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MAJOR ARTICLE
HIV/AIDS
Background. To understand regional burdens and inform delivery of health services, we conducted a systematic review and
meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in human
The impact of the introduction of highly active antiretroviral decline in HIV-related deaths by 40% since 2004 [5, 6]. OIs re-
therapy (ART) on the incidence and mortality of human immu- main the major driver of HIV-associated morbidity and mortal-
nodeciency virus (HIV)associated opportunistic infections ity, accounting for the substantially higher mortality observed in
(OIs) has been well documented in high-income countries LMICs [7], but the ART impact on specic OIs has not been
(HICs). This improved survival has been associated with a pro- well documented, mainly because there is no routine country-
gressive shift in the pattern of comorbidities, with an increasing level monitoring for OIs.
contribution of chronic liver disease due to hepatitis C and B, Reliable data on the relative burden of different OIs before
cardiovascular disease, and non-AIDS malignancies [14]. and after ART initiation in different geographic regions is crit-
In low- and middle-income countries (LMICs), the global ical for planning of health services, including procurement of
rollout of ART has led to >15 million patients on ART, and a relevant drugs and diagnostics. The few previous reviews on
OI incidence either preceded the global scale-up of ART or ad-
dressed only specic OIs or regions [8, 9]. We have undertaken a
Received 12 September 2015; accepted 27 February 2016; published online 6 March 2016.
Correspondence: A. Low, Mailman School of Public Health, Columbia University, 722 W 168th comprehensive systematic review and meta-analysis to estimate
St, 13th Flr, New York, NY 10032 (andrea_low@hotmail.com). the incidence of key OIs in HIV-infected adults before and after
Clinical Infectious Diseases 2016;62(12):1595603 the introduction of ART in LMICs across 3 regions (sub-Saharan
The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of
America. This is an Open Access article distributed under the terms of the Creative Commons Africa, Asia, and Latin America and the Caribbean), and to eval-
Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted uate the magnitude of effect of ART on the incidence of these
reuse, distribution, and reproduction in any medium, provided the original work is properly
cited. DOI: 10.1093/cid/ciw125
OIs during and after the rst year of treatment.
OI Cases Averted by the Use of ART meta-analysis of an effect of ART (P < .20), and where there
The estimated number of HIV-infected adults with CD4 was data available for an average treatment cost per case
counts <200 cells/L for 156 LMICs were obtained from [18], by multiplying the number of OI cases averted by the
2013 Joint United Nations Programme on HIV/AIDS (UN- treatment cost per case. Uncertainty ranges were estimated
AIDS) country estimates [1517]. The number of OI cases from 1000 Monte Carlo draws of the difference in estimates
averted through use of ART for the year 2013 was calculated of risk, assuming a normal distribution.
by applying the difference in estimates of OI risk in ART-
naive participants and in those during their rst year of ART
RESULTS
to the estimated population with a CD4 count 200 cells/L,
for each region. The annual savings per OI averted were The search strategy identied 6816 journal citations and 1025
calculated for OIs where there was some evidence from the conference abstracts; 952 full text reports were screened and
Cryptococcal meningitis
Sub-Saharan Africa 4 RCT, 12 cohorts 186 899 (60175 212) 16461 9/16 (56)
Asia 1 RCT, 8 cohorts 16 655 (5410 904) 8227 5/9 (56)
LAC 3 cohorts 1740 (3181057) 64208 2/3 (66)
Pneumocystis pneumonia
Sub-Saharan Africa 1 RCT, 7 cohorts 183 619 (270175 212) 128499 5/8 (63)
Asia 9 cohorts 10 902 (545040) 26130 7/9 (78)
LAC 6 cohorts 2420 (1231057) <200492 3/6 (50)
Oral candidiasis
Sub-Saharan Africa 2 RCT, 8 cohorts 20 531 (1108409) 200527 1/10 (10)
Asia 1 RCT, 6 cohorts 4152 (661982) 73227 1/7 (14)
LAC 2 cohorts 1217 (1601057) <200477 0/2
Esophageal candidiasis
Sub-Saharan Africa 3 RCT, 5 cohorts 8627 (2482446) <100322 1/8 (13)
Asia 1 RCT, 3 cohorts 2005 (541246) 4373 0/4
LAC 2 cohorts 478 (160318) 477 0/2
Herpes zoster
Sub-Saharan Africa 1 RCT, 7 cohorts 4305 (1011620) 135461 0/8
Asia 4 cohorts 2457 (1081253) 115227 0/4
Clinical response to empiric treatment without imaging or laboratory confirmation or unspecified means of diagnosis is considered nonlaboratory confirmed.
Abbreviations: LAC, Latin America and the Caribbean; NA, data not available; RCT, randomized controlled trial.
a
Laboratory confirmation for cryptococcal meningitis: cerebrospinal fluid cryptococcal antigen or India ink; for Pneumocystis pneumonia: chest radiograph and sputum cytology or clinical
response; for oral candidiasis: fungal culture; for esophageal candidiasis: endoscopy and fungal culture; for herpes zoster or genital herpes simplex: Tzanck smear or polymerase chain
reaction assay; for Kaposi sarcoma: biopsy and histology; for cerebral toxoplasmosis: computed tomographic brain scan, serology, and response to treatment; for Cryptosporidium diarrhea:
modified ZiehlNeelsen stool stain; for all forms of tuberculosis: acid-fast bacilli stain and/or mycobacterial culture; for all bacterial diseases: blood, sputum or stool cultures; for bacterial
pneumonia: chest radiograph.
Summary of Incident Risk, % (95% CI) (No. of Studies) Adjusted Odds Ratioa,b (95% CI)
Cryptococcal 1.7 (1.02.9) (16) 0.7 (.31.9) (4) 6.9 (4.410.3) (1) 0.8 (.51.3) (13) 0.37 (.121.18) . . . 0.47 (.22.99) .02
meningitis
Pneumocystis 2.8 (1.16.9) (10) 1.0 (.71.3) (4) 5.5 (1.420.1) (2) 0.7 (.14.0) (9) 0.13 (.03.62) . . . 0.33 (.101.13) .02
pneumonia
Oral candidiasis 19.1 (13.027.3) (10) 2.3 (1.63.3) (4) 1.2 (.91.5) (1) 5.0 (3.27.7) (7) 0.09 (.03.25) . . . 0.20 (.08.51) <.001
Esophageal 3.0 (1.75.3) (8) 0.2 (.1.7) (1) 13.2 (9.717.4) (1) 1.0 (.52.0) (6) 0.31 (.061.64) . . . . . . .15
candidiasis
Herpes zoster 9.4 (6.713.2) (7) 2.3 (1.63.3) (2) . . . 4.3 (2.38.0) (7) 0.39 (.151.03) . . . . . . .06
Herpes simplex/GUD 6.0 (2.712.8) (10) 1.2 (.27.7) (3) 5.7 (3.48.8) (1) 4.6 (1.811.3) (5) 0.18 (012.03) . . . 0.58 (.047.50) .63
Kaposi sarcoma 1.2 (.62.3) (14) 0.2 (01.5) (3) 2.0 (.48.5) (2) 0.5 (.3.8) (6) 0.13 (.011.70) . . . 0.77 (.115.20) .26
Cerebral 1.1 (.62.1) (11) 0.6 (.21.7) (4) 11.0 (7.815.0) (1) 0.5 (.21.1) (6) 0.12 (.03.57) . . . 0.55 (.211.49) .03
toxoplasmosis
Cryptosporidium 2.0 (.94.6) (6) 0.3 (02.9) (2) . . . 0.5 (.21.3) (3) . . . . . . . . . NA
diarrhea
Mycobacterium 10.0 (8.711.5) (45) 4.2 (3.54.9) (33) 2.8 (1.26.5) (14) 6.8 (4.410.3) (22) 0.36 (.24.55) 0.26 (.15.45) 0.66 (.421.04) <.001
tuberculosis
(unspecified)
Pulmonary 9.0 (6.811.8) (21) 3.5 (2.94.3) (15) 1.0 (.25.8) (3) 4.9 (3.17.7) (15) 0.38 (.22.67) 0.13 (.04.43) 0.52 (.52.91) <.001
0.36 [95% CI, .24.55]; PTB: aOR, 0.38 [95% CI, .22.67]; and showed a reduction in incidence for each OI, although this
EPTB: aOR, 0.43 [95% CI, .25.77]). After the rst year, there was less marked than during the rst year of ART.
was a further reduction in risk for PTB (aOR, 0.13 [95% CI, In the meta-regression analysis of the effect of region on in-
.04.43]) and unspecied tuberculosis (aOR, 0.26 [95% CI, cidence (Supplementary Appendix 3 and Supplementary
.15.45]). Summary risks for unspecied time on ART also Table 1), compared with sub-Saharan Africa, there was an
Figure 3. Summary incident risk of each opportunistic infection by region and overall for antiretroviral therapy (ART)naive patients (A), and during the first year of ART (B).
Abbreviations: GUD, genital ulcer disease; HSV, herpes simplex virus; PCP, Pneumocystis pneumonia; TB, tuberculosis.
antiretroviral therapy (ART). Uncertainty ranges were estimated from 1000 Monte Carlo draws of the difference in estimates of risk between early ART and ART-naive populations, assuming a normal distribution. The total for all opportunistic infections
Cases averted were calculated using Joint United Nations Programme on HIV/AIDS country estimates of the population in each region with a CD4 count <200 cells/L in 2013, for opportunistic infections (OIs) with a P < .20 for evidence of an effect of
$6 551 455 ($4 201 751$8 880 380)
$2 726 188 ($1 966 889$2 915 872)
$1 338 313 ($1 302 460$1 345 192)
. . .
were no signicant regional differences for oral or esophageal
candidiasis, herpes zoster, or GUD.
Cost
There was between-study heterogeneity in incidence of OIs
across studies and regions, and the most important sources of
heterogeneity were baseline CD4 count for cryptococcal menin-
gitis (I 2 = 56.4% for CD4 counts 200499 cells/L) and oral can-
$301.00
$53.97
$3.65
$18.79
$11.14
$182.76
. . .
was identied that predominately explained the source of this
heterogeneity. The use of CTX prophylaxis did not explain the
heterogeneity in incidence of PCP or toxoplasmosis, where esti-
mates of I 2 were high for all categories of CTX exposure.
Total
(OIs) is the median of the sum of 1000 random draws for each OI, and therefore differs from the sum of the medians of number of cases averted by region.
Estimated Number of Opportunistic Infection Cases and Costs Averted During the First Year of Antiretroviral Therapy
595 974629 673) in sub-Saharan Africa, 195 312 (95% CI,
194 096205 071) in Asia, and 38 198 (95% CI, 37 962
40 109) in Latin America. The most common OIs, oral candi-
2158 (17692597)
7740 (74318159)
8156 (77658567)
diasis (366 661 [95% CI, 356 835368 546]) and tuberculosis
1017 (6191383)
(182 017 [95% CI, 173 392190 468]), accounted for the great-
561 (0946)
est number of OIs averted. Estimated cost savings in OI treat- LAC
No. of Cases Averted (95% CI)
2870 (04835)
Asia
DISCUSSION
Global costs per case were not available for cerebral toxoplasmosis.
38 442 (16 22738 457)
Cerebral toxoplasmosisa
Cryptococcal meningitis
ART-naive adults.
Total (95% CI)
Herpes zoster