The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic.
- [Show abstract] [Hide abstract]
ABSTRACT: This randomised, open label, phase I, immunotherapeutic study investigated the effects of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant human growth hormone (rhGH), and therapeutic immunisation (a Clade B DNA vaccine) on combination antiretroviral therapy (cART)-treated HIV-1-infected individuals, with the objective to reverse residual T-cell dysfunction.Methods Twelve HIV-1+ patients on suppressive cART with baseline CD4 T-cell counts >400 cells/mm3 blood were randomised into one of three groups: (1) vaccine, IL-2, GM-CSF and rhGH (n = 3); (2) vaccine alone (n = 4); or (3) IL-2, GM-CSF and rhGH (n = 5). Samples were collected at weeks 0, 1, 2, 4, 6, 8, 12, 16, 24 and 48. Interferon (IFN)-γ, IL-2, IL-4 and perforin ELISpot assays performed at each time point quantified functional responses to Gag p17/p24, Nef, Rev, and Tat peptides; and detailed T-cell immunophenotyping was undertaken by flow cytometry. Proviral DNA was also measured.ResultsMedian baseline CD4 T-cell count was 757 cells/mm3 (interquartile range [IQR] 567–886 cells/mm3), median age 48 years (IQR 42–51 years), and plasma HIV-1-RNA <50 copies/ml for all subjects. Patients who received vaccine plus IL-2, GM-CSF and rhGH (group 1) showed the most marked changes. Assessing mean changes from baseline to week 48 revealed significantly elevated numbers of CD4 T cells (p = 0.0083) and improved CD4/CD8 T-cell ratios (p = 0.0033). This was accompanied by a significant reduction in expression of CD38 on CD4 T cells (p = 0.0194), significantly increased IFN-γ and IL-2 production in response to Gag (p = 0.0122) and elevated IFN-γ production in response to Tat (p = 0.041) at week 48 compared to baseline. Subjects in all treatment groups showed significantly reduced PD-1 expression at week 48 compared to baseline, with some reductions in proviral DNA.Conclusions Multifarious immunotherapeutic approaches in the context of fully suppressive cART further reduce immune activation, and improve both CD4 T-lymphocyte counts and HIV-1-specific T-cell responses (NCT01130376).Vaccine 10/2014; · 3.49 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Patients with advanced stage or recurrent cervical cancer represent a population with limited chemotherapeutic options. More specifically, patients with recurrent disease have a poor salvage rate, with a 5-year survival rate of less than 10%. This year, the first prospective phase III clinical trial exploring the anti-angiogenic agent, bevacizumab, was published, meeting its primary endpoint, with a significant improvement in overall survival. As such, a review of anti-angiogenic therapy in the treatment of this disease is warranted.Therapeutic advances in medical oncology. 11/2014; 6(6):280-92.
- [Show abstract] [Hide abstract]
ABSTRACT: Realizing the full individual and population-wide benefits of antiretroviral therapy for human immunodeficiency virus (HIV) infection requires an efficient mechanism of HIV-related health service delivery. We developed a system dynamics model of the continuum of HIV care in Vancouver, Canada, which reflects key activities and decisions in the delivery of antiretroviral therapy, including HIV testing, linkage to care, and long-term retention in care and treatment. To measure the influence of operational interventions on population health outcomes, we incorporated an HIV transmission component into the model. We determined optimal resource allocations among targeted and routine testing programs to minimize new HIV infections over five years in Vancouver. Simulation scenarios assumed various constraints informed by the local health policy. The project was conducted in close collaboration with the local health care providers, Vancouver Coastal Health Authority and Providence Health Care.Health Care Management Science 01/2015; · 1.05 Impact Factor
www.thelancet.com Vol 368 August 5, 2006 531
The case for expanding access to highly active antiretroviral
therapy to curb the growth of the HIV epidemic
Julio S G Montaner, Robert Hogg, Evan Wood, Thomas Kerr, Mark Tyndall, Adrian R Levy, P Richard Harrigan
“The upshot of this widespread failure to recognize that
AIDS is an exceptional crisis and threat is that the
response to the pandemic is not made commensurate to
the challenges—and so the epidemic escalates even
while it erodes our capacities to check it.”
Dr Peter Piot, UNAIDS Executive Director1
Continuing expansion of the HIV/AIDS pandemic has
been recognised as an exceptional challenge to global
health, international development, and world security.
UNAIDS estimates that there were more than 38 million
people living with HIV at the end of 2005, with just over
4 million new infections that year.2 While most new cases
continue to emerge from developing nations, even in
developed countries HIV incidence remains unacceptably
high.3 The high incidence is not likely to change in the
foreseeable future because: (1) HIV-prevention strategies
are only partly eff ective and remain severely underused;4–10
(2) a preventive vaccine remains elusive;11 and (3) current
treatment strategies cannot eradicate HIV infection.12–15
Nowadays, the exceptional threat to humanity that the
HIV pandemic represents, and the similarly exceptional
interventions that will be needed to stem the relentless
global growth of AIDS deaths and new HIV infections, is
Highly active antiretroviral therapy (HAART), fi rst
introduced in 1996,18–20 substantially reduced AIDS-related
hospital admissions and death rates in both developed
and developing nations.21–23 Despite these encouraging
results, the early optimism generated by HAART was
tempered by regimen complexities, adverse eff ects,
toxicities, and cost.24,25 In the past decade, HAART
regimens have become markedly simpler, better tolerated,
less toxic, and more eff ective.26–28 As a result, expansion of
HAART programmes in developing nations has become
a welcome reality.29 Although concerns have been
expressed with regard to the potential negative eff ects of
suboptimal adherence leading to HIV-drug resistance in
settings where scale-up of HAART is taking place, recent
data suggest that good adherence can be attained in
resource-limited settings and in marginalised populations
in developed nations.30,31
The important role that the provision of HAART has in
the overall strategy to control the advance of the
HIV/AIDS pandemic is now generally agreed. However,
a great deal of attention has been focused on the potential
negative eff ect of HAART on the overall expansion of the
pandemic if enhanced access to the treatment was to
promote an increase in risky behaviours. By contrast, the
potential direct contribution of HAART to reducing the
spread of HIV has received only limited attention. We
Lancet 2006; 368: 531–36
British Columbia Centre for
Excellence in HIV/AIDS,
Providence Health Care
(J S G Montaner MD, R Hogg PhD,
E Wood PhD, T Kerr PhD,
M Tyndall MD, P R Harrigan PhD);
Department of Medicine
(J S G Montaner, R Hogg,
E Wood, T Kerr, M Tyndall,
P R Harrigan); and Department
of Health Care and
Epidemiology (A R Levy PhD),
University of British Columbia,
Dr Julio S G Montaner FCCP Chair,
AIDS Research Program
University of British Columbia/St
Paul’s Hospital, Vancouver, BC
V6Z 1Y6 Canada
examine here the potential role of HAART in HIV
prevention and the resulting eff ect this would have on
the cost-eff ectiveness of the treatment. We also discuss a
theoretical HAART-driven strategy to control the
continued expansion of the HIV/AIDS pandemic.
HAART and HIV prevention
HIV causes AIDS.32 The transmission of HIV from
infected to uninfected people through exposure to an
infected person’s bodily fl uids (mainly semen, vaginal
secretions, breast milk, and blood) is established.33–35
More recently, HAART has been shown to reduce
HIV-1-RNA plasma concentrations predictably to
undetectable concentrations in most treated patients.36
International guidelines have uniformly recognised
that sustained complete suppression of HIV-1-RNA is
needed to achieve a steady increase in CD4-positive
T-lymphocyte (CD4) cell count as well as a benefi cial
clinical response, and to avoid the emergence of drug
resistant HIV mutants.37,38 Furthermore, the use of
HAART leads to a marked reduction in HIV-1 RNA
concentrations in both the female genital tract and in
Evidence of the eff ect of HAART on the prevention of
HIV transmission can be derived from experience in the
mother-to-child-transmission setting. Here, even before
the HAART era, the key role of maternal plasma
HIV-1-RNA concentrations in HIV transmission had
been clearly established.41 Subsequently, clinical trials
have shown that reducing the mother’s plasma
HIV-1-RNA concentration with HAART dramatically
reduces mother-to-child transmission of HIV.42,43 Since
the widespread availability of HAART, mother-to-child
transmission of HIV has become exceedingly rare in
Consistent results have emerged from several studies
of HIV sero-discordant heterosexual couples. In a study
from Uganda, Quinn and colleagues45 showed that viral
load is the main predictor of the risk of heterosexual
transmission of HIV-1, and that transmission is rare in
those with plasma HIV-1-RNA concentrations of less
than 1500 copies per mL. In this study there were no
cases of HIV transmission for couples in which the index
case had plasma HIV-1-RNA of less than 400 copies
per mL. Similarly, in a study from Thailand, Tovanabutra
and co-workers46 showed a dose-response eff ect between
viral load and risk of HIV transmission within
sero-discordant heterosexual couples. No cases of HIV
transmission were seen when the index case’s plasma
HIV-1-RNA was less than 1100 copies per mL in the same
www.thelancet.com Vol 368 August 5, 2006
Additional studies to assess the eff ect of HAART on
HIV incidence in sero-discordant couples have also been
shown reduced HIV transmission. Before the HAART
era, use of zidovudine alone was associated with a 50%
reduction in HIV transmission in a study of Italian
sero-discordant couples.47 In the HAART era, a study of
Spanish sero-discordant couples showed that no HIV
sero-conversions took place in the sexual partners of
HAART treated patients, use of HAART being
independently associated with an 86% reduction in HIV
transmission in multivariate analyses.48 As a result,
Hosseinipour and colleagues49 have asked whether
HAART can be used to curb the spread of HIV. However,
a possible role for HAART in reducing HIV transmission
was substantially tempered by several mathematical
modelling studies, which consistently suggested that any
possible benefi t derived from the use of HAART in this
setting could be readily off set if expanded use of HAART
results in increased HIV-risk behaviour.50–52
These concerns have been alleviated by an ecological
study from Taiwan, which provided compelling evidence
about the eff ect of HAART on HIV transmission.53 The
study showed a 53% reduction in new positive HIV tests
after the introduction of free access to HAART. This
reduction took place without any change in rates of
syphilis, used as a marker of sexual risk behaviour during
the study. In British Columbia, Canada, new HIV
infections fell between 1995 and 1998 after the
introduction of HAART by about 50%, and have remained
unchanged to the present despite a noticeable increase in
syphilis rates (Rekart M, British Columbia Centre for
Disease Control, personal communication).
Further ecological evidence of an eff ect of HAART on
HIV transmission can be derived from a detailed review
of the UNAIDS statistics.2 As shown in the table, in 2005,
about 38 600 000 people were estimated to be living with
HIV or AIDS worldwide, with more than 4 000 000 new
HIV infections and 2 800 000 AIDS-related deaths in that
year. HIV-prevalent cases are the source of new HIV
infections, so investigation of the ratio between new and
prevalent cases on a regional basis is of interest. The
table shows numbers of people living with HIV, numbers
of new HIV infections, and the ratio of new HIV
infections per 100 people living with HIV in 2005 by
region.2 The ratios show clear regional diff erences, which
correlate inversely with regional availability of HAART
(fi gure).54 Use of HAART is fairly widespread in
western and central Europe and North America, inter-
mediate in Oceania and Latin America, and limited in
the rest of the world.
Ecological evidence has some limitations that should
be recognised. The accuracy of the HIV prevalence and
incidence data are not known, and our calculations could
be aff ected by this. Also, the number of transmitted cases
might not be exactly proportional to prevalence of HIV
infection in a given area, because a limited number of
individuals with very high viral load could contribute a
disproportionate number of transmission events. Finally,
HAART might be only one of several factors that
contribute to reduced transmission in areas where such
treatment is accessible. We must stress that we do not
see HAART as a replacement for strengthening of the
prevention eff ort, but rather as an essential part of it.
Cost eff ectiveness of HAART revisited
Traditionally, HAART has been deemed to be cost
eff ective on the basis of patient-centred outcomes;55
however, this fails to consider the eff ect of HAART on
HIV transmission. Regional incidence to prevalence
ratios can be used to estimate the number of new HIV
infections that have failed to materialise in 2005 in any
given region. For example, to raise the index in North
America to the level seen in developing countries, where
access to HAART is limited, would take nearly
100 000 additional HIV infections in North America. The
precise proportion of these missing new infections that
are directly attributable to the use of HAART is not clear;
however, on the basis of the data from Taiwan and
British Columbia, a 50% or so yearly reduction in new
HIV cases can reasonably be attributed to the introduction
of HAART. This proportion would represent about
43 000 new cases in North America in 2005, which in
turn translates to an averted HAART cost of
US$10·3 billion, based on an estimated lifetime treatment
cost, in 2001, of US$241 000 per person treated.55
People living with
New HIV infectionsRatio of new infections
per 100 people living
East Europe and central Asia 1 500 000
(1 000 000–2 300 000)
(250 000–720 000)
(420 000–1 100 000)
(240 000–420 000)
24 500 000
(21 600 000–27 400 000)
7 600 000
(5 100 000–11 700 000)
(48 000–170 000)
1 600 000
(1 200 000–2 400 000)
1 300 000
(770 000–2 100 000)
(550 000–950 000)
38 600 000
(33 400 000–46 000 000)
(150 000–650 000)
(38 000–210 000)
(55 000–290 000)
(26 000–54 000)
2 700 000
(2 300 000–3 100 000)
(530 000–2 300 000)
(3 500–55 000)
(100 000–420 000)
(34 000–65 000)
(18 000–33 000)
4 100 000
(3 400 000–6 200 000)
North Africa and middle east14·5
South and southeast Asia 10·9
Western and central Europe3·1
Based on May, 2006, UNAIDS Report of the global AIDS epidemic.2 Data are number (range) unless otherwise
Table: Estimated HIV/AIDS prevalence, HIV incidence, and ratio of new HIV infections per 100 people
living with HIV/AIDS in 2005 by region
www.thelancet.com Vol 368 August 5, 2006 533
HAART use is estimated to have averted 400 new
infections in British Columbia in 2005. This would
represent a total cost, in 2001, of US$96·4 million of
averted lifetime treatment expenditure, in addition to the
direct health benefi t of HAART to the HIV-infected
individuals. This is particularly striking if we consider
that 3963 individuals received HAART in British
Columbia in that same year for a total HAART cost (using
patented drugs) of US$49 million. On the basis of these
data, HAART, which was already deemed cost eff ective
on a patient-centred basis, has generated an additional
substantial cost saving once its eff ect on HIV transmission
A potential HAART-driven HIV-control strategy
The patient-centred approach to HIV management is
based on the use of HAART to modify the natural history
of the disease with the expectation that HIV infection
will be transformed into a manageable chronic condition.
This approach is supported by many clinical trials and
population-based studies showing that health outcomes,
such as death or progression to AIDS, can be delayed as
long as individuals are highly adherent to therapy and
start treatment with CD4-cell counts of greater than
200 per µL. No additional patient-specifi c benefi t has
been documented when treatment was initiated at earlier
stages of the disease.25 As a result, a large global eff ort is
currently underway to expand access to HAART for
individuals with AIDS-related symptoms or CD4-cell
counts of less than 200 per µL.29 The “3 by 5” plan
proposed to expand the use of HAART regimens to an
additional 3 million HIV positive individuals by 2005.
Despite substantial progress, the “3 by 5” plan has failed
to meet its target.56,57 In fact, the number of new HIV
infections in 2005 was more than double the number of
individuals who started HAART in the same year.
Current estimates are that between 30% and 40% of
HIV-infected individuals globally are in need of HAART.58
In view of the well-characterised and relentless decline of
CD4-cell count in untreated HIV-infected individuals,
most currently infected individuals will become eligible
for HAART within a decade. Most of the 38 million HIV
positive individuals already infected worldwide will
become eligible for HAART therapy by the year 2015.
The continued expansion of the global HIV/AIDS
caseload threatens to make the current HAART strategy
In view of the potential eff ect of HAART on HIV
transmission, what would be the implications of an
alternative prevention-centred strategy for the use of
HAART? This approach would be based on the notion
that new HIV infections are overwhelmingly contributed
to by index HIV-infected individuals who are not on
HAART. A prevention-centred approach would therefore
argue that treating 100% of HIV-infected individuals at
once could greatly reduce HIV transmission. While this
would be costly in the short term, it could prove highly
cost eff ective. The short-term cost of treatment of all
HIV-infected individuals would be more than off set by
the number of new infections that it would prevent. In
fact, as the cohort of today’s HIV-infected individuals on
HAART matures, after about 20–40 years this cohort will
no longer be interacting substantially with the populations
at risk, therefore drastically reducing the likelihood of
new infections. Although treating 100% of HIV-infected
individuals worldwide might not be feasible or even
ethically acceptable at this time, given the state of the
pandemic, consideration of this possibility is worth-
We have, therefore, developed a hypothetical pop-
ulation-based model to illustrate the potential eff ect of a
prevention-centred approach on the worldwide HIV
pandemic (unpublished). The model estimates the rate
of decline in HIV prevalence in low-income and
middle-income countries. We have assumed that all
HIV-infected people would be given therapy in the fi rst
year and that, after the fi rst year, there would be no new
HIV infections. We also assume the cost of HAART
therapy, with use of generic medications, would remain
at the present cost of US$365 per person per year.
However, the model incorporates a moderate increase in
the yearly cost of therapy at 3% per year for future
infl ation. We also assume that the death rate will fall
initially with the use of HAART, but increase to baseline
levels in a stepwise fashion as the population receiving
treatment needs more complicated therapeutic regimens.
This optimistic population-based model shows that, in
45 years, HIV prevalence could be reduced by more than
70 times from more than 7 cases per 1000 people to less
than 0·1 case per 1000. The number of HIV-infected
people could be reduced from 38 million to less than
1 million. The cost of therapy would be about US $7 billion
per year, with costs declining from $15 to $1 billion. Such
a programme would be expected to cost $338 billion over
Data not available
Figure: Estimated percentage of people receiving antiretroviral therapy of those in need as of June 2005
Reproduced from reference 54.
www.thelancet.com Vol 368 August 5, 2006
45 years. The prospect of treating nearly 40 million
HIV-infected individuals worldwide seems daunting
today but, in view of the limited eff ect of current eff orts
on global prevention of new infections, this approach
merits consideration if it can off er a means to control the
relentless growth of the pandemic.
The logistical and infrastructural challenges that lie
ahead for this kind of approach are substantial. Many of
the same structural obstacles that have faced HAART
scale-up programmes, such as poor health infrastructure,
a scarcity of trained health-care workers, and rural-based
populations, would be multiplied many fold. One
additional important concern is the potential for
increased transmission of drug-resistant strains of HIV
with expansion of HAART use. However, drug-resistant
HIV might be less transmissible.59 A study from
Montreal60 showed that increased population rates of
suppression of plasma HIV RNA as a result of HAART
were associated with reduced rates of resistance in the
community. Further reassurance is provided by exam-
ination of the early history of antiretroviral therapy in
developed nations. Between the introduction of
zidovudine in 1986 and HAART in 1996, treatment of
HIV infection relied exclusively on the use of single and
dual nucleoside analogues. Nucleoside resistance in this
context was an almost universal occurrence in treated
individuals within a year of starting therapy. Despite this
resistance, an epidemic of primary-nucleoside-resistant
HIV did not materialise, and in fact the rates of primary
resistance to nucleosides continue to be modest.61–65
Zidovudine and lamivudine remain highly eff ective and
in widespread use in developed nations. As has previously
been proposed, we conclude that fear of emergence of
drug resistance should not prevent expansion of HAART
programmes, even in developing countries.66 However,
any eff ort directed toward the expansion of HAART
programmes should include careful monitoring of
Previous concerns about the cost and acceptability of
HAART regimens have been alleviated in recent years.
The availability of generic stavudine, lamuvidine, and
nevirapine in a fi xed dose combination tablet at US$1 a
day set a precedent by making the expansion of HAART
programmes feasible in developing countries. This
specifi c treatment would not be appropriate for the
implementation of a global universal treatment
programme, because of the potential for nevirapine and
stavudine toxicity. However, an alternative one pill once
daily HAART regimen with a fi xed-dose combination of
tenofovir, emtricitabine, and sustiva is now available.
This represents a simple, safe, and well-tolerated regimen
that would be viable at all stages of the disease; with a
single-dose scheme, without food restrictions, with no
refrigeration needs, and limited need for laboratory
monitoring. This opens the door to consideration of the
eff ect of diff erent levels of expansion of HAART coverage
on HIV transmission.
The present approach to the management of HIV/AIDS
is clearly not sustainable, and the status quo no longer
acceptable if we hope to control the continued growth of
the HIV global pandemic. A prevention-centred approach
to the use of HAART, as discussed here, would be
challenging and would need careful consideration of
associated emerging ethical issues. However, expanded
free access to HAART on a global scale provides a
potential means to curb the growth of the HIV pandemic.
As such, expansion of HAART programmes could have a
major role in the much needed strengthening of the
prevention eff ort. This hypothetical but testable approach
deserves to be urgently and thoroughly evaluated in
highly controlled environments. The global expansion of
HAART programmes now underway provides a unique
opportunity to further characterise the eff ect of HAART
on HIV incidence in various settings. Monitoring of HIV
incidence should be an integral part of HAART expansion
Confl ict of interest statement
J Montaner has received grants from, served as an ad-hoc adviser to,
and spoken at events sponsored by Abbott, Boehringer Ingelheim,
Bristol-Meyers Squibb, Gilead Sciences, GlaxoSmithKline,
Hoff mann-La Roche, Janssen-Ortho, Merck Frosst, Pfi zer, Tibotec,
Trimeris. R Hogg is supported by a Michael Smith Foundation for
Health Research Senior Scholar award. In the past 5 years, he has also
held grant funding from the Canadian Institutes of Health Research and
National Institutes of Health. He has also received funding for research
and continuing medical education programmes from Abbott,
Boehringer Ingelheim, and GlaxoSmithKline. M Tyndall has served on
advisory boards for Abbott, Boehringer Ingelheim, GlaxoSmithKline,
Bristol-Meyers Squibb, and has received research support from Merck
Frosst Canada. A R Levy is supported by a Michael Smith Foundation for
Health Research Senior Scholar award and a Canadian Institutes of
Health Research New investigator award. He is a shareholder in Oxford
Outcomes, a consultancy specialising in contract research for clients in
the life sciences industry, including public sector organisations and
pharmaceutical and other private companies. P R Harrigan has served as
a consultant, received research funding or medical education or both
from Abbott, Boehringer Ingelheim, GlaxoSmithKline, Merck, Roche,
Pfi zer, and Virco. E Wood and T Kerr declare that they have no confl ict
We thank Kelly Hsu for her editorial assistance in the preparation of this
manuscript; and Stephen Smith and Warren O’Briain for their valuable
1 Piot P. Why AIDS is exceptional. Speech given at the London
School of Economics, London, Feb 8, 2005.
2 UNAIDS. 2006 Report on the global AIDS epidemic. Annex 2: HIV/
AIDS estimates and data, 2005. May 2006: http://www.unaids.org/
en/HIV_data/2006GlobalReport/default.asp (accessed July 20,
3 Karon JM, Fleming PL, Steketee RW, De Cock KM. HIV in the
United States at the turn of the century: an epidemic in transition.
Am J Public Health 2001; 91: 1060–68.
4 Wood E, Tyndall MW, Spittal PM, et al. Factors associated with
persistent high-risk syringe sharing in the presence of an
established needle exchange programme. AIDS 2002; 16: 941–43.
5 Strathdee SA, Hogg RS, Martindale SL, et al. Determinants of
sexual risk-taking among young HIV-negative gay and bisexual
men. J Acquir Immune Defi c Syndr 1998; 19: 61–66.
6 Gayle HD. Expanding access to HIV prevention. AIDS Res Ther
2006; 3: 2.
www.thelancet.com Vol 368 August 5, 2006 535
7 USAID, UNAIDS, WHO, CDC, and the POLICY Project. Coverage
of selected services for HIV/AIDS prevention, care, and support in
low- and middle-income countries in 2003. 2004: http://www.
(accessed July 18, 2006).
UNAIDS: Resource needs for an expanded response to AIDS in
low- and middle-income countries, 2005. http://data.unaids.org/
publications/irc-pub06/resourceneedsreport_en.pdf (accessed July
UNAIDS. Financing the expanded response to AIDS: HIV vaccine
and microbicide research and development, 2005. http://www.iavi.
org/fi le.cfm?fi d=34228 (accessed July 20, 2006).
10 Kerr T, Kaplan K, Suwannawong P, Jurgens R, Wood E. The Global
Fund to Fight AIDS, Tuberculosis and Malaria: funding for
unpopular public-health programmes. Lancet 2004; 364: 11–12.
11 Markel H. The Search for eff ective HIV vaccines. N Engl J Med
2005; 353: 753–57.
12 Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying residual
HIV-1 replication in patients receiving combination antiretroviral
therapy. N Engl J Med 1999; 340: 1605–13.
13 Furtado M, Callaway D S, Phair J P, et al. Persistence of HIV-1
transcription in peripheral-blood mononuclear cells in patients
receiving potent antiretroviral therapy. N Engl J Med 1999; 340:
14 Pomerantz R. Residual HIV-1 disease in the era of highly active
antiretroviral therapy. N Engl J Med 1999; 340: 1672–74.
15 Montaner JS, Harris M, Mo T, Harrigan PR. Rebound of plasma
HIV viral load following prolonged suppression with combination
therapy. AIDS 1998; 12: 1398–99.
16 Hogg R, Cahn P, Katabira ET, et al. Time to act: global apathy
towards HIV/AIDS is a crime against humanity. Lancet 2002; 360:
17 Bicego G, Rutstein S, Johnson K. Dimensions of the emerging
orphan crisis in sub-Saharan Africa. Soc Sci Med 2003; 56: 1235–47.
18 Montaner JS, Reiss P, Cooper D, et al. A randomized, double-blind
trial comparing combinations of nevirapine, didanosine, and
zidovudine for HIV-infected patients: the INCAS Trial. JAMA 1998;
19 Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing
nucleoside monotherapy with combination therapy in HIV-infected
adults with CD4 cell counts from 200 to 500 per cubic millimeter.
AIDS Clinical Trials Group Study 175 Study Team. N Engl J Med
1996; 335: 1081–90.
20 Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy
for HIV infection in 1996. Recommendations of an international
panel. International AIDS Society-USA. JAMA 1996; 276: 146–54.
21 Hogg RS, O’Shaughnessy MV, Gataric N, et al. Decline in deaths
from AIDS due to new antiretrovirals. Lancet 1997; 349: 1294.
22 Hogg RS, Heath KV, Yip B, et al. Improved survival among
HIV-infected individuals following initiation of antiretroviral
therapy. JAMA 1998; 27: 450–54.
23 Braitstein P, Brinkhof MW, Dabis F, et al. Mortality of HIV-1-
infected patients in the fi rst year of antiretroviral therapy:
comparison between low-income and high-income countries. Lancet
2006; 367: 817–24.
24 Cote HC, Brumme ZL, Craib KJ, et al. Changes in mitochondrial
DNA as a marker of nucleoside toxicity in HIV-infected patients.
N Engl J Med 2002; 346: 811–20.
25 Wood E, Hogg RS, Harrigan PR, Montaner JSG. When to initiate
antiretroviral therapy in HIV-1-infected adults: a review for
clinicians and patients. Lancet Infect Dis 2005; 5: 407–14.
26 Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz
plus zidovudine and lamivudine, efavirenz plus indinavir, and
indinavir plus zidovudine and lamivudine in the treatment of HIV-1
infection in adults. Study 006 Team. N Engl J Med 1999; 341:
27 van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of
fi rst-line antiretroviral therapy with regimens including nevirapine,
efavirenz, or both drugs, plus stavudine and lamivudine: a
randomised open-label trial, the 2NN Study. Lancet 2004; 363:
28 Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine,
and efavirenz vs zidovudine, lamivudine, and efavirenz for HIV.
N Engl J Med 2006; 354: 251–60.
29 WHO. Progress on global access to HIV antiretroviral therapy: an
update on 3 by 5. Geneva: World Health Organization: page 34.
June 2005: http://www.who.int/3by5/fullreportJune2005.pdf
(accessed July 20, 2006).
30 Mills E, Nachega J, Singh S, et al. Adherence to antiretroviral
therapy in Africa versus North America: a comparative
meta-analysis. JAMA (in press).
31 Farmer P, Leandre F, Mukherjee JS, et al. Community-based
approaches to HIV treatment in resource-poor settings. Lancet 2001;
32 Schechter MT, Craib KJ, Gelmon KA, Montaner JS, Le TN,
O’Shaughnessy MV. HIV-1 and the aetiology of AIDS. Lancet 1993;
33 Kingsley LA, Detels R, Kaslow R, et al. Risk factors for
seroconversion to human immunodefi ciency virus among male
homosexuals: results from the Multicenter AIDS Cohort Study.
Lancet 1987; 1: 345–49.
34 Cameron DW, Simonsen JN, D’Costa LJ, et al. Female to male
transmission of human immunodefi ciency virus type 1: risk factors
for seroconversion in men. Lancet 1989; 2: 403–07.
35 Hardy AM, Allen JR, Morgan WM, Curran JW. The incidence rate
of acquired immunodefi ciency syndrome in selected populations.
JAMA 1985; 253: 215–20.
36 Hogg RS, Rhone SA, Yip B, et al. Antiviral eff ect of double and
triple drug combinations amongst HIV- infected adults: lessons
from the implementation of viral load-driven antiretroviral therapy.
AIDS 1998; 12: 279–84.
37 Hammer, SM; Saag, MS; Schechter, M, et al. Treatment for adult
HIV infection: 2006 recommendations of the International AIDS
Society–USA Panel. JAMA (in press).
38 Department of Health and Human Services. Guidelines for the use
of antiretroviral agents in HIV-1-infected adults and adolescents.
May 4, 2006. http://aidsinfo.nih.gov/ContentFiles/
AdultandAdolescentGL.pdf (accessed July 20, 2006).
39 Cu-Uvin S, Caliendo AM, Reinert S, et al. Eff ect of highly active
antiretroviral therapy on cervicovaginal HIV-1 RNA. AIDS 2000; 14:
40 Vernazza PL, Gilliam BL, Flepp M, et al. Eff ect of antiviral
treatment on the shedding of HIV-1 in semen. AIDS 1997; 11:
41 Fang G, Burger H, Grimson R, et al. Maternal plasma human
immunodefi ciency virus type 1 RNA level: a determinant and
projected threshold for mother-to-child transmission.
Proc Natl Acad Sci USA 1995; 92: 12 100–04.
42 Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal
single-dose nevirapine compared with zidovudine for prevention of
mother-to-child transmission of HIV-1 in Kampala, Uganda:
HIVNET 012 randomised trial. Lancet 1999; 354: 795–802.
43 De Cock KM, Fowler MG, Mercier E, et al. Prevention of
mother-to-child HIV transmission in resource-poor countries:
translating research into policy and practice. JAMA 2000; 283:
44 Karon JM, Fleming PL, Steketee RW, De Cock KM. HIV in the
United States at the turn of the century: an epidemic in transition.
Am J Public Health 2001; 91: 1060–68.
45 Quinn TC, Wawer MJ, Sewankambo N, et al for the Rakai
Project Study Group. Viral load and heterosexual transmission
of human immunodefi ciency virus type 1. N Engl J Med 2000; 342:
46 Tovanabutra S, Robison V, Wongtrakul J, et al. Male viral load and
heterosexual transmission of HIV-1 subtype E in northern Thailand.
J Acquir Immune Defi c Syndr 2002; 29: 275–83.
47 Musicco M, Lazzarin A, Nicolosi A, et al, for the Italian Study
Group on HIV Heterosexual Transmission. Antiretroviral treatment
of men infected with human immunodefi ciency virus type 1
reduces the incidence of heterosexual transmission. Arch Intern
Med 1994; 154: 1971–76.
48 Castilla J, Del Romero J, Hernando V, Marincovich B, Garcia S,
Rodriguez C. Eff ectiveness of highly active antiretroviral therapy in
reducing heterosexual transmission of HIV.
J Acquir Immune Defi c Syndr 2005; 40: 96–101.
49 Hosseinipour M, Cohen MS, Vernazza PL, Kashuba AD. Can
antiretroviral therapy be used to prevent sexual transmission of
human immunodefi ciency virus type 1? Clin Infect Dis 2002; 34:
www.thelancet.com Vol 368 August 5, 2006
50 Blower SM, Gershengorn HB, Grant RM. A tale of two futures: HIV
and antiretroviral therapy in San Francisco. Science 2000; 287:
51 Law MG, Prestage G, Grulich A, Van de Ven P, Kippax S. Modelling
the eff ect of combination antiretroviral treatments on HIV
incidence. AIDS 2001; 15: 1287–94.
52 Velasco-Hernandez JX, Gershengorn HB, Blower SM. Could
widespread use of combination antiretroviral therapy eradicate HIV
epidemics? Lancet Infect Dis 2002; 2: 487–93.
53 Fang CT, Hsu HM, Twu SJ, et al. Decreased HIV transmission after
a policy of providing free access to highly active antiretroviral
therapy in Taiwan. J Infect Dis 2004; 190: 879–85.
54 WHO. Estimated percentage of people on antiretroviral therapy
among those in need, situation as of June 2005. http://www.who.
int/hiv/facts/ARVcov05web.jpg (accessed May 23, 2003).
55 Levy AR, James D, Johnston KM, et al. The direct costs of HIV/
AIDS care. Lancet Infect Dis 2006; 6: 171–77.
56 The Lancet. WHO 2003-08: a programme of quiet thunder takes
shape. Lancet 2003; 362: 179.
57 The Lancet. Predicting the failure of 3 by 5. Lancet 2005; 365: 1597.
58 Anema A, Chan K, McGuire A, Barer JM, Hogg RS. Is “3 by 5”
enough? Recalculating the global need for antiretroviral treatment.
Lancet 2004; 364: 1034–35.
59 Yerly S, Jost S, Telenti A, et al. Infrequent transmission of HIV-1
drug-resistant variants. Antivir Ther 2004; 9: 375–84.
60 Routy JP, Machouf N, Edwardes MD, et al. Factors associated
with a decrease in the prevalence of drug resistance in newly
HIV-1 infected individuals in Montreal. AIDS 2004;
61 Mocroft A, Ledergerber B, Katlama C, et al, for the EuroSIDA study
group. Decline in the AIDS and death rates in the EuroSIDA study:
an observational study. Lancet 2003; 362: 22–29.
62 Pillay D. Current patterns in the epidemiology of primary HIV drug
resistance in North America and Europe. Antivir Ther 2004; 5:
63 Daar ES, Richman DD. Confronting the emergence of
drug-resistant HIV type 1: impact of antiretroviral therapy on
individual and population resistance. AIDS Res Hum Retroviruses
2005; 5: 343–57.
64 Cane P, Chrystie I, Dunn D, et al, for the UK Group on Transmitted
HIV Drug Resistance. Time trends in primary resistance to HIV
drugs in the United Kingdom: multicentre observational study.
BMJ 2005; 331: 1368.
65 Guerrero A, Canizares A, Tomas S, Velasco D, Cartelle M;
Grupo de Estudio de las Resistencias Primarias del VIH en Espana.
Prevalence of antiretroviral drug resistance among previously
untreated Spanish patients infected with HIV.
Enferm Infecc Microbiol Clin 2005; 10: 605–08.
66 Kuritzkes D, Lange J, Zewdie D. World Bank meeting concludes
drug resistance should not prevent distribution of antiretroviral
therapy to poor countries. Nat Med 2003; 9: 1343–44.