Recent Studies Show Concerns With The Use of Tenofovir (Viread), Popular Drug in HIV Treatment

Tenofovir impairs enzyme that stops cells aging

This study let us know that NRTI drugs, already known for causing the damage to mitochondrial DNA that leads to peripheral neuropathy, fat loss and some other side-effects, also exert an effect on cellular DNA, and that in this case tenofovir may be the drug to keep an eye on.

Telomerase shortening is, by definition, a side-effect that won’t start causing symptoms for many years, and the study does provide a cautionary note in discussions about the possibility of very long-term side-effects associated with the use of tenofovir, both in HIV treatment and in pre-exposure prophylaxis.

More information here


************************************************************************************************************************************************

Changes in Fat Mitochondrial DNA and Function in Subjects Randomized to Abacavir+Lamivudine or Tenofovir DF+ Emtricitabine With Atazanavir-Ritonavir or Efavirenz: AIDS Clinical Trials Group Study A5224s, Substudy of A5202

"In conclusion, we have shown significant perturbation in mitochondrial indices after 96 weeks of nonthymidine NRTI containing regimens which were assigned randomly. In the TDF/FTC group, changes in oxidative phosphorylation complex I and complex IV activity levels consistently were inversely correlated with changes in several objective measures of body fat, including in both subcutaneous and visceral compartments"

  Patients with human immunodeficiency virus type 1 (HIV-1) infection receiving thymidine nucleoside reverse-transcriptase inhibitors (NRTIs) experience a high rate of metabolic abnormalities, including lipoatrophy. Depletion of adipose tissue mitochondrial DNA (mtDNA) and impairment of the oxidative phosphorylation system are associated with lipoatrophy induced by thymidine NRTI containing regimens. Mitochondrial oxidative phosphorylation enzymes nicotinamide adenine dinucleotide (reduced; NADH) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) contain polypeptides of mtDNA-encoded subunits and so are affected by mtDNA depletion.
In the current era of nonthymidine NRTI containing regimens, lipoatrophy incidence has significantly decreased but has not been completely prevented . In addition, subjects who have established lipoatrophy while taking thymidine NRTI containing regimens experience only a slow and incomplete resolution of lipoatrophy after switching to nonthymidine NRTI based therapy , putting into question the mitochondrial toxicity.

More information here

************************************************************************************************************************************************

Fortunately, 10 year observational data on the use of TDF show encouraging results in stabilization of reduced creatinine clearance

Association Between Tenofovir Exposure and Reduced Kidney Function in a Cohort of HIV-Positive Patients: Results From 10 Years of Follow-up

 "In this cohort, TDF exposure was associated with reduced kidney function, but the loss in eGFR attributable to TDF is relatively mild in a long-term perspective.

There has been debate about the association between TDF exposure and renal dysfunction and about the clinical impact of the loss in eGFR due to TDF exposure. Our study shows that the association was not of a high magnitude and that the quantified loss in eGFR attributable to TDF is relatively modest after many years of exposure. Importantly, the loss attributable to TDF seems to occur during the first year of exposure and stabilizes after that. Although the loss is maintained, it does not seem to further deteriorate with additional years of exposure. The clinical impact of this association need to be analyzed, taking into account the efficacy of TDF, but it is highly plausible that TDF exposure, although associated with reduced kidney function, has no severe adverse effects over the long term for most HIV-positive patients.”

More information here

Nucleoside and Norvir Free HIV Medication Regimen May Provide an Option for Patients with Kidney Problems

http://www.hivandhepatitis.com/hiv-aids/hiv-aids-topics/hiv-treatment/3629-nrti-sparing-art-with-atazanavir-raltegravir-conflicting-data-for-naive-and-experienced-patients 

 NRTI-sparing antiretroviral regimen of unboosted atazanavir (Reyataz) plus raltegravir (Isentress) suppresses HIV in treatment-naive patients as well as standard 3-drug combinations, but its twice-daily dosing, side effects, and low barrier to resistance limit its appeal. For treatment-experienced people already doing well on atazanavir triple therapy, however, the dual regimen may be an attractive simplification option.

According to the latest U.S. antiretroviral treatment guidelines, preferred first-line regimens consist of a NNRTI, a ritonavir-boosted protease inhibitor, or the integrase inhibitor raltegravir, all combined with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). NRTIs and ritonavir can cause multiple drug toxicities, however, prompting researchers to explore alternative regimens.

My comments:

I bet this nucleoside-free regimen could do even better when it comes to side effects if the Reyataz (atanazavir) dose was cut to 150 mg twice a day instead of the 300 mg twice a day. However, this lower dose of atanazavir has not been tested in combination with raltegravir, so patients should not take the risk to experiment with it.

I think twice a day dosing is not a big deal, no matter how bad pharmaceutical companies and clinicians make twice a day dosing to be. Many patients will be happy to take a twice a day combination if they do not have to be exposed to nucleosides.

I really believe this is a great option for patients who do not want to take nucleosides  due to kidney and bone issues, or who have hypersensitivity to abacavir.

Both raltegravir and atanazavir boost each other, but it seems that raltegravir boosts atanazavir so much that 20 percent of patients experience high bilirubin, a common side effect of atanazavir.

Note: Nucleoside-free combos are not recommended with patients coinfected with Hepatitis B and HIV (Tenofovir, a nucleoside analog, is also a treatment for Hepatitis B)

Dolutegravir, Trii and new abacavir data- How it all ties together

By Nelson Vergel

Powerusa.org

Dr Joe Eron presented new dosing and efficacy phase 2b data on the new GSK integrase inhibitor dolutegravir (DTG, S/GSK1349572) using 50 mg twice a day in patients whose HIV virus has developed resistance to raltegravir (Isentress). Prior data presented in Vienna from a cohort (cohort 1) of patients who took 50 mg once a day showed that patients with one or more Q148+ associated integrase mutations had reduced activity to the drug, so GSK decided to recruit a second cohort (cohort 2)  of patients who took 50 mg twice a day in hopes that the increased blood levels would overcome some of this lower efficacy. Despite a long half life supporting once-daily dosing, the lack of dose proportional increase in exposure above 50 mg precluded using 100 mg once daily.

Adult patients with HIV-1 RNA ≥1000 copies/mL showing genotypic resistance to raltegravir and to ≥2 other ARV classes received 50 mg twice daily of DTG while continuing their failing regimen (without RAL) to day 11, after which the background regimen was optimized with another active agent. Unlike the previously presented 50 mg qd cohort I, eligibility required at least 1 fully active ARV for day 11 optimization.

All patients in this 50 mg bid cohort II with extensive raltegravir resistance (mutations Q148+ others) virus responded compared to 3 of 9 in the 50 mg qd cohort I. The mean reductions in plasma HIV-1 RNA (log10 copies/mL) at day 11 were –1.76  for  50 mg bid cohort II ( a lower but still attractive response of –1.57 for Q148+ virus) and –1.45 for  50 mg qd cohort I ( a reduced response of –0.72 for Q148+ virus). DTG was generally well tolerated:  mild to moderate diarrhea was the most common adverse event (n = 6), while 1 subject experienced 2 severe adverse events (demyelinating polyneuropathy, at day 23; diabetes mellitus, at day 79) considered unrelated to study drug.

 Although the day 11 responses were numerically better in cohort II, the baseline fold change range in virus susceptibility to DTG for cohort II was more limited due to extensive raltegravir related mutations.  46% of patients taking the 50 mg bid dose had one or more Q148 associated mutations that were associated with reduced response to the prior 50 mg qd dose cohort.  Longer-term (24 weeks) assessments in this phase 2b study are ongoing.

The data from cohort 2 provide promise for patients with extensive raltegravir resistance. However, many of these patients are in deep salvage with no remaining active ARVs to construct a viable regimen, so even if DTG works for them they will need another active agent.  Luckily, several companies are currently collaborating in an upcoming expanded access program that will allow these patients at higher risk of disease progression and death to obtain more than one active investigational drugs without waiting three years for all of them to be approved.  I will write about this project in future articles.

DTG will also be tested in naïve patients in head-to-head with raltegravir  in phase 3 studies (using a background of Epzicom  (abacavir (Ziagen) + 3TC (Epivir) ) or Truvada. When I first saw this study design schema, I thought it curious about why GSK decided to include their nucleoside combination Epzicom in their upcoming studies with DTG.

This decision started to make sense when GSK recently made an announcement that they will coformulate dolutegravir with Epzicom (abacavir+epivir) in a pill called Trii.  This coformulation will be competing for treatment naïve market share with other once a day pills (BMS/Gilead’s Atripla, Gilead’s QUAD and Tibotec/Gilead’s TMC278+ Truvada).

The development of Trii for approval as a first line treatment seemed risky to me due  to some compelling but conflicting studies that linked abacavir to cardiovascular risks in patients with HIV.  These data compelled the DHHS guidelines panel to drop abacavir from its list of recommended first line nucleosides for the treatment of naïve HIV positive patients.  So how would GSK ensure that their future Trii coformulation has a prominent place in the recommended regimens for first line treatment of HIV-positive patients?

Shedding some more light on this abacavir-cardiovascular risk issue and GSK’s move to develop the Trii coformulation,  the US Food and Drug Administration (FDA)  presented  a surprising poster on  March 2 that reported  no evidence of an association between abacavir  and increased risk of myocardial infarction (heart attack) in a meta-analysis of 26 randomized trials of the drug.  The meta-analysis included 5028 patients on abacavir and 4804 patients not taking abacavir with a mean follow-up per person of 1.62 years.

It is yet unknown if this new FDA report will enable abacavir to regain its preferred position in first line treatment guidelines.  Whatever the outcome will be for this nucleoside ARV, GSK-ViiV’s decision to  pursue their new Trii coformulation for the treatment naïve indication will provide one more option in the growing arsenal of once daily pills.   Hopefully, this new competition among companies in the once daily market will generate better pricing and worldwide access.

As the abacavir story unfolds, we await for more efficacy and safety data in the next few months on DTG’s use in treatment naïve and experienced patients.

Sources:

DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II. Joseph Eron et al.Univ of North Carolina at Chapel Hill Sch of Med. Oral presentation 151LB

Ding X et al. No association of myocardial infarction with ABC use: an FDA meta-analysis.  Poster abstract 808.


More on:
http://www.retroconference.org/2011/Abstracts/42541.htm

http://www.thebodypro.com/content/art60708.html

More on CROI:
http://www.thebody.com/content/art60501.html