Part Of Combination Antiretroviral Therapy Research Articles

Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial

Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients. Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov, number NCT00369941. 566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per microL or less. The main analysis (with non-completion counted as failure) showed that 86.1% (n=241 patients) of the raltegravir group and 81.9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4.2%, 95% CI -1.9 to 10.3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0.0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 [44.1%]) than those on efavirenz (n=217 [77.0%]; difference -32.8%, 95% CI -40.2 to -25.0, p<0.0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group. Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients. Merck.

Update on the Development of HIV Entry Inhibitors

HIV fusion and entry are two steps in the viral lifecycle that can be targeted by several classes of antiviral drugs. The discovery of chemokines focused the attention on cellular co-receptors used by the virus for entering cells, and on the various steps of such processes that are subject to interactions with small molecules. Intense research has led to a wide range of effective compounds that are able to inhibit these initial steps of viral replication. All steps in the process of HIV entry into the cell may be targeted by specific compounds, grouped into three main classes (attachment inhibitors, co-receptor binding inhibitors and fusion inhibitors), which may be developed as novel antiretrovirals. Thus, several inhibitors of the gp120–CD4 interaction have been discovered (e.g., zintevir and BMS-378806). Small molecule chemokine receptor antagonists acting as HIV entry inhibitors have also been described recently, including those which interact with both the CXCR4 co-receptor (e.g., AMD3100, AMD3465, ALX40-4C, T22, T134 and T140) and CCR5 co-receptor antagonists (TAK-779, TAK-220, E913, AK-602 and NSC 651016 in clinical trials). Recently, a third family of antivirals started to be used clinically (in addition to reverse transcriptase and protease inhibitors), with the advent of enfuvirtide (T20), the first fusion inhibitor to be approved as an anti-HIV agent. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, thus offering the rationale for their combination in therapies for HIV-infected individuals. Many HIV entry and fusion inhibitors are currently being investigated in controlled clinical trials, and a number of them are bioavailable as oral formulations. In 2007, the US FDA approved maraviroc as an anti-HIV agent. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin. Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. Furthermore, in October 2007, the FDA announced the approval of raltegravir for the treatment of HIV-1 infection as part of combination antiretroviral therapy in treatment-experienced patients with evidence of HIV-1 replication despite optimized background antiretroviral therapy. At present, raltegravir is the only drug in the integrase inhibitor class approved for clinical use. With the approval of raltegravir, oral agents targeting all three constitutive viral enzymes, reverse transcriptase, protease and integrase, are now represented in FDA-approved therapies.

A POWERful New Protease Inhibitor for HIV

Protease inhibitors (PIs) are an integral part of combination antiretroviral therapy. However, new drugs are needed for treatment-experienced patients

Raltegravir (MK-0518): An integrase inhibitor for the treatment of HIV-1

In the developed world, access to highly active antiretroviral therapy (HAART) has led to significant reductions in the morbidity and mortality attributed to HIV/AIDS. However, the continual emergence of HIV-1 strains resistant to currently available classes of antiretrovirals highlights the need to develop agents with novel mechanisms of action. Successful completion of the HIV-1 viral life cycle depends in part on the integration of complementary DNA mediated by the enzyme HIV-1 integrase, one of three essential enzymes encoded in the viral genome. The integrase inhibitors have demonstrated the ability to act specifically at the strand transfer step during integration, making HIV-1 integrase a valid and attractive chemotherapeutic target for the treatment of HIV/AIDS. In clinical trials, raltegravir has been shown to be a potent drug with a pharmacokinetic profile that supports a twice-daily dosing schedule. In addition, it has demonstrated a favorable side-effect profile in treatment-naive and -experienced patients and a subset of heavy treatment-experienced patients have been able a achieve virologic suppression with raltegravir as part of combination therapy despite limited treatment options. In October 2007, raltegravir was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 as part of combination antiretroviral therapy in treatment-experienced patients-providing an additional option for the management of the HIV-1 infected individual.

Safety of nevirapine in pregnancy

Nevirapine has been widely used in pregnancy for its efficacy, low pill burden, bioavailability and rapid transplacental transfer. Concern about nevirapine toxicity during pregnancy has emerged over recent years. The aims of the study were to document the frequency of cutaneous and hepatic toxicity secondary to nevirapine use during pregnancy and to compare rates in women starting nevirapine during the current pregnancy with those in women who had commenced nevirapine prior to the current pregnancy. This was a retrospective, comparative, five-centre study carried out in London, UK, in 1997-2003. All HIV-1-infected women who received nevirapine as part of combination antiretroviral therapy (ART) during pregnancy were included in the study. Data on demographics, HIV infection risk, Centers for Disease Control and Prevention (CDC) status, surrogate markers at initiation of therapy, other medications hepatitis B and C virus coinfection and clinical data relating to potential toxicity were collated and analysed. Fifteen of 235 eligible women (6.4%) developed rash and eight (3.4%) developed hepatotoxicity, including four with coexistent rash, giving a combined incidence of 19 potential cases of nevirapine toxicity during pregnancy (8.1%). Alternative causes of rash/hepatotoxicity were suspected in seven cases and only 10 mothers (5.8%) discontinued nevirapine. Of the 170 women who commenced nevirapine during this pregnancy, 13 (7.6%) developed rash and eight (4.7%) hepatotoxicity, a combined incidence of 10%. Only two of 65 women with nevirapine exposure prior to this pregnancy developed rash (3.1%). Nevirapine-containing ART was well tolerated in this cohort of pregnant women. Although pregnancy did not appear to increase the risk of nevirapine-associated toxicity compared to published adult data, CD(4) count may be less predictive of toxicity in pregnancy.

The impact of sex and contraceptive therapy on the plasma and intracellular pharmacokinetics of zidovudine

Zidovudine remains part of combination antiretroviral therapy. Pharmacological studies rely on quantitation of active triphosphates in peripheral blood mononuclear cells. This study evaluated the impact of female sex and contraceptive therapy on zidovudine plasma and intracellular pharmacokinetics and the impact of contraceptive therapy on HIV viral load. Serial plasma and intracellular zidovudine pharmacokinetics following oral and intravenous dosing were determined in 18 men and 20 women treated with zidovudine. Women could repeat pharmacokinetics assessment following 2 months oral or injectable contraceptive therapy. Zidovudine plasma and intracellular mono-, di- and triphosphate concentrations were determined by liquid chromatography tandem mass spectrometry. Plasma and cervical viral loads were determined preceding and following 2 months of contraceptive therapy in women. Men exhibited higher area under the concentration versus time curve for intracellular zidovudine and zidovudine-monophosphate following oral and intravenous dosing and higher zidovudine triphosphate following oral dosing. There was no difference between men and women in plasma zidovudine parameters. Furthermore, contraceptive therapy had no effect on zidovudine plasma or intracellular pharmacokinetics or on plasma or cervical HIV-1 RNA levels. Using an optimized pharmacokinetic design, this study indicated men exhibit significantly higher zidovudine-monophosphate and zidovudine-triphosphate exposure following zidovudine oral administration, having implications for drug toxicity and overall tolerance of zidovudine therapy. The lack of an effect of contraceptive therapy on zidovudine pharmacokinetics is surprising in light of previous pharmacokinetic studies for drugs eliminated primarily through glucuronidation. Contraceptive therapy had no effect on plasma or cervical viral load, results consistent with previous findings.

Impact of Lamivudine on the Risk of Liver-Related Death in 2,041 Hbsag- and HIV-Positive Individuals: Results from an Inter-Cohort Analysis

The impact of lamivudine (3TC) as part of combination antiretroviral therapy (cART) on the risk of liver-related death (LRD) in HIV/hepatitis B virus (HBV)-coinfected patients has not been extensively studied. We performed an analysis involving HIV/HBV-coinfected patients in 13 cohorts who initiated cART. The end-point was LRD--that is, death with concomitant decompensated liver disease (DLD) or hepatocellular carcinoma--as the main cause. Incidence rates of LRD after initiation of cART were expressed as number of events per 100 person-years of follow-up (PYFU). A Poisson regression model adjusted for cohort, gender, mode of HIV transmission, CD4+ T-cell count at cART initiation, liver disease pre-cART, duration of 3TC before cART, and hepatitis C virus was used to assess the association between use of 3TC and risk of LRD. We analysed 2,041 patients. Follow-up after starting cART was 7,648 PYFU (5,569 spent on 3TC-containing regimens) with a median per person of 48 months (range: 2-91). Of the total, 217 subjects died; 57 deaths were liver-related resulting in a rate of 7.5 per 1,000 PYFU [95% confidence intervals (CI): 5.6-9.7]. The relative risk of LRD per extra year of 3TC use was 0.73 (95% CI: 0.59-0.90, P = 0.004). The use of 3TC was associated with a reduced risk of LRD over 4 years of follow-up. This study supports the current view that the use of 3TC as part of cART should be considered in patients who are tested positive for HBsAg.

Maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in pregnancy

To describe the maternal tolerability of nevirapine as part of combination antiretroviral therapy in pregnancy at three HIV centres in Dublin, Ireland and to determine risk factors for development of significant hepatotoxicity. A retrospective study was carried out of all women prescribed nevirapine as part of combination antiretroviral therapy in pregnancy at three HIV centres in Dublin, Ireland (October 2000 to February 2003). Toxicities experienced were graded according to the Division of AIDS toxicity guidelines for adults. Statistical analysis was performed to determine whether there were differences between those that did and those that did not experience significant hepatotoxicity. A total of 123 women initiated nevirapine as part of combination antiretroviral therapy in the study period. Eight women developed significant hepatotoxicity, including two women who died from fulminant hepatitis. Women who experienced more severe hepatotoxicity had higher pretreatment CD4 counts (P=0.01). In this cohort, women who experienced more severe hepatotoxicity had higher pretreatment CD4 counts, lending additional weight to the need for caution in using nevirapine as part of combination antiretroviral therapy in women not requiring antiretroviral therapy for their own health.

New black box warning for ritonavir-boosted tipranavir.

On June 30, 2006, the FDA and Boehringer Ingelheim announced that they will expand the black box warning on tipranavir to include the risk of intracranial hemorrhage (ICH). Evidence for the warning came from clinical trials involving 6840 HIV-infected patients who received ritonavir-boosted tipranavir (500 mg + 200 mg boost, twice daily) as part of combination antiretroviral therapy. Of these patients, 13 (0.2%) had ICH events; 8 died. The median time from initiation of boosted-tipranavir treatment to onset of ICH was 525 days. In …

Impact of Lamivudine on the Risk of Liver-Related Death in 2,041 Hbsag- and HIV-Positive Individuals: Results from An Inter-Cohort Analysis

Background The impact of lamivudine (3TC) as part of combination antiretroviral therapy (cART) on the risk of liver-related death (LRD) in HIV/hepatitis B virus (HBV)-coinfected patients has not been extensively studied. Methods We performed an analysis involving HIV/HBV-coinfected patients in 13 cohorts who initiated cART. The end–point was LRD – that is, death with concomitant decompensated liver disease (DLD) or hepatocellular carcinoma – as the main cause. Incidence rates of LRD after initiation of cART were expressed as number of events per 100 person–years of follow–up (PYFU). A Poisson regression model adjusted for cohort, gender, mode of HIV transmission, CD4+ T-cell count at cART initiation, liver disease pre–cART, duration of 3TC before cART, and hepatitis C virus was used to assess the association between use of 3TC and risk of LRD. Results We analysed 2,041 patients. Follow–up after starting cART was 7,648 PYFU (5,569 spent on 3TC-containing regimens) with a median per person of 48 months (range: 2–91). Of the total, 217 subjects died; 57 deaths were liver-related resulting in a rate of 7.5 per 1,000 PYFU [95% confidence intervals (CI): 5.6–9.7]. The relative risk of LRD per extra year of 3TC use was 0.73 (95% CI: 0.59–0.90, P=0.004). Conclusion The use of 3TC was associated with a reduced risk of LRD over 4 years of follow–up. This study supports the current view that the use of 3TC as part of cART should be considered in patients who are tested positive for HBsAg.

Nevirapine use in HIV-1-infected children.

To evaluate the safety, efficacy, and clinical, virological, and immunological responses in HIV-1-infected children receiving nevirapine as part of combination antiretroviral therapy (ART). A review of case notes of all HIV-1-infected children 96 weeks after starting nevirapine, under a national compassionate access scheme between August 1997 and March 1999 in the UK. Nevirapine was dosed according to the manufacturer's guidelines. Seventy-four children (36 boys, 28 naive to ART) were enrolled, with a median age of 5.2 years, viral load of 5.1 log copies/ml and CD4 lymphocyte count of 13.5%. The liquid formulation and tablets of nevirapine were well tolerated. The proportions of patients achieving undetectable viral load levels at weeks 12, 24, 48 and 96 were 30, 40, 36 and 33%, respectively (intention-to-treat analysis). Of children not on a protease inhibitor who received more than 300 mg/m2/day of nevirapine, 60% had undetectable viral loads at week 96, compared with 17% on recommended doses. Outcomes were similar for patients receiving nevirapine once or twice daily. CD4 cell count percentages increased significantly, with median values sustained above 25% by week 48 onwards. Z-scores for weight and height increased significantly during 96 weeks of treatment. Rash occurred in 20%, of which four (5%) were severe. There were no cases of Stevens-Johnson syndrome. Nevirapine was mostly well tolerated, and was associated with encouraging clinical and immunological responses. Virological responses in this cohort support the use of nevirapine doses greater than 300 mg/m2/day, which is higher than currently recommended by the manufacturers.

Abacavir hypersensitivity reaction.

A hypersensitivity reaction occurs in association with initiation of abacavir therapy as part of combination antiretroviral therapy in approximately 3.7% of patients. The reaction is possibly the result of a combination of altered drug metabolism and immune dysfunction, which is poorly understood. White patients appear to be at higher risk and patients of African descent at lower risk of abacavir hypersensitivity. Clinical management involves supportive measures and discontinuation of abacavir therapy. Rechallenge with abacavir in a hypersensitive patient should be avoided because it might precipitate a life-threatening reaction.

Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that induce allosteric changes in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, thus rendering the enzyme incapable of converting viral RNA to DNA. Unlike nucleoside analogue inhibitors of reverse transcriptase, NNRTIs do not require sequential phosphorylation to elicit antiretroviral activity. There are currently 3 approved NNRTIs: nevirapine, delavirdine and efavirenz. Although possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. Each of the NNRTIs is metabolised to some degree by the cytochrome P450 (CYP) system of enzymes, making them prone to clinically significant drug interactions. In addition, they elicit variable effects on other medications, acting as either inducers or inhibitors of drugs metabolised by CYP. These drug interactions are an important consideration in the clinical use of these agents as a part of combination antiretroviral therapy. Additional factors such as the influence of food and pH on oral absorption, and protein binding, must also be considered.

Clinical uses of non‐nucleoside reverse transcriptase inhibitors

Three non-nucleoside reverse transcriptase inhibitors (NNRTIs) are currently available for treatment of HIV-1 as part of combination antiretroviral therapy. Oral dosing is administered three times daily for delavirdine (DLV), twice daily for nevirapine (NVP), and once daily for efavirenz (EFV). Rash is a common side effect of all three NNRTIs, and early CNS side effects are also frequent with EFV. Hepatotoxicity is relatively uncommon but requires appropriate monitoring. Drug interactions mediated by the cytochrome P450 system are an important consideration when the NNRTIs are administered concomitantly with other drugs, including protease inhibitors (PIs). HIV strains with reduced susceptibility to NNRTIs can occur with a single mutation in the reverse transcriptase (RT) gene. The available NNRTIs exhibit overlapping genotypic resistance patterns, but newer agents may overcome this problem. NNRTIs have been studied in combination with nucleoside RT inhibitors for first-line HIV therapy, where they have shown at least equivalent antiviral efficacy compared with PI-based regimens over 1–2 years of therapy. NVP and EFV have also been studied as a replacement for a PI within a virologically successful regimen, with the aim of preventing or reducing PI toxicities and simplifying the dosing regimen. Such ‘switch’ strategies are successful for certain patients in maintaining virologic suppression for 6 months or more and result in varying degrees of improvement in PI-associated toxicities. NNRTIs may offer a benefit when included in salvage regimens for patients failing PI-based therapy, particularly in patients who have not previously been treated with NNRTIs. NVP has been shown to have a substantial favourable impact on the rate of vertical HIV-1 transmission with a simple, cost-effective regimen. Copyright © 2000 John Wiley & Sons, Ltd.

Simultaneous HPLC Assay for Quantification of Indinavir, Nelfinavir, Ritonavir, and Saquinavir in Human Plasma

HIV protease inhibitors are recommended as part of combination antiretroviral therapy. Dual protease inhibitor therapy is also being used clinically. Consequently, a simultaneous assay for indinavir, nelfinavir, ritonavir, and saquinavir was developed. Indinavir, nelfinavir, ritonavir, and saquinavir were extracted from plasma (250 microL) with methyl-t-butyl ether at basic pH after addition of an internal standard (A-86093). The compounds were separated on a Keystone BetaBasic C4 column (250 x 3 mm i.d.) at 40 degrees C with a mobile phase of acetonitrile-50 mmol/L ammonium formate buffer, pH 4.1 (52:48, by volume) at a flow rate of 0.5 mL/min. Indinavir, nelfinavir, ritonavir, and the internal standard (A-86093) were detected at 218 nm, and saquinavir was detected at 235 nm. The method was validated by analysis of five triplicate analyses of calibrators along with quality-control samples at three different concentrations prepared in human plasma. The extraction recovery was 87-92%. Within-run accuracy for quality-control samples was 6-8%, with CVs of 2-8%. Limits of quantification were 40-50 microg/L for indinavir, nelfinavir, and ritonavir, and 20 microg/L for saquinavir. Cross-validation with a liquid chromatography-mass spectroscopy method for saquinavir and nelfinavir was conducted with patient samples. Regression analysis revealed a good correlation (r(2) >0.94) between methods. Larger variations at concentrations >4000 microg/L were observed with nelfinavir. Interference with drugs commonly used in AIDS patients was not observed. Pharmacokinetic profiles for two patients on dual protease therapy were determined. A reliable and rugged simultaneous HPLC assay for four HIV protease inhibitors was developed. The assay method is convenient for clinical laboratories involved in therapeutic drug monitoring for HIV protease inhibitors. The assay has enough sensitivity to conduct pharmacokinetic studies in patients taking more than one HIV protease inhibitor along with other antiretroviral medications.

Clinical uses of non-nucleoside reverse transcriptase inhibitors.

Three non-nucleoside reverse transcriptase inhibitors (NNRTIs) are currently available for treatment of HIV-1 as part of combination antiretroviral therapy. Oral dosing is administered three times daily for delavirdine (DLV), twice daily for nevirapine (NVP), and once daily for efavirenz (EFV). Rash is a common side effect of all three NNRTIs, and early CNS side effects are also frequent with EFV. Hepatotoxicity is relatively uncommon but requires appropriate monitoring. Drug interactions mediated by the cytochrome P450 system are an important consideration when the NNRTIs are administered concomitantly with other drugs, including protease inhibitors (PIs). HIV strains with reduced susceptibility to NNRTIs can occur with a single mutation in the reverse transcriptase (RT) gene. The available NNRTIs exhibit overlapping genotypic resistance patterns, but newer agents may overcome this problem. NNRTIs have been studied in combination with nucleoside RT inhibitors for first-line HIV therapy, where they have shown at least equivalent antiviral efficacy compared with PI-based regimens over 1-2 years of therapy. NVP and EFV have also been studied as a replacement for a PI within a virologically successful regimen, with the aim of preventing or reducing PI toxicities and simplifying the dosing regimen. Such 'switch' strategies are successful for certain patients in maintaining virologic suppression for 6 months or more and result in varying degrees of improvement in PI-associated toxicities. NNRTIs may offer a benefit when included in salvage regimens for patients failing PI-based therapy, particularly in patients who have not previously been treated with NNRTIs. NVP has been shown to have a substantial favourable impact on the rate of vertical HIV-1 transmission with a simple, cost-effective regimen.

Acute Hypersensitivity with Delavirdine

Delavirdine is an antiretroviral drug now being used as part of combination antiretroviral therapy for the management of human immunodeficiency virus (HIV) infection [1]. It belongs to the non-nucleoside reverse transcriptase inhibitor class of drugs. These drugs are known to induce delayed-type hypersensitivity skin reactions as their commonest toxicity [2]. We would like to report a severe anaphylactic reaction to delavirdine in one of our patients. The patient is a 30-year-old HIV-positive male who was first found to be HIV-positive in January 1991, and has had a number of antiretroviral therapies over the subsequent 6 year period, including zidovudine, zalcitabine, lamivudine and saquinavir. He had no known drug allergies. In December 1997, when the patient was on zidovudine, lamivudine and saquinavir, a decision was made to commence the patient on an alternative regimen because his CD4 count had fallen to 340 cells/mm3 and his viral load had risen to 78000 copies/ml from a nadir of 5900 copies/ml. Unfortunately, the patient decided to discontinue all antiretroviral therapy and his CD4 count subsequently fell to 200 cells/mm3 with his HIV viral load increasing rapidly to 760000 copies/ml. In February, as part of a clinical trial, he commenced therapy with soft gel saquinavir 800 mg three times daily, stavudine 40 mg twice daily, didanosine 400 mg daily and delavirdine 400 mg three times daily. Within 3 days of commencement of the delavirdine he developed an erythematous maculopapular rash on his face and trunk which subsequently spread to his arms and knees, becoming confluent and involved all parts of the body except the upper chest. There was no initial desquamation. The drugs were discontinued 1 week after the commencement of the rash. On discontinuation of the drugs the rash resolved completely over the next 4 days and 1 week later he recommenced one 200 mg dose of delavirdine. At this time he was also receiving intravenous amoxycillin/potassium clavulanate, morphine, metoclopramide and paracetamol. One hour after his delavirdine dose he developed an itchiness over his body followed within the next 2 h by tightness in his chest, difficulty breathing and a red confluent rash over his whole body. The shortness of breath and chest tightness intensified and the patient became extremely distressed. Inspiratory wheezes were noted, pulse was 85/min, oxygen saturation was 97% and blood pressure 120/75 mmHg. During the period of respiratory distress, the patient’s pulse, blood pressure and oxygen saturation remained stable (pulse 90, BP 120/80, saturation 97%). The patient did not respond to phenergan or hydrocortisone but responded quickly to adrenalin and his breathing settled markedly within 40 min and subsequently resolved back to his normal respiratory status within 24 h. The rash that subsequently developed desquamated on his face, hands and legs. We believe that the skin rash and anaphylactic reaction is a side-effect of delavirdine, and wish to alert physicians to the possibility of such severe reaction on rechallenge. Subsequently the patient has recommenced stavudine, didanosine, soft gel saquinavir and nelfinavir without any side-effects. His CD4 count has climbed from 200 to 620 and his viral load has fallen to 2900 copies/ml within 2 weeks of commencing his new regimen. While delayed-type hypersensitivity reactions have been commonly reported with this class of antiviral, immediate anaphylactic reactions appear rare. Caution should be used when considering rechallenging patients with possible delavirdine rashes.