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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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Study Shows High Prevalence of Metabolic Syndrome and Associated Cardiovascular Risk in Older HIV Patients

Metabolic abnormalities and cardiovascular disease are a growing concern for HIV positive people, but there is a lack of specific data about patients older than 50 years of age, who now account for some 25% of all HIV cases in the U.S. As described in the December 1, 2008 issue of AIDS Patient Care and STDs, Oluwatoyin Adeyemi and colleagues conducted a cross-sectional study to determine the prevalence and predictors of the metabolic syndrome among a cohort of older HIV-infected patients, as well as their 10-year Framingham cardiac risk scores.

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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).

20-year Trends in Cancer Incidence among People with HIV and the Impact of Antiretroviral Therapy

As people with HIV live longer due to effective antiretroviral therapy, a growing proportion of illness and death in this population is attributable to causes other than classic AIDS-defining or opportunistic illnesses -- although accumulating evidence suggests that some of these causes may not really be "non-HIV-related."

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CD4 Cell Count Improves with HAART-especially Protease Inhibitors-even if Viral Load Is Not Fully Suppressed

A majority of people currently being treated with combination antiretroviral therapy (ART) live in resource-limited settings, where it is common for patients to remain on virologically failing regimens, typically containing a non-nucleoside reverse transcriptase inhibitor (NNRTI).

As reported at the recent 9th International Congress on Drug Therapy in HIV Infection (HIV9) in Glasgow, Scotland, Andrew Phillips, Amanda Mocroft, and colleagues with the EuroSIDA study aimed to identify the viral load level at which CD4 cells begin to decrease significantly in patients on ART, as well as factors associated with changes in CD4 count.

The analysis included 7231 patients contributing a total of 58,929 CD4 slopes (median 6 per person). CD4 slopes were calculated from 3 consecutive CD4 cell measurements performed while viral load was stable (defined as < 0.5 log10 copies/mL difference between the highest and lowest viral loads). Slopes were calculated over a median 6.6 months.

Results

• Those with 500-999 copies/mL experienced a consistent CD4 cell decrease, ending up almost 75 cells/mm3 below the first measurement.

• Patients on combination ART had more favorable -- that is, more positive or less negative -- mean CD4 slopes than those off therapy at any viral load level.

• Among treated patients, after adjusting for confounding factors, regimens containing a single protease inhibitor (PI) (mean CD4 slope 43 cells/mm3) or a ritonavir-boosted PI (47 cells/mm3) were associated with more positive CD4 slopes than NNRTI-based regimens (31 cells/mm3) or triple-nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) regimens (30.2 cells/mm3) (P < 0.0001).

"The results from our study would suggest that some treatment with combination ART is better than none, but also that better CD4 count increases are obtained by using a PI or ritonavir-boosted PI-based regimen than by using an NNRTI-based regimen," the investigators concluded.

Based on these findings, they recommended that, "Patients with stable viremia unable to fully suppress HIV replication should continue therapy and consideration should be given to the use of a PI-based regimen."

Royal Free and University College Medical School, London, UK; University Hospital, Zurich, Switzerland; Medizinische Poliklinik, Munich, Germany; Hospital Saint-Antoine, Paris, France; Medical University, Bialystok, Poland; Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, Netherlands; Copenhagen HIV Programme, Panum Institute, Copenhagen, Denmark; Copenhagen HIV Programme, Panum Institute and Centre for Viral Disease KMA, Rigshospitale, Copenhagen, Denmark.

12/9/08

Reference

AN Phillips, B Ledergerber, JR Bonger, and others. Rate of change in CD4 counts in patients with stable HIV viremia. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008.Journal of the International AIDS Society 11(Suppl 1): O17. November 10, 2008.

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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ICAAC 2008: Atherosclerosis, Coronary Plaques, and Heart Rhythm Changes in People with HIV

Cardiovascular disease is a growing concern as people with HIV live longer, but the complex relationship between HIV infection itself, immune activation triggered by the virus, and antiretroviral drugs used to treat it remains poorly understood. Three studies presented at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) in late October shed further light on factors associated with cardiovascular risk in HIV positive patients.

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Advanced Liver Disease in People with HIV

As HIV positive people live longer due to effective antiretroviral therapy, liver disease has become an increasingly important cause of illness and death in this population.

In some cases, advanced liver disease in people with HIV is related to coinfection with hepatitis B or C virus (HBV or HCV), certain antiretroviral drugs are known to cause liver toxicity, and in other cases the cause of liver disease is unclear. Three presentations at the recent 9th International Congress on Drug Therapy in HIV Infection (HIV9) in Glasgow discussed end-stage liver disease (ESLD), advanced liver fibrosis, and severe portal hypertension in HIV-infected individuals.

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Second-line Regimens Twice as Likely to Fail as Initial Therapy

Treatment failure is twice as likely with second-line antiretroviral regimens compared with initial therapy, according to a study presented at the recent 9th International Congress on Drug Therapy in HIV Infection in Glasgow, Scotland.

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