Minutes to Midnight: Why the Quad is a no win for the drug resistant and treatment experienced

Current_Research_and_Opinions_200The HIV community has been abuzz with the August FDA approval of what had been termed “the Quad”, the second one-pill-once-a-day combination antiretroviral drug. Marketed by Gilead under the name Stribild, the drug contains two NRTIs (tenofovir and emtricitabine), an integrase inhibitor (elvitegravir) and an integrase booster (cobicistat) and is approved for use in treatment naïve patients with either drug resistant or wild type virus.

In comparison to Atripla, the first one-pill-once-a-day combination antiretroviral medication that has become the most widely used drug in people infected with HIV both in the U.S. and PEPFAR-partner countries, Stribild was found to be non-inferior (of the same or slightly better efficacy) to Atripla and have a “generally acceptable” safety profile.

Atripla is two NRTIs (tenofovir and emtricitabine, called Truvada) and an NNRTI (efavirenz). While it’s approval has been highly anticipated by both HIV clinicians and patients, there are several issues that need to be taken into consideration when hailing it as a significant advancement in the treatment of HIV and predicting the effect this new treatment will have on the HIV pandemic.

As we have seen success with current HAART, an increasing number of patients are on these drugs for longer periods of time and data is beginning to emerge on the consequences of chronic use of ARVs. The issues with treatment adherence, viral evolution and cross-resistance are resulting in rising drug resistance and data on the world’s most popular NRTI, tenofovir (part of the Truvada combination), has demonstrated nephrotoxicity. As Truvada and Atripla have been positioned at first line therapy, are the most popular ARVs in the world, Atripla and Stribild share an NRTI backbone and elvitegravir and raltegravir confer cross-resistance, patients who are resistant to Truvada and Atripla will also be resistant to Stribild. There are also concerns over the recent approval by the FDA of Truvada (tenofovir and emtricitabine) for pre-exposure prophylaxis (PrEP). HIV-negative people on Truvada PrEP who still become infected are at risk of developing resistance to tenofovir and/or emtricitabine, which would eliminate both Atripla and Stribild as treatment options from the initiation. Resistance mutations often have degrees of cross-resistance or class-wide resistance, so the development of a mutation in the virus of a person on one HAART regimen may also make other related drugs inactive, wiping out several treatment options in the process, even some that the person has never used.

Further significantly limiting the number of patients who are eligible for this drug, due to concerns about nephrotoxicity and renal excretion, the inability to safely use the drug to treat patients with creatinine clearances of less than 70mL/min and need to stop using it if creatinine clearance falls below 50 mL/min. Increased creatinine levels and kidney damage occurred, including cases of Fanconi syndrome and proximal tubular dysfunction, all in patients taking Stribild. In a study published in the April 2012 issue of AIDS, tenofovir was found to be associated with an increased risk of kidney damage and chronic kidney diseases that increases over time, which does not immediately appear reversible. There was a 34% increased risk of proteinuria/year and a 33% increase annually in chronic kidney disease risk, which was found to be independent of other potentially confounding factors including age, diabetes, high blood pressure, smoking, HCV co-infection and various HIV infection parameters. As the drug causes diarrhea (reported by 22% of study participants taking Stribild), there is an increased risk of dehydration, which will exacerbate renal function if the volume depletion is severe enough and compound the issue of renal toxicity.

The impairment in renal function is through to be associated with cobicistat. As a CTP3A4 and CYP2D6 inhibitor, there is significant potential for drug-drug interactions, enhancement of side effects, new side effects and alteration of effectiveness of other medications commonly prescribed to HIV patients in addition to HAART; the full range of interactions is unknown. Also of note, idiopathic protease gene mutations and protease inhibitor resistance developed in 9 and 3 participants taking Stribild.

NRTIs are a vital component of effective HAART regiments, often referred to as “the backbone”, and are included in all recommended regimens of expert bodies in the U.S. and Europe. Studies on HAART regimens that do not contain any NRTIs, “nuke sparing”, have shown they are not as durable or robust. This has been demonstrated with different drug classes, including integrase inhibitors and protease inhibitors, which are less prone to fail when constructed around a strong NRTI backbone. HAART regiments can be thought of as the defense in football. The role of NRTIs is that of the linebacker; no matter how good the rest of the defensive line is, the defense’s success is significantly determined by the It is important to note that the primary rationale behind nuke sparing is based on the long-term toxicities of some current popular NRTIs and the lack of effective NRTIs available for patients with drug resistant virus. Given these issues, there is a critical need to develop new, more active, less toxic NRTIs for drug resistant and treatment experienced HIV patients.

As mentioned above, a strong NRTI backbone is essential to an effective and durable HAART regimen. However, the extensive use of Truvada means that patients who fail these regimens often have drug resistance and drug mutations are archived latently in long-lived cells and can become activated years later or circulate at levels not easily detected with current technology. Subsequently, the number of effective, tolerable HAART regimens available to treatment experienced patients are often very limited; there may be more than 20 ARV drugs on the market but only 3 or 4 effective sequential regimens can be constructed. A new NRTI with the right characteristics would significantly improve treatment options for drug resistant patients: effective against common resistance mutations, not be subject to cross-resistance, not cause cross- or class-resistance, safe and well tolerated and able to be used with available HIV drugs in non-inferior HAART regimens.

The NRTI pipeline is disturbingly dry. BMS-986001 is a Phase II thymidine analogue, like AZT and d4T, being developed as an alternative to AZT for treatment naïve patients. GS-7340 is a Phase II tenofovir pro-drug, so it has cross-resistance with tenofovir and will have the same interactions. The most promising candidate, which also happens to be closest to the goal line, is apricitabine (ATC) in Phase III by Avexa.

ATC has been found to have no cross resistance with other NRTIs, no resistance development up to 144 weeks, be very well tolerated and be used in combination with all other available ARV drugs, with the exception of 3TC and FTC as no two cytidine analogues should be used together. ATC is active against the M184V and L74V mutations and TAMs and no resistance has developed in patients on treatment for up to at least 144 weeks. It has a safety profile at least as good as that of FTC and 3TC, and demonstrated no evidence of mitochondrial, bone marrow, pancreatic, hepatic and renal toxicities. The FDA has approved a registration study of 300 patients whose options for effective HAART treatment are limited by drug resistance and/or tolerability with the primary endpoint of a reduction in viral load at day 14 on functional ATC monotherapy. On day 14 the background regimen will be changed to two new active ARVs, all patients will continue on ATC and safety, durability and resistance evaluated.

Where are big pharma and the ACTG? Big pharma is licensing fewer, earlier stage ARV candidates and concentrating exclusively on once daily combination drugs for treatment naïve patients or PrEP and market share among well-suppressed treatment experienced patients. Drug resistant and treatment-experienced patients are a growing market segment. ATC is in late stage clinical development for treatment experienced patients, currently dosed twice daily and not easily incorporated into once daily combination drugs. While once daily combination medications are no doubt extremely successful in treatment naïve patients, they are much less so for treatment-experienced patients who require a more individual approach to construct an effective, tolerable and durable regimen. The current domination of once daily combination drugs for HIV does not benefit a significant and growing segment of the patient population. ATC is the most promising and advanced NRTI candidate and the completion of its clinical development should be prioritized for federally facilitation via an HIV clinical trials network.

Written by Mariel Selbovitz, MPH

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