International AIDS Society Newsletter, no. 21

IASI
INTERNATIONAL
AIDS SOCIETY

cells and the drug resistant conferring single
point mutations are all reasons why drug resistant HIV readily and rapidly emerges in
patients treated with a single drug (4-6). The
most effective way to prevent drug resistance is
through the use of combination therapies.
When HIV replication is suppressed to levels
below 50 copies/ml in plasma, drug resistant
virus is much less likely to emerge.
With 16 drugs approved to treat HIV
infection, why then is drug resistance such a
major problem in the developed world? There
are many answers to this question, all of which
provide relevant insights for health policy
makers launching ART scale-up programs.
Regimens with suboptimal potency, the only
ones available when ART was introduced in
1987, lead to drug resistance (7, 8). Poor
adherence, due to either complex or toxic regimens, leads to drug resistance (9). Continued
treatment in the face of incomplete viral suppression, sometimes the only treatment
option, leads to higher and higher levels of
drug resistance (10). And finally, rates of drug
resistance are increasing because drug resistant
virus can be spread through vertical or horizontal transmission (11, 12).
The extent of drug resistance has been
examined in a number of settings in the developed world. In urban areas of the United
States, the prevalence of drug resistance among
patients with recent HIV infection has shown
alarming trends increasing from 3.5% in
1995-98 to 14% in 1999-2000 (13). Data
from Europe show a more heterogeneous pattern with increasing rates in Britain and a
recent reduction in Switzerland (14, 15). The
prevalence of drug resistance in chronically
treated patients under care in the United States
in 1996 was recently reported (16). Among the
patients without suppression of HIV, about
three quarters had evidence of reduced susceptibility to at least one drug. Although on the
surface, this rate is alarming, the history of
drug development and the frequent use of
sequential, incremental therapy in these
patients probably contributed to these findings. Nevertheless, a tour of any clinic in the
developed world today would reveal a substan
tial proportion of patients with drug resistant
HIV. Perhaps the single most important lesson
that we have learned in the brief, but dramatic
history of HIV therapeutics is that without
proper therapeutic strategies, drug resistance
can abolish the effectiveness of our therapies in
rapid time.
There have been several strategies aimed at
containment of drug resistance.
Recommended first line therapies include only
regimens that can effectively suppress HIV
replication. Simpler regimens with less toxicity and co-formulations have been developed to
improve adherence and tolerance (17). Drug
resistance testing is performed on patients
prior to treatment and those failing treatment
in order to avoid prescribing regimens that
incompletely suppress the virus (18).
Adherence, patient education and support are
emphasized in patient management (19).
Finally, drug level monitoring and directly
observed therapy are examples of additional
strategies under evaluation that could help
contain drug resistance.
Drug Resistance in Resource Limited Settings
Not surprisingly, there are already reports of
circulating strains of drug resistance HIV in
resource limited settings. In the Ivory Coast, a
survey of 68 patients with a prior history of
ARV treatment who were enrolling in a UN
Access Program revealed that at least one drug
resistance mutation was present in 57% of
samples tested (20). A small study of 16
patients in Uganda also showed significant
levels of drug resistance. Even a single dose of
nevirapine can lead to drug resistance. In one
study, 19% of pregnant women exposed to
nevirapine to prevent perinatal transmission of
HIV had genotypic resistance mutations associated with nevirapine 6-8 weeks after their
treatment (21). Drug resistance has also been
reported in Asia and South America (22, 23).
There are factors that exist in resource limited settings not present in the developed
world that could increase rates of drug resistance. As discussed in the reports of drug resistance from Africa, interruption of drug supply
or the ability of patients to pay for drugs leads

to interruptions in therapy. The use of generic
drugs is increasing, and some co-formulated
preparations may not contain optimal dosing.
The majority of patients prescribed therapy
will likely be at more advanced stages of HIV
disease, with higher viral loads and hence at
higher risk for drug resistance. Short course
regimens that incompletely suppress HIV
given during pregnancy could also potentially
increase rates of drug resistance. We also have
much to learn about the patterns of drug resistance among the HIV strains circulating
around the world. Recent reports highlight
different resistance patterns that may be based
on HIV subtype (24). Both baseline polymorphisms and pathways of resistance on therapy
may be subtype dependent (25, 26).
Containment of drug resistance in resource
limited settings will depend on a number of
important factors - endorsements of WHO
ART treatment guidelines, access to continuous ARV drug supply and effective adherence
and education programs. Drug resistance testing will not likely be available for individual
patient management. Instead, surveillance
efforts will be needed to guide optimal first
and second line treatment regimens, and to
identify trends in drug resistance in both naive
and treated populations. This is where the
WHO/IAS surveillance program will meet a
critical need.
Status of WHO/IAS Surveillance Program
The WHO and IAS have pledged support to
the development of a Global HIV Drug
Resistance Surveillance Program and developed an action plan outlining program goals
and objective. A preliminary survey elicited
interest in participation from numerous institutions and investigators throughout the
world. During the International AIDS
Conference in Barcelona, core committees are
meeting to establish the scientific agenda, discuss surveillance procedures and develop standards for laboratory testing. Committees will
also organize efforts directed at capacity building, technology transfer and training. Systems
to ensure accurate and rapid data dissemination are being developed. A pilot study involv
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