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HIV Meds Quarterly, 2011 Spring Issue

for Health Care Providers

HIV Meds Quarterly, 2011 Spring, Entire Issue

Darunavir + Raltegravir without NRTIs

A number of studies in recent years have evaluated ARV combinations that avoid NRTIs. Most of these have consisted of a boosted PI with either an NNRTI or an integrase inhibitor (dual therapy), or a boosted PI alone (monotherapy). These combinations have shown variable results but generally have not been as effective as standard initial regimens. Nevertheless, it was reasonable to expect that the combination of ritonavir-boosted darunavir plus raltegravir, two very potent and well tolerated ARVs, would be highly effective. At the 18th Conference on Retroviruses and Opportunistic Infections in Boston, however, researchers presented surprising and disappointing efficacy data from a small noncomparative AIDS Clinical Trials Group (ACTG) evaluation of this regimen.(1)

At baseline, the 112 treatment-naive subjects had a median HIV RNA level of 4.9 log10 copies/mL (44% >100,000 copies/mL) and median CD4 count of 271 cells/µL, and they had no darunavir or raltegravir resistance-associated mutations. They took darunavir/ritonavir (800/100 mg once daily) plus raltegravir (400 mg twice daily), with high reported levels of adherence and few significant adverse effects. At week 24 and week 48, only 79% and 71%, respectively, had HIV RNA levels of <50 copies/mL. By week 48, a total of 28 subjects had confirmed virologic failure (11 did not achieve virologic suppression, 17 had virologic rebound after initial suppression). Integrase resistance was found in 5 of 25 subjects in whom resistance testing was done, with mutations at position N155 in all 5 subjects, and at Q148 in 2 subjects. No darunavir-associated mutations were detected. Virologic failure was associated with higher baseline HIV RNA (odds ratio for RNA >100,000 copies/mL: 3.76) and with lower CD4 counts. Additionally, all those with emergent integrase resistance had HIV RNA of >100,000 copies/mL at baseline.

Clinical Bottom Line
The virologic failure rate of darunavir/ritonavir + raltegravir in this study was substantial, and significantly higher than that reported in studies of either agent combined with NRTIs.(2,3,4) This finding was not explained by poor adherence, adverse effects, or previously described drug interactions. Pharmacokinetic data, which were collected but not presented at the conference, may yet help to elucidate this issue. It is not clear why this combination of ARVs performed so poorly, but clearly it should not be used as a stand-alone regimen, particularly for patients with high baseline viral loads. Meanwhile, NRTI-sparing strategies should continue to be approached with caution, pending the emergence of study results that demonstrate efficacy of specific combinations.

References

  1. Taiwo B, Zheng S, Gallien S, et al; ACTG A5262 Team. Results from a single-arm study of DRV/r + RAL in treatment-naive HIV-1-infected patients (ACTG A5262). In: Programs and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 551.
  2. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008 Jul 31;22(12):1389-97.
  3. Lennox JL, DeJesus E, Lazzarin A, et al; STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009 Sep 5;374(9692):796-806.
  4. Eron J, Rockstroh J, Reynes J, et al; QDMRK Study Team. QDMRK, a Phase III study of the safety and efficacy of once daily vs twice daily RAL in combination therapy for treatment-naive HIV-infected patients. In: Program and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 150LB.

Raltegravir: Inferior Results with Once-Daily Dosing

Data from the randomized double-blind QDMRK study of once-daily vs twice-daily dosing of raltegravir were presented at CROI. The basic findings had been announced at the end of 2010 in a press release from the manufacturer, but this was the first time the study results were made available in full.

In QDMRK, antiretroviral-naive individuals without NRTI resistance were randomized to raltegravir at a dosage of either 800 mg once daily (QD) (n = 386) or 400 mg twice daily (BID) (n = 389), along with tenofovir + emtricitabine (FTC). The groups were well matched at baseline; the geometric mean HIV RNA was about 69,000 copies/mL, with 40% having RNA levels of <100,000 copies/mL; the mean CD4 count was 285 cells/µL. At 48 weeks, HIV RNA was suppressed to <50 copies/mL in 83.2% of the QD group and 88.9% of the BID group; a similar difference between groups was seen at the <400 copies/mL threshold. By the study criteria, the QD raltegravir regimen proved to be inferior to the BID regimen. Based on these results, the study was terminated upon recommendation of the Data Monitoring Committee.

The underperformance of QD raltegravir was seen primarily in subjects with baseline HIV RNA >100,000 copies/mL; in this group, only 74% of the QD raltegravir recipients achieved HIV RNA levels of <50 copies/mL, compared with 84% of the BID recipients. Similarly, in those with low CD4 counts at baseline (≤200 cells/µL), the rate of virologic suppression was lower in the QD group (71% and 81%, respectively). In subjects with baseline HIV RNA levels of <100,000 copies/mL, the QD raltegravir regimen approached, but did not match, the virologic efficacy of BID raltegravir (89.1% vs 91.9%, respectively).

There were no significant differences in adverse events between treatment groups. Pharmacokinetic evaluations showed that raltegravir trough concentrations were substantially lower (5-6 times) in the QD arm compared with the BID arm, suggesting at least a partial explanation for the study findings. Among subjects with confirmed virologic failure for whom resistance testing could be done, virus in 9 of 27 QD subjects had mutations associated with resistance to both raltegravir and FTC, whereas 11 had FTC resistance alone. In the BID arm, a lower proportion had resistance: 2 of 12 subjects had raltegravir + FTC resistance mutations, and 4 had FTC resistance alone.

Clinical Bottom Line
In subjects with baseline HIV RNA levels of >100,000 copies/mL, QD raltegravir + tenofovir/emtricitabine clearly yielded inferior virologic results, and high rates of emergent integrase inhibitor resistance. In subjects with lower viral loads, the difference in virologic failure rates of the two treatment groups was not statistically significant, although the QD group had a slightly lower rate of virologic suppression (a small numeric difference favoring BID raltegravir was seen in each comparison shown [eg, time to loss of virologic response and virologic failure rates in lower as well as in higher HIV RNA strata], a point emphasized by the presenter). It is not known whether there are subsets of patients for whom QD raltegravir may be a viable option (eg, those with low baseline viral loads, and those with stable virologic suppression who request regimen simplification), but QD raltegravir should be considered cautiously, and on an individual basis.

On the other hand, this study showed that recipients of BID raltegravir + tenofovir/emtricitabine had extremely high rates of virologic suppression, including persons with high baseline HIV RNA viral load; this regimen is confirmed as an effective and tolerable option for initial antiretroviral therapy.

References

Joseph J, Rockstroh J, Reynes J, et al; QDMRK Study Team. QDMRK, a Phase III study of the safety and efficacy of once-daily vs twice-daily RAL in combination therapy for treatment-naive HIV-infected patients. In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 150LB.

Hepatitis C Infection and Telaprevir

There is a huge need for improved treatments for hepatitis C, particularly in patients with HIV/HCV coinfection and subgroups thereof (eg, African Americans, those with genotype 1 virus), in whom rates of HCV cure are particularly low with standard therapies. Investigational drugs in new classes, so-called direct antiviral agents (DAAs), given in combination with pegylated interferon and ribavirin, have been shown to improve rates of sustained virologic response (SVR) in HCV-monoinfected patients, and several studies presented at CROI this year provided data on efficacy of new agents (in particular the HCV protease inhibitors telaprevir and boceprevir) in HCV-monoinfected patients.(1,2) And, importantly, the researchers offered a first glimpse of data on efficacy and safety of telaprevir in HIV/HCV-coinfected persons.(3) This was an interim analysis, examining data only through week 12 (of a planned 48-week treatment course) on 41 patients undergoing treatment in a Phase IIA double-blind study of telaprevir vs placebo, each in combination with peginterferon alfa-2a and ribavirin. Patients had genotype 1 HCV, no previous HCV treatment, and were either a) on no ART with CD4 counts of ≥500 cells/µL and HIV RNA levels of <100,000 copies/mL; or, b) on ART with CD4 counts of ≥300 cells/µL and suppressed HIV. Subjects receiving ART were on either atazanavir/ritonavir or efavirenz with tenofovir/emtricitabine (or lamivudine). Patients within each group were randomized to telaprevir or placebo for the first 12 weeks of therapy, and all were treated with peginterferon alfa-2a and ribavirin (for a planned total of 48 weeks). (In the efavirenz group, the telaprevir dosage was increased to compensate for a known interaction with efavirenz.) The treatment groups were generally well matched at baseline for HCV and HIV factors; the median CD4 count was >500 cells/µL.

By intention-to-treat (ITT) analysis, virologic response rates at weeks 4 and 12 were substantially higher in telaprevir recipients than in controls. At week 4, 70% in the telaprevir groups combined and 5% in the placebo groups combined achieved undetectable HCV RNA levels (rapid virologic response, RVR). At week 12, 68% of telaprevir recipients and 14% of controls had undetectable HCV RNA levels (complete early virologic response, EVR). Of the telaprevir groups, response rates were lower in the atazanavir/ritonavir subgroup at each time point than in either the no-ART or the efavirenz subgroup, though the sample size was small, and conclusions about relative efficacy cannot be made.

HCV virologic failure was seen in 3 telaprevir recipients and 3 placebo recipients (no resistance data were available), and no loss of HIV control was seen in ART recipients. In the no-ART group, a decrease in HIV RNA was seen, consistent with the interferon effect seen in other studies. Median trough concentrations of telaprevir were similar in each ART group and the no-ART group, whereas median trough concentrations of atazanavir, efavirenz, and tenofovir decreased up to 20% in the telaprevir groups, a result that reportedly was similar in placebo groups (data not shown). Telaprevir recipients had higher rates of certain adverse events, including nausea, vomiting, anorexia, fever, pruritus, and rash, compared with controls, but few patients discontinued treatment because of adverse events.

Clinical Bottom Line
RVR and EVR are important predictors of successful HCV treatment (SVR), so it is very promising to see that treatment with telaprevir + peginterferon alfa-2a and ribavirin yields impressively high EVR rates in coinfected genotype 1 patients. SVR results from this study should be presented later this year, and Phase III studies of both telaprevir and boceprevir in HIV/HCV-coinfected patients are under way. These agents are expected to be approved by the U.S. Food and Drug Administration in 2011, and studies of other DAA drugs are in clinical trials.

The availability of these new DAA agents is expected to significantly advance the treatment of HCV in both monoinfected and HIV/HCV-coinfected patients, but many complex treatment issues require study, including basic issues such as length of therapy, the timing and duration of DAA therapy, optimizing outcomes in hard-to-treat patient groups, management of HCV resistance to these agents, and drug-drug interactions. Importantly, both telaprevir and boceprevir appear to have significant interactions with PIs and NNRTIs, via CYP P450 effects, and these have not been well studied. An excellent overview of HCV therapy, titled "New Antiviral Therapies in the Management of HCV Infection," was given by Stefan Zeuzem at the CROI conference.

References

  1. Sulkowski M, Poordad F, McCone J, et al. BOC combined with P/R for treatment-naive patients with HCV genotype-1: SPRINT-2 Final Results. In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 115.
  2. Gordon S, Bacon B, Lawitz E, et al. HCV RESPOND-2 final results: High sustained virologic response among genotype-1 previous non-responders and relapsers to pegIFN/RBV when re-treated with BOC + PEGINTRON/RBV. In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 116.
  3. Sulkowski M, Dieterich D, Sherman K, et al. Interim analysis of a phase 2a double-blind study of TVR in combination with pegIFN-alfa2a and RBV in HIV/HCV co-infected patients. In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 146LB.

Rilpivirine Redux

The primary results of the Phase III studies of the NNRTI rilpivirine, presented this summer at the International AIDS Conference, showed that the overall efficacy of rilpivirine and efavirenz (each given with 2 NRTIs) in treatment-naive patients was the same (see "Rilpivirine [TMC278] in Initial TherapyLink will take you outside the VA website. VA is not responsible for the content of the linked site."). However, rates of virologic failure were higher in the rilpivirine arm, whereas rates of adverse events were higher in the efavirenz arm. Additional analysis of the data, presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), helps to characterize the causes and consequences of virologic failure in rilpivirine recipients.

Efficacy data from the week 48 pooled ECHO and THRIVE studies show that rates of virologic failure (HIV RNA level <50 copies/mL) were higher in rilpivirine recipients with baseline HIV RNA >100,000 copies/mL than in those with lower viral loads (77% vs 90%), whereas, in efavirenz recipients, the differences according to baseline HIV RNA were much more modest (81% vs 84%, respectively). Not surprisingly, suboptimal adherence (assessed by pill count) also was associated with virologic failure, but the effect was seen more strongly in the rilpivirine treatment arm. In patients with pretreatment HIV RNA >100,000 copies/mL, the effect of suboptimal adherence was particularly striking in those treated with rilpivirine: virologic failure was seen in 50% of study subjects, compared with 17% of those taking efavirenz. (Note: The numbers of patients in these subanalyses are small; statistical comparisons could not be made.)

Of the patients with virologic failure on rilpivirine, about two thirds had NNRTI resistance and two thirds had NRTI resistance (mostly M184I or M184V), and more than half had resistance involving both classes. Decreased susceptibility to rilpivirine was associated with the following mutations: E138K/G/Q/R, K101E/P, H221Y, and Y181C/I/V.

Clinical Bottom Line
These data help to characterize patients who are at greater risk of treatment failure with rilpivirine--specifically those with high baseline viral loads and those who are not closely adherent to their ARV regimens, with the highest risk involving those who fit both categories. For many patients, however, rilpivirine is likely to offer a reasonable alternative to efavirenz for initial therapy, and one with less risk of adverse effects. If it receives FDA approval, it is expected to be available in a coformulation with tenofovir/emtricitabine, as a 1-pill once-daily regimen

References

Rimsky L, Eron J, Clotet B, et al. Characterization of the resistance profile of TMC278: 48-week analysis of the Phase III studies ECHO and THRIVE. In: Program and abstracts of the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2010; Boston. Abstract H-1810.

Updates to the Database of ARV Drug Interactions

The following table summarizes recent additions to the HIV InSite . For a full description of the updates, including references to the studies from which the data were derived, go to the database, click on a specific drug name, and search for the interacting agent.

New ARV Interactions (September 2010-March 2011)
Drug OneDrug TwoClinical EffectsMechanismsManagement
Source: McNicholl I. HIV InSite Database of Antiretroviral Drug InteractionsLink will take you outside the VA website. VA is not responsible for the content of the linked site.. University of California San Francisco: Center for HIV Information; 2011.
AtazanavirPitavastatinPossibly ↑ pitavastatin effects Start at lowest dosage and titrate to effect
Atazanavir
(atazanavir 300 mg QD with ritonavir 100 mg QD)
Rosuvastatin↑ rosuvastatin effectsDo not coadminister

Alternative agents:
pravastatin, atorvastatin
DarunavirBuprenorphine Inhibition of CYP450 3A4 by darunavir/ritonavirNo dosage adjustment necessary
DarunavirMethadoneMay ↓ methadone effects (eg, withdrawal) Monitor for signs and symptoms of methadone withdrawal; some patients may need ↑ in the methadone dosage
DarunavirNevirapinePossibly ↑ darunavir effects; possibly ↑ nevirapine effects No dosage adjustment necessary
DarunavirRifabutin↑ darunavir and rifabutin effectsInhibition of CYP450 3A4 by darunavir↓ rifabutin dosage to 150 mg QOD when combined with darunavir/ritonavir
DarunavirRosuvastatinNo change in lipid-lowering ability within 35-day study period Avoid coadministration if possible; if used, use caution and start at 5 mg daily
Efavirenz
(400 mg QD)
Proguanil
(300 mg, single dose)
Possibly ↓ antimalarial effectsPossible inhibition of CYP450 2C19 by efavirenz; possible induction of P-gp by efavirenzDosage adjustment not established
Efavirenz
(600 mg QHS)
Proguanil
(100 mg with 250 mg atovaquone, single dose)
↑ atovaquone glucuronidation; induction of CYP450 3A4 by efavirenzDosage adjustment not established
Etravirine
(200 mg BID with darunavir/ritonavir 600/100 mg BID)
Maraviroc↑ maraviroc effectsInhibition of CYP450 3A4 by darunavir/ritonavir↓ maraviroc to 150 mg BID
Etravirine
(200 mg BID)
Maraviroc Induction of CYP450 3A4 by etravirine↑ maraviroc to 600 mg BID when used with etravirine
FosamprenavirParoxetine↓ paroxetine effects Titrate paroxetine to effect
FosamprenavirRosuvastatin No dosage adjustment necessary
IndinavirAtovaquone No dosage adjustment necessary
Lopinavir/ritonavirBupropion↑ bupropion effectsPossible induction of CYP450 2B6 and UGT enzymes
Lopinavir/ritonavirEchinacea No dosage adjustment necessary
Lopinavir/ritonavirKetoconazole↑ ketoconazole effects; ↓ lopinavir/ritonavir effects Manufacturer recommends against using high dosages of ketoconazole (>200 mg daily)

Alternative agents: fluconazole
Lopinavir/ritonavirRosuvastatin↑ rosuvastatin effects Do not coadminister

Alternative agents: pravastatin, atorvastatin
MaravirocRaltegravir No dosage adjustment necessary
RaltegravirAntacids No dosage adjustment necessary
RitonavirColchicine↑ colchicine effectsInhibition of CYP450 3A4 by ritonavirFor treatment of gout, ↓ colchicine dosage to 0.6 mg for a single dose, then 0.3 mg 1 hour later; dose not to be repeated earlier than 3 days; for prophylaxis of gout, ↓ colchicine dosage to 0.3 mg QD if on 0.6 mg BID prior to PI therapy or ↓ colchicine dosage to 0.3 mg QOD if on 0.6 mg QD prior to PI therapy
Ritonavir
(200 mg BID)
Tadalafil↑ tadalafil effects (eg, hypotension, priapism)Inhibition of CYP450 3A4 by ritonavirDo not exceed 10 mg tadalafil every 72 hours
Ritonavir
(500 mg or 600 mg BID)
Tadalafil↑ tadalafil effects (eg, hypotension, priapism)Inhibition of CYP450 3A4 by ritonavirDo not exceed 10 mg tadalafil every 72 hours
ZidovudineAtovaquone ↑ zidovudine effectsInhibition of glucuronidation by atovaquoneNo dosage adjustment necessary

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