A Case of Possible Darunavir/Ritonavir-Induced Peripheral Neuropathy

Abstract

A 65-year-old man, M.S.M., known as being HIV infected for 20 years, presented with muscle ache and progressive weakness 3 months after initiation of darunavir as a part of his antiretroviral therapy (ART). The patient's treatment included darunavir/ritonavir 600/100 mg twice daily, plus a backbone of didanosine and abacavir which were the backbone in his previous regimen for several years according to his drug resistance profile. Three months after initiation of darunavir/ritonavir the patient exhibited clinical symptoms of severe pain and progressive weakness of his lower limbs; he was unable to walk and was totally wheelchair-bound. Severe sensory peripheral polyneuropathy was revealed on electromyogram (EMG). All medications, including ART, were stopped. Within two months, concomitantly with initiation of raltegravir, etravirine and emcitricabine/tenofovir, the patient recovered, gained weight, resumed walking and his CD4 counts rose from 270 to 450 cells/mm³. A second EMG study 3 months after initiation of his new ART regimen showed compete recovery of the previously diagnosed peripheral neuropathy. In this report, we present a case of severe HIV-1-related acute demyelinating polyneuropathy which initiated after new generation PI darunavir/ritonavir was given and resolved after cessation of the drug without the use of immune-based therapies. The variety of HIV-related polyneuropathies will be discussed.

Case Presentation

A 65-year-old white man, M.S.M., known as being HIV infected for 20 years; clade B; hepatitis A-, B-, and C-negative; and a nonsmoker, presented with muscle ache and progressive weakness. The patient had normal blood pressure (120-110/80 mm Hg), fasting blood glucose of 60 to 80 mg%, and thyroid function within normal limits.

The patient was on antiretroviral therapy (ART) from 1996 and his compliance was excellent. His ART history included efavirenz (EFV), which was stopped because of unbearable nightmares and nevirapine (NVP), which was stopped because of abdominal pain, swelling, and flatuses. The patient was virologically suppressed (viral load [VL] <20 copies/mL) and CD4 counts were above 500 cells/mm³ on lopinavir/ritonavir (LPV/r; 400/100 mg twice daily [BID]), abacavir (ABC) 300 mg BID, and didanosine (ddI) 400 mg once daily (QD) for 7 years. Having elevated levels of low-density lipoprotein cholesterol (160-180 mg%), high-density lipoprotein 30 to 35 mg%, and triglycerides (above 250 mg%) in spite of triple lipid-lowering drug therapy (rosuvastatin 10 mg/d, ezetimibe 10 mg/d, and ciprofibrate 100 mg/d), was attributed to LPV/r. Since rosuvastatin levels may increase in the presence of LPV/r, only 10 mg/d were given. A switch of his ART was suggested in an attempt to improve his dyslipidemia.

In February 2007, darunavir/ritonavir (DRV/r), a new protease inhibitor (PI) at that time, was suggested as a replacement for LPV/r. The patient consented and the LPV/r was switched to darunavir/ritonavir 600/100 mg BID, plus his previous backbone of ddI 400 mg QD plus ABC 300 mg BID for the last 7 years according to his drug resistance profile.

Three months after initiation of DRV/r, the patient exhibited clinical symptoms of severe pain and progressive weakness of his lower limbs; he was unable to walk and was totally wheelchair-bound.

Severe sensory peripheral polyneuropathy was revealed on electromyogram (EMG). All medications, including ART, were stopped.

Soon after, the clinical state of the patient deteriorated rapidly, that is, loss of appetite, 10 kg weight loss within a month, lymphadenopathy, anemia (hemoglobin dropped from 13 g% to 8.5 g%), and elevation of liver enzymes up to 10 times the upper limit of normal, and the patient was admitted to the hospital. Because of the clinical signs and symptoms, lactic acid levels were measured several times and the highest level was 0.9 mmol/L (normal levels 0.5-2.2 mmol/L).

His CD4 count dropped from 440 to 270 cells/mm³. Interestingly, the patient’s HIV-VL remained <20 copies/mL. Reviewing his history, it was found that the patient’s lowest CD4 ever was 210 cells/mm³ and his highest VL was 2250 copies/mL, both 7 years prior to the described event (in 2000).

After a full investigation in the hospital, including gastroscopy, colonoscopy, chest and abdomen computed tomography scan, and liver ultrasound, no other pathology was revealed. Because of his clinical deterioration and the drop in his CD4 count, a new combination ART was given empirically, based on his history and previous drug mutations. The new ART included raltegravir 400 mg BID, etravirine 400 mg QD, and emcitricabine/tenofovir (TDF) 200 mg/245 mg QD.

Within 2 months the patient recovered clinically, gained weight, his lymphadenopathy disappeared, he resumed walking, and his CD4 counts rose to 450 cells/mm³.

Three months after starting his new ART combination, EMG showed a normal pattern without signs of peripheral neuropathy or myopathy.

To the best of the author's knowledge, this is the first description of DRV-associated peripheral polyneuropathy. It should be stressed that the coadministration with ddI, a well-known neurotoxic ART (nART), could be a facilitating factor for the development of such a severe peripheral polyneuropathy in an HIV-infected patient for 20 years. It should be stressed that the patient was on a ddI-containing regimen about 7 years prior to the development of peripheral polyneuropathy without showing any clinical symptoms prior to this event.

The well-known nARTs—stavudine, zalcitabime, and ddI—are not prescribed any more in the developed world and are not listed in the HIV treatment guidelines either in the United States or Europe because of their high neurotoxic potential.

Review of the Literature

An HIV infection is an important cause of inflammatory neuropathies. In fact, demyelinating polyneuropathies are diagnosed in a third of HIV-positive patients referred for peripheral nerve disease. ^{1 ,2} It is possible to distinguish 2 forms of disease, acute and chronic demyelinating polyneuropathy (AIDP and CIDP). The AIDP has a rapid onset and progression, and often develops during HIV seroconversion or during early HIV infection. On the other hand, CIDP is more common in the middle to late stages of HIV disease and has a slower onset and progression over several weeks or months. The HIV-related inflammatory neuropathies can be further distinguished into a subtype associated with HIV infection per se and an antiretroviral (ARV) toxic neuropathy associated with the use of ARV agents. Both AIDP and CIDP are characterized by progressive, ascending weakness with early loss of reflexes. ^{3 ,4} The response to immune-based therapies (including plasmapheresis or intravenous immunoglobulin) is similar to that seen in non-HIV-associated AIDP and CIDP. ⁵

Antiretroviral therapy has resulted in declines in the incidences of HIV-associated dementia, central nervous system disorders, and opportunistic infections. However, sensory neuropathies are still prevalent as the most frequent neurological disorders associated with HIV infection and its treatment with ART. ^{1 –3} Ellis et al report that the prevalence of distal sensory polyneuropathy (DSP) is 57% in the ART era. ⁴

Two major types of HIV-associated distal sensory peripheral neuropathies were described, primary HIV-associated DSP (HIV-DSP) and ART toxic neuropathy (ATN), together which affect approximately 30% to 67% of the patients with advanced HIV disease. ^{5 ,6}

The HIV-DSP is the most common sensory neuropathy in HIV infection with a reported 1-year incidence in an advanced patient cohort selected for neurologic disease risk of 36% and 21% in the pre-ART and ART eras, respectively. ⁷

The ATN is associated with nART, such as dideoxynucleoside analogs, dideoxycytidine, and dideoxythymidine and shares most clinical features of HIV-DSP except that neuropathy develops while taking the nART.

The ATN is the most common cause for toxicity of ART in sub-Saharan Africa, countries which still dispense nART as a part of the ARV. ^{5 ,6,8 –10}

The pathology of HIV-DSP involves a length-dependent degeneration of both small and large peripheral nerve fibers, but the pathogenesis is unknown. ^{6 ,11,12} The pathogenesis of ATN is believed to reflect inhibition of γ-DNA polymerase by nARTs leading to reduced mitochondrial DNA content and therefore to mitochondrial dysfunction. ¹³

Reduced mitochondrial DNA levels in subcutaneous fat obtained by punch skin biopsies have been associated with ATN. ^14,15 The signs/symptoms of HIV-DSP and ATN resemble common neuropathies encountered in clinical practice, including diabetic- and alcohol-associated neuropathy.

Symptoms include numbness, paresthesia, burning sensation, and stabbing pain. Common signs include reduced or absent ankle reflexes relative to patellar reflexes and reduced or absent vibration sensation in the toes, and decreased pain and temperature sensation in a stocking/glove distribution.

No US Food and Drug Administration-approved therapies exist for HIV-associated sensory neuropathies with treatment limited to symptomatic measures with limited efficacy. ¹

Higher plasma HIV-1 RNA and lower CD4 counts before the initiation of ART increased the risk of HIV-DSP in the pre-ART era. ^{16 ,17} Risk factors in the ART era have been investigated. ^{7 ,18 –23} Data suggest that risk factors include prolonged exposure to ART, ²⁴ PI exposure, ²⁵ and lipid-lowering drugs (statins and fibrates). ^{26 ,27} Diabetes mellitus is a common cause of sensory neuropathy, and ART, especially PIs, is associated with the development of diabetes mellitus. ²⁸ Ances et al ²⁹ report that the risk of HIV-DSP is associated with diabetes and hypertriglyceridemia but not with other metabolic syndrome components.

The interaction between metabolic syndrome and HIV is unclear. The patient’s height has been identified as a risk factor for peripheral neuropathy in diabetes ²⁹ and recently in HIV infection when using nARTs. ³⁰

In this report, we present a case of severe HIV-1-related AIDP which initiated after new generation PI DRV/r was given and resolved after cessation of the drug without the use of immune-based therapies.

In a large survey by Evans, peripheral neuropathy was found in 30% of the patients on ART, whereas about one-third of that number also had symptoms. ³¹ The following variables were associated with higher odds of peripheral neuropathy while on nART: older patient age, PI use, black race, and current CD4 count 351 to 500 cell/mm³. Viral suppression or current CD4 count was not associated with symptomatic peripheral neuropathy (SPN). ³¹

Aging appears to increase this vulnerability ^{32 ,33} making age one of the most notable and consistent risk factors for peripheral neuropathy. Given the rapidly aging HIV population due to highly efficient ART, the intersection of aging and increased risk of neuropathy portends ongoing challenges from this complication for HIV therapeutics.

Several risk factors for peripheral neuropathy are present in the described patient in this article. The patient is 65 years old, is tall (180 cm height), and used PI (DRV), 1 nART (ddI), and statins. Care should be taken in using such a combination when complaints of limb pain and weakness are described by HIV-infected individuals.

It may be that patients on a combination of nART and PIs versus patients on nART without PIs are inherently different, potentially biasing the estimate of the PI causative of peripheral neuropathy. However, the PI association was estimated while controlling for disease characteristics, demographics, and concomitant therapy. This will be critically important as second-line therapies are introduced in developing world sites where it may be common to pair nART with a PI in salvage regimens.

There are conflicting data raising the link between PI-containing regimens and the induction of neuropathy. The studies that report prevalence estimates by exposure to PI and/or nucleoside reverse transcriptase inhibitors (NRTIs) show great variation. In fact, the variation across studies is greater than the difference in neuropathy among exposed and nonexposed patients within studies. The prevalence estimates of neuropathy among populations exposed to any NRTI ranged from 20% to 49% and from 5.0% to 40.5% among NRTI nonexposed patients. ^34–37 The prevalence among patients exposed to PI ranged from 17.8% to 53.9%, whereas the prevalence among nonexposed patients was reported as 22.8% and 35.5%. ^{34 ,36,38}

Factors predicting recovery from neuropathy were studied. The results show a strong influence with advancing age, reducing the risk of recovery. It is also notable that statin use appears to decrease the chance of recovery from symptomatic neuropathy, a factor that could be of considerable clinical importance. Diabetes associated with insulin use also predicts less chance for reversal of symptomatic neuropathy, suggesting that combining the diabetic risk with nART-induced mitochondrial deficits may be a particularly troublesome neurotoxic situation.

African American patients had increased risk of peripheral neuropathy, which did not extend to SPN. The cause of this apparent risk is unknown, but higher risk of diabetes, hypertension, and potentially other genetic or pharmacokinetic risks could be considered.