Drugs used to treat PCP pneumonia and tuberculosis, the most common AIDS-defining illnesses, are significantly more likely to cause adverse reactions in HIV-positive patients than HIV-negative individuals, according to a review article published in the September edition of the Annals of Pharmacotherapy. The authors also found that HIV-positive individuals who were taking anticonvulsants were more likely to experience adverse events than HIV-negative patients who were taking this type of drug.
Adverse drug reactions are a common complication of HIV infection, and it is known that infection with HIV increases the overall risk of experiencing an adverse reaction to a drug. Although many of the drug-related side-effects experienced by HIV-positive patients are predictable and similar to those seen in the general population, other adverse drug reactions are more unpredictable and related to alterations in the way HIV-positive individuals metabolise drugs, or to immune damage caused by HIV.
Investigators wished to determine the incidence, symptoms and possible causes of adverse drug reactions caused by three common classes of treatment that are regularly used in HIV-positive patients. These were sulfonamides for the treatment of PCP pneumonia; anticonvulsants for the treatment of convulsions, pain caused by peripheral neuropathy, and bipolar depression; and, antimycobacterials used to treat tuberculosis. Reports of adverse reactions in HIV-positive patients taking these types of medication were identified in medical literature published between 1980 and 2005.
Sulfonamide antibiotics
PCP pneumonia is a significant cause of illness and death amongst individuals with untreated HIV. Standard treatment for PCP pneumonia is the sulfonamide antibiotic co-trimoxazole. HIV-negative individuals treated with co-trimoxazole have an adverse drug reaction rate of approximately 8% with mild skin and gastrointestinal side-effects being most commonly reported. Serious adverse events related to treatment with co-trimoxazole are rarely reported in HIV-negative patients who receive the drug. However, amongst HIV-positive individuals, the incidence of adverse drug reactions is much higher, with studies reporting rates between 44% and 100%. It should however be noted that significantly higher doses of co-trimoxazole are used to treat PCP pneumonia in HIV-positive patients than are needed to treat infections in HIV-negative individuals.
Studies in HIV-positive children also indicate a high incidence of adverse reactions to co-trimoxazole, with one study suggesting that 40% of children who received the drug developed side-effects to it.
Attention was then turned to other sulfonamide antibiotics. Dapsone is an alternative sulfonamide antibiotic therapy for PCP pneumonia and and sulfadiazine is a treatment for toxoplasmosis. However, these too can cause serious side-effects, including a hypersensitivity reaction involving the skin, kidneys and liver. Of particular concern is the increased incidence of the potentially life-threatening Stevens-Johnson syndrome experienced by HIV-positive patients who are treated with these drugs: this occurs very rarely amongst HIV-negative patients who receive dapsone or sulfadiazine, but in up to 4% of HIV-positive individuals.
Side-effects associated with sulfonamide antibiotics are thought to be caused by a number of factors including bioactivation, direct cellular damage, increased oxidative stress, and poor detoxification.
Antimycobacterial drugs
It is estimated that eleven million individuals are infected with both HIV and tuberculosis worldwide, and in resource-limited countries tuberculosis is the leading cause of illness and death amongst HIV-positive patients.
First-line treatment for tuberculosis in HIV-positive patients is the same as that used in the general population and consists of a combination of antimycobacterial drugs. Four drugs – isoniazid, rifampicin, pyrazinamide and ethambutol - are taken for the first two months of treatment. This is then followed by a further four months of treatment with isoniazid and rifampicin.
A Canadian study found that HIV-positive patients taking tuberculosis therapy were four times more likely than HIV-negative patients to develop an adverse reaction to their treatment. Fever and rash were the most commonly reported symptoms. A further study, conducted in the Cameroon, found that although only 1% of HIV-negative patients developed an adverse drug reaction to their tuberculosis therapy, this rate increased to 23% amongst patients with HIV, with two HIV-positive patients dying of Stevens-Johnson syndrome.
In resource-limited settings, thiacetazone, due to its low cost, is considered an alternative drug to rifampicin for the continuation phase of tuberculosis therapy being taken with isoniazid for six months. But one study found that regimes containing thiacetazone were associated with an 18-fold increase in severe skin side-effects in HIV-positive patients compared to HIV-negative controls. Furthermore, the side-effects experienced by the HIV-negative controls were generally mild, but three fatalities occurred amongst patients with HIV. Another study showed that 5% of HIV-positive children treated with thiacetazone developed Stevens-Johnson syndrome.
Immune activation and the severity of HIV disease are suggested by the authors as a major cause of adverse drug reactions to antimycobacterials experienced by patients with HIV.
The investigators conclude by calling for further research, particularly into the “the mechanisms of increased hypersensitivity to anticonvulsants and antimycobacterial drugs in patients with HIV.” They believe that such research would not only illuminate why these side-effects occur, but also lead to a better understanding of HIV disease itself.
Anticonvulsants
Seizures in patients with HIV can be caused by brain lesions, the effects of HIV on the brain, or drug toxicitiy. Studies suggest that seizures occur in an estimated 11 – 17% of HIV-positive patients not in receipt of potent anti-HIV therapy, and although one study found that this fell to 3% of antiretroviral-treated patients, this is still higher than the 1- 2% reported in HIV-negative patients.
Anticonvulsants are also used by HIV-positive patients to relieve pain associated with peripheral neuropathy and as a therapy for bipolar depression.
Physiologic changes experienced by HIV-positive individuals are thought to affect the distribution, absorption and elimination of anticonvulsants making individuals who are taking them more vulnerable to side-effects. The investigators draw particular attention to the low levels of serum albumin seen in many HIV-positive patients.
High rates of hypersensitivity reactions (up to 14%) occur amongst HIV-positive patients taking so-called aromatic anticonvulsants such as primidone, phenobarbital, carbamazepine, and phenytoin. However, second-generation anticonvulsants such as lamotrigine and gabapentin are less likely to interact with other drugs commonly used in HIV care and are therefore used extensively in patients with HIV. Studies suggest that lamotrigine and gabapentin are no more likely to cause adverse events in HIV-positive patients than a placebo.
Lin D et al. Increased adverse drug reactions to antimicrobials and anticonvulsants in patients with HIV infection. The Annals of Pharmacotherapy 40: 1594-1601, 2006.