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.

What strategies to boost production of affordable fixed-dose anti-retroviral drug combinations for children in the developing world?

BACKGROUND: No more than 8% of HIV positive children needing treatment in low- and middle-income countries have access to antiretroviral drugs (ARVs). Children presently account for about 4% of all treated patients, while for equitable access they should make up at least 13%. AIMS: This study explores key issues, implications and interaction dynamics to boost production of easy-to-use and affordable fixed-dose combination (FDC) ARVs for children in the developing world. Potentials for equitable solutions are examined including priority steps and actions, appropriate treatment options and reliable forecasting methods for paediatric ARVs, as well as combination incentives to generic companies against market unattractiveness and enforced intellectual property (IP) rights. Moreover, implementation strategies to enhance the development and production of affordable ARV paediatric formulations and appropriate supply systems to ensure availability are investigated. RESULTS: The current market for FDC paediatric ARVs is already substantial and will only grow with improved and scaled up diagnosis and monitoring of children. This provides an argument for immediate increase of production and development of FDC ARVs for children. These formulations must be low cost and included in the list of Essential Medicines to avoid children continuing to lag behind in access to treatment. Access-oriented, long-term drug policy strategies with the ability to pass muster of governments, the UN system, as well as generic and research-based enterprises are needed to let children gain expanded and sustained access to FDC ARVs. Under the requirements listed above, IP-bound Voluntary License (VL) flexibilities do appear, if coupled with substantial combination incentives to generic firms, as a fitting tool into the needs. Policies must consider enhancing human resource capacity in the area of caregivers and social and health workers aiming to spread correct information and awareness on effectiveness and rationale of FDC ARVs for children. Policies should urge that paediatric ARV treatment programmes entwine with extant interventions on prevention of mother-to-child transmission, as well as with HIV treatment initiatives focused on mothers and household members. Policies, again, should consider centralising functions and pooling resources to help overcome drug supply barriers. WHO's brokering role in VL-based agreements between wealthy and developing country industries, as well as its technical guidance in setting international standards should not be waived while looking for sustained access to optimised ARV treatments for children. Strategies discussed in this paper, while taking unavoidability of marketing and profit rules into account, look closely into the trade and drug policy directions of China and India according to frontier crossing implications of their IP management trends as well as their multi-faceted penetration strategies of both the wealthy and under-served markets the world over.

Tenofovir (Viread(R)) access for poor countries.

Gilead Sciences announced that it will make its drug tenofovir available at cost in all of Africa, and in some of the poorest countries elsewhere.

Tenofovir DF expanded access. Criteria for U.S. program.

An important new drug is now available through a special program for patients with advanced AIDS who have failed approved therapies.

Efavirenz (Sustiva): oral liquid expanded access program for children and adolescents ages 3-16.

A liquid form of efavirenz, still classified as experimental, will be made widely available through an expanded-access study for children who cannot easily take the capsules.

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.

Efavirenz (Sustiva) expanded access now to 400 CD4.

AIDS: Merck Pharmaceuticals has relaxed the criteria for expanded access for efavirenz (Sustiva or DMP-266). Under the new guidelines, patients who have ever had a CD4 count below 400 can now participate; earlier guidelines limited the program to those with counts below 50 within the last 90 days. European entry criteria will change shortly. Efavirenz must be used in conjunction with another antiretroviral that the patient has not taken previously. The drug is not recommended for use as monotherapy, and patients who have failed on non-nucleoside reverse transcriptase inhibitors are less likely to benefit from Sustiva because of a common mutation. Contact information is given for enrolling in the program.^ieng

Efavirenz expanded access.

AIDS: Dupont Merck announced an expanded access program for Efavirenz (Sustiva, DMP 266). The non-nucleoside reverse transcriptase inhibitor is taken just once a day, and 88 percent of people taking it in combination with indinavir achieved undetectable viral load. The program is open to people with CD4 counts below 400 who have no other viable treatment options. A contact telephone number is provided for further information.^ieng