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 Wednesday at the 7th International AIDS Society Conference
on HIV Pathogenesis, Treatment and Prevention 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 of St. Vincent's Centre for Applied Medical
Research in Sydney
and colleagues therefore undertook a large meta-analysis of antiretroviral
clinical trials through to 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 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 vs low viral load,
efficacy according to the latest US 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 randomised 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 to 1999, 43 during
2000 to 2002, 61 during 2003 to 2005, 31 during 2006 to 2008 and 17 during the most
recent period, 2009 to 2010. Most studies (131) had a duration of 48 weeks, 60
lasted for 96 weeks and 25 continued for 144 weeks; the overall 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 co-infected 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).
Looking at the regimens 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, nine studies (5%) included the newer
integrase inhibitor class, while 12 (4%) looked at regimens containing only
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).
About one-third of participants were using
regimens classified as 'preferred' or 'alternative' in the 2012 US Department of Health and Human Services (DHHS)
antiretroviral therapy guidelines. Two-thirds of study
regimens had some sort of food restrictions, and they included an average of
six pills per day taken in two daily doses.
Focusing on the NRTIs, the most frequently used
'backbone' was AZT (zidovudine or Retrovir)
plus 3TC (lamivudine or Epivir), the
drugs in the Combivir fixed-dose combination pill. This was followed by
tenofovir (Viread) plus FTC
(emtricitabine or Emtriva), the NRTIs
in the Truvada, Atripla, Complera/Eviplera and Stribild co-formulations. In addition,
27 studies evaluated d4T (stavudine or Zerit) plus 3TC, 26 looked at abacavir (Ziagen) plus 3TC (the drugs in Kivexa or Epzicom), 20 tested d4T plus ddI (didanosine or Videx) and nine tested tenofovir plus