March 2009

Top 10 HIV/AIDS Stories of 2008

1. New Gene Silencing Technique May Have Potential as AIDS Therapy
A gene-silencing technique, called “siRNA,” short for “short interfering” or “silencing” RNA, was introduced into mouse models that had been developed to mimic a human HIV patient who is immunocompromised, also known as a “humanized mouse model.” siRNA has been shown to “stick” to specific genes, specifically the T cells that HIV infects, and cause them to become “silent” or inoperative. In this study, it controlled viral replication and prevented the CD4 T cell loss that is associated with HIV. The siRNA has been administered in direct injections to animal models, which requires repeat administrations. Another available administration approach is a genetically engineered siRNA virus that becomes a part of the patient’s stem cells, and eventually T cells. These T cells will produce siRNA and the hope is that the cells will then be immune to HIV. The virus “silencers” will be available lifelong in the patient since they are now part of his/her genome. siRNA will be a part of latent HIV T cells, so when the cell becomes active, the siRNA can become active and fight the infection. More research is needed in humans but the research done in humanized mouse models are promising.

Kumar P, Ban H-S, Kim S-S. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell. 2008 Aug 22;134:577-86.

2. American College of Physicians Now Recommend Routine HIV Screening
In a call-to-action targeted to physicians and on the heels of the 2006 CDC Revised HIV Testing Recommendations, The American College of Physicians recommended routine screening for HIV for all patients over age 13, regardless if any risk factors are present. The reason for this is that a large number of people (about 20,000 out of the 1 million new cases each year) in the United States transmit HIV each year without knowing they are infected. The premise of the recommendation is that if patients know they are infected, they will not be as likely to transmit the disease, which will help to prevent about 2% of new HIV cases each year. Higher risk patients (for example, those who share injection drug needles or engage in risky sexual behavior) should be tested frequently and repeatedly, the ACP recommends. Another reason for this recommendation is the ease of test facilitation—it can be performed quickly and simply during a routine examination.

American College of Physicians. ACP Recommends Routine HIV Screening for all Patients. Updated 2008 Dec 1. Accessed 2009 Feb 6. Found at: http://www.acponline.org/pressroom/hiv_screen.htm

Qaseem A, Snow V, Shekelle P, et al. Screening for HIV in health care settings: a guidance statement from the American College of Physicians and HIV Medicine Association. Ann Int Med. 2009 Jan 20;150:125-31.

3. Consequences of Missed Doses (Not All Are the Same)
This study investigated the effects that missing doses could have on HIV patients by examining the relationship of adherence patterns (sustained treatment interruption vs. missed doses dispersed throughout treatment) to NNRTIs (efavirenz or nevirapine) with subsequent virologic rebound. It was found that each consecutive day off therapy and/or a treatment interruption of more than 2 days increased the risk of virologic rebound. The researchers concluded that sustained NNRTI treatment interruption increases the risk of virologic rebound (HIV RNA >400 copies/mL) more than the same number of missed doses which were interspersed throughout the study’s treatment period. This shows that patients with incomplete adherence can still achieve virologic control, especially if they limit sustained NNRTI treatment interruptions.

Parienti J-J, Das-Douglas M, Massari V, Guzman D, Deeks SG, et al. (2008) Not All Missed Doses Are the Same: Sustained NNRTI Treatment Interruptions
Predict HIV Rebound at Low-to-Moderate Adherence Levels. PLoS ONE 3(7): e2783. doi:10.1371/journal.pone.0002783

4. Effects of Resuming Treatment After Interruption
The SMART Study Group compared HIV patients who underwent either continuous or interrupted treatment. It eventually became clear that the patients with interrupted treatment experienced more infections, so they then began continuous treatment like the control group. CD4 cell counts, blood virus levels, and numbers of new HIV-related infections and deaths were compared between the two groups. Patients in the “interrupted treatment” group who resumed continuous treatment still had a slightly higher risk for HIV-related infections and death, compared with those who had been receiving continuous treatment from the beginning. The conclusion of this study, which is similar to Parienti, et al, is that patients who stop and then resume treatment are at a higher risk for complications than those who never stop treatment at all.

SMART Study Group. Risk for Opportunistic Disease and Death after Reinitiating Continuous Antiretroviral Therapy in Patients with HIV Previously Receiving Episodic Therapy. A Randomized Trial. Ann Int Med. 2008 Sep 2;49;289-99.

5. A Mathematical Analysis of When to Initiate HIV Treatment
The optimal time to initiate therapy in HIV patients is unclear. Early, aggressive treatment may cause intolerable side effects and hasten viral resistance, but waiting to treat is associated with an increased risk of progression to AIDS. This study examined newly-diagnosed HIV patients with varying viral loads and of various ages. Because risks and benefits are difficult to compare due to the length of time over which they are experienced, a mathematical model may be helpful. The model developed by the researchers showed that starting treatment earlier, at a CD4 T cell count of 500 cells/mm3 or less, would provide greater quality of life than starting at a lower CD4 count, for patients 30 years or older (regardless of viral load), and in patients with a viral load > 30,000 copies/mL and who are over 40 years of age. In patients over 50 years of age, later treatment initiation is preferred because this group experienced more harm due to earlier therapy initiation since they were more susceptible to drug toxicity. A limitation of this study is that it did not consider cost, or evaluate the appropriateness of subjects’ antiretroviral therapy regimens. This earlier treatment threshold was still favored after the consequences (toxicity, development of resistance) of antiretroviral therapy were considered. In conclusion, earlier treatment initiation improved life expectancy, even though earlier therapy hastened accumulation of resistance mutations and reduced future drug options. The authors noted that new treatments will further favor earlier treatment as new drugs will be more likely to overcome resistance, should it develop in the future.

Braithwaite RS, Roberts MS, Chang CCH, et al. Influence of alternative thresholds for initiating HIV treatment on quality-adjusted life expectancy: a decision model. Ann Intern Med. 2008;148:178-85.

6. When to Initiate Treatment—Guidance Based on a Randomized, Controlled Trial
This study compared patients who were antiretroviral therapy (ART)-naïve, or who had not been receiving ART for 6 months or more before randomization. One group received ART therapy at CD4 count of >350 cells/µL, which would receive continuous ART (viral suppression group), while the other group’s ART was deferred until CD4 count dropped to 250 cells/ µL (or until CD4 cell percentage declined to <15%, or symptoms of HIV developed). This group, the drug conservation group, would receive intermittent ART. The CD4 count was 148 cells/ µL lower in the drug conservation group than in the viral suppression group, and the proportions of participants with viral RNA levels ≤ 400 copies/mL at 12 and 24 months were 10% and 25% in the drug conservation group, and 59% and 56% in the viral suppression group, respectively. The rate of overall opportunistic disease or death, serious non-AIDS complications, and all-cause mortality were significantly less in the viral suppression group than in the drug conservation group. This study suggests that the risk of death, opportunistic diseases, and serious non-AIDS complications can be reduced by earlier versus deferred use of ART, and may outweigh any risks associated with the use of ART itself, but must be confirmed in a larger trial.

SMART Study Group. Major clinical outcomes in antiretroviral therapy (ART)-naïve participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008;197:1133-44.

7. New Drug Approval of 2008: Etravirine
Etravirine (Intelence ®) is a NNRTI which is the first in its class to show activity against HIV-1 strains displaying the mutations that are associated with resistance to efavirenz (Sustiva ®) and nevirapine (Viramune ®), other NNRTIs. Etravirine’s efficacy has been seen in conjunction with darunavir/ritonavir, protease inhibitors. The trials which established its efficacy included patients on failing ART combination regimens, with at least one NNRTI resistance-associated mutation. The incidence of mild-to-moderate rash was significantly greater in the treatment group versus placebo, usually occurred in the second week, and rarely led to treatment discontinuation. Other adverse effects were similar to the control group in terms of incidence and severity. The study results suggest that etravirine may be effective after virologic failure on first-generation NNRTIs.

Lascar M, Cartledge JD. New protease inhibitors and non-nucleoside reverse transcriptase inhibitors. J HIV Therapy. 2008;13(2):40-44.

9. Interrupting Antiretroviral Therapy for High CD4 Counts Increase Risks
In this study, two treatment groups were defined. The viral suppression group took antiretroviral therapy continuously, while the drug conservation group underwent a CD4 cell-count guided interruption of antiretroviral therapy. The drug conservation group stopped therapy when the CD4 cell count was >350 cells/ µL, and reinitiated therapy when the CD4 cell count fell to <250 cells/ µL. Basically, the drug conservation group experienced an increased risk in opportunistic diseases or death from any cause in comparison to the viral suppression group. A strength of this study is its large sample size (5,472 patients). This shows that the continuous use of antiretroviral therapy, regardless of CD4 cell count, is beneficial.

SMART Study Group. Inferior clinical outcome of the CD4 cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4 cell counts and HIV RNA levels during follow-up. Jj Infect Dis. 2008;197:1145-55.

Editor:

CAPT Scott Giberson
Principal Consultant

HIV/AIDS Program

Indian Health Service
301-443-2449 (office)
Scott.giberson@ihs.gov

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