Computational models can predict response to HIV therapy without a genotype and may reduce treatment failure in different resource-limited settings.

OBJECTIVES: Genotypic HIV drug-resistance testing is typically 60%-65% predictive of response to combination antiretroviral therapy (ART) and is valuable for guiding treatment changes. Genotyping is unavailable in many resource-limited settings (RLSs). We aimed to develop models that can predict response to ART without a genotype and evaluated their potential as a treatment support tool in RLSs. METHODS: Random forest models were trained to predict the probability of response to ART (≤400 copies HIV RNA/mL) using the following data from 14 891 treatment change episodes (TCEs) after virological failure, from well-resourced countries: viral load and CD4 count prior to treatment change, treatment history, drugs in the new regimen, time to follow-up and follow-up viral load. Models were assessed by cross-validation during development, with an independent set of 800 cases from well-resourced countries, plus 231 cases from Southern Africa, 206 from India and 375 from Romania. The area under the receiver operating characteristic curve (AUC) was the main outcome measure. RESULTS: The models achieved an AUC of 0.74-0.81 during cross-validation and 0.76-0.77 with the 800 test TCEs. They achieved AUCs of 0.58-0.65 (Southern Africa), 0.63 (India) and 0.70 (Romania). Models were more accurate for data from the well-resourced countries than for cases from Southern Africa and India (P < 0.001), but not Romania. The models identified alternative, available drug regimens predicted to result in virological response for 94% of virological failures in Southern Africa, 99% of those in India and 93% of those in Romania. CONCLUSIONS: We developed computational models that predict virological response to ART without a genotype with comparable accuracy to genotyping with rule-based interpretation. These models have the potential to help optimize antiretroviral therapy for patients in RLSs where genotyping is not generally available.

Fosamprenavir (GW433908)/ritonavir in HIV-infected patients: efficacy and safety results from the Spanish Expanded Access Program.

INTRODUCTION: The use of protease inhibitors (PI) has led to a decrease in HIV-1-related mortality and morbidity. The objective of this study was to collect safety data on treatment with fosamprenavir/ritonavir (FPV/r) 700/100mg BID in HIV-infected patients through an expanded access program. PATIENTS AND METHODS: Prospective, multicenter, noncomparative study in HIV-1 infected adults, for whom a regimen containing FPV/r 700/100mg BID was appropriate. RESULTS: A total of 678 patients were included in the intention-to-treat (ITT) and safety population. The on-treatment (OT) population contained 587 patients: 76% male, 98% Caucasian, and median age 41 years. Median CD4 cell count was 351 cells/microL, HIV-RNA was 3 log copies/mL, and 49% of patients were in CDC class C. After 24 weeks of treatment, serum viral load decreased a median of 1.3 log copies/mL and 73% of patients had <400 copies/mL (P<.0001 vs. baseline); 48-week results were similar. CD4 cell count increased a median of 49 and 62 cells/microL at 24 and 48 weeks, respectively. Adverse events (AEs) associated with the study medication occurred in 21% of patients. CONCLUSIONS: Ritonavir-boosted fosamprenavir as part of antiretroviral therapy is a potent, safe treatment in real-life clinical circumstances.

Prezista (darunavir, TMC-114) approved; may be important treatment advance.

A major new antiretroviral has been approved, for patients resistant to more than one protease inhibitor. There is no information yet on risk/benefit compared to standard treatments for first-line use. Tibotec, which developed the drug and is now part of Johnson & Johnson, showed price restraint and avoided setting a new record high price, which other companies have done.

Cardiovascular considerations in patients treated with HIV protease inhibitors.

Highly active antiretroviral therapy (HAART) has dramatically reduced mortality from HIV infection, transforming it in many cases to a chronic condition. However, protease inhibitors (PIs), which are integral components of most HAART regimens, are commonly associated with a host of metabolic disturbances that may increase the risk of cardiovascular disease in patients with HIV infection, potentially counteracting some of the positive health effects of PIs. Dyslipidemia is of particular concern. The Adult AIDS Clinical Trials Group has established preliminary guidelines to evaluate and treat PI-associated dyslipidemia. A number of strategies exist for the management of PI-based dyslipidemia in HAART recipients; their advantages and disadvantages should be considered when treating patients with HIV infection.

Use of complementary and alternative therapies in HIV-infected patients.

The use of complementary and alternative medicine (CAM) therapies is widespread in many chronic illnesses, including human immunodeficiency virus (HIV) infection. The objective of this study was to determine the impact of increasingly effective antiretroviral therapy on the use of CAM in an HIV-positive patient population. A written survey was given to 191 HIV-positive outpatients. Participation was voluntary and anonymous. One hundred twenty-eight patients (67%) used CAM at some time to control HIV and 76 (40%) of the patients were currently using CAM. The major forms of CAM used were exercise (43%), lifestyle changes (38%), dietary supplements (37%), counseling (27%), herbal medications (26%), megavitamins (24%), and prayer therapy (24%). One hundred forty-one patients (74%) used a protease inhibitor medication, 28 (15%) used a protease inhibitor sparing regime, and 22 (11%) had no current or prior antiretroviral use. Eighty-two (43%) patients indicated that their doctor knew they used CAM and 56 patients (29%) received their information about CAM from a doctor or other health care professional. Of 128 patients who used CAM, 90 (70%) felt CAM improved their quality of life. Income of $15,000 or more per year and discontinuation of medications by patients for any reason in the past were the best predicators of CAM use for patients in general and also those on protease inhibitor therapy. CD(4) count, educational status, year of HIV diagnosis, and martial status were not effective predictors of CAM use. Use of CAM remains widespread among patients with HIV infection even with the availability of effective, yet noncurative antiretroviral therapy and does not correlate with type of antiretroviral therapy used or clinical status.

Kaletra (ABT-378/r) approved.

Details and information sources on Kaletra (lopinavir plus low-dose ritonavir), a protease inhibitor approved last week.

Bridging the gap. Bringing new antiretroviral medications into the clinic.

Highly active antiretroviral therapy (HAART) is a strategy in which clinicians introduce potent combinations of antiretroviral medications early in the course of HIV infection. The intent is to suppress viral replication as completely as possible to forestall irreversible immune system damage. Antiretroviral agents fall into two major classes reverse transcriptase inhibitors and protease inhibitors. Each class interferes with viral replication at a different point in the viral life cycle. Recent research findings demonstrate clearly that antiretroviral treatment should begin as soon as the patient is willing and able to take the multidrug regimens. The best strategy for meeting the challenge of antiretroviral resistance is prevention. If you completely halt viral replication with potent therapy, the development of resistant strains is prevented.

Drug watch.

AIDS: Current research findings and treatment issues related to a number of drugs are briefly outlined. Topics include T-20, a reformulation of ddI, PMPA, chicoric acid, Omniferon (alpha leukoferon), and Mepron. Also discussed is a non-nucleoside reverse transcriptase inhibitor called calanolide A, which is synthesized from a tree native to Malaysian rain forests. An update is provided on Panretin, a gel which is used to treat KS lesions. Contact information is provided.^ieng

ABT-387/r early access program expanded further.

AIDS: In November, Abbott Laboratories expanded its early access program criteria for ABT-378/r in the United States. Patients who have up to 200 CD4 T cells and who have failed numerous antiretroviral regimens are now eligible for the program. In February 2000, the program will be expanded further. At that time, patients who have no viable therapy with any of the approved antiretrovirals may have access to ABT-378/r regardless of their viral loads, CD4 T cell counts, or history of protease inhibitor use. Contact information is provided.^ieng

Antiretroviral agents: the next generation.

AIDS: Four new drugs have been developed to overcome the limitations of the currently available anti-HIV drugs, including inconvenient schedules, side effects, and drug interactions. It is hoped that abacavir, efavirenz, adefovir dipivoxil, and amprenavir will be widely available in the near future. Abacavir, a nucleoside reverse transcriptase inhibitor with a twice-daily schedule, offers good bioavailability and generally mild side effects. Efavirenz, a non-nucleoside reverse transcriptase inhibitor with a once daily schedule, may produce side effects such as rash and dizziness. Adefovir dipivoxil, a nucleotide analog with once daily dosing, can cause carnitine depletion and carnitine supplementation is recommended. Amprenavir, a protease inhibitor with twice-daily dosing, has rather mild side effects. Information on efficacy, availability, and resistance for each of these drugs is given.^ieng

Ritonavir capsule manufacturing problems will require switch to liquid formulation.

AIDS: Abbott Laboratories has halted production of Ritonavir (Norvir) capsules due to a manufacturing problem which caused the drug to crystallize, disrupting the rate with which it dissolves. Current supplies will run out in August, and patients will need to switch to the liquid formulation of the drug. The liquid formulation provides the same dosage as the capsules, but pharmacists may need to call the physician to authorize the change. The primary drawback to the liquid formulation is its bad taste, which can be masked with certain strong-tasting foods. Further information is available on Abbott's web site or directly from the company. Contact information is provided.^ieng

Nelfinavir access in Canada.

AIDS: Due to the licensing of Nelfinavir in Canada, Agouron Pharmaceuticals will stop enrolling subjects into its Nelfinavir expanded access program. Current participants will continue receiving the drug under the program for up to 90 days following licensing or when private insurance coverage is granted. A toll-free number is provided for those needing help with finding payment options for Nelfinavir.^ieng

Amprenavir (Agenerase) now available in expanded access.

AIDS: Patients whose current treatment uses a protease inhibitor and has failed can participate in an expanded access program for amprenavir (Agenerase), a new protease inhibitor (PI) from Glaxo Wellcome and Vertex Pharmaceuticals, Inc. Several protocols are described, along with some of the participation criteria. Contact information is provided.^ieng