Enfuvirtide (Fuzeon, T-20) has been lifesaving for many treatment-experienced individuals, yet substantial numbers of patients have bothersome injection site reactions (ISRs). In many instances, these adverse events demoralize patients and contribute to diminished ART adherence. Until recently, there was no alternative to enfuvirtide for most patients, but the availability of new antiretroviral (ARV) medications is rapidly changing that situation. Raltegravir is particularly attractive as a substitute for enfuvirtide in virologically suppressed individuals. It has no cross-resistance with agents from other ARV classes, is potent, and is very tolerable. The results of a small nonrandomized study presented at the 15th Conference on Retroviruses and Opportunistic Infections offer reassurance that a raltegravir substitution strategy is likely to be successful for appropriate patients.

Raltegravir (400 mg twice daily) was substituted for enfuvirtide in 35 patients with stable virologic suppression (HIV RNA of <50 copies/mL on enfuvirtide for a median of 24 months) who had significant ISRs on enfuvirtide-containing regimens. The patients continued their other ARV medications. After a median of 7 months (range 1-13 months), 34 patients continued to have HIV RNA <50 copies/mL, and 1 had a viral load of 60 copies/mL after 2 previous measurements of <50 copies/mL. All patients had resolution of ISRs, and none had adverse events attributable to raltegravir.

Although additional data may be required to determine the efficacy of this treatment strategy, it appears that substitution of raltegravir for enfuvirtide in patients with virologic suppression is effective and safe in the short term; and the study results reinforce a strategy that many clinicians have been pursuing empirically.

References

Harris M, Larsen G, Montaner J. Outcomes of patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston. Abstract 799.

Clinicians often prefer ritonavir-boosted atazanavir (ATV/r) to unboosted ATV for use in initial therapy, and this strategy is recommended by the adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services. Data to support this practice have been scanty, however, and ATV/r has not been adequately compared with standard-of-care protease inhibitor-boosted regimens for treatment-naive individuals. The results of a study presented at the 15th Conference on Retroviruses and Opportunistic Infections in February 2008 provide solid evidence of the efficacy and tolerability of ATV/r in initial therapy.

CASTLE, a large (883 subjects) randomized, open-label noninferiority study, compared ATV/r with lopinavir/ritonavir (Kaletra, LPV/r) in antiretroviral-naive patients. The two treatment groups were well matched at baseline; the median HIV RNA viral load was 5 log ₁₀ copies/mL and the median CD4 count was just above 200 cells/µL. Each protease inhibitor was given in combination with tenofovir + emtricitabine (Truvada); the LPV/r was given twice daily, in the soft-gel formulation. At 48 weeks, the proportion of patients in the two groups with HIV RNA <50 copies/mL was not significantly different: 78% in the ATV arm and 76% in the LPV arm . ATV/r performed as well as LPV/r in patients with baseline HIV RNA >100,000 copies/mL as well as in those with lower baseline viral loads. The increase in CD4 count in the two groups was similar: 203 cells/µL for the ATV arm, and 219 cells/µL for the LPV arm. Increases in fasting cholesterol and triglyceride levels were seen more frequently in LPV/r recipients, as were nausea and diarrhea; hyperbilirubinemia was seen more frequently in ATV/r recipients.

References

Molina J-M, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine ARV-naive HIV-1-infected subjects: The CASTLE study, 48-week results. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston. Abstract 37. U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. January 29, 2008. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7 . Accessed February 28, 2008.

Atazanavir (ATV) requires an acidic gastric environment in order to be absorbed. H2-receptor blockers and proton pump inhibitors (PPIs) may cause decreases in serum ATV levels by neutralizing gastric acidity, and many data have demonstrated this effect. Although these data are heterogeneous, the adverse pharmacokinetic effect of acid-lowering medications on ATV appears to be greater:

		With PPIs as opposed to H2 blockers (and the effect is much greater with both PPIs and H2 blockers than with antacids such as Rolaids, Tums, and Maalox)

		When they are taken with unboosted ATV as opposed to ritonavir-boosted ATV (ATV/r)

		When they are taken shortly before the ATV dose

Several dosing strategies for avoiding this pharmacokinetic effect have been tested, with varying results. A summary of data on these strategies can be found in the article referenced below. The manufacturer of ATV recently announced new recommendations for the use of ATV in patients taking acid-lowering medications. They are as follows:

Antiretroviral-Naive Patients

		The use of unboosted ATV is not recommended.

		H2 blockers: ATV/r 300/100 mg daily; H2 blocker dosage not to exceed the equivalent of famotidine 40 mg twice daily; give ATV/r with the H2 blocker, and/or >10 hours after the H2 blocker.

		PPIs: ATV/r 300/100 mg daily; PPI dosage not to exceed the equivalent of omeprazole 20 mg once daily, with the PPI to be taken approximately 12 hours before ATV/r.

Antiretroviral-Experienced Patients (in whom higher serum ATV levels may be important for virologic efficacy)

		The use of unboosted ATV is not recommended.

		H2 blockers: if tenofovir is used in the regimen, give ATV/r 400/100 mg daily. Administer H2 blocker as for antiretroviral-naive patients, detailed above.

		The use of PPIs is not recommended.

Antacids and buffered medications: ATV should be taken 2 hours before or 1 hour after these medications.

It should be noted that the data on which these recommendations are based are varied in their quality and their results. The virologic impact of the interactions between H2 blockers or PPIs and ATV remains unclear, as does the therapeutic effect of administering ATV with these agents according to the new recommendations. Pending further information, these medications should be used cautiously in patients taking ATV.

References

Béique L, Giguère P, la Porte C, et al. Interactions between protease inhibitors and acid-reducing agents: a systematic review. HIV Med. 2007 Sep;8(6):335-45. Reyataz [patient information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2007. Available at: http://packageinserts.bms.com/pi/pi_reyataz.pdf . Accessed February 27, 2008.

It is thought that protease inhibitors, which are renally cleared to only a small degree, require no dosage adjustment for patients with renal insufficiency and those on hemodialysis (HD). However, few studies have been conducted to evaluate this assumption.

A recent study of atazanavir (ATV) in HIV-uninfected patients with kidney disease, performed by the manufacturer, found that patients with severe renal impairment (who were not on HD) had higher mean serum ATV exposure (AUC) and minimum concentrations (Cmin) than did matched controls with normal kidney function. Surprisingly, although ATV was not cleared by HD, subjects on HD had substantially lower ATV levels than controls (AUC 42% lower on HD days, 28% lower on non-HD days). The mechanism for this effect is not known. Pending further study, the manufacturer recommends that treatment-experienced patients on HD should not be treated with ATV, and that patients with severe renal impairment who are not on HD should be treated with ritonavir-boosted ATV at usual doses.

References

Agarwala S, Eley T, Child M, et al. Pharmacokinetics of atazanavir in severely renally impaired subjects including those on hemodialysis. In: Program and abstracts of the 8th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2007; Budapest. Abstract 2. Reyataz [patient information]. Princeton, NJ: Bristol-Myers Squibb. December 2007. Available at: http://packageinserts.bms.com/pi/pi_reyataz.pdf . Accessed February 27, 2008.

The reported rate of hypersensitivity reaction (HSR) to abacavir is approximately 5-8% among whites of European ancestry and 2-3% among African Americans. Abacavir HSR has been strongly associated with the major histocompatability complex class 1 allele HLA-B*5701. The prevalence of this allele varies across populations. A recent study provides strong evidence that pretreatment screening for HLA-B*5701 and avoidance of abacavir in patients with the allele significantly decreases risk of abacavir HSR.

PREDICT-1, a double-blind study, randomized more than 1,900 HIV-infected patients to immediate treatment with abacavir (control group) vs prospective HLA-B*5701 testing and withholding of abacavir from those with HLA-B*5701. All patients who developed clinically suspected HSR, and a group of 100 patients without HSR, were subsequently screened for true (immunologically confirmed) abacavir hypersensitivity by skin patch testing.

Results from this study of primarily white subjects showed an overall HLA-B*5701 prevalence of 5.6%. No cases of HSR occurred in patients who screened negative for HLA-B*5701 (negative predictive value = 100%), whereas immunologically confirmed HSR occurred in 2.7% of controls (p < .001). Importantly, because abacavir HSR is a clinical diagnosis, the proportion of false-positive (suspected) HSR cases also was significantly lower in the screened group (3.4%) than in the control group (7.8%; p < .001).

This study demonstrates that HLA-B*5701 testing identifies persons at high risk of abacavir HSR. The results of this study require confirmation in nonwhite populations, but it appears that screening for HLA-B*5701 and avoiding abacavir in patients with the HLA-B*5701 allele substantially decreases (or perhaps eliminates) the risk of true abacavir HSR, which can be serious, and it also decreases the likelihood of mistaken diagnosis of HSR, which leads to unnecessary (and permanent) discontinuation of abacavir. Note that HLA-B*5701 testing is not a substitute for proper patient counseling and astute clinical judgement.

The U.S. Department of Health and Human Services' Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents now recommend screening for HLA-B*5701 before initiating treatment with abacavir. For patients who test negative for HLA-B*5701, the guidelines categorize abacavir + lamivudine as a "preferred" nucleoside backbone for use in initial antiretroviral therapy.

References

Mallal S, Phillips E, Carosi G, et al; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008 Feb 7;358(6):568-79. Available at http://www.ncbi.nlm.nih.gov/pubmed/18256392 . Accessed April 7, 2008. Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1-128. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf . Accessed April 7, 2008.

Etravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) approved by the U.S. Food and Drug Administration in January 2008, is active against many HIV strains that are resistant to first-generation NNRTIs. It is likely to play an important role in the treatment of individuals with NNRTI resistance mutations. Etravirine, however, has therapeutically significant interactions with many other antiretroviral (ARV) drugs, and with other medications, that may substantially affect the efficacy or toxicity of an ARV regimen that contains etravirine. It is important to consider these potential pharmacokinetic interactions when selecting the other agents that will accompany etravirine in the ARV regimen, particularly the protease inhibitors.

Etravirine is a substrate of the cytochrome P450 enzyme system (CYP3A4, CYP2C9, and CYP2C19); it is also an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Etravirine decreases serum concentrations of atazanavir, maraviroc, and raltegravir, and it increases concentrations of fosamprenavir. Etravirine levels are significantly decreased by tipranavir, full-dose ritonavir, efavirenz, and nevirapine. They are modestly decreased by darunavir, saquinavir, and tenofovir, and are increased by lopinavir/ritonavir. These and other interactions are incompletely studied, but based on current information, etravirine should not be given with other NNRTIs, unboosted protease inhibitors, atazanavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir. If used with certain other interacting ARVs, dosage adjustment or close monitoring of the patient may be required.

For recommendations on administration of etravirine with other antiretrovirals, see the table below. Note that etravirine also interacts with many nonantiretroviral medications. For information on these, see product label or the HIV InSite Database of Antiretroviral Drug Interactions .

Etravirine Interactions with Other Antiretrovirals

Interacting ARV	Pharmacokinetic Effects	Recommendations and Comments
Abbreviations: AUC = area under the plasma concentration-time curve; BID = twice daily; C max = maximal plasma concentration; C min = minimal plasma concentration; ETV = etravirine; PI = protease inhibitor Color code: do not coadminister caution may be coadministered; no dosage adjustment required
Nucleoside/Nucleotide Analogues
Didanosine (ddI)	ddI: no significant change in levels ETV: ↑ AUC 11%	Not clinically significant
Tenofovir (TDF)	TDF: ↑ C min 19%; ↑ AUC 15%; ↑ C max 15% ETV: ↓ C min 18%; ↓ AUC 19%	Not thought to be clinically significant
Nonnucleoside Reverse Transcriptase Inhibitors
Delavirdine (DLV)	ETV: anticipate ↑ levels	Do not administer with ETV
Efavirenz (EFV)	EFV: anticipate ↓ levels ETV: ↓ AUC 41%	Do not administer with ETV
Nevirapine (NVP)	NVP: anticipate ↓ levels ETV: ↓ AUC 55%	Do not administer with ETV
Protease Inhibitors (Unboosted)
Atazanavir (ATV)	ATV: ↓ C min 47%; ↓ AUC 17% ETV: ↑ C min 58%; ↑ AUC 50%; ↑ C max 47%	ETV should not be used with unboosted PIs
Fosamprenavir (FPV)	Not studied; significant ↑ in FPV levels expected
Indinavir (IDV)	IDV: ↓ AUC 46% ETV: ↑ AUC 51%
Nelfinavir (NFV)	Not studied; ↑ NFV levels expected
Ritonavir (RTV) (600 mg BID)	ETV: ↓ AUC 46%
Saquinavir (SQV)	SQV: ↓ AUC 52%
Protease Inhibitors (Ritonavir Boosted)
Atazanavir (ATV)-r	ATV: ↓ C min 38%; ↓ AUC 14% ETV: ↑ AUC 30%; ↑ C max 30%	Do not administer with ETV
Darunavir (DRV)-r	DRV: no significant change in levels ETV: ↓ C min 49%; ↓ AUC 37% (ETV 100 mg BID)	Pharmacokinetic studies of ETV 200 mg + DRV-r versus ETV 200 mg alone have not been conducted; it is not known whether dosage adjustment of ETV is necessary In clinical studies, regimens containing DRV-r + ETV were more effective than those containing DRV-r without ETV
Fosamprenavir (FPV)-r	FPV: ↑ C min 77%; ↑ AUC 69%; ↑ C max 62%	Dosage adjustment not established; do not administer with ETV
Indinavir (IDV)-r	Not studied	Do not administer with ETV
Lopinavir (LPV)-r (Kaletra)	LPV: ↓ C min 8%; ↓ AUC 19% ETV: ↑ C min 23%; ↑ AUC 17%; ↑ C max 15%	No dosage adjustment appears to be necessary
Saquinavir (SQV)-r	SQV: ↓ C min 29%; ↓ AUC 37% ETV: ↓ C min 29%; ↓ AUC 33%	Clinical significance of decreased SQV and ETV levels is unknown; dosage adjustment not established
Tipiranavir (TPV)-r	TPV: ↑ C min 24%; ↑ AUC 18% ETV: ↓ C min 82%; ↓ AUC 76%	Do not administer with ETV
Fusion Inhibitors
Enfuvirtide (ENF)	Anticipate no significant change in ENF or ETV levels	No dosage adjustment required
Chemokine Coreceptor Antagonists
Maraviroc (MVC)	MVC: ↓ C min 29%; ↓ AUC 53%; ↓ C max 60% ETV: no significant change in levels	Dosage adjustment required: ↑ MVC dosage to 600 mg BID (if ETV is given with MVC + DRV-r or other compatible RTV-boosted PI, ↓ MVC dosage to 150 mg BID)
Integrase Inhibitors
Raltegravir (RAL)	RAL: ↓ C min 34%; ↓ AUC 10% ETV: no significant change in levels	Clinical significance of decreased RAL levels is not clear; no information available on dosage adjustment

References

Intelence [prescribing information]. Raritan, NJ: Tibotec Therapeutics; January 19, 2008. Available at www.fda.gov/cder/foi/label/2008/022187lbl.pdf . March 1, 2008. Alcorn K. Pfizer Advises Maraviroc Dose Increase if Combined with Etravirine . Aidsmap. London: National AIDS Manual (NAM); July 20, 2007. Accessed Feb. 28, 2008. Baede P, Piscitelli S, Graham N, et al. Drug Interactions with TMC125, a Potent Next Generation NNRTI. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2002; San Diego. Abstract A-1827. Harris M, Zala C, Woodfall B, et al. Pharmacokinetics (PK) and safety of adding TMC125 to stable regimens of saquinavir (SQV), lopinavir (LPV), ritonavir (RTV) and NRTIs in HIV+ adults. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver. Abstract 575b. Kakuda T, Schöller-Gyüre M, Peeters M, et al. Pharmacokinetic interaction study with TMC125 and TMC114/rtv in HIV-negative volunteers. In: Program and abstracts of the XVI International AIDS Society Conference; August 13-18, 2006; Toronto. Abstract TUPE0086. Kakuda T, Schöller-Gyüre M, Woodfall B, et al. TMC125 in combination with other medications: summary of drug-drug interaction studies. In: Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow. Abstract PL5.2. Piscitelli SC, Baede P, Van't Klooster G, et al. TMC125 Does not Alter Lopinavir/Ritonavir (LPV/RTV) Pharmacokinetics in Healthy Volunteers. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2002; San Diego. Abstract A-1824. Scholler M, Kraft M, Hoetelmans R, et al. Significant decrease in TMC125 exposures when co-administered with tipranavir boosted with ritonavir in healthy subjects. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 583. U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. January 29, 2008 . Accessed February 28, 2008.