rates. The two delayed rebounders had significant increases in CTLs to more than one viral antigen following vaccination (at the late-breaker session, the timing of the treatment interruption was showed on the viral rebound data slide, but not on the CTL rebound data slide). One rapid rebounder had a monospecific response to gag, while the other had CTL response to the vaccination. After 4-8 months off therapy, the delayed rebounders had RNA levels of 3.75 and 2.52 log, while the rapid rebounders had 3.55 and >4.70 logs after 4 months off therapy. The authors speculated that “Therapeutic vaccination can enhance cellular immune responses that are temporally associated with suppressed HIV-1 rebound kinetics after discontinuation of HAART.” (Jin et al., abstract LB12)

Comment:This small, uncontrolled study did not display results significantly different from those of Garcia et al. [see below], whose study involved three STI cycles post-viral suppression, but no “therapeutic” vaccination. The Garcia study showed 4/9 “lower rebounders” developed anti-HIV CTLs during their STIs, similar to the 2/4 “slower rebounders” reported on here. In the final question of the conference, Luís Montaner of the Wistar Institute pointed out that, as the study lacked controls, it was difficult to interpret. [Of the three late-breaking STI papers, only the Deeks study was well-controlled.]

B. Chronic HIV Infection (CHI), Viral Load Suppressed

4. Virus rebounding during STI differs from that detected in latent reservoirs.

Tae-Wook Chun and colleagues from NIAID threw another wrench into current theory by reporting that the viral rebound observed upon treatment cessation may not come exclusively from the pool of latently infected, resting CD4 cells harboring replication-competent HIV. They used quantitative microculture and heteroduplex mobility assays to compare viral RNA from reservoirs before and from plasma after rebound in nine patients who underwent an STI in a clinical trial (the NoHRT study, Davey 1999). Rebound and reservoir RNA were identical in just two of nine patients, and diverged in seven of nine. While this disparity could result from sampling error (the RNA may have rebounded from latent cells in another, unmeasured compartment), but the paper also suggested that the RNA may rebound from another, as-yet unidentified reservoir, where active replication may be ongoing despite HAART. Possibilities include tissue macrophages and microglia in the central nervous system (Chun et al., abstract 239).

5. Viral setpoint not altered after two years of HAART followed by STI.

Hatano and colleagues from NIAID measured plasma viral load from 12 patients who achieved good viral suppression (<50 copies/ml) on HAART and then went off antiretroviral therapy. Viral control on HAART was achieved in a median of 48 days and maintained for a mean 661 days; HAART was discontinued because of patient preference (4), toxicity (3), illness (1) or for protocol reasons. The length of the treatment interruption (TI) was a median 55 days (range 14-168, mean 66). The median difference between pre- and post-HAART viral load was 0.45 logs (mean 0.65). Eight patients had post-HAART viral load values higher than pre-HAART; four had lower values. The median duration between pre- and post-HAART values was 2,168 days (5.9 years). “After discontinuing HAART most individuals had rebounds in their viral burden approximating pre-HAART levels, even after a significant lapse of time approaching six years. Our data suggest that HAART with good viral suppression for almost two years may not alter intrinsic viral setpoints.” (Hatano et al., abstract 349)

6. Low viral load during treatment interruption may not reflect a therapeutic effect. 

Sherer and colleagues from Chicago identified 13 HIV infected individuals who achieved a viral load below 500 copies a minimum of 90 days after stopping antiretroviral therapy (median 2.5 years, range 3 months – 5.6 years). There were no striking features of the prescribed antiretroviral regimens. Only two patients received intermittent therapy, and two were treated during primary HIV infection (PHI). All remained HIV antibody positive. Pre-therapy viral loads (available for 7/13 patients) were very low (<500-9,000 copies). Three of ten patients were heterozygous for the CCR5 deletion; 2/12 had clade A HIV. “Isolated cases of individuals with low or undetectable HIV RNA upon stopping therapy do not [appear to be] evidence of an exceptional therapeutic effect.” (Sherer et al., abstract 351)

Comment:What was the denominator here (e.g., how many other patients went of therapy and didn’t achieve a viral load below 500 copies)?

7. ddI/hydroxyurea followed by STI may provide better immune control than HAART followed by STI. 

Lori and colleagues conducted a case-control study comparing nine individuals receiving ddI and hydroxyurea (HU) in the PANDA cohort with eight individuals on HAART. “Unlike HAART patients, PANDAs have low but detectable viremia and vigorous HIV-specific cellular immune responses.” PANDAs and matched HAART controls interrupted therapy for eight weeks. Matching criteria before the STI included the duration of previous treatment (>2 years), CD4 and CD8 counts. Failure during STI was defined as a viral load rise to over 10,000 copies or CD4 drop to below 200. Five of eight HAART patients failed by week six and had to restart therapy, whereas no PANDA had to restart during eight weeks of follow-up [what happened after eight weeks?].

Pre-STI CD4 Pre-STI CD8 Pre-STI viral load
HAART 549 874 < 50 copies (7/8)
ddI/HU 495 805 > 50 copies (8/9)


Failure within 8 weeks (RNA>10,000 or CD4<200) Rise in viral load by STI week 6 CD4+CD8 change during STI
HAART 5/8 (62.5%) 97 – 16,863 (+2.25 log10) +323
HU 0/9 (0%) 843 – 1,596 (+0.27 log10) stable stable


“In conclusion, reconstitution of HIV-specific cellular immune responses obtained during the treatment of chronically infected patients was associated with the control of viral rebound during treatment interruption.” (Lori et al., abstract 352)

Comment:This case-matched control study would be more compelling if it were randomized.

8. STIs augment HIV-specific CD4 and CTL responses in some individuals with CHI who previously controlled HIV with HAART. 

Papsavvas 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. During the STI, the five previously suppressed individuals were able to “significantly increase broad antiviral T-helper and IFN-gamma secreting CD8 T-cell responses as a result of complete treatment interruption.” There were “substantially fewer changes” in the control group. The STI group experienced significant increases in anti-HIV T-helper responses against p24 and gp160 “preceding significant increases in IFN-gamma secreting CD8 T-cell responses against viral envelope antigens.” After a median 46 day STI, three subjects restarted HAART and achieved 98.86% reductions in plasma viremia by 21 days and maintained or further increased the cell-mediated anti-HIV responses. The remaining two subjects stayed off therapy, maintained high cell-mediated responses, and maintained RNA below 1,080 copies. “These observations provide the first demonstration that CD4 and CD8-mediated cellular immune responses against autologous HIV-1 are augmented as a result of temporary treatment interruption in a subset of chronically infected individuals.” (Papasavvas et al., abstract 353).

Comment: This small, uncontrolled study suggests that CD4-mediated help may be required to stimulate anti-HIV CD8 activity.

9. Randomized STI trial in virally suppressed chronic infection shows only transient HIV-specific immune responses in a minority of participants, but is safe.

Ruiz and colleagues from Barcelona assessed virologic and immunologic changes during an STI in 25 chronically-infected individuals who achieved long-lasting (&37;2 years) viral suppression and a CD4/CD8 ratio of &37;1 on HAART. They were randomized to stay on HAART (group 1, N=13) or interrupt for a maximum of 30 days or until the viral load increased over 3,000 (group 2, N=12), then resuming the same prior ART. Ninety days after rechallenge, a second STI was begun. Viral rebound kinetics were measured every two days during the two STI periods in group 2 and every three months in group 1. FACS and proliferation assays were carried out before and after the first STI; genotypic resistance was measured when treatment resumed. 2/12 patients did not rebound after 30 days during the first STI; only 1 maintained viral load <20 during the second STI. Among the rest, viral load became detectable >20) for a median of 14 and 15 days during the first and second STIs. Viral load rose exponentially with a mean half-life of 1.6 and 2.2 days during the first and second STIs. CD4 and CD8 percentages did not change during STIs, but CD38+ (activation) expression rose significantly in response to viral rebound. Four patients (33%) gained T-helper responses to recall antigens, and two of these (16.5%) developed HIV-specific p24 responses during the first STI. Only recall antigen T-helper responses were maintained by the start of the second STI. Drug resistance was not observed. The investigators concluded that STIs were not associated with CD4 reductions or clinical complications after two years of effective viral suppression; that virus rebounded in most but not all patients; that virus was effectively controlled upon rechallenge; and that “HIV-specific helper T-cell responses may require subsequent cycles of STI to keep viral replication under control.” (Ruiz et al., abstract 354)

10. HAART+IL-2 followed by an STI while continuing IL-2 elicits viral rebound followed by partial immune control, resulting in detectable viremia below pre- treatment setpoint. 

Smith and colleagues from New York and San Jose selected 9 chronically infected “aviremic” individuals with normal circulating lymphocyte counts on HAART plus daily low-dose interleukin-2 (IL-2) therapy. “Upon cessation of HAART, but continuation of IL-2, plasma HIV became detectable in all individuals in 19 + 3 days, then increased rapidly over 2 weeks (doubling time 2 + 0.2 days) to a peak of 348,123 + 232,811 RNA molecules/ml. Remarkably, the virus concentration then decreased progressively over the next 4 weeks, reaching a low stable level of 26,086 + 8,087 RNA molecules/ml, <10% of the peak concentration (p<0.001). Moreover, this level was significantly lower than the mean viral load prior to HAART [emphasis added, see viral setpoint not altered after HAART alone, Hatano et al., above] (70,315 + 20,459). CD4 counts dropped by 24% compared to baseline (p<0.01) just after the peak of viremia. CD8 cells rose to 200% of baseline (p<0.01) and remained high while viremia declined. “Thus, contrary to previous assumptions, chronic HIV infection does not preclude the development of effective immune reactivity to HIV.” Additional trials of HAART cessation while continuing IL-2 “to permit endogenous HIV antigenic stimulation … [and] promote the expansion of antigen-activated CD8+ T cells, now appear warranted.” (Smith et al.,
abstract 355)

11. Randomized HAART vs. IL-2/HAART study suggests IL-2 may not affect virus production, latent infection, or immunologic control. 

Presenting data at odds with the previous IL-2 report, Stellbrink and colleagues reported on a randomized comparison of HAART alone versus HAART plus IL-2 in 56 patients with over 350 CD4 cells or recent seroconversion. Viral load and CD4 counts were measured at days 0, 14, 28 and monthly; and after treatment discontinuation at weeks 1, 2, 4 and 8. Lymph nodes were biopsied before treatment and after six months of maintaining viral load below 50 copies. 120 HIV negative controls were used for normalizing age-matched T cell subsets. Median age was 41, median CD4 count 410, median CD8 count 878, and HIV RNA 4.83 log. IL-2 did not affect the magnitude or kinetics of plasma viral load drop, but did increase the rate of normalization of CD4 counts. Viral replication was detected in the follow-up lymph node biopsies of 11/15 non-IL-2 and 10/16 IL-2 patients (non-significant). Proviral DNA levels and decay kinetics did not differ between the two groups. After treatment discontinuation, RNA rebounded rapidly and was transiently higher than baseline. “One IL-2 patient subsequently cleared viremia in the absence of therapy. Conclusions: Despite a strong and durable immunomodulatory effect, IL-2 has no persistent effect on virus production or latent infection in vivo [or] immunological control over HIV infection.” (Stellbrink et al., abstract 240)

Comment:Whereas the Smith patients were selected, the Stellbrink patients were randomized.

12. Lymph node RNA rebounds in parallel to plasma RNA during STI.

Orenstein and colleagues compared lymph node architecture, HIV RNA and protein expression in lymph nodes from 5 individuals fully suppressed on HAART and following viral rebound after treatment interruption. Lymph nodes (LN) were excised after at least one year of HAART with CD4>600 and viral load <50, and then after viral rebound. “LN at baseline on HAART were quiescent to mildly hyperplastic … they had no detectable follicular dendritic cell (FDC) associated HIV RNA or p24 protein and only rare mononuclear cells (MNC) expressing RNA (one LN) or p24 (two LN). Plasma viral load after a 1-2 month STI ranged from 329 to 3.2 million. CD4 counts declined by 5-48% and did so most in those with the highest viral rebound. Four of 5 second LN biopsies (80%) were more hyperplastic than the initial LN; “the fifth showed paracortical hyperplasia but no germinal centers.” Cellular HIV RNA in the second LN paralleled plasma viremia. Cell activation increased. “Quiescent LN from individuals on extended treatment with HAART rapidly became hyperplastic and activated following one to two months of treatment interruption. Virus expression in LN MNC parallels the rebound in plasma viremia and fall in CD4 cells.” The lymph node photographs in Orenstein’s poster were a chilling reminder of the fact that the viral rebound seen after STIs visually resembles that seen during chronic, progressive HIV infection. (Orenstein et al., abstract 358)

Comment:What would happen to viral expression in lymphoid tissue if anti-HIV cellular immune responses returned in association with blunting of plasma viremia?

13. Viral load does not rebound during an eight day STI after HAART suppression.

Kilby and colleagues from the University of Alabama at Birmingham (UAB) conducted an 8-day STI followed by rechallenge in 5 individuals with chronic infection who had maintained plasma viremia below 200 copies for at least six months. All five had detectable RNA before HAART and four were undetectable (<20) on HAART. Eight day rebound kinetics were similar in the 4 with RNA<20 and the 1 whose RNA was 100 on HAART; the latter actually did not experience a rebound. The two subjects whose virus rebounded re-suppressed after rechallenge. Three subjects had a lymph node (LN) biopsy at day 8; there was no increase in RNA+ cells above the low pre-STI level. CD4 cells dropped slightly but significantly during the STI and returned to baseline after 30 days of HAART. Activated CD4 and CD8 cells also increased, even in those whose viral RNA did not rise during the STI. (Kilby et al., abstract 359)

Comment:The eight-day STI here may be too short to show much.

14. French group reports no immunologic benefit to brief treatment interruption. 

Carcelain and colleagues from Paris studied HIV-specific T cell responses and HIV control after repeated (3 or 4) 7-21 day treatment interruptions in three individuals whose viral load had stayed <20 copies and whose CD4 count risen to >400 for at least two years on HAART. Five control patients whose virus rebounded during the first six months of HAART were also studied. The investigators measured RNA levels, HIV p24-specific T helper proliferation and IFN-gamma production, CD8 responses and T cell activation. Before treatment interruption, there were no significant CD4 and weak CD8 responses to HIV. In patient 1, three 7 day interruptions did not induce viral rebound or T helper stimulation. In patient 2, HIV-specific CD4 responses increased only at the first rebound. In patient 3, these responses occurred at each interruption but were transient. HIV-specific CD8 cell frequencies did not increase. Interferon gamma producing CD4 cells were observed after the TI, but the cells were rapidly deleted after virus replication resumed. (Carcelain et al., abstract 356)

Comment:These were brief STIs. Virus may need to rebound to higher levels for longer durations to induce more durable HIV-specific responses; see the similar low rebound observed in the Kilby study described above (abstract 359).

15. Preliminary results from Swiss study indicate viral rebound may be blunted after three STIs. 

Fagard and colleagues reported early results from the Swiss Intermittent Treatment Trial (SITT). Eligible patients were antiretroviral naive before HAART, did not experience treatment failure during HAART, maintained viral load <50 for at least 6 months, and were NNRTI naive. Treatment is stopped for two weeks and resumed for eight weeks, in four cycles. At week 40, treatment is suspended unless viral load rebounds to over 5,000. Endpoints include the amplitude of rebounds, and the number of patients with viral load <5,000 and CD4>400 without ART after week forth. 57 of a projected 120 patients enrolled between April-September 1999. Pre-HAART median CD4 count was 398, viral load 4.56 logs. Median pre-SITT HAART duration was 22 months; median CD4 count on starting SITT was 700. By the reporting deadline, 16 patients had two STIs and 4 had three STIs. Viral rebound in the first STI occurred in 28/43 (65%) and during the second STI in 12/16 (75%, p=NS). The two rebounds were similar in amplitude (p=0.2).

Two-Week Viral Rebounds in 4 SITT Patients over 3 STIs


1st STI

2nd STI

3rd STI














< 10

< 10

< 10


After 7 weeks retreatment, 3/20 evaluable and compliant patients did not achieve viral load <50 (RNA = 62, 105 and 147). One had a fever and sore throat at the end of the first STI; viral load here was 925,000. “Very early results in the few patients with 3 treatment stops are modestly encouraging.” (Fagard et al., abstract 458)

16. Four of 9 (44%) CHI, previously suppressed patients anti-HIV CD4 and CD8 responses in parallel with control of viral rebound after 3 STIs. 

In a late-breaker presentation, Garcia and colleagues from Barcelona reported on 10 chronically infected patients given three consecutive STI cycles after 52 weeks of d4T, 3TC and ritonavir or indinavir whose viral load had been <20 copies for >32 weeks and whose CD4 count was over 500. They were given three four-week STIs; after the first two, HAART was resumed for 12 weeks and stopped again if viral load went back below 20 copies; after the third cycle, they were kept off HAART until the viral load reached a new setpoint. Baseline plasma viral load was <20 copies in all cases and <5 copies in 7/10 cases (1st STI) and in 7/9 cases (2nd and 3rd STI). Viral rebound occurred in all cases with a mean doubling time of 2.23, 3.38 and 3.25 days over the three STIs. At the second STI, in 4/9 patients (44.4%) viral rebounded to levels similar to baseline and then dropped spontaneously by 0.8, 0.8, 1.3 and 2.09 logs respectively. “These 4 patients developed strong and broad CTL responses and a strong CD4+ lymphocyte proliferative response to HIV-1 antigens.” After the third STI, the viral load setpoint appeared significantly lower than baseline in four of seven patients. Drug resistance mutations were not detected after any of the STIs.
Recovery of HIV- specific immune responses (CD4 proliferative and CD8 cytotoxic) correlated with spontaneous control of viremia. HIV-Specific Immune Responses – Barcelona STI Study

Before During Before During Before During
N 10 10 9 9 7 7
CD4 0 0 0 4 0 5
CTL ND ND 0 5 0 5


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.” Drug resistance did not emerge during the STIs, but CD4 counts dropped, and took at least six months from rechallenge to recover. (Garcia et al., abstract LB11)

C. Chronic HIV Infection (CHI), Viral Load Unsuppressed 

17. Two of four salvage STI patients experienced increases in CSF HIV RNA and white count. 

Price and colleagues from San Francisco reported on four patients, three of whom took a twelve week STI after treatment failure and had their cerebrospinal fluid (CSF) sampled via lumbar puncture (LP) at baseline, weeks 3, 6 and 12 weeks; the fourth was observed in a study of CSF response to new or changed ART. HIV RNA was measured in peripheral blood (PB) and CSF.

In two subjects PB RNA rose by less than ½ a log during the STI and the CSF RNA was maintained in a nearly fixed proportion. In the other two patients, however, whose PB RNA rose by ½ – 1 log, their CSF RNA rose by 2-3 logs, as did the WBC. The two “showed a disproportionate increase in local [CSF] infection and related host cell response”; however, there were no overt neurological symptoms. (Price et al., abstract 306).

18. STIs in virologic failures after partial suppression on PIs result in reversion of PI- resistance to PI-sensitivity, CD4 drops and RNA rebounds, and return of a fitter viral phenotype.

In perhaps the most impressive, detailed, and well-controlled STI study presented at the 7th Retrovirus Conference, Steven Deeks and colleagues from U.C. San Francisco addressed a number of high-priority research issues in a single study. They were seeking to:

  • Examine the virologic, immunologic and clinical impact of STIs compared with continuingpartially-suppressive PI-containing therapy in a heavily-pretreated population with detectable viral load and few treatment options;
  • Confirm or refute Veronica Miller’s provocative data regarding the reversion to wild-type virus seen in 67% (26/39) partially suppressed, highly-drug experienced patients in the Frankfurt Clinic Cohort;
  • Measure the kinetics of viral reversion to wild-type, if observed;
  • Relate viral reversion to viral rebound and CD4 declines;
  • Relate viral reversion in vivo to replicative capacity (hopefully a good surrogate for ‘fitness’) in vitro (though it is unclear whether replicative capacity = virulence)
  • Measure CD4 cell turnover by the deuterated glucose method

Deeks and colleagues randomized patients to undergo an STI or stay on partially suppressive PI- containing HAART. Eligible patients had virologic failure for at least 12 months, a viral load >2,500, had been on a stable regimen for at least ten weeks, and were willing to discontinue therapy. Eighteen patients were randomized to a twelve-week STI. Phenotypic resistance (Virologic assay), HIV RNA, and CD4 counts were measured weekly for 12 weeks, then every 4 weeks. Replicative fitness was measured (see abstract 233). Among the 18 STI patients, the baseline CD4 count was 254; the baseline RNA 4.6 log; the median prior PI therapy duration 36 months (of which virologic failure had been evident for 31 months), the median decrease in PI susceptibility 56-fold. After the three-month STI, the median CD4 decrease was 94 cells (range -28 to -128) and the median viral load increase was 0.82 log (range 0.34-0.92). (Patients were encouraged to resume therapy if the CD4 count dropped by half or the viral load rose over one log.) Virus reverted to PI-susceptible in 16/17 patients [higher than the 67% rate in the Frankfurt cohort]. The mean time to reversion was 8.5 weeks, however, it ranged widely from 2-15 weeks.

Importantly, in most patients, phenotypic resistance to most or all drugs dropped precipitously and simultaneously. In other words, a true wild-type virus re-emerged all at once, rather than sequentially. Moreover, this wild-type reversion was highly correlated with a steep viral RNA rebound and CD4 drop which contrasted with milder changes observed in the first weeks of the STI. Greater PI resistance and higher viral load over baseline values were associated with delayed reversion (p=0.04, 0.003). Nucleoside resistance persisted, though at lower levels, after reversion to a PI-susceptible virus in 7/17 patients. “Replicative fitness (relative to wild-type virus) increased from a median 22.3% to 67.1% (p=0.004). Resistant virus identical to baseline was cultured from PBMCs 12 to 36 weeks after therapy discontinuation in 4 of 8 patients showing phenotypic reversion” in plasma virus.” Thus, drug- resistant virus remained archived in proviral DNA in half the cases measured. It’s possible that resistant virus could occur in non-sampled cells; more importantly, virologic results of rechallenge remain to be determined. “Discontinuing therapy was associated with either decreased T cell half- life or decreased CD4 production.” These T cell turnover data were not shown in the late-breaker due to time constraints. The abstract concluded that “These data suggest that antiretroviral therapy [at least with a PI] is associated with continued immunologic and virologic benefit, despite high level resistance. This benefit may reflect, in part, the maintenance of a less fit virus” [abstract].” “Interrupting therapy is often associated with biphasic increases in VL and decreases in CD4 cells, reversion to wild-type virus (often abrupt but with variable time course), [and] increased replication capacity” [presentation]. (Deeks et al., abstract and presentation LB10)

Comment:If more STI studies were as well-controlled, prospective, and data-intensive as this one, progress in STI research would accelerate.

D. References

Altfeld M, Rosenberg ES, Eldridge RL, Poon S, Mukherjee JS, Phillips M, Goulder PJ, Walker BD. Increase in breadth and frequency of CTL responses after structured therapy interruptions in individuals treated with HAART during acute HIV-1infection. Abstract 357, Seventh Conference on Retroviruses & Opportunistic Infections (CROI), San Francisco, 2000.

Carcelain G, Tubiana R, Mollet L, Samri A, Calvez V, Delaugerre C, Jouy N, Debre P, Katlama C, Autran B. Intermittent interruptions of antiretroviral therapy in chronically HIV-infected patients do not induce immune control of HIV. Abstract 356, 7th CROI, 2000.

Chun, T-W, Davey R, Ostrowski M, Engel D, Mullins J, Lane C, Fauci A. Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia following discontinuation of highly active antiretroviral therapy. Abstract 239, 7th CROI, 2000.

Davey RT, Bhat N, Yoder C, et al. The NoHRT trial: a prospective study of cessation of HAART in HIV- infected patients after prolonged viral suppression. Abstract I-269, 39th ICAAC, San Francisco, 1999.

Deeks SG, Wrin T, Hoh R, Troiano J, Liegler T, Hayden M, Petropolous C, Hellmann N, Barbour J, Grant RM, McCune JM, Hellerstein M. Virologic and immunologic evaluation of structured treatment interruptions (STI) in patients experiencing long-term virologic failure. Abstract LB10, 7th CROI, 2000.

Fagard C, Lebraz M, Tortajada C, Garcia F, Bernasconi E, Battegay M, Gunthard H, Furrer HJ, Vernazza P, Oxenius A, Phillips R, Yerly S, Gatell J, Perneger T, Erb P, Perrin L, Hirschel B. SITT: a prospective trial of strategic treatment interruptions. Abstract 458, 7th CROI, 2000.

Garcia F, Plana M, Ortiz GM, Soriano A, Vidal C, Cruceta A, Arnedo M, Pantaleo G, Pumarola T, Nixon DF, Miro JM, Gatell JM. 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 CROI, 2000.

Hatano H, Vogel S, Metcalf J, Yoder C, Dewar R, Davey R, Polis M. Plasma viral loads approximate pre- HAART levels after discontinuation of HAART. Abstract 349, 7th CROI, 2000.

Jin X, Ramanathan M, Barsoum S, Bauer D, Chen D, Hurley A, Ramratnam B, Murray J, El Habib R, Zhang L, Perelson A, Ho DD, Markowitz M. Discontinuation of HAART after a course of therapeutic vaccination with ALVAC1452 and rgp160 may be associated with delayed viral rebound kinetics. Abstract LB12, 7th CROI, 2000.

Kotler DP. Coming of age: metabolic complications of antiretroviral therapy., February 2000.

Kilby JM, Saag MS, Goepfert PA, RD Hockett RD, Saha BK, Bucy RP. Significant delay in plasma vRNA rebound during a scheduled treatment interruption in HIV-1 chronically infected patients previously on effective therapy. Abstract 359, 7th CROI, 2000.

Lori F, Foli A, Maseratt R, Seminari E, Minoli L, Alberici F, Lisziewicz J. Control of viremia after treatment interruption. Abstract 352, 7th CROI, 2000. Orenstein JM, Bhat N, Yoder C, Fox C, Polis M, Metcalf J, Kovacs J, Falloon J, Walker R, Masur H, Lane HC, Davey R. Rapid activation of lymph nodes upon interrupting HAART in HIV-infected patients after prolonged viral suppression. Abstract 358, 7th CROI, 2000.

Papasavvas E, Ortiz GM, Gross R, Sun J, Moore EC, Heymann JJ, Moonis M, Gallagher B, Shull J, Nixon DF, Kostman JR, Montaner LJ. Boosting of HIV-1-specific cellular immune responses in chronically infected persons after treatment interruption. Abstract 353, 7th CROI, 2000.

Powderly W. The clinical impact of metabolic dysfunction and the future of antiretroviral therapy. Symposium S24, 7th CROI, 2000.

Price RW, Hoh R, Drews B, Deeks S, Grant R. Changes in cerebrospinal fluid (CSF) after interruption of antiretroviral therapy (ART): accelerated rise in CSF HIV-1 RNA and accompanying CSF pleocytosis. Abstract 306, 7th CROI, 2000.

Ruiz L, Martinez-Picado J, Romeu J, Negredo E, Tuldra A, Tural C, Clotet B. Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. Abstract 354, 7th CROI, 2000.

Sherer R, Dutta B, Anderson R, Laudette-Aboulhab J, Kamarulzaman A, D’Amico R, Paton N, Abdullah MS, Pollard R, Cooley T, Flavin M, Xu Z-Q. No detectable HIV RNA in thirteen individuals months after stopping antiretroviral therapy. Abstract 351, 7th CROI, 2000.

Smith KA, Jacobson EL, Sohn T, Warren D, Emert R, Giordano M, Juitenberg J, Waters CA. Cessation of HAART plus daily low-dose interleukin 2 to promote immunity to HIV. Abstract 355, 7th CROI, 2000.

Stellbrink HJ, Van Lunzen J, Westby M, O’Sullivan E, Cammack N, Adam A, Weitner L, Kuhlmann B, Hoffmann C, Horst H, Fenske S, Schmidt-Hartnack G, Aries SP, Dalhoff K, Schneider C, Degen O, Hufert FT, Tenner-Racz K, Racz P. Influence of interleukin-2 (IL-2) on productive and latent HIV infection and viral rebound. Abstract 240, 7th CROI, 2000.

Zala C, Salomon H, Gun A, Raboud J, Pampuro S, Perez H, Cahn P, Montaner JSG. Viral load rebound upon discontinuation of d4T + ddI + NVP with or without hydroxyurea (HU) during primary HIV infection (PHI). Abstract 558, 7th CROI, 2000.


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