A sequential approach to identify the offending ...

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Case Report

A sequential approach to identify the offending medication in HIV sero-positive patients having hypersensitivity to fixed dose combination of HAART Nivedita Dutta a,∗ , Rajyasree De a , Shantasil Pain b , Dolanchampa Modak c,a , Subhasish Kamal Guha c,a a

Department of Centre of Excellence in HIV Care, Calcutta School of Tropical Medicine, 108 Chittaranjan Avenue, Kolkata 700073, West Bengal, India1 Department of Medicine, North Bengal Medical College & Hospital, West Bengal, India c Department of Tropical Medicine, Calcutta School of Tropical Medicine, 108 Chittaranjan Avenue, Kolkata 700073, West Bengal, India b

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Article history: Received 3 October 2013 Received in revised form 4 February 2014 Accepted 5 February 2014 Keywords: Antiretroviral adverse effects Drug rash Rash in HIV/AIDS Sequential approach

a b s t r a c t Aim: Hypersensitivity to the anti-retroviral agents is a common problem encountered in the treatment of HIV/AIDS patients. However, in resource-limited settings, where only fixed-dose combinations of the drugs are the only available option and expensive facilities of pharmacological analysis are not available, isolating the offending agent can be a challenging task. Background: We, at our centre, follow a protocol to isolate such offending drug – a protocol of gradual de-challenge and re-challenge – by a method of exclusion. Materials and Methods: Here, we have described a series of four cases, providing examples of usage of our own protocol to isolate the offending drug by a method of exclusion. Results and Conclusion: In a resource-limited setting, where we have to use fixed-dose combination of anti-retroviral agents, management of a patient with drug hypersensitivity is a problem. Our protocol of systematic de-challenge and re-challenge, as exemplified in these cases, can be of help where expensive facilities are not available. © 2014 Polish AIDS Research Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

1. Introduction Drug hypersensitivity with cutaneous manifestations is more common in individuals living with HIV [1]. With the advent of triple drug Highly Active Anti-Retroviral Therapy (HAART) regimen, the job of identification of the causal or offending agent for drug induced hypersensitivity is a challenging one. The clinical spectrum of hypersensitivity reactions observed in HIV-infected individuals is clinically similar to that seen in patients without HIV infection, ranging from mild cutaneous symptoms to severe systemic manifestations within 6 weeks of drug initiation [1]. Commonly observed cutaneous symptoms are urticaria,

∗ Corresponding author at: Tower 6, Flat-7/6, Ruchira Residency, 369 Purbachal Kalitala Road, On E.M. By Pass, Kolkata 700078, West Bengal, India. Tel.: +91 09831124545; fax: +91 33 22123704. E-mail addresses: [email protected], [email protected] (N. Dutta), de [email protected] (R. De), [email protected] (S. Pain), [email protected] (D. Modak), [email protected] (S.K. Guha). 1 Tel.: +91 33 22123704; fax: +91 33 22123704. E-mail address: [email protected].

erythema, morbilliform and maculopapular confluent eruptions, with or without mucosal lesions. Systemic involvement is characterized by fever, rigors, arthralgia, and myalgia with internal organ involvement like hepatitis, pericarditis, pneumonitis, myocarditis and nephritis. The pathogenesis of drug hypersensitivity in a HIV-positive individual may involve a concurrent viral or opportunistic infection, immune dysregulation or increased susceptibility of HIV infected individuals to oxidative stress [2]. Sometimes, it is difficult to know with certainty that there is an association between the use of a particular drug and the adverse event. Hence confounding conditions like another coexisting illness, immune reconstitution syndromes, viral or bacterial infections, have to be ruled out if it occurs within the same time frame. The history of multiple medications, both antiretroviral and others also complicates the scenario. 2. Drug hypersensitivity in HIV Skin rashes in HIV-positive individuals have been classified into four different grades by Division of AIDS, National Institute of Allergy and Infectious Diseases, USA. Severe skin eruptions like

http://dx.doi.org/10.1016/j.hivar.2014.02.004 1730-1270/© 2014 Polish AIDS Research Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Please cite this article in press as: N. Dutta, et al., A sequential approach to identify the offending medication in HIV sero-positive patients having hypersensitivity to fixed dose combination of HAART, HIV & AIDS Review (2014), http://dx.doi.org/10.1016/j.hivar.2014.02.004

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2 Table 1 Rashes are graded as:. Grade 1

Grade 2

Grade 3

Grade 4

Erythema, Pruritus

Diffuse maculopapular rash or dry desquamation

Vesiculation or moist desquamation or ulceration

Any one of: mucous membrane involvement, suspected Stevens Johnsons (TEN), erythema multiforme exfoliative dermatitis

Source: Division of AIDS, National Institute of Allergy and Infectious Diseases; USA-Modified.

Stevens Johnson’s Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) develop in less than 0.5% of HIV patients [3]. Blistering affecting less than 10% of body surface area is termed as SJS, more than 30% is classified as TEN, and the grey zone from 10 to 30% is known as the overlap syndrome [4]. Commonly involved are the conjunctiva, oral and genitourinary mucosa (Table 1). 3. Antiretrovirals Worldwide, rash is commonly noted with the use of NonNucleoside Reverse Transcriptase Inhibitors (NNRTIs) – incidence of drug hypersensitivity & rash has been reported in 10–17% of patients [3]. While the incidence of moderate to severe rash is approximately 8–12%, rash-related discontinuation rates range from 2 to 10% [5]. Presence of genetic predisposition to drug hypersensitivity has been proven with the case of abacavir which is strongly associated with the class I MHC allele, HLA-B*5701. Hence, recent trend in resource-unlimited settings is to stress on the preventive screening for its sensitivity before initiation. Screening and exclusion of the other drugs are however difficult – clinical monitoring is the only way to find out the offending agent. Nevirapine, a NNRTI, has been shown to be associated with more severe types of skin rash and reactions. Rash has been documented in over 35% of patients started on nevirapine [6]. Severe reactions associated with fever and hepatitis have occurred in approximately 5% of those initiating nevirapine [7] and SJS/TEN occurs in approximately 0.3% [8]. Efavirenz (EFV), another NNRTI, has also been documented to cause rash in 10-27% of patients – mostly showing isolated rash with little or no systemic symptoms [9]. Hence, patients with EFV rashes usually do not require discontinuation of the drug; symptomatic treatment with antihistamines or topical steroids are sufficient [10]. As both NVP and EFV belong to the same class of NNRTI and have a possibility of sharing drug related hypersensitivity the use of EFV is commonly avoided by the clinicians once hypersensitivity to any of these drugs is reported. Although there are reports of drug hypersensitivity with nearly all antiretroviral drugs, still the most commonly associated ones include: abacavir, a nucleoside analogue; the nonnucleoside reverse transcriptase inhibitors (NNRTIs; nevirapine, efavirenz, delavirdine); atazanavir, darunavir, fosamprenavir, all HIV protease inhibitors and enfuvirtide, an HIV fusion inhibitor. Pruritus, maculopapular rash, urticaria, have been reported in 5–7% of the patients treated with Tenofovir. Zidovudine has been seen to cause very rarely mild to moderate skin rash. Rate of maculopapular rash with Lopinavir has been estimated to be around 4% [11]. A mild rash has been described in HIV-infected patients treated with atazanavir with an incidence of 6% [12]. Among second generation NNRTIs, Etravirine is associated with skin rash – which is reported to be its main toxicity – most commonly mild to moderate in severity and self-limiting in nature, although some severe and fatal cases have also been reported [13]. Even the newer class of anti-retroviral drugs like Integrase Inhibitors are also associated with drug rash. The first USFDA-approved Integrase Inhibitor – Raltegravir – was associated with skin rash [14].

As mentioned, adverse drug reactions or idiosyncratic reactions often compromise good care of HIV-positive individuals. If the rashes are of low grade without any systemic symptoms or mucosal involvement, then the patient may be treated through the rash requiring only the support of antihistaminic medications. Otherwise, stoppage of the offending regimen is usually warranted and re-challenge with the offending drug should be done very cautiously to avoid fatal consequences. Identification of the offending drug for any drug-induced hypersensitivity reaction is of paramount importance and depends on careful evaluation of the temporal relationship, the effects of sequential dechallenge and rechallenge, and, at the same time, exclusion of other causes [4]. As drug-induced rash is a major cause of drug withdrawal causing interruption of antiretroviral treatment contributing to the high level of attrition encountered in HIV treatment at outpatient clinics, clinicians have no option but to shift a large number of patients to protease inhibitors in the first line ART regimens due to hypersensitivity to drugs. Patients are thus deprived of the NNRTI based first line essential medications and rapid switchover to Protease Inhibitors (PI) regimens at an early stage leaves little future options for patients when drug resistances begin to appear. In a resource limited setting as in India where the clinicians have to depend on their own practical judgment, they have to be extra cautious not to jump onto biased opinions and reject essential drugs in the antiretroviral regimen. Rather a stepwise sequential approach would be more practical to search for the offending drug which attempts to pin down the offender saving the other vital options. Here we are going to present four cases of druginduced rash depicting the sequential approach practiced at the State AIDS Clinical Experts Panel at the Centre of Excellence in HIV Care, Kolkata, West Bengal, India to find out the offending drug. 4. Method HIV/AIDS prevention and treatment in India is under the umbrella of the National AIDS Control Organisation (NACO) – the Centres of Excellence (COE) in HIV Care are nodal centres under NACO which provide comprehensive care for persons affected by HIV, impart training and undertake second line rollout of patients who show failure with first line drugs. All patients with history of intolerance to ART are referred to SACEP for expert opinion-State AIDS Clinical Experts Panel (SACEP) review the patients referred with suspected treatment failure and drug toxicities. As per the NACO Guidelines, Co-trimoxazole is given to all patients with CD4 below 250 cells/␮L for two weeks prior to starting Anti-Retroviral Treatment (ART).ART is started with two NRTI Zidovudine(AZT)/Tenofovir(TDF)/Lamivudine(3TC) with one NNRTI – Nevirapine(NVP)/Efavirenz(EFV), usual combination is AZT/3TC/NVP – therefore hypersensitivity with this regimen may be attributable to any of the three drugs. Rash, which is morbilliform, maculopapular, with no systemic or mucosal involvement does not require discontinuation of the drug. Often patients develop advanced Grade 3 or 4 rash for which they are unable to continue the first line medications and are referred to the COE for

Please cite this article in press as: N. Dutta, et al., A sequential approach to identify the offending medication in HIV sero-positive patients having hypersensitivity to fixed dose combination of HAART, HIV & AIDS Review (2014), http://dx.doi.org/10.1016/j.hivar.2014.02.004

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expert opinion. Most drug reactions are usually caused by any of the NNRTI, i.e NVP or EFV but cases have been documented showing hypersensitivity to Lamivudine or even rarely to Zidovudine. Till date, at our nodal centre we have documented 2 cases of rash with both NNRTI and ATV, 3 cases with AZT rash, 11 cases of 3TC rash, 52 cases of rash to both NNRTI and over a hundred patients have been documented with rash to only NVP. Among the first-line anti-retrovirals, the single most common offending agent is nevirapine [4], it is substituted with Efavirenz in cases where severity of rashes has not reached Grade 3 or 4, or in other words there has neither been any mucosal involvement or systemic symptoms. Wit et al., reporting the results of the ATHENA Cohort Study suggested that majority (>90%) of HIVinfected patients with CD4 counts >200 cells/␮L who had preceding Nevirapine-associated rash could tolerate Efavirenz well suggesting that use of EFV is safe in these cases [15]. Nevertheless most clinicians are unwilling to restart patients on EFV once severe rashes are documented with NVP, as both are from the same class of NNRTI and unfortunately, shift the patient to PI based regimen, thereby limiting their future treatment options. The WHO-Uppsala Monitoring Centre (WHO-UMC) causality assessment system is frequently used to classify the causality assessment of drug adverse reactions and categorize the relationship between an offending drug and the observed adverse reaction as certain or definite, probable, possible and unlikely or doubtful. A definite reaction was one that followed a reasonable temporal sequence after a drug or in which a toxic drug level had been established in body fluids or tissues and was confirmed by improvement on withdrawing the drug and reappeared on re-exposure. Probable reactions are unlikely to be attributed to disease or other drugs, with reasonable time relationship to drug intake. A possible event could be explained by disease or other drugs. Unlikely or doubtful events are those where the time relationship is improbable. At our setting, relationship between the drug and the observed adverse reactions, mostly are of either ‘probable’ or ‘possible’ category; as a result, a sequential approach with dechallenge and rechallenge is commonly performed (Table 2). Here are a few unusual cases which highlight the clinical method of sequential dechallenge and rechallenge adopted at our centre to single out the offender drug. Though NNRTIs are the usual offending agent, in this series we are presenting examples of hypersensitivity to some usually well-tolerated drugs – namely, Lamivudine and Zidovudine. 4.1. Case report 1 A 43-year-old HIV seropositive asymptomatic male, with baseline CD4 234 cells/␮L was started on antiretroviral treatment with regimen Zidovudine, Lamivudine and Nevirapine. He had tolerated Co-trimoxazole prophylaxis for 2 weeks prior to starting ART. After 21 days of ART initiation he presented with diffuse erythematous morbilliform rashes over both arms, chest, spreading gradually to involve the back and the whole trunk. On physical examination he was afebrile, with no systemic symptoms and no mucosal involvement. Routine blood investigations were within normal range (serial serum tryptase for anaphylaxis were not done in limited resource settings). First drug to be suspected was Nevirapine. After a span of 3 weeks when almost all lesions had disappeared he was started on regimen with Zidovudine, Lamivudine and Efavirenz. Similar rashes but with a more widespread distribution reappeared within 12 days. All drugs were stopped until complete resolution of lesions. Cotrimoxazole was never restarted to avoid confusion. Suspecting NNRTI to be the offender he was next started on a protease inhibitor based combination of Zidovudine, Lamivudine, Atazanavir boosted with Ritonavir but rashes reemerged after only 7 days. As Zidovudine and Lamivudine were the common

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Fig. 1. Case report 1.

denominator in all three ARV regimens, next suspect was Lamivudine. Rechallenge was done with Zidovudine and Lamivudine and rashes reappeared after two doses. Finally to close the search for the causative agent only Zidovudine was given which was well tolerated. He was started on regimen with Tenofovir, Zidovudine, Efavirenz and did not develop any rash. We may conclude that in this case Lamivudine was the offending agent (Fig. 1). 4.2. Case report 2 An HIV seropositive woman aged 33 years, with Stage 1 disease and baseline CD4 348 cell/␮L developed Grade 2 pruritic, erythematous, maculopapular rashes after 25 days of initiation of Antiretroviral with Zidovudine, Lamivudine and Nevirapine. Suspecting nevirapine to be the offender, the regimen was changed to Zidovudine, Lamivudine, Efavirenz. Within 3 days the patient returned with extensive pruritic, papular rashes with few blistering over the arms and upper chest. Physical examination revealed conjunctival congestion and this time, she was febrile. Cotrimoxazole had not been given. All medicines were discontinued for 4 weeks until complete resolution of the rashes. She was then started on Zidovudine, Lamivudine, Atazanavir with ritonavir boostering. On the 3rd day patient returned with reappearance of rashes and all drugs were again stopped. The only 2 ART that were common to all regimens were Zidovudine and Lamivudine; hence clinical suspicion was that either of them was responsible for hypersensitivity. Patient was given a trial of Zidovudine and Lamivudine under observation with available emergency facilities to manage severe allergy or anaphylaxis. Diffuse erythema appeared after the third dose. All ART was stopped for 7 days and then she was given a trial with only Zidovudine. Vesiculations and morbilliform rashes emerged only after a single dose. The rechallenge yielded definite temporal relationship and it was finally concluded that Zidovudine was the causal drug (Fig. 2). 4.3. Case report 3 HIV seropositive 31 year old female with baseline CD4 280 cells/␮L presented with Grade 4 rash after 21 days of initiation of Antiretroviral regime with Zidovudine, Lamivudine and Nevirapine. Rash was associated with low grade fever, oral ulcers, conjunctival congestion, and blistering over forearms, back and legs. Lesions involved less than 10% of her body surface area. All medications were stopped until complete resolution of the rashes. Cotrimoxazole was not given. Systemic examination was unremarkable. Following complete resolution she was started on

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Table 2 The sequential approach with dechallenge and rechallenge is summarized.

PI based regimen with Zidovudine, Lamivudine, Ritonavir boosted Atazanavir. Only after intake of a single dose of Zidovudine, Lamivudine she complained of severe urticaria, and examination showed erythema with blanching. As in the previous cases, clinical

suspicion was that Zidovudine or Lamivudine might be the offending drug. Patient was rechallenged with only Zidovudine for 5 days under observation, which was well tolerated. Definite inference was drawn by exclusion – hypersensitivity to Lamivudine. She

Please cite this article in press as: N. Dutta, et al., A sequential approach to identify the offending medication in HIV sero-positive patients having hypersensitivity to fixed dose combination of HAART, HIV & AIDS Review (2014), http://dx.doi.org/10.1016/j.hivar.2014.02.004

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Fig. 2. Case report 2.

was advised regimen excluding Lamivudine and till date she is on triple drug of Zidovudine, Tenofovir, Efavirenz. 4.4. Case report 4 In another similar case a 39-year-old man, seropositive with baseline CD4 333 cells/␮L and initial regimen Zidovudine, Lamivudine and Efavirenz returned to ART clinic only 8 days after initiation of antiretroviral regimen with widespread erythematous blanching rash. As per National guidelines Cotrimoxazole was not given. His SGPT was raised and hence NVP was not advised. After all rashes had evaded he was started on treatment with Zidovidine, Lamivudine, Atazanavir boosted with Ritonavir. Only after 4 days he presented at emergency with fever, papular pustular rashes over chest, back and both arms. All medicines were stopped and he was treated as inpatient symptomatically with antihistaminics. After all rashes had resolved he was rechallenged with only Zidovudine and Lamivudine for 7 days. As these two drugs were tolerated by the patient and therefore by exclusion either Efavirenz or Atazanavir was the offender he was next started on Zidovidine, Lamivudine, Lopinavir boosted with Ritonavir. This regimen was well tolerated by him (Fig. 3). 5. Discussion Worldwide, significant progress has been made in the development of antiretroviral medications with an array of drugs to choose an ideal regimen. However, confronted with cases of drug

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hypersensitivity, it is still a challenge for the clinicians in a resource limited setting to determine with certainty the offending drug. A major problem in drug-monitoring studies is the lack of a reliable method of assessing the causal relation between drugs and adverse events. Lack of detailed history taking techniques and inadequate documentation make the job more difficult. Often sequential dechallenge and rechallenge is the only rational tool left for causality assessment. The fine line between WHO-UMC defined classes like certain, possible or probable drug causing hypersensitivity often remains unclear. Especially in situations where fixed dose antiretroviral formulations are the only available option supplied by the Government Programme, determining the ‘causal offender’ may be a big challenge. In a resource-limited setting like ours, particularly when we have only fixed-dose combination HAART at our disposal, managing a patient with drug rash is a challenging task. Pharmacological analysis would be of limited help as the patient is receiving multiple drugs. Rigorous statistical causality analysis is also often not feasible. Practices of evidence-based medicine can be of help to isolate the most probable offending agent – the most probable offending agent should be the one which is most often reported to be associated with such adverse reactions. Therefore, we have developed this logical sequential approach of dechallenge and rechallenge – where the most common offending agent is discontinued first and we look for clinical improvement of rash; if the rash does improve, we restart the discontinued drug and look for the less probable agents. After a patient develops hypersensitivity to NVP, depending on the grade of rash (grade 1 or 2), patients are reinitiated with another NNRTI – EFV – only if the preceding rash had low grade severity with no mucosal involvement. With severe anaphylaxis or allergy the next recommendation is to start with a protease inhibitor based regimen. After resolution of the rashes either RTV boosted ATV or LPV is added. To eliminate any overlapping of symptoms Cotrimoxazole and other drugs with potential of rash are withheld till the offender is identified. If rashes reappear with PIs, next suspicion is NRTI intolerance which forms the common backbone. While stopping drugs with long half-life and low genetic barrier for development of drug resistance (e.g. NVP, EFV), often the dual NRTI backbone of the regimen is continued for 1–2 weeks to prevent emergence of resistant mutants. When the need for rechallenge arises, among the 3 drugs AZT/TDF/3TC, AZT or TDF are the preferred drug for rechallenge, as although there are reports of rash with AZT or TDF but the incidence is very low. As 3TC has very low genetic barrier for drug resistance (M184V) [16], therefore it is never re-challenged alone while reintroducing antiretroviral in sequential drug challenge. On the other hand a minimum 3 Thymidine Analogue Mutations [17] are needed for clinically significant drug resistance in AZT or TDF and hence they have high genetic barriers for development of resistance (K65R), making them the preferred agent for rechallenge and trials.

Financial disclosure This is a case series, describing the events in the antiretroviral toxicities. So, there is no added financial issues.

Conflict of interest statement

Fig. 3. Case report 4.

The authors share no financial or personal interests in such cases and they are free to declare so.

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Acknowledgements We would like to extend our sincere thanks to the Prof. (Dr.) Nandita Basu, Director, Calcutta School of Tropical Medicine, Kolkata, for providing the permission to study the cases. We sincerely appreciate the help and support received from the Dr. B.B. Rewari, National Programme Officer, National AIDS Control Organization (NACO) and thank him for his full cooperation and assistance given during the course of this study. References [1] S.A. Coopman, R.A. Johnson, R. Platt, R.S. Stern, Cutaneous disease and drug reactions in HIV infection, N Engl J Med 328 (1993) 1670–1674. [2] E. Phillips, S. Mallal, Drug hypersensitivity in HIV, Curr Opin Allergy Clin Immunol 7 (August (4)) (2007) 324–330. [3] A. Carr, D.A. Cooper, Adverse effects of antiretroviral therapy, Lancet 356 (October) (2000) 1423–1430. [4] M. Chaponda, M. Pirmohamed, Hypersensitivity reactions to HIV therapy, Br J Clin Pharmacol 7 (1) (2011), pp. 5/659–671/659. [5] A. Sivadasan, O.C. Abraham, P. Rupali, et al., High rates of regimen change due to drug toxicity among a cohort of South Indian adults with HIV infection initiated on generic, first-line antiretroviral treatment, J Assoc Physicians India 57 (2009) 384–388. [6] P. Barreiro, V. Soriano, E. Casas, et al., Prevention of nevirapine-associated exanthema using slow-dose escalation and/or corticosteroids, AIDS 14 (2000) 2153–2157.

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