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Antiretroviral Treatment Interruption Is Associated with Evidence of Kidney Dysfunction in SMART Study

Evidence continues to accumulate showing that antiretroviral treatment interruption, as evaluated in the large SMART trial, is a potentially risky strategy. A new study, published in the January 2, 2009 issue of AIDS, sheds further light on kidney dysfunction in this setting.

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A Review of HIV Monotherapy with Ritonavir-boosted Protease Inhibitors

There is increasing interest in the simplification of combination antiretroviral therapy in order to lower pill burden, improve convenience, and reduce the costs of HIV treatment.

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Adherence Is Reduced in Patients Who Don't Think They Need Antiretroviral Treatment

Adherence is a key contributor to optimal response to antiretroviral therapy. Many factors influence good or poor adherence, including an individual's perceived need for treatment, according to a study published in the December 1, 2008 Journal of Acquired Immune Deficiency Syndromes.

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HIV9: More Data Demonstrate Similar Efficacy of Abacavir and Tenofovir

As previously reported, ACTG study 5202 was partially halted this past March after interim results showed that among treatment-naive patients with a high baseline HIV viral load (> 100,000 copies/mL), abacavir/lamivudine (the drugs in the Epzicom coformulation pill) did not suppress HIV as well as tenofovir/emtricitabine (the drugs in the Truvada pill) when both were used in combination with either efavirenz (Sustiva) or ritonavir-boosted atazanavir (Reyataz). Four cohort studies presented at the recent 9th International Congress on Drug Therapy in HIV Infection in Glasgow provided further evidence regarding the relative efficacy of the abacavir/lamivudine and tenofovir/emtricitabine backbones. 

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Gilead Plans Clinical Trial of 4-in-1 Antiretroviral Combination Pill Containing Experimental Integrase Inhibitor Elvitegravir

The development of combination pills containing 2 or more antiretroviral drugs has reduced the "pill burden" and improved the convenience of HIV treatment. As reported last week by the Bloomberg financial news service, Gilead is now planning studies of a new all-in-one "quad" antiretroviral pill containing the NRTIs tenofovir and emtricitabine (the same ones in Atripla and Truvada) plus the company's experimental integrase inhibitor elvitegravir and a boosting agent, making it the first-ever 4-drug antiretroviral coformulation.

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Antiretroviral Therapy during Primary HIV Infection Offers Little Lasting Benefit

Over almost 3 decades of the AIDS epidemic, researchers have sought to determine whether very early treatment, during primary or acute infection, might lead to ongoing suppression -- or even permanent eradication -- of HIV.

Two recently published studies looked at the benefits of very early treatment in large clinical cohorts.

CASCADE

Investigators with the CASCADE cohort collaboration compared immunological, virological, and clinical outcomes in patients initiating combination antiretroviral therapy (ART) of different durations within 6 months of seroconversion versus those who deferred therapy in accordance with the evolving standard of care. Results were published in the November 30, 2008 issue of AIDS.

CASCADE includes 23 cohorts of HIV positive patients in Canada, Europe, and Australia. More than 1000 individuals identified during primary HIV infection were included in the study if they seroconverted after January 1, 1996 and were at least 15 years of age at the time of seroconversion. Those with at 2 or more CD4 cell measurements below 350 cells/mm3 or an AIDS diagnosis within the first 6 months following seroconversion were excluded.

Of 348 early-treatment patients (34%) who started combination ART soon after seroconversion, 147 stopped therapy after 6 months (n = 38), 6-12 months (n = 40), or more than 12 months (n = 69); 675 patients (66%) deferred therapy.

CD4 counts and HIV viral load measurements for early-treatment patients following treatment cessation were compared with the corresponding treatment-free period for participants in the deferred-treatment group.

Results

• HIV RNA fell and CD4 cell count rose while the early-treatment patients were on therapy.

• CD4 cell loss was steeper in the early-treatment group during the first 6 months after ART cessation than in the deferred-treatment group during the same time period.

• However, the subsequent rate of loss was similar in the early-treatment and deferred-treatment groups (P = 0.26).

• Patients treated for more than 12 months appeared to maintain higher CD4 counts following ART cessation.

• But 6 months after cessation, those treated for 12 months or less had CD4 counts comparable to those of untreated patients.

• CD4 counts fell from a mean 550 cells/mm3 at the time of seroconversion to:

• 234 cells/mm3 in deferred-treatment patients;

• 241 cells/mm3 in early-treatment patients who stopped therapy within 6 months;

• 304 cells/mm3 in early-treatment patients who remained on therapy for 6-12 months;

• 430 cells/mm3 for early-treatment patients who continued therapy for more than 12 months (only this difference was statistically significant).

• Taking early treatment for a short period during primary infection did not delay the need for standard ART later on.

• There was no difference in HIV viral load set-points between the early-treatment and deferred-treatment groups (P = 0.57).

• AIDS rates were similar in both groups (about 3%), but death rates were higher in the deferred-treatment group (0.6 vs 1.8%; P = 0.05).

• Most deaths in the deferred-treatment group were due to non-AIDS causes, including some -- such as bacterial infections and non-AIDS malignancies -- that appear to be associated with immune suppression.

"Transient combination ART, initiated within 6 months of seroconversion, seems to have no effect on viral load set-point and limited beneficial effect on CD4 cell levels in individuals treated for more than 12 months," the study authors concluded. "Our findings suggest that the early immunologic gain from initiating early combination antiretroviral therapy within the 6 months following HIV seroconversion is unlikely to be maintained."

ANRS PRIMO and SEROCO

In the second study, French researchers compared outcomes among 170 patients in the ANRS PRIMO cohort who started antiretroviral treatment during primary infection and 123 never-treated seroconverters in the SEROCO cohort. Results appeared in the November 2008 Journal of Acquired Immune Deficiency Syndromes.

While the CASCADE participants may have been treated too late to see a benefit -- within the first 6 months after seroconversion -- patients in the PRIMO cohort started within 3 months.

Results

• After patients in the PRIMO cohort interrupted therapy, their CD4 cell counts fell rapidly during the first 5 months, and more slowly thereafter.

• The timing of treatment initiation had no influence on the rate of CD4 cell decline.

• A larger CD4 cell increase during therapy was associated with a steeper decline and a larger loss of CD4 cells after treatment interruption.

• The mean CD4 cell loss 3 years after treatment interruption was 383 cells/mm3.

• In the SEROCO cohort, the CD4 cell decline was less steep, with a 3-year loss of 239 cells/mm3.

• As a result, mean CD4 counts were similar -- at about 400 cells/mm3 -- 3 years after treatment interruption (PRIMO) or after HIV infection (SEROCO).

In conclusion, the study authors wrote, "These data question the benefit of a limited course of combination ART even when initiated within 3 months after primary HIV infection diagnosis."

12/9/08

References

N Pantazis, G Touloumi, P Vanhems, and others (CASCADE collaboration). The effect of antiretroviral treatment of different durations in primary HIV infection. AIDS 22(18): 2441-2450. November 30, 2008. (Abstract).

R Seng, C Goujard, L Desquilbet, and others (ANRS PRIMO and SEROCO Study Groups). Rapid CD4+ Cell Decrease After Transient cART Initiated During Primary HIV Infection (ANRS PRIMO and SEROCO Cohorts). Journal of Acquired Immune Deficiency Syndromes 49(3): 251-258. November 2008 (Abstract).