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Library Volume 1, Issue 2: Resistance Reporter©Journal Review

 

Our expert staff, along with Resistance Reporter©'s highly-respected editorial board, sorted through numerous recent journals for articles related to HIV resistance and hand-picked 5 scientifically-important presentations to cover in this issue. These selections have been grouped into two sections that provide clinically-relevant information related to a certain topic. The selections and summaries we have provided are of truly noteworthy research; hot links to the abstracts and suggestions for related reading makes broadening your existing knowledge on a complex topic logical and easy.

  • Section 1: Select articles related to factors that support changing or maintaining treatment in patients with incomplete vial suppression-"hold 'em or fold 'em" data

  • Section 2: Select articles related to the process of determining which patients will benefit from new treatments

Section 1 (Section 2 Also Available)

Select articles related to factors that support changing or maintaining treatment in patients with incomplete vial suppression-"hold 'em or fold 'em" data


Interruption of Enfuvirtide in HIV-1 Infected Adults with Incomplete Viral Suppression on an Enfuvirtide-Based Regimen

J Infect Dis 2007;195(3):387-391, Deeks SG et al.

Patients who take enfuvirtide (ENF) are often heavily treatment experienced and have few, if any, other fully active agents for use in their antiretroviral regimen-a situation that often results in incomplete virologic suppression. Previous studies have shown that some antiretroviral viral agents such as 3TC continue to exert anti-HIV activity despite the presence of mutations that render resistance to the drug. To explore whether ENF continues to exert anti-HIV activity despite the presence of ENF resistance mutations, 25 individuals who had incomplete virologic suppression for the preceding 4 weeks stopped the ENF component of their regimen but continued to take all other agents. Genotypic analysis of multiple clones was performed on samples from the first 11 subjects studied. At baseline, 8 individuals had enfuvirtide resistance mutations present in all clones, whereas 3 individuals showed a mixture of mutant and wild-type clones. Prospective follow-up revealed that ENF discontinuation produced a small but immediate and significant increase in viral load (median HIV-1 RNA increase of 0.22 log10 copies/mL at Week 2, P=.046; 0.11 log10 copies/mL at Week 4, P=.006). This increase occurred immediately after interruption of the drug and before any measurable change in genotypic or phenotypic resistance, which suggests that the drug had some residual activity, at least in some individuals. Most patients demonstrated a loss of genotypic and phenotypic drug resistance by 8-16 weeks in the absence of ENF. The new virus populations that emerged were more efficient at infecting target CD4 T cells than the preceding ENF-resistant populations.


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Evolution of Drug Resistance in HIV-Infected Patients Remaining on a Virologically Failing Combination Antiretroviral Therapy Regimen

AIDS. 2007;21(6):721-732, Cozzi-Lepri A et al.

This retrospective study assessed the resistance profiles over time of 110 patients from the EuroSIDA cohort who remained on antiretroviral therapy despite incomplete virologic suppression. Between the time when the first genotypic test was performed and the second test was performed, a median of 6 months later, patients developed an average of 1.96 new mutations, defined in accord with the International AIDS Society mutation list. These genotypic changes resulted in an average loss of 1.25 active drugs over those 6 months. Patients who initially had low-level resistance to their failing regimen tended to accumulate the greatest number of new mutations. Despite the development of new resistance mutations, viral loads and CD4+ cell counts generally remained stable in all patients, demonstrating that the regimens were still partially active. The authors concluded that these and other study results bolster the current view that patients with relatively less resistant virus have the most to lose by staying on failing regimens, and that such patients should have their treatment modified to include at least 2 new active agents, if possible, to prevent the development of additional resistance. However, those with highly resistant viruses have few remaining mutations to acquire, and generally do well over the medium term (e.g., 6-12 months) As a sound switch is not viable among these patients, their management remains a challenge and strategies for maintaining a failing regimen (such as recycling drugs to which the patients' virus is resistant or targeting only the RT gene) need to be properly evaluated in randomized studies.


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RELATED ARTICLES:

o    Morse C, Maldarelli F. Enfuvirtide antiviral activity despite rebound viremia and resistance mutations: fitness tampering or a case of persistent braking on entering? J Infect Dis. 2007;195(3):318-321.

o    Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296(7):827-843.

o    Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis. 2005;192(9):1537-1544.

o    Napravnik S, Keys JR, Quinlivan EG, Wohl DA, Mikeal OV, Eron JJ Jr. Triple-class antiretroviral drug resistance: risk and predictors among HIV-1-infected patients. AIDS. 2007;21(7):825-834.

o    Goetz MB, Ferguson MR, Han X, et al. Evolution of HIV resistance mutations in patients maintained on a stable treatment regimen after virologic failure. J Acquir Immune Defic Syndr. 2006;43(5):541-549.



 

Section 2 (Section 1 Also Available)

Select articles related to the process of determining which patients will benefit from new treatments


Efficacy and Safety of Darunavir-Ritonavir at Week 48 in Treatment-Experienced Patients with HIV-1 Infection in POWER 1 and 2: a Pooled Subgroup Analysis of Data from Two Randomized Trials

Lancet. 2007;369(9568):1169-1178, Clotet B et al.

Pooled 24-week results from the POWER 1 and 2 trials demonstrated the potency of darunavir/ritonavir (DRV/r) in treatment-experienced patients with at least 1 primary protease inhibitor (PI) mutation. The current analysis was performed on the subgroup of POWER 1 and 2 patients who were assigned to receive DRV/r 600/100 mg bid-the currently approved DRV/r dose-for a total of 48 weeks to determine whether the results were durable out to 1 year. These 110 individuals were compared with 120 control patients who received a comparator PI (CPI); all patients received optimized background therapy (OBT). Most control patients discontinued therapy, primarily due to virologic failure, before 48 weeks (81%), whereas 79% of patients receiving DRV/r remained on treatment for the entire study period. The primary endpoint of at least a 1 log10 copies/mL reduction in viral load from baseline was reached by 61% of DRV/r-treated patients compared with 15% of CPI-treated patients (P<.0001). Moreover, 45% of patients receiving DRV/r attained a viral load below 50 copies/mL versus only 10% of patients receiving a CPI (P<.0001). CD4+ cell count increases paralleled virologic responses for the 2 groups (increases of 102 vs 19 cells/mm3, respectively; P<.0001). Patients who received a greater number of active agents in their OBT and who had fewer DRV resistance mutations at baseline attained better treatment responses. Fewer adverse events were reported in patients receiving DRV/r versus a CPI after adjustment for treatment exposure, and favorable safety and tolerability profiles were noted for DRV/r-treated patients.


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HIV Type 1 Chemokine Coreceptor Use Among Antiretroviral-Experienced Patients Screened for a Clinical Trial of a CCR5 Inhibitor: AIDS Clinical Trial Group A5211.

Clin Infect Dis. 2007;44(4):591-595, Wilkin TJ et al.

Several CCR5 inhibitors are currently being investigated in clinical trials. One of these, maraviroc, the CCR5 closest to FDA approval and available in expanded access, has shown activity in treatment-experienced patients. Unfortunately, these agents are not active against CXCR4-tropic virus or dual/mixed-tropic virus, which are common HIV-1 species in treatment-experienced patients. Wilkin reported on the demographic and clinical characteristics associated with chemokine coreceptor use among treatment-experienced patients who were screened for eligibility for a CCR5 inhibitor study. 50% of 391 total patients with coreceptor results were excluded from the study due to infection with dual/mixed-tropic virus (n=178) or X4-tropic virus (n=16). An additional 12 of 118 patients (10%) originally classified as having R5-tropic virus who entered into the study were subsequently found to harbor dual/mixed-tropic virus approximately 1 month after the screening evaluation but before CCR5 inhibitor initiation, which likely represents variability of the assay in testing samples with low-level dual-tropic or X4-using variants, rather than a true change in coreceptor use. Patients with dual/mixed-tropic virus had a significantly lower median CD4+ cell count than those with R5-tropic virus (103 vs 170 cells/mm3; P<.001), but dual/mixed-tropic virus was commonly observed in patients across all CD4+ cell count strata. The study researchers of AIDS Clinical Trial Group A5211 observed a high prevalence of D/M viral populations in a highly treatment-experienced population screened for a clinical trial of a CCR5 inhibitor. In this group, lower CD4+ cell counts were associated with a higher prevalence of D/M virus, although D/M virus was common among patients at all CD4+ cell count strata. These results suggest the importance of assessing coreceptor phenotype before use of CCR5 inhibitors.


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Safety and Efficacy of the HIV-1 Integrase Inhibitor Raltegravir (MK-0518) in Treatment-Experienced Patients with Multidrug-Resistant Virus: a Phase II Randomized Controlled Trial

Lancet. 2007;369(9569):1261-1269, Grinsztejn B et al.

Raltegravir (RAL), formerly known as MK-0518, blocks the integration of HIV into the DNA of host cells and hence belongs to a novel antiretroviral drug class. In this blinded, dose-ranging, phase II study, 179 triple-class experienced patients were randomized 1:1:1:1 to RAL 200, 400, or 600 mg bid or to placebo. All participants had documented genotypic/phenotypic resistance to at least 1 drug in each standard antiretroviral class, a viral load of more than 5000 copies/mL, and a CD4+ cell count greater than 50 cells/mm3. Background therapy was optimized for patients based on resistance test results. An intent-to-treat analysis performed after 24 weeks of treatment found that the mean reduction in viral load from baseline was 1.80-1.87 log10 copies/mL for patients receiving RAL plus OBT compared with a reduction of 0.35 log10 copies/mL for those receiving placebo plus OBT (all Ps<.0001). Undetectable viral loads (< 50 copies/mL) were attained by 56%-67% of patients assigned to RAL versus 13% of those assigned to placebo (all Ps <.0001). Increases in CD4+ cell count were also significantly greater for RAL-treated patients versus placebo-treated patients (63-113 vs 5 cells/mm3; all Ps<.0001). No significant differences in safety or tolerability were found between the RAL and placebo groups.


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RELATED ARTICLES:

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