Studies and strategies with existing drugs

David Margolis,

Monotherapy or no therapy at all: is this the new direction of HIV therapy?

As the pendulum governing prescription of antiretroviral therapy swings farther away from “hit hard and hit early” towards “the treatment is worse than the disease”, clinicians around the world are testing ways to minimise exposure to antivirals. Trials examining drug interruption or cycled therapy, as well as using fewer drugs, were presented. Clinicians should consider these concepts carefully, without forgetting the evolving benefits of potent, simpler, and less toxic drugs, or the difficulty of achieving full functional immune reconstitution once severe immunodeficiency has been allowed to develop, and recent evidence that minor populations of resistant HIV can expand when therapy is interrupted.

BASTA: when enough is enough

Maggiolo reported the interim findings of a treatment interruption study called “BASTA”. [1]

Patients durably suppressed to HIV-RNA <50 copies/mL with stable CD4 >800 cells/mm3 were randomised (2:1) to either interrupt or to continue their ongoing treatment. Therapy was to be restarted if CD4 count <400 cells/mm3. Of 114 patients enrolled, 76 stopped therapy while 38 continued it.

At roughly 20 months, about 25% of patients assigned continuous therapy had stopped therapy, presumably due to fatigue or toxicity. Multivariate analysis found that only the CD4 nadir value predicted CD4 cell decline (P< 0.001). For those whose lowest CD4 count was <200 cells/mm3, the median time to restarting therapy was 6.9 months. For those with a T-cell nadir of 200-350 cells/mm3 therapy was restarted in a median of 14.1 months, and 17.8 months for those with a nadir of 350-500 cells/mm3. No patient with a CD4 count nadir of >500 had to restart treatment.

This adds to the findings of previous clinic cohort observational studies that suggest that if one does not need HAART when HAART was started, it is safe to stop. Additional biomarkers that could aid in the identification of patients at low or high risk of progression off therapy are needed.

A second Italian group took a similar approach in an observational, retrospective, multicentre study of a group of 140 patients whose CD4 count pre-interruption was >500 cells/mm3, HAART for >12 months (median of 3.5 years), and a CD4 nadir >250 cells/mm3. [2]

Criteria for restarting treatment were: a confirmed CD4 count <350 cells/mm3 and the patient willingness. At treatment discontinuation, median CD4 count was: 804 cells/µL, median VL was 1.70 log 10 copies/mL.

At the time of the presentation 75 of 137 (56%) were still off therapy. Some 24.3% had experienced a CD4 decline to below 350 cells/mm3, and 22.1% restarted treatment before CD4 dropped below 350 cells/mm3. The median time to restarting HAART for any reason was 104 weeks (95% CI: 79-169). Median time was only 52 weeks, however, if CD4 at nadir was >350 cells/mm3. Independent predictors of therapy resumption were: CD4 nadir; months with undetectable viral load; slope of CD4 pre-ART and most recent VL vs the level at interruption.

A cost of interruption

But lunch is not free. Barreiro and colleagues presented findings for a cohort that had de-intensified therapy in which therapy was later re-intensified. [3]

One hundred and eighty-seven HIV+ patients on HAART (69 on PIs and 116 on NNRTIs), with CD4 counts >350 cells/mm3 and HIV-RNA <50 copies/mL substituted ddI 400 mg qd plus hydroxyurea 500 mg bid for their NRTI+NNRTI or NRTI+PI regimen. HAART therapy was restarted for viral rebound >10,000 copies/mL.

Overall, 21% of patients who moved to ddI-HU showed viral rebounds >10,000 copies/mL (19 on PIs and 20 on NNRTIs).

All patients who then resumed a PI-based regimen suppressed viraemia to <50 copies/mL. However, 55% (16 of 29) who restarted an NNRTI failed to attain HIV-RNA <50 copies/mL (p<0.001). Genotypic analysis could not be performed in all failures, but NNRTI resistance did not predominate. However, this observation does add to the concern that if NNRTIs are discontinued in a suboptimal setting, their therapeutic potency may be lost. It is still unclear if strategies such as stopping NNRTIs one to two days before the rest of the regimen is stopped will avoid the induction of NNRTI resistance.

Back to monotherapy?

Gathe in Houston, with collaborators in Dallas, challenged the field by testing the safety and efficacy of Kaletra (LPV/r) alone in treatment-naive patients. [4]

Gathe pointed out that monotherapy, if it could be shown to be effective, could avoid many of the high costs and synergistic toxicities of combination antiretroviral therapy. It should be noted that if multiple nucleosides can effectively control HIV replication in some patients, PI monotherapy with a sufficiently high barrier to resistance might control HIV as well.

Consenting patients enroled in this open-label, unsponsored trial. There were no CD4 or VL criteria for entry, and 28 males and two females (White 60%, Hispanic 20%, Black 20%) who entered had a mean CD4 count of 169.5 cells/mm3 and viral load of 262,020 copies/mL. Lopinavir/ritonavir was dosed in a weight-based fashion, three capsules BID or four capsules BID if >70kgs. Patients intensified therapy at week 12 with saquinavir or tenofovir/3TC if desired.

At 24 weeks (or last observation) only one subject had not achieved <400 copies/mL HIV RNA. This subject had baseline VL 500,000 and had declined to a nadir of 1,510, but rebounded to 4,270 at week 32 when saquinavir was added. At that time genotype showed only L63P, phenotype was wild type, and an adequate LPV trough was measured.

However, two subjects were lost to follow-up, one was deported, two stopped therapy due to GI intolerance, one was nonadherent, and one had TDF/3TC added when active HBV was discovered. So by ITT, nine of 30 failures determined by viral load >400 copies/mL were seen by week 24 (70%). Twenty-one of 22 patients on treatment at 24 weeks had achieved <400 copies/mL (95%). No other significant AE’s were reported and no triglyceride elevations >Grade 2 were observed.

CrixiLop: two boosted protease inhibitors alone (Indinavir + Kaletra)

Of potential relevance to the concept of PI monotherapy, the CrixiLop Cohort Study challenged the therapeutic potency of boosted PIs alone in a salvage setting. [5]

Staszewski and colleagues studied 23 heavily pre-treated HIV-positive patients in the Frankfurt HIV Cohort who were experiencing treatment failure with NRTI resistance or intolerance. Salvage therapy consisted of indinavir (800 mg bid) plus LPV/r (400/100mg bid) without additional RTIs or any other ART. All but one subject were male, with median age 40 years, prior exposure to 10.5 drugs and 3.5 PIs, viral load 5.2 log copies/mL, CD4 count 116 cells/mm3.

At a median follow up of 28 weeks, 17 (61%) patients remained on IDV/LPVr. eight discontinued due to IDV intolerance and three due to virologic failure. Viral load had declined 2.4 logs (range 1.30-5.6) and 1.9 logs (range 1.5-5.2) at weeks 12 and 24 respectively. The remaining six patients had no persistent response. Median CD4 count rose 70 cells/mm3 at week 24. IDV dose was decreased in six patients, and LPV/r doses in three due to intolerance.

Clearly many questions about the baseline PI sensitivity of these patients and the durability of this response need to be answered, but the initial virologic response in patients exposed to multiple PIs is impressive.

Vive la resistance

Weird viruses: NNRTI resistance is not always predicted genotype

Petropoulos reported the rare discovery of viral isolates with high-level resistance to HIV-1 NNRTIs when assayed by Virologics phenotype despite the absence of known NNRTI resistance mutations. [6]

In a dataset of 18,034 samples, 48 isolates were identified that exhibited >10-fold resistance to at least one NNRTI in the absence of well-characterised NNRTI mutations (98G, 101E, 103N/S, 106A/M, 225H, 230L, 236L, or any mutation at position 100 181, 188, 190 or 227). Of these 10 encoded K101P and 13 the combination of K103R and V179D.

The remainder of isolates contained other changes that have not yet been associated with NNRTI resistance. While this phenomenon is rare, it is useful to remember how much we have still to learn about the resistance of HIV to our drugs, and an illustration of the use of the phenotype assay to identify resistance not reported in a genotype assay.

The reverse could also rarely occur, as it is conceivable that rare isolates with clinical resistance may not demonstrate significant fold resistance in phenotype assays.

Is there a clinical consequence to the “pathway” of resistance?

Under the selective pressure of a given drug combination, a specific pattern of resistance mutations tends to emerge if therapy fails. It is not yet known if a given pattern or “pathway” predicts a durable or transient response to second-line therapy. Such knowledge might guide decisions about initial and subsequent therapy.

Van Houtte and colleagues examined prevalence and phenotypic resistance of RT mutation combinations found in over 31,400 clinical viral isolates from routine testing at Virco between January 2001 and February 2003. [7]

Two “pathways” to resistance against NRTIs with mutations 41L, 210W, and 215Y/F or 67N, 70R, and 219Q/E/N/R in HIV-1 reverse transcriptase have been suggested. The prevalence and phenotypic resistance of these combinations (termed NAMs or nucleoside analogue mutations) and the “non-pathway” 44D/E, 118I and 184V/I mutations in clinical isolates were examined. Resistance profiles came from Virco’s matched genotype/phenotype dataset.

Thirty-eight per cent of isolates have >1 NAMs (mean 2.7). Nearly half of these were phenotypically resistant to AZT (>4-fold). Median fold change in sensitivity to AZT in isolates with >3 NAMs ranges from three to 37 when the 3TC resistance mutation M184I/V was present, and from six to 52 when it was absent. The 41-210-215 “pathway” predominates in this data set (34% of the isolates) versus 67-70-219 (15%) with some overlap. Two-, three-, and four-NAM sets in the 41-210-215 pathway were on average more resistant to all NRTIs than those in the 67-70-219 pathway. Whether this predicts a poorer response to second-line therapy remains to be seen.


  1. Maggiolo F, Ripamonti D, Gregis G et al. Individualised structured treatment interruptions: results of a randomised, controlled study (BASTA). 43rd ICAAC, September, 2003; Abstract H-448
  2. Mussini C, Cozzi-Lepri A, Borghi V et al. CD4-guided treatment interruptions: a new therapeutic strategy. 43rd ICAAC, September, 2003; Abstract H-856.
  3. Barreiro PM, de Mendoza C, Nez M et al. Negative impact of drug holidays in HIV-infected patients on non-nucleoside reverse transcriptase inhibitors. 43rd ICAAC, September, 2003; Abstract H-857
  4. Gathe JC , Washington M, Piot D et al. Preliminary pilot data on the safety and efficacy of Kaletra (LPV/r) dosed alone for the treatment of HIV in ARV-naïve patients: greater than or equal 24 data. 43rd ICAAC, September, 2003; Abstract H-845.
  5. Staszewski S, Dauer B, Gute P et al. The CrixiLop Cohort Study: preliminary results from a salvage study of HIV-positive patients treated with indinavir (IDV) and lopinavir/ritonavir (LPV/r) without the addition of reverse transcriptase inhibitors (RTI). 43rd ICAAC, September, 2003; Abstract H-853.
  6. Petropoulos CJ, Chappey C, Parkin NT et al. High-Level resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the absence of known resistance mutations. 43rd ICAAC, September, 2003; Abstract H-451.
  7. Van Houtte M, Lecocq P, Mckenna P et al. Phenotypic resistance and prevalence of specific nucleoside analog mutation combinations (NAMs) in reverse transcriptase in a dataset of recent HIV-1 clinical isolates. 43rd ICAAC, September, 2003; Abstract H-907


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