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IAS 2013: First-line Antiretroviral Therapy has Improved Over Time, Meta-analysis Shows

The effectiveness of initial antiretroviral treatment has improved markedly over the years, but many people still do not achieve full HIV suppression and a majority end up going off their initial regimen for various reasons, according to a large meta-analysis presented at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this week in Kuala Lumpur.

Countless clinical trials of first-line antiretroviral drugs have been conducted over the course of the HIV epidemic, but it can be hard to see the bigger picture of how well initial antiretroviral therapy (ART) has performed overall, and difficult to compare individual studies with variable patient inclusion criteria and outcome measures. A broader overview could help inform the development of treatment guidelines.

Frederick Lee from St. Vincent's Centre for Applied Medical Research in Sydney and colleagues therefore undertook a large meta-analysis of antiretroviral clinical trials through the end of December 2012, gathering study data from MEDLINE, clinical trial registries, conference abstracts, drug label information, and data provided by pharmaceutical companies.

The researchers included prospective trials that enrolled treatment-naive adults with HIV, followed participants for at least 48 weeks, and used an intent-to-treat (ITT) efficacy analysis. The meta-analysis excluded retrospective studies and those that evaluated regimens not currently recommended due to toxicity or poor effectiveness.

The primary measure was overall efficacy, or the proportion of patients with undetectable viral load <50 copies/mL in all studies over the maximum follow-up period. Secondary analyses included changes in efficacy over time, efficacy for individuals with high versus low viral load, efficacy according to the latest U.S. treatment guidelines, and predictors of efficacy and treatment failure.

The researchers identified 114 relevant studies, which included 216 study arms and a total of 40,124 participants. Most (196 studies) were randomized and 68 included a placebo control group. There were 50 Phase 2 trials, 96 Phase 3 studies, and 70 Phase 4 or post-market studies. Looking at study funding, 123 were sponsored by the pharmaceutical industry, 55 were academic, and 38 were classified as both.

Only 10 of the included studies were conducted prior to the widespread availability of effective combination ART in the mid-1990s. A total of 53 studies were conducted during 1997-199, 43 during 2000-2002, 61 during 2003-2005, 31 during 2006-2008, and 17 during the most recent period, 2009-2010. Most studies (131) had a duration of 48 weeks, 60 lasted for 96 weeks, and 25 continued for 144 weeks; the mean duration was 82 weeks.

Overall, most participants (76%) were men, 65% were white or Caucasian, and 27% were black or of African descent. By HIV risk group, about half were men who have sex with men, 38% were heterosexual, and 10% had a history of injection drug use. Collectively, the average CD4 count was quite high at 248 cells/mm³, but 12% had previously received a diagnosis of AIDS; 10% were coinfected with hepatitis C.

Lee explained that his team did not have access to data about individual study participants, but he did note that patient characteristics had shifted over time (including more women and people with less advanced disease in later years, for example).

About one-third of participants were using regimens classified as "preferred" or "alternative" in the 2012 DHHS antiretroviral therapy guidelines. Regimens included an average of 6 pills per day, taken in 2 daily doses, and two-thirds had some sort of food restrictions.

Looking at types of drugs evaluated in the trials, 49% included a non-nucleoside reverse transcriptase inhibitor (NNRTI), 24% included ritonavir-boosted protease inhibitors, and 14% included unboosted protease inhibitors. In addition, 9 studies (5%) included the newer integrase inhibitor class, while 12 (4%) looked at regimens containing only nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

Focusing on the NRTIs, the most frequently used "backbone" was zidovudine (AZT, Retrovir) plus lamivudine (3TC, Epivir), the drugs in the Combivir fixed-dose combination pill. This was followed by tenofovir (Viread) plus emtricitabine (FTC or Emtriva), the NRTIs in the Truvada, Atripla, Complera, and Stribild co-formulations. In addition, 27 studies evaluated stavudine (d4T or Zerit) plus lamivudine, 26 looked at abacavir (Ziagen) plus lamivudine (the drugs in Epzicom or Kivexa), 20 tested stavudine plus didanosine (ddI or Videx), and 9 tested tenofovir plus lamivudine.

Efficacy Results

• Taken as a whole, the overall efficacy of first-line ART evaluated in the studies was 60%.
• Effectiveness decreased with longer time on a regimen: among participants evaluated for 48 weeks, efficacy was 66%, falling to 60% in 96-week evaluations and 52% in 144-week evaluations.
• Overall, 25% of participants stopped ART during their studies.
• Discontinuation rates rose with longer time on therapy, from 20% in 48-week studies, to 28% in 96-week studies, to 34% in 144-week studies.
• 11% of study drug discontinuations were due to "patient decision," 8% were due to adverse events or side effects, and nearly 4% were due to virological failure.
• While the overall 60% rate of viral suppression was surprisingly low, treatment effectiveness did improve over time.
• Before 2000 the combined efficacy was just 47%, rising to 52% during 2000-2002, 64% during 2003-2005, 74% during 2006-2008, and finally 82% after 2008.
• Regimens containing integrase inhibitors -- which were studied in later years -- worked best, with an efficacy of 84%.
• Boosted protease inhibitor and NNRTI regimens performed similarly, with efficacy of 67% and 61%, respectively.
• All-NRTI regimens (51%) and unboosted protease inhibitors (42%) produced the lowest efficacy.
• Looking at widely used modern NRTI backbones, tenofovir/emtricitabine (73%), tenofovir/lamivudine (69%) and abacavir/lamivudine (63%) performed best, followed by zidovudine/lamivudine (48%).
• Regimen components classified as "preferred" in the DHHS treatment guidelines produced an overall efficacy of 75%, compared with 65% for those classified as "alternative."
• Preferred regimens were also less likely to result in treatment discontinuation, 20% vs 25%, respectively.
• There was a significant 8% difference in efficacy between study participants with higher (>100,000 copies/ml) vs lower pre-treatment viral load.

Based on these findings, the researchers concluded, "Overall mean efficacy of initial ART is low," at just 60%, and "most patients will interrupt initial ART."

"Despite focus on coformulation, fewer daily pills and doses [are] not independent predictors of overall efficacy," they added.

Factors that predicted greater treatment success included use of tenofovir/emtricitabine versus abacavir/lamivudine, and use of integrase inhibitors versus NNRTIs or boosted protease inhibitors -- a finding that held for patients with high viral load.

This analysis "calls into question antiviral potency at high viral loads," Lee said.

Although U.S. and European treatment guidelines have not included viral load ART initiation thresholds for several years, the investigators suggested that they should perhaps recommend that patients start therapy before viral load reaches 100,000 copies/mL.

Speaking from the audience, Daniel Kuritzkes of Brigham and Women's Hospital, a member of the DHHS guidelines panel, opined that these findings validated current treatment advice. "It turns out that a bunch of experts sitting around looking at data actually get it right," he said.

7/9/13

Reference

FJ Lee, J Amin, and A Carr. Efficacy of initial antiretroviral therapy: a meta-analysis of 40,124 adults with up to 144 weeks' follow-up. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract WEAB0104.