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HIV/AIDS • CID 2007:45 (15 October) • 1093
HIV/AIDSREVIEW ARTICLE
Adverse Effects of Highly Active Antiretroviral
Therapy in Developing Countries
Ramnath Subbaraman,
1
Sreekanth Krishna Chaguturu,
2
Kenneth H. Mayer,
3
Timothy P. Flanigan,
3
and Nagalingeswaran Kumarasamy
4
1
Yale School of Medicine, New Haven, Connecticut;
2
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston;
3
Division of Infectious Diseases, Miriam Hospital, Brown University, Providence, Rhode Island; and
4
YR Gaitonde Centre for AIDS Research and
Education, Voluntary Health Services, Chennai, India
Recent increases in access to highly active antiretroviral therapy (HAART) have made the management of drug
toxicities an increasingly crucial component of human immunodeficiency virus (HIV) care in developing
countries. The spectrum of adverse effects related to HAART in developing countries may differ from that in
developed countries because of the high prevalence of conditions such as anemia, malnutrition, and tuberculosis
and frequent initial presentation with advanced HIV disease. The severity of adverse effects may vary as a
result of host genetics and diagnostic delays attributable to inadequate laboratory monitoring. This article
reviews current knowledge about toxicities related to HAART in resource-limited regions, which are in the
process of rapid treatment scale-up. We conclude that initiating HAART before advanced immunosuppression,
titrating doses in single-pill drug combinations to differences in patients’ body weights, providing more
intensive laboratory monitoring during the initial months of therapy, and providing access to less-toxic
nucleoside reverse-transcriptase inhibitors may decrease the incidence of toxicities related to HAART in re-
source-limited regions.
Although the HIV-AIDS epidemic continues to spread
in the developing world [1], reductions in the price of
HAART for HIV-infected individuals in resource-con-
strained regions have made treatment increasingly ac-
cessible [2]. HIV care facilities in developing countries
have witnessed dramatic decreases in mortality that are
similar to those previously recorded in developed coun-
tries [3–5]. One by-product of increased access to
HAART, however, is that management of antiretroviral
drug–related toxicities is becoming an important com-
ponent of HIV care in developing countries.
The spectrum of adverse effects associated with
HAART may vary between developed and developing
countries for several reasons. First, economic con-
Received 11 August 2006; accepted 8 June 2007; electronically published 6
September 2007.
Reprints or correspondence: Dr. N. Kumarasamy, YR Gaitonde Centre for AIDS
Research and Education, Voluntary Health Services, Tidel Park Rd., Taramani,
Chennai 600113, India (kumarasamy@yrgcare.org).
Clinical Infectious Diseases 2007;45:1093–1101
2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4508-0026$15.00
DOI: 10.1086/521150
straints limit the repertoire of accessible antiretroviral
medications, making a handful of drugs responsible for
most toxicities in developing countries [6]. Second,
prohibitory laboratory monitoring costs may occasion-
ally delay the diagnosis of specific toxicities, thereby
increasing their severity. Third, comorbid conditions
that are more prevalent in resource-limited regions,
such as anemia and malnutrition; initial presentation
with advanced immunosuppression; use of concomi-
tant antituberculosis therapy (ATT); and use of herbal
medications [7] may influence the incidence of adverse
effects. Finally, host genetics may be associated with
drug toxicities [8]; this is a relevant issue, because most
antiretroviral drugs have been validated in developed
countries (primarily in white populations) but are now
being widely used in developing countries, where the
vast majority of HIV-infected people live.
This article reviews research on the adverse ef-
fects associated with HAART in the context of rapid
treatment scale-up, focusing on drugs predominant-
ly used in resource-constrained regions. Two related
challenges in the management of antiretroviral ther-
1094 • CID 2007:45 (15 October) • HIV/AIDS
apy—coadministration of HAART with ATT and immune re-
constitution syndrome (IRS)—will also be discussed.
NUCLEOSIDE REVERSE-TRANSCRIPTASE
INHIBITORS (NRTI
S
)
Stavudine
Next to lamivudine, stavudine is the most commonly used
NRTI, because of its relatively low cost [9, 10]. Stavudine is
the NRTI that is most often associated with mitochondrial
toxicity, which results in high rates of lipoatrophy, peripheral
neuropathy, lactic acidosis, and pancreatitis [11].
Peripheral neuropathy. From 10% to 21% of persons ex-
posed to stavudine developed peripheral neuropathy in devel-
oped countries [12, 13]. Although symptoms usually resolve
after prompt discontinuation of stavudine therapy, persistent
symptoms in a subset of patients may be problematic in de-
veloping countries, where many persons rely on physical labor
for survival and usually do not have disability insurance.
Cohort studies from Cameroon, India, and Thailand found
peripheral neuropathy rates that were similar to or, surprisingly,
lower than those in developed countries [6, 14–16]. It is hard
to establish whether these lower rates reflect underascertain-
ment biases (e.g., short follow-up periods and insensitive
screening tools). However, 56% of patients in a Malawian co-
hort developed peripheral neuropathy while receivingstavudine
therapy [17]. The authors noted that one-third of their patients
had a body weight
!60 kg, for which a 30-mg dose of stavudine
is recommended; however, only the 40-mg dose was available
in the fixed-dose combination (FDC) used in the study. This
highlights the necessity of the availability of FDCs with varied
doses to minimize toxicity, especially in malnourished patients.
Lipodystrophy and metabolic complications. The preva-
lence of stavudine-associated lipodystrophy in western studies
has reached as high as 50%–63% [18–20]. However, many of
these studies included patients who also received protease in-
hibitors (PIs), which independently cause lipodystrophy. The
risk has been shown to be greater for those initiating HAART
with a low CD4 cell count [21, 22] and a low body mass index
(BMI; calculated as the weight in kilograms divided by the
square of the height in meters) [23]. Because stavudine-asso-
ciated lipodystrophy commonly presents as lipoatrophy (i.e.,
fat loss in the cheeks, arms, and buttocks), malnutrition com-
plicates its diagnosis. Careful assessment is needed to differ-
entiate lipoatrophy from general wasting to prevent unneces-
sary modifications of therapy.
Some data suggest that ethnic variability effects the incidence
of lipodystrophy. White race may be an independent risk factor
for the development of lipodystrophy [22, 24, 25]. Although a
small South Korean cohort had a 3.5% rate of lipodystrophy
[26], multiple subsequent east Asian cohorts have shown rates
similar to those in western studies [27–29]. Only 17% of pa-
tients in 2 southeast Asian cohorts developed lipodystrophy,
compared with 24.8% of patients in a Rwandan cohort and
46.1% in an Indian cohort [30–33].
The tendency of stavudine-associated lipoatrophy to affect
facial features raises concerns that the widespread use of the
drug in developing countries may increase stigma and decrease
HAART adherence [31]. A study of 410 patients of Chinese
ethnicity in Singapore found that lipodystrophy affected social
relations for 23% of the patients and mood for 36% [27].
However,
!1% of the patients wanted to discontinue therapy
because of this toxicity. In contrast, a smaller study suggested
that 14% of Brazilian patients considered therapy discontin-
uation because of this adverse effect [34]. Because toleration
of lipodystrophy may be culturally specific, region-specific re-
search may help determine the viability of stavudine use in
different countries.
Although zidovudine sometimes causes lipodystrophy, sta-
vudine is more strongly associated with this adverse effect [31,
35–37]. Therefore, one approach for reducing the incidence of
lipodystrophy would be to substitute zidovudine for stavudine
6–12 months after HAART initiation, when lipodystrophy may
begin to develop [35]. This allows antiretroviral roll-out pro-
grams to briefly take advantage of the lower cost and better
initial tolerability of stavudine. Also, stavudine-containing
HAART is associated with resolution of anemia in many pa-
tients within 6 months after initiation [38–41]. Because anemia
is a relative contraindication for zidovudine use, stavudine ther-
apy could bridge the way to zidovudine therapy by reducing
the risk for anemia. Even after lipodystrophy develops, substi-
tuting another NRTI for stavudine may result in partial recovery
[11, 42–44].
Of all the NRTIs, stavudine therapy has been most strongly
associated with dyslipidemia and hyperglycemia in western
studies [45–47]. Similar metabolic changes were present in pa-
tients in an Indian cohort treated with stavudine and zido-
vudine and in a cohort of patients of Chinese ethnicity treated
with non–PI-containing HAART [27, 31]. As access to HAART
increases, patients in developing countries may increasinglyface
the cardiovascular consequences of altered metabolism.
Lactic acidosis. Although relatively infrequent, multiple
cohort studies [48–52] and case reports [53–58] from devel-
oping countries highlight concerns about timely diagnosis of
life-threatening stavudine-induced lactic acidosis, for which
women may be at a higher risk [49, 50, 52]. Pilot studies from
Haiti and South Africa found that point-of-care testing with
handheld devices measuring lactic acid levels (e.g., using finger
stick blood samples) facilitated timely diagnosis of hyperlac-
tatemia and prevented unnecessary regimen modifications in
patients without increased serum lactate levels [59, 60]. Such
devices may be beneficial as HIV care is decentralized to rural
HIV/AIDS • CID 2007:45 (15 October) • 1095
locations, where lactic acid testing in laboratories may be
unavailable.
Zidovudine
Myelosuppression. Anemia is common in developing coun-
tries, particularly among HIV-infected individuals [61–63], and
generally worsens with disease progression [64–66]. High back-
ground levels of anemia may preclude zidovudine use in many
patients. Zidovudine-related anemia usually occurs within 3
months after therapy initiation [6]. Risk factors include high
zidovudine dosage, increased treatment duration, low CD4 cell
count, and preexisting anemia [65, 67, 68]. Studies from Ni-
geria, Coˆte d’Ivoire, Haiti, and India have found rates of zi-
dovudine-related anemia of 3%–12% [5, 6, 69–71].
A study from Coˆte d’Ivoire suggested synergistic toxicity be-
tween zidovudine and cotrimoxazole. Among 498 patients al-
ready receiving cotrimoxazole prophylaxis, the introduction of
zidovudine-containing HAART resulted in one-half of the co-
hort developing severe neutropenia. Complete recovery oc-
curred in nearly all patients after discontinuation of cotrimox-
azole therapy, suggesting that this toxicity was attributable to
a drug-drug interaction between these 2 myelosuppressive
drugs [70].
Among patients who discontinue stavudine therapy because
of toxicity, those who cannot substitute zidovudine therapy
because of persisting anemia may be left with no options, be-
cause these are the least expensive NRTIs in resource-limited
regions [9, 10]. This highlights the need for increased access
to NRTIs with different toxicity profiles, such as tenofovir and
abacavir, in developing countries.
NONNUCLEOSIDE REVERSE-TRANSCRIPTASE
INHIBITORS (NNRTI
S
)
Nevirapine
Nevirapine is the most commonly used NNRTI in developing
countries because of its lower cost, compared with efavirenz
[9, 10].
Hypersensitivity rash. Hypersensitivity rash occurred in
16%–20% of patients in studies in developed country [68, 72,
73]. Two US studies that disaggregated data by ethnicity found
that mostly persons of Mexican origin and some persons of
South American origin were at a higher risk [74, 75]. Data do
not suggest a higher risk of rash among other ethnic groups,
with most studies in developing countries finding rates similar
to or lower than those in developed countries. Cohorts from
Haiti, India, Thailand, and Malawi found nevirapine-associated
rash rates of 3%–26% [5, 6, 15–17, 76]. Female patients may
be at an increased risk for nevirapine-associated rash [76–79].
Initiating patients on a lower lead-in dosage of nevirapine
of 200 mg once daily, followed by escalation to the full 200-
mg twice daily dosage after 2 weeks, helps prevent severe rashes,
such as Stevens-Johnson syndrome [72]. The use of FDCs in
developing countries does not enable clinicians to titrate ne-
virapine therapy initiation. Without appropriate physician ed-
ucation, the use of the full nevirapine dose in FDCs for patients
beginning HAART may increase the incidence of life-threat-
ening rashes. Although nevirapine therapy can safely be re-
placed with efavirenz therapy for those who experience adverse
reactions, because there is little evidence of rash cross-toxicity
between the 2 drugs [76, 80], this substitution is often pre-
cluded by the higher cost of efavirenz in developing countries
[10].
Hepatotoxicity. The incidence of drug-related hepatitis in
US and European trials has ranged from 1% to 10% [72, 81–
83]. Cohorts from Haiti, Thailand, India, Zambia, and Malawi
found similar rates of nevirapine-associated hepatotoxicity,
ranging from
!1% to 7% [5, 6, 15–17, 84].
A South African study reported a 17% incidence of serious
hepatotoxicity (i.e., alanine aminotransferase and aspartate
aminotransferase levels
15 times the upper limit of normal)
among 385 patients receiving nevirapine-based regimens, com-
pared with no cases of hepatotoxicity among 83 patients re-
ceiving efavirenz-based regimens [85]. Female patients with a
BMI
!18.5 had a 50% incidence of serious hepatotoxicity. Leith
et al. [86] argued that the high mean CD4 cell count of 398
cells/mL at treatment initiation in this cohort may explain this
elevated hepatitis rate. A retrospective analysis of prior studies
found a 12-fold increased risk of severe hepatotoxicity in
women with CD4 cell counts
1250 cells/mL, compared with
women with CD4 cell counts
!250 cells/mL (resulting in a
“black box” warning for nevirapine [87]); the risk for men
increased at CD4 cell counts
1400 cells/mL [86, 88, 89]. Of
note, studies from Thailand and Zambia have not found this
association between nevirapine-induced hepatotoxicity and
CD4 cell count [84, 90]. The authors of the South African
study argued that race and BMI, rather than baseline CD4 cell
count, accounted for the high hepatotoxicity rate [91], because
studies have found decreased nevirapine clearance in individ-
uals with a low BMI, of black race, or with particular phar-
macogenetic profiles [92, 93]. Thai ethnicity may also be a risk
factor for nevirapine-associated hepatotoxicity [89]. Additional
research is needed to clarify the complex relationship between
race/ethnicity, baseline CD4 cell count, and the risk of nevi-
rapine-induced hepatitis.
A Thai study found that 17 (18.6%) of 91 patients receiving
nevirapine therapy developed serious hepatitis [94], which may
be explained by the high prevalence of hepatitis B virus (HBV)
and hepatitis C virus (HCV) coinfection in this cohort. Similar
to findings in western studies [95], HBV-infected patients in
this study had a higher hepatotoxicity rate (57.4%) than did
HBV-uninfected patients, and patients with HCV had a hep-
atotoxicity rate of 72.2%. Conversely, long-term nevirapine use
1096 • CID 2007:45 (15 October) • HIV/AIDS
Table 1. Overlapping toxicities associated with antiretroviral and antituberculosis drugs.
Toxicity Antiretroviral drugs Antituberculosis drugs
Hepatitis Nevirapine, protease inhibitors Rifampicin, isoniazid, pyrazinamide, ethionamide
Rash Nevirapine, efavirenz, abacavir Rifampicin, isoniazid, quinolones
Anemia, neutropenia Zidovudine Rifampicin, isoniazid
Nausea, vomiting Zidovudine, ritonavir, indinavir Rifampicin, pyrazinamide, quinolones,
ethionamide
Peripheral neuropathy Stavudine, didanosine, zalcitabine Isoniazid, ethambutol, cycloserine
CNS symptoms Efavirenz Streptomycin, quinolones, cycloserine
may increase the rate of progression to cirrhosis in HBV-HCV
coinfected patients [96]. The authors of the Thai study, there-
fore, suggest that nevirapine use might be contraindicated in
regions where HBV-HCV coinfection screening is unavailable
and where background prevalence is
110% [94]. Prevention of
nevirapine-associated liver toxicity, therefore, requires attention
to multiple factors prior to HAART initiation, including female
sex, high CD4 cell count at initiation, low BMI, low albumin
level [85], HBV-HCV coinfection, use of ATT, and, possibly,
race/ethnicity.
Efavirenz
Neuropsychiatric disorders. Neuropsychiatric disorders are
the most concerning adverse effects associated with efavirenz
therapy with regard to tolerability and adherence. In western
cohorts, one-half of patients have these symptoms at initiation
of efavirenz therapy, but these symptoms usually resolve within
1 month [97]. People of African descent with a variant of
hepatic enzyme CYP2B6 may experience slower clearance of
efavirenz from plasma and increased neurotoxicity [98–100].
A study from Haiti supports this data on ethnic differences.
The study found that 46 (10%) of 452 patients discontinued
efavirenz therapy because of persistent neurotoxicity [5]; this
rate is higher than that found in US studies [97]. A study from
Coˆte d’Ivoire also found a high neurotoxicity rate (69%) after
initiation of efavirenz therapy [101, 102]. In contrast to the
Haitian study, these symptoms resolved in most patients by the
third month of therapy, with only 1 patient of 808 patient-
months of follow-up discontinuing therapy because of neu-
rotoxicity. Additional research clarifying the influence of eth-
nicity on efavirenz plasma levels may lead to dose adjustments,
which may decrease rates of neurotoxicity in particular
populations.
OVERLAPPING TOXICITIES OF HAART AND
ATT
Dean et al. [103] highlighted the problem of overlapping tox-
icities when they found a high incidence (54%) of adverse
events in a cohort of 188 patients coinfected with HIV and
tuberculosis. These toxicities (table 1), which occurred at a
higher rate than in previous control groups of HIV-infected
patients treated with ATT in the pre-HAART era, led to inter-
ruption of HAART or ATT regimens in one-third of patients
[103]. Nevirapine has multiple overlapping toxicities with ATT
drugs, especially rifampicin [104]. A Thai study indicated that
patients receiving ATT while receiving nevirapine therapy had
a 7.4-fold increased risk of developing hepatitis and a 3-fold
increased risk of developing a rash [105].
One small cohort found a high incidence (55%) of peripheral
neuropathy in patients receiving both stavudine and isoniazid
therapies [106], and another study found peripheral neurop-
athy to be the most common toxicity in a cohort of patients
coinfected with HIV and tuberculosis [103]. Patients receiving
both drugs should be closely monitored and should receive
supplemental pyridoxine therapy to reduce the risk of isoniazid-
related neurotoxicity. Finally, as patients begin to experience
failure of first-line, NNRTI-based regimens (with tuberculosis
being the most common infection marking clinical failure),
overlapping toxicities associated with ATT and PIs, such as
hepatitis, will become increasingly important in developing
countries.
IRS
IRS, a paradoxical worsening of clinical status after HAART
initiation, is increasingly recognized as an adverse consequence
of antiretroviral therapy [107–111]. Developing countries may
have a higher incidence of IRS as a result of a higher burden
of opportunistic infections and frequent therapy initiation in
patients with low CD4 cell counts, both of which are risk factors
for IRS [112–116]. For example, HIV-infected patients receiving
care from Medicins Sans Frontieres programs in sub-Saharan
Africa, southeast Asia, and Central America had a median CD4
cell count of 48 cells/mL at HAART initiation, placing many at
a high risk for IRS [117].
Unlike in developed countries, tuberculosis is the most com-
mon pathogen involved in IRS in resource-limited countries.
Indian and Thai studies found IRS rates of 15% and 13%,
respectively, among patients coinfected with HIV and tuber-
culosis after the initiation of HAART [118, 119]. Such cases
are difficult to differentiate from cases of multidrug-resistant
HIV/AIDS • CID 2007:45 (15 October) • 1097
tuberculosis, as highlighted in 2 Indian case reports [120, 121].
Other reported presentations of IRS that may be more common
in developing countries include exacerbations of leprosy [122,
123], leishmaniasis [124, 125], and Mycobacterium bovis infec-
tion (acquired through bacille Calmette-Gue´rin vaccination)
[126].
CONCLUSIONS
This review illuminates a few common trends in HAART-re-
lated toxicities that are relevant to developing countries. First,
initiation of antiretroviral therapy at advanced stages of AIDS
has implications beyond the obvious risk of morbidity and
mortality due to opportunistic infections. Low CD4 cell count
at treatment initiation is a risk factor for multiple adverse ef-
fects, including stavudine-induced peripheral neuropathy [127,
128], lipodystrophy [21, 22], and lactic acidosis [11, 129]; zi-
dovudine-induced myelosuppression [67]; didanosine-induced
pancreatitis [130]; and IRS [113]. Moreover, the high burden
of opportunistic infection in patients with low CD4 cell counts
increases overlapping toxicities between HAART and oppor-
tunistic infection treatments—a problem of particular concern
for patients receiving ATT. Therefore, earlier HAART initiation,
before the development of a low CD4 cell count and oppor-
tunistic infection, may reduce the incidence of adverse effects.
Increased access to HIV testing services, with the aim of en-
gaging more patients in long-term follow-up, may help achieve
this goal. Second, although fixed-dose combinations of HAART
are highly effective and increase adherence [14, 16], they may
lead to increased toxicity when used improperly. Roll-out pro-
grams should ensure that FDCs are available in doses that are
appropriate for a patient’s body weight, as well as allow for a
run-in period of a lower dose of nevirapine.
Third, most adverse effects can be ascertained through an
appropriate clinical examination for specific symptoms and
signs, including neuropsychiatric problems (due to efavirenz-
related toxicity), fatigue with conjunctival pallor (due to zi-
dovudine-related anemia), and peripheral wasting (due to sta-
vudine-related lipodystrophy). Implementation of protocols for
regular clinical screening of patients, especially during the initial
months of therapy, may help detect toxicities earlier. As sug-
gested by a Kenyan study, early detection may also be facilitated
by training family or community volunteers to identify tox-
icities [131]. In addition, facilities for laboratory monitoring
of specific toxicities are a crucial component of scale-up of
antiretroviral therapy. Current World Health Organization
guidelines recommend liver enzyme and hemoglobin investi-
gations only when patients are symptomatic [9]; however, be-
cause most cases of nevirapine-related hepatitis and zidovu-
dine-induced anemia occur during the initial months of
therapy, more intensive laboratory monitoring during this time
may prevent severe toxicity.
Finally, by reducing antiretroviral drug options, toxicities
may have a significant socioeconomic impact on low-income
patients in developing countries. In studies from Haiti and
South India, adverse effects were the primary reason for therapy
modification [5, 132]. Currently, most government roll-out
programs in resource-constrained regions provide few or no
second-line drugs [133, 134]. Therefore, increased access to
less-toxic first-line drugs and less-expensive second-line drugs
is needed to cope with this issue. Specifically, patients will ben-
efit if government programs ensure access to tenofovir or aba-
cavir therapy for the small subset of patients who experience
adverse reactions associated with both stavudine and zidovu-
dine therapies, as well as with PIs for patients who cannot
tolerate both nevirapine and efavirenz.
Although few data are available on tenofovir, abacavir, and
PI use in developing countries, these medications can be an-
ticipated to have their own specific benefits and complications
in resource-limited regions. A multisite trial in Africa found
tenofovir therapy to be associated with a 1.3% rate of significant
nephrotoxicity, which was comparable to other regimens [135].
Because abacavir therapy may cause a hypersensitivity rash,
abacavir use may possibly complicate diagnosis of nevirapine-
induced rash in patients initiating both medications. As pre-
viously noted, PI use may be problematic in patients receiving
ATT, not only because of overlapping hepatotoxicity, but also
because of drug-drug interactions with rifampicin [136].
Despite the problems associated with toxicities, the distri-
bution of HAART in developing countries should not be dis-
couraged, especially when these life-saving medications remain
unavailable to the majority of patients in need [2]. However,
excellent clinical follow-up is simultaneously required to man-
age the morbidity associated with HAART.
Acknowledgments
We thank the staff of the YRG Centre for AIDS Research and Education
for their generous facilitation of this study.
Financial support. Fogarty-Ellison Overseas Fellowship in Global
Health and Clinical Research (3 D43 TW000237-13S1 to R.S.) and Lifespan-
Tufts-Brown Center for AIDS Research (5P30AI042853-09 to K.H.M.).
Potential conflicts of interest. K.H.M. has a research grant from Gilead
Sciences. All other authors: no conflicts.
References
1. Joint United Nations Programme on HIV/AIDS (UNAIDS), World
Health Organization. AIDS epidemic update: December 2005. Geneva:
UNAIDS, 2005. Available at: http://www.unaids.org/epi/2005/doc/
EPIupdate2005_pdf_en/epi-update2005_en.pdf. Accessed 24 Febru-
ary 2006.
2. Joint United Nations Programme on HIV/AIDS, World Health Or-
ganization (WHO). Progress on global access to HIV antiretroviral
therapy: an update on 3
by 5
June 2005. Geneva: WHO, 2005. Avail-
able at: http://www.who.int/hiv/pub/progressreports/3by5%20Pro
gress%20Report_E_light.pdf. Accessed 3 July 2006.
3. Kumarasamy N, Solomon S, Chaguturu SK, et al. The changing nat-
ural history of HIV disease: before and after the introduction of
1098 • CID 2007:45 (15 October) • HIV/AIDS
generic antiretroviral therapy in southern India. Clin Infect Dis
2005; 41:1525–8.
4. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral
therapy on incidence of tuberculosis in South Africa: a cohort study.
Lancet 2002; 359:2059–64.
5. Severe P, Leger P, Charles M, et al. Antiretroviral therapy in a thousand
patients with AIDS in Haiti. N Engl J Med 2005; 353:2325–34.
6. Kumarasamy N, Lai A, Cecelia AJ, et al. Toxicities and adverse events
following generic HAART in south Indian HIV-infected individuals
[abstract P189]. In: Proceedings of the 7th International Congress on
Drug Therapy and HIV Infection (Glasgow, United Kingdom). 2004.
7. Mills E, Foster BC, van Heeswijk R, et al. Impact of African herbal
medicines on antiretroviral metabolism. AIDS 2005; 19:95–7.
8. Hetherington S, Cutrell A, Edwards M, Spreen W, Steel H. Risk factor
analysis of hypersensitivity reactions to abacavir: retrospective analysis
of 25 clinical trials [abstract 527]. In: Proceedings of the 1st Inter-
national AIDS Society Conference on HIV Pathogenesis and Treat-
ment (Buenos Aires, Argentina). 2001.
9. World Health Organization (WHO). Scaling up antiretroviral therapy
in resource-limited settings. Geneva: WHO, 2004. Available at: http:
//www.who.int/hiv/pub/prev_care/en/arvrevision2003en.pdf. Ac-
cessed 3 July 2006.
10. Management Sciences for Health, Rational Pharmaceutical Manage-
ment Plus Program. Review of antiretroviral therapy guidelines in
select countries of Africa and the Caribbean: a challenge for opti-
mizing treatment and product supply. 2005. Available at: http://
www.who.int/3by5/amds/en/Standard_Treatment_Guidelines-Final
.pdf. Accessed 3 July 2006.
11. McComsey G, Lonergan JT. Mitochondrial dysfunction: patient mon-
itoring and toxicity management. J Acquir Immune Defic Syndr
2004; 37(Suppl 1):S30–5.
12. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiret-
rovirals: risk factors, incidence and management. Drug Safety 1998;
19:481–94.
13. Scarsella A, Coodley G, Shalit P, et al. Stavudine-associated peripheral
neuropathy in zidovudine-naive patients: effect of stavudine exposure
and antiretroviral experience. Adv Ther 2002; 19:1–8.
14. Laurent C, Kouanfack C, Koulla-Shiro S, et al. Effectiveness and safety
of a generic fixed-dose combination of nevirapine, stavudine, and
lamivudine in HIV-1–infected adults in Cameroon: open-label mul-
ticentre trial. Lancet 2004; 364:29–34.
15. Anekthananon T, Ratanasuwan W, Techasathit W, Sonjai A, Suwan-
agool S. Safety and efficacy of a simplified fixed-dose combination of
stavudine, lamivudine and nevirapine (GPO-VIR) for the treatment
of advanced HIV-infected patients: a 24-week study. J Med Assoc Thai
2004; 87:760–7.
16. Pujari SN, Patel AK, Naik E, et al. Effectiveness of generic fixed-dose
combinations of highly active antiretroviral therapy for treatment of
HIV infection in India. J Acquir Immune Defic Syndr 2004; 37:
1566–9.
17. van Oosterhout JJ, Bodasing N, Kumwenda JJ, et al. Evaluation of
antiretroviral therapy results in a resource-poor setting in Blantyre,
Malawi. Trop Med Int Health 2005; 10:464–70.
18. Saint-Marc T, Partisani M, Poizot-Martin I, et al. A syndrome of
peripheral fat wasting (lipodystrophy) in patients receiving long-term
nucleoside analogue therapy. AIDS 1999; 13:1659–67.
19. Heath KV, Hogg RS, Chan KJ, et al. Lipodystrophy-associated mor-
phological, cholesterol and triglyceride abnormalities in a population-
based HIV/AIDS treatment database. AIDS 2001; 15:231–9.
20. Bernasconi E, Boubaker K, Junghans C, et al. Abnormalities of body
fat distribution in HIV-infected persons treated with antiretroviral
drugs: the Swiss HIV cohort study. J Acquir Immune Defic Syndr
2002; 31:50–5.
21. Arpadi SM, Cuff PA, Horlick M, Wang J, Kotler DP. Lipodystrophy
in HIV-infected children is associated with high viral load and low
CD4
+
-lymphocyte count and CD4
+
-lymphocyte percentage at base-
line and use of protease inhibitors and stavudine. J Acquir Immune
Defic Syndr 2001; 27:30–4.
22. Lichtenstein KA, Delaney KM, Armon C, et al. Incidence of and risk
factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1–in-
fected patients. J Acquir Immune Defic Syndr 2003; 32:48–56.
23. McComsey G, Maa JF. Host factors may be more important than
choice of antiretrovirals in the development of lipoatrophy. AIDS Read
2003; 13:539, 542, 559.
24. Lichtenstein KA, Ward DJ, Moorman AC, et al. Clinical assessment
of HIV-associated lipodystrophy in an ambulatory population. AIDS
2001; 15:1389–98.
25. Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution
of nucleoside analogue reverse transcriptase inhibitors to subcuta-
neous fat wasting in patients with HIV infection. AIDS 2000; 14:
1309–16.
26. Chang KH, Kim JM, Song YG, Hong SK, Lee HC, Lim SK. Does race
protect an oriental population from developing lipodystrophy in HIV-
infected individuals on HAART? J Infect 2002; 44:33–8.
27. Paton NI, Earnest A, Ng YM, Karim F, Aboulhab J. Lipodystrophy
in a cohort of human immunodeficiency virus-infected Asian patients:
prevalence, associated factors, and psychological impact. Clin Infect
Dis 2002; 35:1244–9.
28. Ho TT, Chan KC, Wong KH, Lee SS. Indinavir-associated facial lip-
odystrophy in HIV-infected patients. AIDS Patient Care STDS
1999; 13:11–6.
29. Fraser HE, Ishihara M, Miller JE, et al. Prevalence survey of lipo-
dystrophy in HIV-positive patients in Japan [abstract 017]. In: Pro-
gram and abstracts of the 2nd International Workshop on Adverse
Drug Reactions and Lipodystrophy (Singapore). Singapore: Interna-
tional Medical Press, 2000.
30. Puttawong S, Prasithsirikul W, Vadcharavivad S. Prevalence of lipo-
dystrophy in Thai HIV-infected patients. J Med Assoc Thai 2004; 87:
605–11.
31. Pujari SN, Dravid A, Naik E, et al. Lipodystrophy and dyslipidemia
among patients taking first-line, World Health Organization–
recommended highly active antiretroviral therapy regimens in western
India. J Acquir Immune Defic Syndr 2005; 39:199–202.
32. Tin EE, Bowonwatanuwong C, Desakorn V, Wilairatana P, Krudsood
S, Pitisuttithum P. The efficacy and adverse effects of GPO-VIR (sta-
vudine+lamivudine+nevirapine) in treatment-naive adult HIV pa-
tients. Southeast Asian J Trop Med Public Health 2005; 36:362–9.
33. van Griensven J, De Naeyer L, Mushi T, Obarijoro S, Gazille C,
Zachariah R. How common is lipodystrophy after at least 1 year of
WHO first line antiretroviral treatment in Kigali, Rwanda [abstract
WEPE0140]? In: Program and abstracts of the 16th International AIDS
Conference (Toronto, Canada). Toronto, Canada: International AIDS
Society, 2006.
34. Fernandes AP, Sanches R, Mill J, Castelar L, Donadi E. Facing lipo-
dystrophy [abstract TUPEO869]. In: Program and abstracts of the
16th International AIDS Conference (Toronto, Canada). Toronto,
Canada: International AIDS Society, 2006.
35. Saghayam S, Chaguturu SK, Kumarasamy N, Solomon S, Mayer KH,
Wanke C. Lipoatrophy is the predominant presentation of HIV-as-
sociated lipodystrophy in southern India. Clin Infect Dis 2004; 38:
1646–7.
36. Nolan D, Mallal S. The role of nucleoside reverse transcriptase in-
hibitors in the fat redistribution syndrome. J HIV Ther 2004; 9:34–40.
37. van der Valk M, Casula M, Weverlingz GJ, et al. Prevalence of li-
poatrophy and mitochondrial DNA content of blood and subcuta-
neous fat in HIV-1–infected patients randomly allocated to zidovu-
dine- or stavudine-based therapy. Antivir Ther 2004; 9:385–93.
38. Subbaraman R, Singh S, Cecelia AJ, et al. Resolution of anemia with
use of highly active antiretroviral therapy (HAART) among HIV-
infected patients in southern India [abstract THPE0113]. In: Program
and abstracts of the 16th International AIDS Conference (Toronto,
Canada). Toronto, Canada: International AIDS Society, 2006.
39. Berhane K, Karim R, Cohen MH, et al. Impact of highly active an-
HIV/AIDS • CID 2007:45 (15 October) • 1099
tiretroviral therapy on anemia and relationship between anemia and
survival in a large cohort of HIV-infected women: women’s intera-
gency HIV study. J Acquir Immune Defic Syndr 2004; 37:1245–52.
40. Moore RD, Forney D. Anemia in HIV-infected patients receiving
highly active antiretroviral therapy. J Acquir Immune Defic Syndr
2002; 29:54–7.
41. Moyle G, Sawyer W, Law M, Amin J, Hill A. Changes in hematologic
parameters and efficacy of thymidine analogue-based, highly active
antiretroviral therapy: a meta-analysis of six prospective, randomized,
comparative studies. Clin Ther 2004; 26:92–7.
42. McComsey GA, Paulsen DM, Lonergan JT, et al. Improvements in
lipoatrophy, mitochondrial DNA levels and fat apoptosis after re-
placing stavudine with abacavir or zidovudine. AIDS 2005; 19:15–23.
43. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nu-
cleoside analogs in patients with HIV lipoatrophy: a randomized trial.
JAMA 2002; 288:207–15.
44. Moyle GJ, Baldwin C, Langroudi B, Mandalia S, Gazzard BG. A 48-
week, randomized, open-label comparison of three abacavir-based
substitution approaches in the management of dyslipidemia and pe-
ripheral lipoatrophy. J Acquir Immune Defic Syndr 2003; 33:22–8.
45. Galli M, Ridolfo AL, Adorni F, et al. Body habitus changes and met-
abolic alterations in protease inhibitor-naive HIV-1–infected patients
treated with two nucleoside reverse transcriptase inhibitors. J Acquir
Immune Defic Syndr 2002; 29:21–31.
46. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of
tenofovir DF vs stavudine in combination therapy in antiretroviral-
naive patients: a 3-year randomized trial. JAMA 2004; 292:191–201.
47. Sobieszczyk ME, Hoover DR, Anastos K, et al. Prevalence and pre-
dictors of metabolic syndrome among HIV-positive and negative
women [abstract WEPE0147]. In: Program and abstracts of the 16th
International AIDS Conference (Toronto, Canada). Toronto, Canada:
International AIDS Society, 2006.
48. Hosseinipour M, Ingiliz P, Kanyama C, et al. Clinical features of lactic
acidosis in Malawi [abstract CDB0665]. In: Program and abstracts of
the 16th International AIDS Conference (Toronto, Canada). Toronto,
Canada: International AIDS Society, 2006.
49. Bolhaar M, Karstaedt A. A significant increase in incidence of lactic
acidosis and symptomatic hyperlactaemia in women on HAART in
Soweto [abstract WEPE0169]. In: Program and abstracts of the 16th
International AIDS Conference (Toronto, Canada). Toronto, Canada:
International AIDS Society, 2006.
50. Kimani DK, File´n F, Nderitu M, Van Engelgem I, Suleh A, Zachariah
R. Characteristics and outcomes of patients with symptomatic hy-
perlactatemia, on a first-line antiretroviral regimen of stavudine, la-
mivudine and nevirapine (d4T/3TC/NVP) in an urban district hos-
pital setting in Kenya [abstract WEPE0150]. In: Program and abstracts
of the 16th International AIDS Conference (Toronto, Canada). To-
ronto, Canada: International AIDS Society, 2006.
51. Mwebaze PS, Castelnuovo B, Byakwaga H, et al. Nucleoside-associated
lactic acidosis in HIV-1–infected African patients [abstract WEPE
0155]. In: Program and abstracts of the 16th International AIDS Con-
ference (Toronto, Canada). Toronto, Canada: International AIDS So-
ciety, 2006.
52. Luke C, Mfenyana G, Pawinski R, Moosa Y, Easterbrook PJ. High
incidence of lactic acidosis (LA) at an antiretroviral (ARV) treatment
site in Kwazulu-Natal (KZN), South Africa [abstract CDB0702]. In:
Program and abstracts of the 16th International AIDS Conference
(Toronto, Canada). Toronto, Canada: International AIDS Society,
2006.
53. Sheng WH, Hsieh SM, Lee SC, et al. Fatal lactic acidosis associated
with highly active antiretroviral therapy in patients with advanced
human immunodeficiency virus infection in Taiwan. Int J STD AIDS
2004; 15:249–53.
54. Lai HY, Chen JH, Tsai PP, Ho MW, Shen WC. Hepatic steatosis and
pancreatitis associated with the use of stavudine in a patient with
HIV infection. AJR Am J Roentgenol 2004; 183:1605–7.
55. Cho BC, Han SH, Choi SH, et al. A case of lactic acidosis caused by
stavudine in an AIDS patient. Korean J Intern Med 2004; 19:66–9.
56. Marra A, Lewi D, Lanzoni V, et al. Lactic acidosis and antiretroviral
therapy: a case report and literature review. Braz J Infect Dis 2000;
4:151–5.
57. Cornejo-Juarez P, Sierra-Madero J, Volkow-Fernandez P. Metabolic
acidosis and hepatic steatosis in two HIV-infected patients on sta-
vudine (d4T) treatment. Arch Med Res 2003; 34:64–9.
58. Patel AK, Patel K, Patel J. Lactic acidosis in HIV-1 infected patients
receiving antiretroviral therapy. J Assoc Physicians India 2004; 52:
666–9.
59. Ivers LC, Mukherjee JS. Point of care testing for antiretroviral ther-
apy–related lactic acidosis in resource-poor settings. AIDS 2006; 20:
779–80.
60. Mathee S, Abrahams M, Jackson N, et al. Point of care lactate testing
is an effective measure in supporting the WHO first-line regimen in
settings with a high incidence of stavudine-related toxicity [abstract
MOPE0085]. In: Program and abstracts of the 16th International
AIDS Conference (Toronto, Canada). Toronto, Canada: International
AIDS Society, 2006.
61. Erhabor O, Ejele OA, Nwauche CA, Buseri FI. Some haematological
parameters in human immunodeficiency virus (HIV) infected Afri-
cans: the Nigerian perspective. Niger J Med 2005; 14:33–8.
62. O’Brien ME, Kupka R, Msamanga GI, Saathoff E, Hunter DJ, Fawzi
WW. Anemia is an independent predictor of mortality and immu-
nologic progression of disease among women with HIV in Tanzania.
J Acquir Immune Defic Syndr 2005; 40:219–25.
63. van Lettow M, West CE, van der Meer JW, Wieringa FT, Semba RD.
Low plasma selenium concentrations, high plasma human immu-
nodeficiency virus load and high interleukin-6 concentrations are risk
factors associated with anemia in adults presenting with pulmonary
tuberculosis in Zomba district, Malawi. Eur J Clin Nutr 2005; 59:
526–32.
64. Belperio PS, Rhew DC. Prevalence and outcomes of anemia in in-
dividuals with human immunodeficiency virus: a systematic review
of the literature. Am J Med 2004; 116(Suppl 7A):27S–43S.
65. Sullivan PS, Hanson DL, Chu SY, Jones JL, Ward JW. Epidemiology
of anemia in human immunodeficiency virus (HIV)-infected persons:
results from the multistate adult and adolescent spectrum of HIV
disease surveillance project. Blood 1998; 91:301–8.
66. Wills TS, Nadler JP, Somboonwit C, et al. Anemia prevalence and
associated risk factors in a single-center ambulatory HIV clinical co-
hort. AIDS Read 2004; 14:305, 310, 313–5.
67. Richman DD, Fischl MA, Grieco MH, et al. The toxicity of azidoth-
ymidine (AZT) in the treatment of patients with AIDS and AIDS-
related complex: a double-blind, placebo-controlled trial. N Engl J
Med 1987; 317:192–7.
68. Carr A, Cooper D. Adverse effects of antiretroviral therapy. Lancet
2000; 356:1423–30.
69. Idoko JA, Akinsete L, Abalaka AD, et al. A multicentre study to
determine the efficacy and tolerability of a combination of nelfinavir
(VIRACEPT), zalcitabine (HIVID) and zidovudine in the treatment
of HIV infected Nigerian patients. West Afr J Med 2002; 21:83–6.
70. Moh R, Danel C, Sorho S, et al. Haematological changes in adults
receiving a zidovudine-containing HAART regimen in combination
with cotrimoxazole in Coˆte d’Ivoire. Antivir Ther 2005; 10:615–24.
71. Shah I. Adverse effects of antiretroviral therapy in HIV-1 infected
children. J Trop Pediatr 2006; 52:244–8.
72. Pollard RB, Robinson P, Dransfield K. Safety profile of nevirapine, a
nonnucleoside reverse transcriptase inhibitor for the treatment of
human immunodeficiency virus infection. Clin Ther 1998; 20:
1071–92.
73. Warren KJ, Boxwell DE, Kim NY, Drolet BA. Nevirapine-associated
Stevens-Johnson syndrome. Lancet 1998; 351:567.
74. Derisi M, Ballard C, Abulhosn K, Colwell B, Barber E, Matthews WC.
Sulfa-associated rash and race are risk factors for non-nucleoside
reverse transcriptase inhibitor-associated rash [abstract 61]. In: Ab-
1100 • CID 2007:45 (15 October) • HIV/AIDS
stracts of the 7th Conference on Retroviruses and Opportunistic In-
fections (San Francisco, CA). San Francisco: Foundation for Retro-
virology and Human Health, 2000.
75. Gangar M, Arias G, O’Brien JG, Kemper CA. Frequency of cutaneous
reactions on rechallenge with nevirapine and delavirdine. Ann Phar-
macother 2000; 34:839–42.
76. Ananworanich J, Moor Z, Siangphoe U, et al. Incidence and risk
factors for rash in Thai patients randomized to regimens with ne-
virapine, efavirenz or both drugs. AIDS 2005; 19:185–92.
77. Antinori A, Baldini F, Girardi E, et al. Female sex and the use of anti-
allergic agents increase the risk of developing cutaneous rash asso-
ciated with nevirapine therapy. AIDS 2001; 15:1579–81.
78. Mazhude C, Jones S, Murad S, Taylor C, Easterbrook P. Female sex
but not ethnicity is a strong predictor of non-nucleoside reverse tran-
scriptase inhibitor-induced rash. AIDS 2002; 16:1566–8.
79. Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in
nevirapine rash. Clin Infect Dis 2001; 32:124–9.
80. Soriano V, Dona C, Barreiro P, Gonzalez-Lahoz J. Is there cross-
toxicity between nevirapine and efavirenz in subjects developing rash?
AIDS 2000; 14:1672–3.
81. Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in HIV-1–in-
fected patients receiving nevirapine-containing antiretroviral therapy.
AIDS 2001; 15:1261–8.
82. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL.
A comprehensive hepatic safety analysis of nevirapine in different
populations of HIV infected patients. J Acquir Immune Defic Syndr
2003; 34(Suppl 1):S21–33.
83. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of
and risk factors for severe hepatotoxicity associated with antiretroviral
combination therapy. J Infect Dis 2002; 186:23–31.
84. Cantrell R, Chi B, Mulenga L, et al. Incidence and predictors of
hepatotoxicity among patients receiving nevirapine (NVP)–
containing antiretroviral therapy (ART) in Zambia [abstract
WEPE0172]. In: Program and abstracts of the 16th International AIDS
Conference (Toronto, Canada). Toronto, Canada: International AIDS
Society, 2006.
85. Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity
associated with nevirapine use in HIV-infected subjects. J Infect Dis
2005; 191:825–9.
86. Leith J, Piliero P, Storfer S, Mayers D, Hinzmann R. Appropriate use
of nevirapine for long-term therapy. J Infect Dis 2005; 192:545–6;
author reply, 546.
87. Viramune [package insert]. Ridgefield, CT: Boehringer Ingelheim,
2005. Available at: http://www.bidocs.com/renetnt:/Prescribing+In
formation/PIs/Viramune/Viramune.pdf. Accessed 3 July 2006.
88. Jamisse L, Balkus J, Hitti J, et al. Nevirapine-associated hepatic toxicity
among HIV-1–seropositive pregnant women in Mozambique [ab-
stract WEPE0173]. In: Program and abstracts of the 16th International
AIDS Conference (Toronto, Canada). Toronto, Canada: International
AIDS Society, 2006.
89. Storfer S, Leith J, Piliero P, Hall D. Analysis of hepatic events within
the 2NN study: Controlling for ethnicity and CD4
+
count at initiation
of nevirapine therapy [abstract PE9.6/2]. In: Program and abstracts
of the 10th European AIDS Conference (Dublin, Ireland). 2005.
90. Phanuphak N, Apornpong T, Intarasuk S, Teeratakulpisarn S, Phan-
uphak P. Toxicities from nevirapine in HIV-infected males and fe-
males, including pregnant females with various CD4 cell counts [ab-
stract 21]. In: Program and abstracts of the 12th Conference on
Retroviruses and Opportunistic Infections (Boston, MA). Alexandria,
VA: Foundation for Retrovirology and Human Health, 2005.
91. Sanne I, Rousseau F, Bartlett JA, Lederman MM. Reply to Leith et
al. J Infect Dis 2005; 192:546–7.
92. de Maat MM, Huitema AD, Mulder JW, Meenhorst PL, van Gorp
EC, Beijnen JH. Population pharmacokinetics of nevirapine in an
unselected cohort of HIV-1–infected individuals. Br J Clin Pharmacol
2002; 54:378–85.
93. Haas DW, Bartlett JA, Andersen JW, et al. Pharmacogenetics of ne-
virapine-associated hepatotoxicity: an adult AIDS clinical trials group
collaboration. Clin Infect Dis 2006; 43:783–6.
94. Law WP, Dore GJ, Duncombe CJ, et al. Risk of severe hepatotoxicity
associated with antiretroviral therapy in the HIV-NAT cohort, Thai-
land, 1996–2001. AIDS 2003; 17:2191–9.
95. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD.
Hepatotoxicity associated with nevirapine or efavirenz-containingan-
tiretroviral therapy: role of hepatitis C and B infections. Hepatology
2002; 35:182–9.
96. Pineda JA, Macias J. Progression of liver fibrosis in patients coinfected
with hepatitis C virus and human immunodeficiency virus undergoing
antiretroviral therapy. J Antimicrob Chemother 2005; 55:417–9.
97. Molina JM, Ferchal F, Rancinan C, et al. Once-daily combination
therapy with emtricitabine, didanosine, and efavirenz in human im-
munodeficiency virus–infected patients. J Infect Dis 2000; 182:
599–602.
98. Barrett JS, Joshi AS, Chai M, Ludden TM, Fiske WD, Pieniaszek HJ
Jr. Population pharmacokinetic meta-analysis with efavirenz. Int J
Clin Pharmacol Ther 2002; 40:507–19.
99. Pfister M, Labbe L, Hammer SM, et al. Population pharmacokinetics
and pharmacodynamics of efavirenz, nelfinavir, and indinavir: adult
AIDS clinical trial group study 398. Antimicrob Agents Chemother
2003; 47:130–7.
100. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz
and central nervous system side effects: an adult AIDS clinical trials
group study. AIDS 2004; 18:2391–400.
101. Danel C, Moh R, Messou E, et al. Short-term tolerance of efavirenz
in HIV-infected african adults participating in the TRIVACAN ANRS
1269 trial, Abidjan, Coˆte d’Ivoire [abstract 53]. In: Program and ab-
stracts of the 2nd International AIDS Conference on HIV Pathogen-
esis and Treatment (Paris, France). 2003.
102. Boyle BA. Issues in antiretroviral toxicity. AIDS Read 2003; 13:459,
463–4, 468, 469, 479.
103. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in
HIV-infected persons in the era of highly active antiretroviral therapy.
AIDS 2002; 16:75–83.
104. Swaminathan S, Luetkemeyer A, Srikantiah P, Lin R, Charlebois E,
Havlir DV. Antiretroviral therapy and TB. Trop Doct 2006; 36:73–9.
105. Manosuthi W, Chumpathat N, Chaovavanich A, Sungkanuparph S.
Safety and tolerability of nevirapine-based antiretroviral therapy in
HIV-infected patients receiving fluconazole for cryptococcal prophy-
laxis: a case-control study. BMC Infect Dis 2005; 5:67.
106. Breen RA, Lipman MC, Johnson MA. Increased incidence of periph-
eral neuropathy with co-administration of stavudine and isoniazid in
HIV-infected individuals. AIDS 2000; 14:615.
107. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al. Immune
reconstitution inflammatory syndrome: emergence of a unique syn-
drome during highly active antiretroviral therapy. Medicine (Balti-
more) 2002; 81:213–27.
108. Buckingham SJ, Haddow LJ, Shaw PJ, Miller RF. Immune reconsti-
tution inflammatory syndrome in HIV-infected patients with my-
cobacterial infections starting highly active anti-retroviral therapy.
Clin Radiol 2004; 59:505–13.
109. French MA, Price P, Stone SF. Immune restoration disease after an-
tiretroviral therapy. AIDS 2004; 18:1615–27.
110. Hirsch HH, Kaufmann G, Sendi P, Battegay M. Immune reconsti-
tution in HIV-infected patients. Clin Infect Dis 2004; 38:1159–66.
111. Sungkanuparph S, Vibhagool A, Mootsikapun P, Chetchotisakd P,
Tansuphaswaswadikul S, Bowonwatanuwong C. Opportunistic infec-
tions after the initiation of highly active antiretroviral therapy in
advanced AIDS patients in an area with a high prevalence of tuber-
culosis. AIDS 2003; 17:2129–31.
112. Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk
factors for immune reconstitution inflammatory syndrome during
highly active antiretroviral therapy. AIDS 2005; 19:399–406.
HIV/AIDS • CID 2007:45 (15 October) • 1101
113. Cheng VC, Yuen KY, Chan WM, Wong SS, Ma ES, Chan RM. Im-
munorestitution disease involving the innate and adaptive response.
Clin Infect Dis 2000; 30:882–92.
114. French MA, Lenzo N, John M, et al. Immune restoration disease after
the treatment of immunodeficient HIV-infected patients with highly
active antiretroviral therapy. HIV Med 2000; 1:107–15.
115. Lortholary O, Fontanet A, Memain N, et al. Incidence and risk factors
of immune reconstitution inflammatory syndrome complicatingHIV-
associated cryptococcosis in France. AIDS 2005; 19:1043–9.
116. Michailidis C, Pozniak AL, Mandalia S, Basnayake S, Nelson MR,
Gazzard BG. Clinical characteristics of IRIS syndrome in patients with
HIV and tuberculosis. Antivir Ther 2005; 10:417–22.
117. Tassie JM, Szumilin E, Calmy A, Goemaere E; Medecins Sans Fron-
tieres. Highly active antiretroviral therapy in resource-poor settings:
the experience of Medecins Sans Frontieres. AIDS 2003; 17:1995–7.
118. Kumarasamy N, Chaguturu S, Mayer KH, et al. Incidence of immune
reconstitution syndrome in HIV/tuberculosis-coinfected patients after
initiation of generic antiretroviral therapy in India. J Acquir Immune
Defic Syndr 2004; 37:1574–6.
119. Manosuthi W, Kiertiburanakul S, Phoorisri T, Sungkanuparph S. Im-
mune reconstitution inflammatory syndrome of tuberculosis among
HIV-infected patients receiving antituberculous and antiretroviral
therapy. J Infect 2006; 53:357–63.
120. Vallabhaneni S, Kumarasamy N, Wing EJ, Flanigan TP. A diagnostic
dilemma in a patient receiving antiretroviral and antituberculosisther-
apy. AIDS Read 2005; 15:72–5.
121. Swaminathan S, Padmapriyadarsini C, Narendran G, Thomas BE,
Anand S, Rajyalakshmi A. Immune reconstitution syndromefollowing
initiation of antiretroviral therapy in a patient with HIV infection
and multidrug-resistant tuberculosis. Indian J Chest Dis Allied Sci
2005; 47:299–304.
122. Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflam-
matory syndrome associated with HIV and leprosy. Arch Dermatol
2004; 140:997–1000.
123. Lawn SD, Wood C, Lockwood DN. Borderline tuberculoid leprosy:
an immune reconstitution phenomenon in a human immunodefi-
ciency virus–infected person. Clin Infect Dis 2003; 36:e5–6.
124. Ridolfo AL, Gervasoni C, Antinori S, et al. Post-kala-azar dermal
leishmaniasis during highly active antiretroviral therapy in an AIDS
patient infected with leishmania infantum. J Infect 2000; 40:199–202.
125. Blanche P, Gombert B, Rivoal O, Abad S, Salmon D, Brezin A. Uveitis
due to Leishmania major as part of HAART-induced immune resti-
tution syndrome in a patient with AIDS. Clin Infect Dis 2002; 34:
1279–80.
126. Sharp MJ, Mallon DF. Regional bacillus Calmette-Gue´rin lymphad-
enitis after initiating antiretroviral therapy in an infant with human
immunodeficiency virus type 1 infection. Pediatr Infect Dis J 1998;
17:660–2.
127. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neu-
ropathy in HIV-infected patients on monotherapy versus those on
combination therapy with didanosine, stavudine and hydroxyurea.
AIDS 2000; 14:273–8.
128. Lichtenstein KA, Armon C, Baron A, et al. Modification of the in-
cidence of drug-associated symmetrical peripheral neuropathy by host
and disease factors in the HIV outpatient study cohort. Clin Infect
Dis 2005; 40:148–57.
129. John M, Mallal S. Hyperlactatemia syndromes in people with HIV
infection. Curr Opin Infect Dis 2002; 15:23–9.
130. Moore RD, Keruly JC, Chaisson RE. Incidence of pancreatitis in HIV-
infected patients receiving nucleoside reverse transcriptase inhibitor
drugs. AIDS 2001; 15:617–20.
131. Ilako F, Kimura M, Wanjiku L, Marston B. Assessment of common
adverse drug reactions and complications of ART using community
volunteers in Kibera, Nairobi, Kenya [abstract WEKC203]. In: Pro-
gram and abstracts of the 16th International AIDS Conference (To-
ronto, Canada). Toronto, Canada: International AIDS Society, 2006.
132. Kumarasamy N, Vallabhaneni S, Cecelia AJ, et al. Reasons for mod-
ification of generic highly active antiretroviral therapeutic regimens
among patients in southern India. J Acquir Immune Defic Syndr
2006; 41:53–8.
133. National AIDS Control Organization of India (NACO). National
guidelines for implementation of antiretroviral therapy. New Delhi:
NACO, 2004. Available at: http://www.nacoonline.org/guidelines/
ART_Guidelines.pdf. Accessed 3 July 2006.
134. National Department of Health of South Africa. National antiretro-
viral treatment guidelines. South Africa: Minuteman Press, 2004.
Available at: http://www.doh.gov.za/docs/factsheets/guidelines/art
guide04-f.html. Accessed 3 July 2006.
135. Reid A, Sto¨hr W, Walker S, Ssali F, Munderi P, Gilks C. Glomerular
dysfunction and associated risk factors following initiation of ART in
adults with HIV infection in Africa [abstract THAB0105]. In: Program
and abstracts of the 16th International AIDS Conference (Toronto,
Canada). Toronto, Canada: International AIDS Society, 2006.
136. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the
era of effective antiretroviral therapy. Am J Respir Crit Care Med
2001; 164:7–12.
