HIV This Week

Repik A, Richards KH, Clapham PR. The promise of CCR5 antagonists as new therapies for HIV. Curr Opin Investig Drugs 2007;8:130-9.

The chemokine receptors CCR5 and CXCR4 were identified as HIV-1 co-receptors in 1996. Since then, a range of agents that bind these receptors and potently block HIV-1 infection have been described, including monoclonal antibodies, peptides and modified chemokines. However, small organic molecules that bind CCR5 are currently the most promising of the co-receptor antagonists for the potential treatment of HIV. These agents are now in advanced stages of clinical development and should soon augment current therapies, as well as being candidates for inclusion in microbicides. Unlike existing drugs that target HIV proteins (e.g., reverse transcriptase and protease), co-receptor antagonists bind receptors encoded by the host. As a consequence, blockade of these receptors may result in immunosuppressive effects or other disorders. Furthermore, co-receptor inhibitors may also be more toxic than currently available HIV therapies, and it is not yet clear whether they will become candidates for first-line therapy. Nonetheless, safer, less toxic versions of such inhibitors may be achievable in the future. The use of CCR5 inhibitors as a second-line treatment increases the possibility that these reagents will select for more pathogenic CXCR4-using variants. The development of effective CXCR4 antagonists for dual treatment would be beneficial; however, whether long-term treatment with antagonists of the widely expressed CXCR4 receptor is feasible without toxicity is unknown. This review discusses the current status of CCR5 antagonists, their modes of action and their development for therapeutic use.

Editors’ note : This review highlights the challenges of finding treatments that will both block HIV’s use of the immune system and allows the immune system to continue functioning. At the conference in February on Retroviruses and Opportunistic Infections in Los Angeles, promising short term (24 weeks) results comparing the addition of a CCR5 inhibitor to a background regimen alone showed more patients achieved undetectable virus and toxicity was not higher. More trials are needed to confirm these findings and assess the durability of both the effects on viral load and low toxicity.

Krakovska O, Wahl LM. Optimal drug treatment regimens for HIV depend on adherence. J Theor Biol 2007 Jan 23; [Epub ahead of print]

 Drug therapies aimed at suppressing the human immunodeficiency virus (HIV) are highly effective, often reducing the viral load to below the limits of detection for years. Adherence to such antiviral regimens, however, is typically far from ideal. Krakovska and Wahl have previously developed a model that predicts optimal treatment regimens by weighing drug toxicity against CD4(+) T-cell counts, including the probability that drug resistance will emerge. The authors use this model to investigate the influence of adherence on therapy benefit. For a drug with a given half-life, the authors compare the effects of varying the dose amount and dose interval for different rates of adherence, and compute the optimal dose regimen for adherence between 65% and 95%. Their results suggest that for optimal treatment benefit, drug regimens should be adjusted for poor adherence, usually by increasing the dose amount and leaving the dose interval fixed. The authors also find that the benefit of therapy can be surprisingly robust to poor adherence, as long as the dose interval and dose amount are chosen accordingly.  

Editors’ note : This is an interesting conclusion from a theoretical modelling study but whether it could have practical application in clinical practice to reduce the risk of viral resistance to antiretroviral drugs and improve treatment responses without increasing toxicity remains to be determined.

Ramchandani SR, Mehta SH, Saple DG, Vaidya SB, Pandey VP, Vadrevu R, Rajasekaran S, Bhatia V, Chowdhary A, Bollinger RC, Gupta A. Knowledge, attitudes, and practices of antiretroviral therapy among HIV-infected adults attending private and public clinics in India. AIDS Patient Care STDS 2007;21:129-42.

India has approximately 5.2 million persons infected with HIV. Although antiretroviral therapy (ART) is being widely introduced in public clinics, many HIV-infected persons still seek care via the private sector. A cross-sectional survey was conducted in 2004 at six public and private sites to characterize the knowledge, attitudes, and practices (KAP) of ART among patients with HIV receiving care in India. Of 1667 persons surveyed, 609 (36%) had heard of ART and 19% of these persons reported that ART could cure HIV. Twenty-four percent reported that they were currently taking ART, with 18% of these patients not actually on ART according to their provider. Major barriers to taking ART were cost (33%), lack of knowledge of ART (41%), and deferral by physician (30%). More than half of all public and private patients had not heard of CD4 (57%) or viral load testing (80%), and even fewer had received these tests (32% and 11%, respectively). Private clinic attendees were almost 4 times more likely to be on ART (35% versus 9%, p < 0.0001), more likely to be male, have a higher education, be partnered, have a higher income, and have had a CD4 or viral load (p < 0.0001). Overall, low levels of ART knowledge and access were observed among HIV infected patients, with access to ART being particularly low among patients attending public clinics. Ramchandani and colleagues conclude that in order to make widespread dissemination of ART effective in India, further educational and programmatic efforts are likely needed to optimize access, treatment awareness, and compliance among patients with HIV.

Editors’ note : Treatment literacy programmes for individuals, families and communities have been shown to be important elsewhere in creating demand and supporting adherence but this study suggests that health care providers need more training in patient education techniques and that financial barriers need to be examined and reduced.