Auxiliary Therapy

“Several drugs in common use have well characterized HSRs [hyper-sensitivity reactions], as typified by ß-lactam antibiotics – the most frequent cause of cutaneous drug reactions. Reactions mostly affect the skin [typically exanthema, nonimmediate urticaria, Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis or acute generalized exanthematous pustulosis (AGEP)], but can manifest as DHS [drug hypersensitivity syndrome, with symptoms like fever, malaise and “internal organ involvement of varying severity”], most commonly involving the liver, lungs and/or kidneys. Serious systemic HSRs are also associated with anticonvulsants, sulfonamide antimicrobials [often given to HIV-positive people], dapsone [ditto] and allopurinol. Rechallenge after an initial reaction can cause a more intense and immediate reaction. Controlled rechallenge (drug provocation testing), either with the culprit drug or a pharmacologically related agent, is therefore contraindicated following most DHS, with the risk of a more severe reaction weighing heavily against any therapeutic benefit.”

“A 19-year-old man was diagnosed with HIV 3 months earlier, with a self-reported history of purple skin lesions that appeared 2 years before and spontaneously remitted. At diagnosis he had extensive nodal and mucocutaneos KS [Kaposi’s Sarcoma], with a CD4 cell count of 182 cells/ml (13%) and a viral load of 21 000 copies/ml. He started antiretroviral therapy with lamivudine, stavudine, indinavir and ritonavir…He experienced an initial flattening of the KS lesions after 52 days, and was hospitalized with fever, vomiting and diarrhoea. Based on the time between the initiation of HAARTand an increase in CD4 cell numbers at the onset of the symptoms (an increase of CD4 cell count from 182 to 322 cells/ml in 18 days, last viral load 1840 copies/ml), IRIS was diagnosed by his original attending physician, who prescribed prednisone 20 mg twice a day and the patient was discharged. After 2 weeks of prednisone, he experienced an explosive growth of mucocutaneous [internal skin] lesions, facial oedema [swelling] and haemorrhagic [bleeding] lesions in both eyes. He reported that he perceived the oral lesions growing in a matter of hours, and was referred to our institution. An emergency tracheotomy was performed, steroids were withdrawn and a first cycle of 2mg vincristine and 15 mg bleomycin was administered. He developed Streptococcus pneumoniae purulent otitis media and thrombocytopenia. He was discharged with a silver cannulae, oral amoxycillin and unchanged HAART. Three weeks later he was hospitalized with epistaxis and profuse bleeding of the exophytic lesion in the oral cavity. Antiretroviral therapy was stopped, platelet aphaeresis was transfused and 5 days later a second course of bleomycin and vincristine was administered. He was discharged with a marked remission of all KS lesions as well as of the lymphoedema. He resumed HAART 2 weeks later…In the present case, a life-threatening exacerbation of KS shortly after steroids were used to treat IRIS was seen. In other corticoid-related KS manifestations in the literature, the onset was not explosive nor life threatening, and all remitted by simply removing steroids. The potential additive effects of IRIS with steroid use in KS, contraindicates its use as an anti-inflammatory therapy ISSN 0269-9370 Q 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 663”

“Cytomegalovirus (CMV) retinitis is one of the most devastating complications of the acquired immunodeficiency syndrome (AIDS) and the most common ocular opportunistic infection among patients with AIDS. It is a necrotizing, blinding form of retinitis…In the multivariate model, only steroid use was a statistically significant predictor of CMV retinitis”

“The protease inhibitor class of antiretroviral agents is associated with the unwanted side effect of hypertriglyceridemia, which is usually treated with either…statins…or fibrates. However, since statin therapy is intrinsically immunomodulatory, we questioned whether the T-cell response of patients who received PI-based therapy plus statin differed from the response of patients on PI therapy alone or on PI therapy with a fibrate…35 patients who had received ritonavir/saquinavir-based antiretroviral therapy for 5 or more years were evaluated and stratified into four treatment groups…T-cell responses were similar in all four groups before they were exposed to lipid-lowering agents. After the addition of lipid-lowering agents, absolute CD4 T-cell responses were lower in the statin group than in [the other three] groups, when measured after 6, 12, and 18 months of treatment.”

“PCP [Pneumocystis carinii pneumonia] accounted for 39 of 116 (33%) AIDS-defining illnesses. Kaplan–Meier survival curves did not demonstrate a statistically significant difference in the rate of disease progression for children who began PCP prophylaxis within 6 months of birth compared with those untreated [i.e. PCP treatment was of no value]”

“A total of 167 adverse events were recorded in 99 (54%) of the 183 patients for whom data on therapy [either for TB alone, or for TB and AIDS] were available. Adverse events led to cessation or interruption of either their TB or HIV therapy in 63 [34%]. The most common side effects noted were peripheral neuropathy [21%; damage to peripheral nerves], rash [17%], gastrointestinal [10%; e.g. nausea, vomiting, abdominal pain, diarrhea], hepatitis [6%; liver disease] and neurological events [7%; e.g. seizures, memory loss, optical nerve damage, paranoid psychosis]...Other adverse events [include] Arthralgia [joint pain]...Drug hypersensitivity excluding rash...Hyperuricaemia/gout...Pancreatits [inflammation of the pancreas]...anaemia...pigmentation...neutropenia...retro-orbital pain...and cholestasis”

“In addition to previous clinical and laboratory publications this work by Kwak and colleagues has provided a firm scientific rationale to support the use of statins as adjunct immunosuppressive agents in organ transplantation. [Statins are often used to counteract the increase of lipids induced by HAART, but consequently increase immune suppression in people who are already immune-suppressed]”

“myelosuppression [deficiency of white blood cell production] and neutropenia [deficiency of one type of white blood cells responsible for clearing bacteria and cellular debris] may result from any one of several medications commonly used in HIV-infected patients [including nucleoside analogs AZT, 3TC, ddI, ddC and d4T as well as anti-PCP therapies Trimethoprim, Pyrimethamine and Pentamidine]”

“In January 1998 a 26 year old man who was HIV positive started taking stavudine..., didanosine..., and nevirapine...because of a falling CD4 count (250x10^6/l), high viral load (81,747 copies/ml), and symptoms related to HIV. He was receiving no other treatment. He had no additional risk factors for pancreatitis. Response to treatment was good: the viral load decreased to undetectable levels, the CD4 count increased to 470x10^6/l, and the symptoms improved, enabling the patient to resume full time employment. In June 1999 the viral load increased to 1390 copies/ml despite the patient's adherence to treatment, so treatment was intensified with hydroxyurea 500 mg twice daily (Hydrea, Bristol-Myers Squibb). The viral load decreased to 237 copies/ml. The patient began to experience malaise and pain in the upper abdomen. This was attributed to the hydroxyurea, which was stopped after 42 days. The symptoms worsened, and three weeks later he was admitted to hospital with severe pain, vomiting, fever, tenderness of the upper abdomen, and guarding...Computed tomography showed changes consistent with pancreatitis. All drugs were stopped. The patient made an uneventful recovery with conservative treatment. He is no longer taking antiretroviral drugs”

“We report a case of sarcoidosis beginning after 2 months of interleukin-2 (IL-2) therapy in a patient with HIV who had undetectable plasmatic viral load under HAART and we discuss possible mechanisms...IL-2 [Interleukin-2] plays a pivotal role in the pathology of sarcoidosis [formation of nodules in the lungs, liver, lymph nodes and salivary glands].”

“RhuIL-10 [Recombinant Inter-Leukin 10] was generally well tolerated. [Out of 39 HIV-positive subjects] 2…required discontinuation due to thrombocytopenia [deficiency of platelets]. 1 patient…who had chronic hepatitis B and C infections discontinued drug because of elevated liver function tests…Fatigue, headache, nausea and dizziness occurred moer frequently in subjects receiving rhuIL-10 than…placebo (8/29 vs. 1/10, 8/29 vs. 2/10, 6/29 vs. 1/10 and 4/29 vs. 0/10 for each adverse event, respectively).”

“the potential benefit gained from an increase in the number of CD4 cells needs to be balanced against the toxic effects of the treatment. In the study by Davey et al, 54% of the patients receiving IL-2 [Interleukin-2] with HAART had serious adverse effects compared with 16% of patients receiving HAART alone. Studies demonstrating a clinical benefit from IL-2 therapy are needed before it is adopted as a complementary option in conjunction with antiretroviral therapy.”

“IL-2 [Interleukin-2] recipients experienced more adverse events than recipients of ART [standard antiretroviral therapy, not including IL-2] alone. The most common toxic effects experienced by IL-2-treated patients were constitutional symptoms of fever, fatigue, and myalgias of varying severity. Per protocol-defined guidelines, mild-to-moderate symptoms were managed by scheduled administration of alternating acetaminophen and ibuprofen, oral hydration, oral narcotics to control rigors, and rest. More serious or sustained symptoms were managed by omitting a scheduled dose, dosage reduction, or both, as required. Despite these measures, serious (at least grade 3) adverse events occurred in 20 (54%) of 37 evaluable IL-2 recipients and 7 (16%) of 43 ART recipients.”

“A higher proportion of those on combination therapies with and without PIs [Protease Inhibitors] reported taking vitamin and mineral supplements in the past 3 months compared with those in the monotherapy (41%), no treatment (31%) and HIV-negative (30%) groups. A significantly lower proportion of those on PIs reported injecting drugs (20% versus 50%) and drinking any alcohol (47% versus 64%) than the other groups combined [meaning that better health in people taking PIs could be, at least in part, due to factors other than the drugs]”

“Among severely ill patients, mortality was 3-fold higher when corticosteroids were given according to CDC guidelines. Our findings suggest that that the utility of adjunctive corticosteroids in severe PCP needs to be revisited.”

“We present a case of paradoxical clinical deterioration during antituberculosis therapy in an HIV-infected adult with pulmonary TB. The clinical course was characterized by marked cervical and mediastinal adenopathy accompanied by fever and weight loss during simultaneous treatment of TB and HIV disease”

“We recently treated a patient with intractable ulcerative colitis complicated with Pneumocystis carinii pneumonia in whom sulfamethoxazole/trimethoprim caused pneumonitis. The pneumonitis was difficult to differentiate from worsening of the infection or the appearance of another opportunistic infection.”

“The present study reveals a relationship between the occurrence of adverse reactions to TMP-SMZ [strong antibiotics often given to HIV-positive people to prevent pneumocystis carinii pneumonia] and the course of HIV infection. Adverse reactions to TMP-SMZ were associated with a more rapid progression to AIDS and death and with a more rapid decline in CD4+ cell counts...A low CD4+ cell count, repeated CD4+ cell counts below 200/mm3, T cell reactivity at baseline, and...the use of antiretroviral agents before the start of prophylaxis were also statistically associated with a more rapid progression to AIDS and death”

“the use of systemic corticosteroids in immunocompromised patients is generally to be avoided. Patient 3…did not demonstrate any contraindications to corticosteriod therapy. Unfortunately, it appears his disease was exacerbated [resulting in retinal detachment and complete blindness in both eyes] by the corticosteroid use”

“Glucocorticoids caused immunosuppression, provide selective growth advantage to various microorganisms including the fungi, and enhance replication or reactivation of latent viruses (e.g. EBV, CMV, Kaposi's sarcoma-associated herpes viruses)…A very strong linear correlation exists between saliva cortisol level and concentration of free cortisol in blood…High circulating levels of glucocorticoids suppress immune and inflammatory responses…Our study population consisted of 23 HIV-positive subjects (18 males and 5 females, ages 24-48 yr) and 14 HIV-seronegative controls matched for age, ethnicity and gender…12 of these HIV-infected subjects were asymptomatic…2…had pseudomembranous candidiasis…two had severe HIV-related periodontitis, and one patient had histologically confirmed oral Kaposi's sarcoma (KS). All the HIV-positive patients were from the intravenous drug use risk group…Kaposi's sarcoma (KS), a tumor which has become epidemic in HIV-infected patients, often presents with oral lesions. Corticosteroid therapy has been linked with increased risk of KS in both HIV-infected and non-infected patients…Another frequent HIV/AIDS-associated oral lesion is necrotizing ulcerative gingivitis (NUG). Prior to the AIDS era, NUG in the developed world was primarily a disease of young adults subjected to the stress of military life and/or college examinations. Such individuals usually have high salivary cortisol levels. In the developing world, it was exclusively a disease of malnourished children who generally had high blood levels of cortisol. We therefore conclude that increased levels of corticosteroids in blood and saliva may be of some relevance to the frequency and clinical progression of some common HIV/AIDS-associated oral lesions.”

“Drug reactions are common in patients infected with human immunodeficiency virus (HIV). Administration of trimethoprim-sulfamethoxazole (TMP-SMZ) is associated with adverse reactions in 40% to 80% of HIV-infected patients. However, pulmonary reactions have been rare...We report a patient who developed two episodes of acute pulmonary edema [fluid on the lungs] after administration of ibuprofen [although perhaps TMP-SMZ was involved]”

“Thirty-nine patients who have not had a transplant have been reported to have KS associated with corticosteroid therapy…The authors studied 10 patients with the appearance of KS during corticosteroid therapy (6 men, 4 women; age range, 42-79 years)…Most patients had received prednisone, one had received triamcinolone, and one had received betamethasone and methylprednisolone…The interval between initiation of steroid therapy and appearance of KS lesions ranged from 3 months to more than 36 months…4 patients experienced complete regression of the KS lesions: in one after steroid withdrawal, in one after steroid withdrawal and radiation therapy, in one with no change in steroid dosage, and in one with radiation therapy. 4 patients experience partial regression after reduction or withdrawal of steroids. In two patients there was no progression after reduction of the steroid dosage. One of the patients who had a partial regression…exhibited progression of the lesions after reinstitution of steroid therapy.”

“Both drug-induced eosinophilic pneumonias and interstitionephritides may occur after treatment with sulfonamides and penicillin. Reports about the glomerular [filtration portion of kidneys] diseases due to these drugs are rare [but one is reported in this paper]”

“This study monitored adverse drug reactions during treatment for tuberculosis [in Zambia] over an 18 month period (1 April 1990 to 31 October 1991) in 237 children with a clinical diagnosis of tuberculosis (125 boys and 112 girls; 88/237 (37%) infected with HIV-I) and 242 control children (149 boys and 93 girls; 26/242 (11%) infected with HIV-I). 22 (9%) of the 237 children with tuberculosis developed hypersensitivity skin reactions during the course of treatment…12 (55%) of the 22 children who reacted adversely to treatment developed the Stevens-Johnson syndrome. All 12 of these children with the Stevens-Johnson syndrome were infected with HIV [HIV antibody-positive, to be precise]. The mortality among these children who developed the Stevens-Johnson syndrome was 91% (11 of 12 died within three days of the onset of the reaction). No further reactions were observed in the 11 children who recovered from the cutaneous hypersensitivity reactions after thiacetazone was discontinued over a period of six months of further treatment of tuberculosis.”

“The rapid response of the infiltrate and peripheral blood eosinophilia to withdrawal of trimethoprim-sulfamethoxazole and corticosteroids is suggestive of drug-induced disease in this case”

“The [CDC] has recommended prophylaxis for [PCP] in patients with HIV infection who have had a previous episode of [PCP], have [low CD4 immune cell counts]...Unfortunately, 29-50% of patients with HIV infection develop adverse reactions to this regimen. The most common of these have been rash, fever, nausea, altered taste, pruritis [rash], leukopenia [depletion of leukocytes, white blood cells], thrombocytopenia [loss of platelets, blood clotting cells] and hepatitis. We now describe a patient who developed fever and acute hypoxemia mimicking early PCP as a complication of trimethoprim-sulfamethoxazole prophylaxis”

“We report on a patient who developed hypersensitivity pneumonitis induced by trimethoprim [bactrim]”

“a 23-year-old homosexual man with human immunodeficiency virus infection developed progressive exertional dyspnea [difficulty in breathing]...[after diagnosing pneumocystis carinii pneumonia] the patient was started on oral TMP/SMX [sulfa antibiotics]...after 7 days he developed patchy erethema and hives over his trunk and arms. These resolved after one day off medication. He did well until dyspnea recurred...and in response took another dose of his prescribed TMP/SMX. He quickly became flushed, diaphoretic, more dyspneic, nauseated and experienced vomiting and diarrhea. A bifrontal headache developed [which resolved after TMP/SMX was withdrawn again]...Re-exposure to TMP/SMX can indeed mimic progression of the underlying pulmonary infection”

“Adverse reactions to trimethoprim-sulfamethoxazole [Bactrim, Septra] are common in persons with [AIDS]. These reactions typically consist of fever, rash and/or neutropenia [depletion of neutrophils, white blood cells]...We observed transient hypotension [low blood pressure], fever, hypoxemia [lack of oxygen in the blood] and pulmonary infiltrates following reinstitution of trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia [PCP] in 2 patients with AIDS. Differentiating this type of reaction...from sepsis or from worsening opportunistic pulmonary infection is important in the management of these patients [i.e. therapy can cause symptoms that are very similar to the disease]”

“Co-trimoxazole has been associated with severe damage to internal organs and neurological symptoms and signs...We report here a case of cerebromedullospinal disconnection association with lesions of the kidney, lung, and pancreas and cardiac arrhythmia after treatment with co-trimoxazole”