Growing pain

As people with HIV live longer, they are facing pains old and new. David McLay reports on peripheral neuropathy and arthritis.

Oh, these pains! Are they HIV or are they age? It can be difficult to know when to mention an ache or a pain because it may be HIV-related, and when to chalk it up to the body’s natural decline. Considerable attention is given to life-threatening conditions such as heart disease and diabetes among people with HIV, now that effective HIV treatments are leading to a longer life with the virus. But less attention is paid to painful conditions, such as peripheral neuropathy and arthritis, which can sometimes cast a heavy cloud over the seemingly sunny prospect of a longer life.

It can be a struggle to get pain and its underlying cause acknowledged, so it is refreshing when a doctor leads the way. In this case, it’s Dr Sarah Cox, consultant in palliative medicine at London’s Chelsea and Westminster Hospital, and the condition is peripheral neuropathy (PN) - a neurodegenerative condition often associated with changes in sensation in the extremities. “HIV PN is a common problem that is probably under-recognised in HIV,” says Dr Cox, who treats many of the HIV-positive people with PN who seek care at the hospital.

Across the English Channel in Amsterdam, Dave R would probably agree. HIV-positive since 2004, Dave was diagnosed with peripheral neuropathy in 2009, though the 61-year-old recalls feeling early symptoms of the condition three years earlier. “I was feeling as though I was walking on bare bones, with no fat or muscle to cushion the impact. That wasn’t happening all the time but it was the first time I became aware of problems with my feet.” Dave also lives with painful arthritic back problems, but that’s another story. (See Joint and muscle pain, below, for more on rheumatic conditions and HIV.)

A lag between symptoms and diagnosis is not uncommon. Dave feels: “Diagnosis can take forever. There are so many side-effects of HIV medication that can confuse the picture and if you have other problems as well, it’s difficult to pin down what causes what and why, especially in the first stages of neuropathy, which are generally fairly mild.”

He continues, “The symptoms trundle along from month to month, sometimes hitting plateaux but gradually getting worse until you need to press your case somewhat harder.” Fortunately for Dave, his doctor and other doctors, including Sarah Cox, are listening.

Increasing incidence

PN, officially known as HIV-associated sensory neuropathy, affects sensation in the limbs, generally the feet and much less frequently the hands. There can be a loss of sensation or an overly painful reaction to touch. Severe burning pain or a ‘pins and needles’ feeling is also common.

PN can be caused by advancing HIV infection itself or by antiretroviral drugs.¹

While the virus does not infect neurons (nerve cells), there is evidence that HIV infection leads to damage to the axon - the long, conducting ‘wire’ - of the neuron and to the myelin sheath that surrounds and protects the axon.² Nerve destruction results in altered sensation signals being sent to the central nervous system. Not surprisingly, PN is more common in advanced HIV disease.

Some older antiretroviral drugs, particularly the so-called d-drugs, d4T (stavudine, Zerit), ddI (didanosine, Videx) and ddC (zalcitabine, Hivid – now withdrawn from the market), also cause mitochondrial toxicity, which can lead to neuronal dysfunction and death.³

HIV peripheral neuropathy is a common problem that is probably under-recognised in HIV. Dr Sarah Cox, Consultant in palliative medicine, Chelsea and Westminster Hospital

Remarkably, while rates of most HIV-associated neurological conditions (conditions related to the nervous system) have decreased since the introduction of effective antiretroviral therapy, rates of PN have increased, with prevalence estimates ranging from 9 to 60% of HIV-positive people who have access to antiretroviral therapy.

“We had expected to find that HIV PN incidence would fall as HIV treatment is more effective and we use less of the nucleosides implicated,” Dr Cox says. “We are still trying to understand what other factors might be maintaining the prevalence of HIV PN.”

HIV-related neuropathy tends to emerge gradually, while antiretroviral-related neuropathy emerges more rapidly and can usually be stopped from worsening by stopping the drug.

The CHARTER study – a prospective, observational study of over 1500 people with HIV in the US that looked at the impact of antiretroviral therapy on neurological function – reported that 57.2% of participants had at least one sign of PN. Of those, 60.8% reported a sensory symptom of PN and 38% reported some level of pain.⁴ Put in the context of the entire study population, one in five (21.8%) were living with PN pain. PN is also a serious issue in developing countries where the use of implicated drugs, particularly d4T, is still common.

The CHARTER study also assessed the impact of PN on quality of life, and showed that depressive symptoms were more common among those with PN pain. Moreover, pain was almost twice as likely among people with depression. Not surprisingly, the study reported that people with mild, moderate or severe pain scored more poorly on the quality-of-life subscale of the Medical Outcome Study HIV Health Survey (MOS-HIV), a validated scale of health and wellbeing among people with HIV. Moreover, people with PN pain were more likely to be unemployed and to need help with daily living.

Many of the factors normally associated with an increased risk of PN are those that would be expected. Having another condition which can also lead to PN increases the risk. Low CD4 cell counts, lowest-ever (nadir) CD4 cell count and high viral load – all signs of a weakened immune system and advanced disease – also increase the risk. Being older (and being taller) also increases the risk of PN... not such good news for people with HIV who are on successful therapy and now expecting near-normal lifespans. PN may be another one of those things – along with such issues as the long-term effects of antiretroviral therapy and what appears to be premature ageing - that more and more people with HIV can expect to face as they live with a chronic infection.

Living with PN

Diagnosis of PN is based on symptoms (what people feel and tell their doctors about) and signs (physical indications noticed by a doctor during an exam). Certain neurological tests are carried out in some centres in order to distinguish HIV PN from PN resulting from its many other possible causes including:

• Diabetes or insulin resistance
• Heavy alcohol consumption
• Thyroid disease
• Syphilis
• Kidney disease
• Vitamin B12 deficiency
• Other infections (shingles, CMV).

Neuropathy related to HIV or antiretrovirals usually affects both sides of the body symmetrically, whereas other types may not. When investigating pain symptoms, doctors routinely check for these other conditions. If any are diagnosed, they can be treated.

“When a diagnosis of HIV PN is made,” Dr Cox says, “we would start by explaining what HIV PN is, how it may have been caused and what to expect.” Then the first goal is to prevent further damage by identifying any aggravating factors and trying to control or eliminate them. This includes proper management of the HIV infection. Neurotoxic drugs are identified and stopped or replaced with a safer alternative if possible. In addition to the d-drug antiretrovirals, other potentially neurotoxic drugs used in HIV include dapsone (for PCP prophylaxis), isoniazid and ethambutol (tuberculosis drugs), thalidomide (a treatment for apthous ulcers, or canker sores, in the mouth) and certain cancer drugs.

At present we don’t know how to cure or reverse neuropathy: attempts to develop therapies that promote the regeneration of destroyed nerves have so far failed. Dr Cox says: “We explain that we cannot reverse the condition and that treatments we offer will be to mask the symptoms.”

Treatment options for neuropathic pain can be grouped into five broad classes: anticonvulsants; antidepressants; non-specific analgesics; topical treatments; and complementary therapies. However, Dr Cox adds, “In terms of treatment, many of the usual treatments for pain in neuropathy have been shown not to work in HIV PN.” Moreover, there are no treatment options for other symptoms of PN, such as numbness or tingling.

In 2010, a systematic review and meta-analysis co-authored by Dr Cox reported on the results of 14 prospective, double-blinded, randomised, placebo-controlled trials of treatment options for HIV PN.⁵ The authors concluded that only two available treatments – smoked medicinal marijuana and high-dose topical preparations of capsaicin – showed efficacy.⁶ Marijuana needs no introduction; capsaicin is the active ingredient in chilli peppers and is used in many topical painkilling preparations such as Qutenza, where its pain-stimulating effect paradoxically seems to overwhelm the signals that cause chronic pain.⁷ First-line treatments, including the anticonvulsants lamotrigine, pregabalin and gabapentin (see below), tricyclic antidepressants such as amitriptyline, the anti-arrhythmic drug mexiletine, the amino acid (and popular supplement) acetyl-L-carnitine and low-dose topical capsaicin (0.75%) were no better than placebo at decreasing PN pain in people with HIV.

While the systematic review and meta-analysis results showed no efficacy with many treatments, they may still have some merit. Some drugs may work for some individuals. Also, combining treatments, which is common, may result in at least partial relief. Doctors will prescribe familiar painkillers first before moving on to stronger ones such as opiates and PN-specific medications such as amitryptiline.

The value of doing your own research is that you can walk into a doctor's appointment strengthened by knowledge. Dave R

Dr Cox also advises her patients on how to live with PN day to day. “We point out the particular problems associated with loss of ability to distinguish when something is hot and how it is important to test bath temperature with an elbow rather than feet. We advise individuals to inspect the bottom of their feet for damage and be very careful breaking in new shoes. I usually suggest they avoid walking barefoot.”

Dave has tried six different drugs alone or in combination, and all have been “unsuccessful in taming the pain”. He is weaning himself off oxycodone, preferring for now to live with the pain: “I try to mentally control the pain and relax as much as possible plus accept that the pain is there and not try to fight it by tensing up or becoming too depressed.”

In addition to managing the pain, learning about the condition has also helped Dave. “Very early on, I was more than a little frustrated at the lack of information available to HIV patients with neuropathy,” he recalls. So he set up a website, originally in Dutch and now also in English, along with a blog to provide information about neuropathy, from which people can make their own decisions and ask their own questions while sharing the experiences of others. The blog is available at www.neuropathyandhiv.blogspot.com.

According to Dave, “The value of doing your own research is that you can walk into a doctor’s appointment strengthened by knowledge and maybe not be so confused when you walk out. Neuropathy is not an easy thing to explain; if you have some idea beforehand it will help enormously.”

Finally, Dave points out the importance of a support network. “Having chosen wisely, make friends of your two main healthcare providers: your home doctor [GP] and your HIV specialist. It’s a long journey with neuropathy; you need to have someone on your side who knows what you and they are talking about.”

As for family and friends, he adds, “They won’t understand what’s happening to you and possibly after several weeks of moaning, will be distinctly unsympathetic too. If possible, take a family member or a friend with you to a consultation with your doctor. It’s vital that you’re taken seriously because, otherwise, you can feel very lonely while you’re suffering. You’re going to need a listening ear or a shoulder to cry on at some stage in the future.” Sound advice, indeed.

Treatment options for PN

Note that many of these have not been proven to be effective in treating HIV PN.

Anticonvulsants – gabapentin, pregabalin, lamotrigine

Antidepressants – TCAs (tricyclic antidepressants) such as amitriptyline and nortriptyline; SNRIs (serotonin-norepinephrine reuptake inhibitors) such as duloxetine and venlafaxine

Nonspecific analgesics – NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen, naproxen and paracetamol (acetaminophen); opioid analgesics such as oxycodone, fentanyl and morphine

Topical treatments – lidocaine and capsaicin

Complementary therapies – acetyl-L-carnitine, co-enzyme Q10, cannabis, hypnosis, acupuncture and acupressure

Joint and muscle pain

Burning and stinging feet are not the only pain that people with HIV are facing as they look towards a long life with the virus. As Dave R can attest: along with PN, he lives with arthritic back problems, which he suspects are in part due to playing rugby during his school years. While Dave’s arthritic condition preceded HIV infection, many other people with HIV are finding that rheumatic diseases – diseases of the muscles and joints – can be true pains in the proverbial.

Rheumatic conditions include a broad spectrum of conditions that affect the joints and musculoskeletal system. Familiar conditions include different forms of arthritis, systemic lupus erythematosus (SLE or lupus), fibromyalgia (muscle pain) and gout. They can be mildly painful at best and debilitating at worst.

Many rheumatic conditions are autoimmune conditions and have long been a part of HIV disease. There are several potential mechanisms to explain how HIV can lead to rheumatic disease. Among them is that HIV particles are similar to other antigens in the body. Infection with HIV can cause the body to initiate an autoimmune response that can underlie conditions such as arthritis or lupus.

Before the introduction of ART, estimates of the prevalence of rheumatic disease in people with HIV ranged from 11 to 72%, with joint pain affecting 5 to 45% of people. Different forms of arthritis were common, as well as muscle weakening. In the ART era, the prevalence has been reported as approximately 9%.⁸

Along with the decrease in prevalence, the types of diseases have also changed. Less common are exotic beasts such as diffuse infiltrative lymphocytosis syndrome (DILS, a painless condition that causes swelling of the salivary and tear glands and often lymph nodes) and spondyloarthritis (inflammation of the joints in the spine), while musculoskeletal problems, such as osteopenia (low bone mineral density), and infections still occur.⁹ Starting antiretroviral therapy can cause IRIS (immune reconstitution inflammatory syndrome), which can lead to new cases or reactivation of pre-existing cases of rheumatic conditions such as rheumatoid arthritis or lupus.

In untreated HIV infection, rheumatoid arthritis and lupus are dampened because a weakened immune system is not able to produce the cytokines, cellular messaging chemicals like tumour necrosis factor (TNF), that are involved in the ongoing inflammation underlying these diseases. Restoring the immune system reactivates these pathways leading to flare-ups. The symptoms of IRIS usually get better spontaneously, but can be very severe while they are happening.

Gout and its precursor hyperuricaemia (high levels of uric acid in the blood) also have a high prevalence among people with HIV. Hyperuricaemia has been reported in up to 42% of people with HIV, and gout is about tenfold more common than in HIV-negative people. Hyperuricaemia has been linked to certain antiretroviral drugs, specifically ddI and d4T. The mitochondrial toxicity associated with these drugs is thought to cause changes in the body’s metabolism that lead to increased levels of uric acid in the blood.

Finally, fibromyalgia was the second most common rheumatic condition in a cross-sectional US study of HIV-positive people taking ART. Seventeen percent of people reported the syndrome, which includes long-term, body-wide pain and tenderness in soft tissues including the joints, muscles and tendons.

Living with arthritis and muscle pain

There are no guidelines for the treatment of rheumatic conditions in people with HIV. However, most therapies used in the general population appear safe and effective among people with HIV when used prudently.¹⁰ The UK Royal College of Physicians’ guidelines for the treatment of rheumatoid arthritis recommend a combination of agents: short-term glucocorticoids to reduce inflammation, agents from a class called the DMARDs (disease-modifying anti-rheumatic drugs) and agents called biologics. People also use NSAIDs (see Treatment options for PN, above) or COX-2 inhibitors (another sort of anti-inflammatory drug) to manage the pain associated with the condition.

DMARDs include drugs such as methotrexate, hydroxychloroquine and sulfasalazine. Methotrexate was originally avoided in people with HIV because it suppresses the immune system. However, it is now used with careful monitoring of CD4 count and viral load.¹¹

Hydroxychloroquine is used to treat both rheumatoid arthritis and lupus, and is used in people with HIV. It has antiretroviral properties: in early studies, high doses of the drug were comparable to AZT (zidovudine, Retrovir) monotherapy in controlling viral replication.

Biologics are another option for treating certain joint conditions. They are artificially synthesised analogues of naturally occurring proteins that block the action of inflammatory cytokines such as TNF, and include etanercept and the monoclonal antibodies adalimumab and infliximab. Since TNF-alpha enhances HIV replication in test-tube studies, researchers speculate that these TNF-alpha blockers may have antiretroviral activity. Clinical studies of these drugs in HIV-positive people are in their early stages, but look promising. The drugs do not seem to exacerbate HIV disease and appear to be relatively safe if used prudently and with regard for the potential for other infections.

People living with arthritis often try to manage the condition through changes in their diet and supplementation, and many claim some success. Supplements with anecdotally reported success include glucosamine and chondroitin, fish oils or omega-3 fatty acid supplements, gamma-linolenic acid (found in evening primrose, blackcurrant seed or borage seed oils) or other herbal therapies such as feverfew or willow bark extract. Other people adjust their diet, excluding gluten or other common food allergens, or following a vegetarian or Mediterranean diet. Quality placebo-controlled studies report some benefit linked to some of these dietary changes and supplements: people often feel fewer symptoms and some measures of disease improve. However, there is not one option that is clearly better and so, just as with HIV, people often try different approaches and see what works for them.

Remember, it is important to tell your HIV healthcare team about anything you are taking, including supplements and herbal remedies, in case there are interactions with your HIV treatment.