Initial anti-HIV regimens: two drugs can be better than three
The systematic review and meta-analysis by Rachel Jordan and
Colleagues and even more the accompanying editorial by Charles Carpenter
leave the reader with the idea that the higher is the number of drugs you
start with in all HIV1-infected individuals, the better. I do not think
that experience "in the real world" (outside clinical trials) supports
this notion.
Jordan and Colleagues excluded studies of "less than 12 weeks
duration" (i.e., included studies of very short duration which are of
doubtful significance) and considered entirely different patients
categories, as "more patients were asymptomatic" and "mean baseline CD4
counts ranged from 83 to 660 cells per microliter". Finally, "follow-up
was not always clearly reported".
In addition to the above, important weaknesses, if one looks
carefully at figure 4, it can be observed that the studies with fewer
participants either do not show differences in disease progression or
death between triple and double therapy or are in favour of double
therapy, the only exceptions being the INCAS studies. The two largest
studies (PISCES), in contrast, are clearly in favour of triple therapy. As
in most meta-analyses and reviews, it appears quite difficult to explain
and reconcile such striking differences.
In my opinion, whenever choosing an antiretroviral regimen a
fundamental point is the CD4 cell count. If this is fairly low (i.e.,
below 200 per microliter), and even more if the patient is symptomatic,
the benefit of triple therapy is generally higher than the benefit of
double therapy; if the count is higher (and especially when higher than
300 cells per microliter), the superiority of triple over double therapy
in the long-term is far from being demonstrated.
In my experience, poor compliance rather than resistance explains the
vast majority of cases of failure of antiretroviral regimens, if "failure"
has to mean not just "virological failure" (i.e., detectable plasma HIV-
RNA) but "immunological failure" (i.e., decrease in CD4 cell number), the
latter being the really important "failure" which can lead to clinical
progression; "in the real world" triple drug therapies bear higher and
more serious side-effects and lead to lower compliance.
The level of CD4 cell decline required to initiate antiretroviral
therapy has been reconsidered (Pomerantz RJ. Initiating antiretroviral
therapy during HIV infection. Confusion and clarity. JAMA 2001; 286: 2597-
99), and early start (5 years ago a "must")(Carpenter CC, Fischl MA,
Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral
therapy for HIV infection in 1997. Updated recommendations of the
International AIDS Society-USA Panel. JAMA 1997; 277: 1962-69) is no
longer regarded as beneficial.
In my opinion, time has come to reconsider not only when, but also
what to start with: if the CD4 cell count is higher than 300 per
microliter and the subject is asymptomatic, double antiretroviral therapy
still has a place.
Competing interests:
No competing interests
03 April 2002
Sandro Vento
Associate Professor of Infectious Diseases, Department of Pathology, University of Verona
Rapid Response:
Initial anti-HIV regimens: two drugs can be better than three
The systematic review and meta-analysis by Rachel Jordan and
Colleagues and even more the accompanying editorial by Charles Carpenter
leave the reader with the idea that the higher is the number of drugs you
start with in all HIV1-infected individuals, the better. I do not think
that experience "in the real world" (outside clinical trials) supports
this notion.
Jordan and Colleagues excluded studies of "less than 12 weeks
duration" (i.e., included studies of very short duration which are of
doubtful significance) and considered entirely different patients
categories, as "more patients were asymptomatic" and "mean baseline CD4
counts ranged from 83 to 660 cells per microliter". Finally, "follow-up
was not always clearly reported".
In addition to the above, important weaknesses, if one looks
carefully at figure 4, it can be observed that the studies with fewer
participants either do not show differences in disease progression or
death between triple and double therapy or are in favour of double
therapy, the only exceptions being the INCAS studies. The two largest
studies (PISCES), in contrast, are clearly in favour of triple therapy. As
in most meta-analyses and reviews, it appears quite difficult to explain
and reconcile such striking differences.
In my opinion, whenever choosing an antiretroviral regimen a
fundamental point is the CD4 cell count. If this is fairly low (i.e.,
below 200 per microliter), and even more if the patient is symptomatic,
the benefit of triple therapy is generally higher than the benefit of
double therapy; if the count is higher (and especially when higher than
300 cells per microliter), the superiority of triple over double therapy
in the long-term is far from being demonstrated.
In my experience, poor compliance rather than resistance explains the
vast majority of cases of failure of antiretroviral regimens, if "failure"
has to mean not just "virological failure" (i.e., detectable plasma HIV-
RNA) but "immunological failure" (i.e., decrease in CD4 cell number), the
latter being the really important "failure" which can lead to clinical
progression; "in the real world" triple drug therapies bear higher and
more serious side-effects and lead to lower compliance.
The level of CD4 cell decline required to initiate antiretroviral
therapy has been reconsidered (Pomerantz RJ. Initiating antiretroviral
therapy during HIV infection. Confusion and clarity. JAMA 2001; 286: 2597-
99), and early start (5 years ago a "must")(Carpenter CC, Fischl MA,
Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral
therapy for HIV infection in 1997. Updated recommendations of the
International AIDS Society-USA Panel. JAMA 1997; 277: 1962-69) is no
longer regarded as beneficial.
In my opinion, time has come to reconsider not only when, but also
what to start with: if the CD4 cell count is higher than 300 per
microliter and the subject is asymptomatic, double antiretroviral therapy
still has a place.
Competing interests: No competing interests