Is the best HIV drug bad for muscle? Isentress increases CPK

CPK is creatine phosphokinase, an enzyme found mainly in the heart, brain, and skeletal muscle. It is tested by taking a blood sample.

High CPK can indicate muscle destruction, heart attacks, central nervous sysmtem issues, and others. Long term exposure of high CPK can load up your kidneys, and may cause muscle loss and weakness.

A CPK blood test is usually not included in the usual lab work unless you ask for it. Sometimes we have no symptoms when CPK is high, but most of the time we have body aches and soreness. CPK can increase with exercise, but if you exercise frequently and you have baseline CPK info, you can tell what may be drug induced after you start a certain medication.

To make sure your high CPK is not induced by heavy exercise, do not exercise for 5 days and have another test done after that.

Some medications can also increase CPK. Among them are amphotericin B, ampicillin, some anesthetics, blood thinners, aspirin, clofibrate, dexamethasone, furosemide, alcohol, and cocaine. HIV medications like Isentressand Selzentry have also been reported to increase CPK in some patients.

Low thyroid function can also be a cause of high CPK, so get it checked.

There is no treatment. If CPK gets really high, doctors try to switch you to another medication, but it is very difficult for some patients to switch since they have no other options.

Some doctors prescribe corticoid steroids to reduce whatever the inflammation may be, but this is not a cure. Corticoid steroids can lower bone density, cause water retention and fat gain, and have been linked with joint bone dealth (necrosis), so they are not a good option to stay on for the long term.

If you are taking statins with or without fibrates, high CPK may indicate muscle related problems that these drugs can cause in some people. Statins (with or without fibrates) can cause rhabdomyolysis which can cause dustruction of muscle tissue in few patients and increase CPK. Some patients have anecdotally reported improvements of this problem by taking Coenzyme Q-10 (statins lower it) and a good antioxidant formula.

In the old days of heavy AZT use, we used to experience muscle myopathy and high CPKs that were sometimes successfully treated with L-Carnitine. I have not seen any data on the use of this supplement for high CPK induced by newer HIV drugs. I use it but my CPK is still higher than normal (If I do not exercise for 2 weeks, my lowest CPK is 400)

In my opinion, high CPK is an under diagnosed issue in aging HIV patients and one that needs to be researched. I am tired of companies denying that their drugs do not cause it. Hopefully, a researcher will read this post and think about innovative ways to manage this side effect.

The HIV-1 integrase inhibitor raltegravir is associated with rare cases of rhabdomyolysis, and pooled safety data from Phase II and III clinical trials show a higher rate of grade 3-4 creatine kinase (CK) elevation in patients receiving raltegravir versus controls (4.2% versus 2.5%). We compared the frequency of skeletal muscle toxicity in HIV-infected adults receiving raltegravir compared to a control group not receiving raltegravir, analysed for associated factors and also assessed for evidence of myocardial toxicity.

This published report shows that raltegravir (Isentress) can increase CPK in some patients:

Is Raltegravir Bad for Muscle?

Investigators from Australia followed up on reports of CK elevation from clinical trials of raltegravir by conducting a prospective study assessing CK elevations, myalgias, and myopathy in HIV-infected persons receiving (n=159) or non receiving (n=159) raltegravir (CW O016).  Skeletal muscle toxicity was defined as either: (1) isolated CK elevation; (2) myalgia without motor weakness; (3) proximal myopathy on physical examination; or (4) rhabdomyolysis. 

More on this study: http://www.natap.org/2012/AdverseReactComor/AdverseReactComor_04.htm

GSK- ViiV start their phase 3 study for their second generation integrase inhibitor (dolutegravir) in raltegravir experienced patients

http://clinicaltrials.gov/ct2/show/NCT01328041?term=dolutegravir&rank=1

For more on dolutegravir:

Report from CROI 2011

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.