HIV This Week

Novel approaches to inhibiting HIV-1 replication.

Adamson CS, Freed EO. 2009 Antiviral Res. Sep [Epub ahead of print]

Considerable success has been achieved in the treatment of HIV-1 infection, and more than two-dozen antiretroviral drugs are available targeting several distinct steps in the viral replication cycle. However, resistance to these compounds emerges readily, even in the context of combination therapy. Drug toxicity, adverse drug-drug interactions, and accompanying poor patient adherence can also lead to treatment failure. These considerations make continued development of novel antiretroviral therapeutics necessary. In this article, the authors highlight a number of steps in the HIV-1 replication cycle that represent promising targets for drug discovery. These include lipid raft microdomains, the RNase H activityof the viral enzyme reverse transcriptase, uncoating of the viral core, host cell machinery involved in the integration of the viral DNA into host cell chromatin, virus assembly, maturation, and budding, and the functions of several viral accessory proteins. The authors discuss the relevant molecular and cell biology, and describe progress to date in developing inhibitors against these novel targets.

For abstract access click here: 1

Editors’ note: Once inside the cell, HIV takes advantage of host cell factors and pathways, harnessing our machinery to promote its own replication. Having described the HIV life cycle, this article briefly reviews the classes of drugs that we currently have (more than 20 antiretroviral drugs have been licensed to date): entry inhibitors (fusion inhibitors and CCR5 antagonists), reverse transcriptase inhibitors (non-nucleoside and nucleoside, i.e. NNRTI and NRTI), protease inhibitors, and integrase inhibitors. Then, accompanied by many colourful figures, the authors present an array of potential new therapeutic targets that include viral-host protein interactions or cellular targets. It will be a challenge for virology and biology (chemical, structural, molecular, and cell) to determine whether we can block HIV’s use of these interactions or cellular targets for multiple steps of its own replication without creating toxicity for us, since we need these proteins and cellular factors for a variety of our own functions. 

Hill A, van der Lugt J, Sawyer W, Boffito M. AIDS. 2009; 23:2237-45

Ritonavir has been evaluated at boosting doses of 50-800 mg daily with seven protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, saquinavir and tipranavir. Minimizing the boosting dose of ritonavir could improve tolerability and lower costs. A MEDLINE search identified 17 phamacokinetic trials using different ritonavir doses with protease inhibitors. The dose of ritonavir used was correlated with plasma levels of each boosted protease inhibitor. For the five pharmacokinetic trials of lopinavir/ritonavir, a meta-analysis was used to estimate the effects of lopinavir dose versus ritonavir dose on lopinavir pharmacokinetics. Saquinavir, fosamprenavir and darunavir were boosted equally well by lower (50-100 mg) versus higher doses of ritonavir. Indinavir, tipranavir and lopinavir were boosted more by higher ritonavir doses. Data on atazanavir were inconclusive. The ritonavir dose-dependence of boosting effects did not correlate with their bioavailability or their effects on ritonavir plasma levels. Atazanavir and indinavir raised plasma ritonavir levels by 69-72%, whereas saquinavir had no effects on ritonavir. Darunavir, lopinavir, tipranavir and fosamprenavir all lowered ritonavir plasma levels. For the meta-analysis of lopinavir/ritonavir trials, the 200/150 mg twice daily (b.i.d.) dose of lopinavir/ritonavir (one Meltrex 200/50 mg tablet and one ritonavir 100 mg b.i.d.) showed lopinavir area under the curve and minimum concentration similar to the standard 400/100 mg b.i.d. dose. It may be possible to use three protease inhibitors (saquinavir, amprenavir and darunavir) with lower doses of ritonavir. A 200/150 mg b.i.d. dose of lopinavir/ritonavir could lower costs while maintaining very similar lopinavir plasma levels to the standard dose. New pharmacoenhancer drugs may need to be used at different doses to boost different antiretrovirals.

For abstract access click here: 1 

Editors’ note: A boosted protease inhibitor plus two nucleoside analogues (NRTIs) are recommended by WHO for second line antiretroviral treatment, with atazanavir and lopinavir being the preferred options. For boosted protease inhibitors, an optimal safety profile depends on both the choice of protease inhibitor and the lowest dose of ritonavir possible. The dose-ranging pharmacokinetic trials that are reported in the public domain here suggest that the pharmacokinetics of lopinavir are highly dependent on the dose of ritonavir used, as well as the lopinavir dose. This suggests that a crossover dose-ranging trial of lopinavir/ritonavir would help determine whether 400/100 mg versus 200/150 mg doses, for example, provide the optimum pharmacokinetics with lowest toxicity.