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Abstract

Background

Antiretroviral therapy is associated with adverse events (AEs). The most frequently reported AE associated with lopinavir/ritonavir (LPV/r) containing regimens is diarrhea. The objective of this meta-analysis is to describe the incidence, prevalence, and duration of diarrhea in individuals taking LPV/r.

Methods

This is a meta-analysis of Abbott-conducted clinical trials. Inclusion criteria included prospective randomized clinical trials with the LPV/r tablet formulation and had AE data (moderate/severe diarrhea) available through 48 weeks of treatment.

Results

Three trials (total 1469 participants) met the inclusion criteria. In all, 11.2% of participants reported moderate/severe diarrhea by week 8, with median time to resolution of 7.4 weeks. The overall 48-week incidence of moderate/severe diarrhea was 15.5%. The discontinuation rate due to moderate/severe diarrhea was 1.3%.

Conclusions

Moderate/severe diarrhea occurred in less than 1 in 6 participants taking LPV/r, typically started in the first 8 weeks of treatment and infrequently resulted in premature discontinuation.

Keywords

lopinavir diarrhea meta-analysis

Introduction

The development of virally suppressive antiretroviral (ARV) regimens has improved disease outcomes for individuals infected with HIV. Current standard of care for treatment of an antiretroviral regimen-naive patient with HIV-1 infection consists of a 3-drug regimen selected from at least 2 different classes of ARV regimens including either a protease inhibitor (PI), a nonnucleoside reverse transcriptase inhibitor (NNRTI), a CCR5 co-receptor antagonist, or an integrase inhibitor coadministered with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).¹ Antiretroviral therapy (ART) reduces morbidity and mortality and has dramatically increased survival times of HIV-infected patients to nearly the life expectancy of healthy persons not infected with HIV.^2,3 However, ART is also associated with development of adverse events (AEs). While ARV regimens can be associated with serious AEs, most AEs associated with ARV regimen are considered mild to moderate in nature, are typically self-limiting, and are often manageable. Each class is associated with AEs that can be described as an inconvenience, rather than a life-threatening experience, by most patients. Nevertheless, these AEs can become excessively bothersome, resulting in a decreased quality of life. For example, NRTIs are possibly associated with lipoatrophy, NNRTIs are associated with rash, dream disturbances, and lipoatrophy, and PIs are associated with gastrointestinal (GI) disorders.^4,5 Gastrointestinal disorders most commonly associated with PI usage include nausea, vomiting, abdominal pain, and diarrhea.⁶ While all PIs are associated with diarrhea, differing rates of diarrhea have been reported for individual drugs within this class.⁶

Although diarrhea can be associated with treatment regimens including PIs, diarrhea can also be related to HIV infection itself.⁷ Chronic diarrhea in HIV-infected patients is multifactorial and complex. It can result from opportunistic infections, changes in the intestinal microbial flora, ARV regimen treatment, viral GI infections, food-borne illnesses, or a combination of these factors.^6,7 Diarrhea is also associated with ARV regimens other than PIs. This was demonstrated during monotherapy with the NRTI lamivudine (3TC) in which diarrhea was the most common AE.⁸ Thus, there is potential for additive effects of combination therapies since more than 1 ARV regimen of a combination regimen may contribute to diarrhea. Gastrointestinal AEs are a leading reason that patients switch ART.⁹ Therefore, understanding the prevalence and mechanism of GI AEs as well as ways to prevent or treat the symptoms would benefit patients.

Lopinavir/ritonavir (LPV/r) is a co-formulated HIV-1 PI, comprising lopinavir (200 or 100 mg) and ritonavir (50 or 25 mg). The LPV/r is indicated in combination with other ARV medications for the treatment of HIV-1 infection in antiretroviral regimen-naive and experienced adult and pediatric patients.^10

–14 In general, ARV regimens containing LPV/r are well tolerated.^10,11,15 The most frequently observed AE associated with LPV/r-containing regimens is diarrhea.^10,11 The objective of this meta-analysis is to describe the frequency, duration, and severity of diarrhea; reported usage or prescription of antidiarrheal agents; and factors associated with diarrhea in 1469 participants who participated in 3 randomized, open-label, multicenter, phase III clinical trials utilizing the tablet formulation of LPV/r.

Methods

Data Abstraction

We identified clinical questions that could be addressed directly from Abbott clinical trials involving the use of the LPV/r tablet formulation, with a focus on moderate-to-severe diarrhea. Data were abstracted based on the following questions: (1) What is the overall incidence and prevalence of diarrhea at various time points? (2) What is the time to resolution? (3) How many participants are prescribed or reported using concomitant antidiarrheal medications? (4) What are the most common concomitant antidiarrheal medications? (5) What is the discontinuation rate of LPV/r treatment due to diarrhea? (6) What demographic or disease characteristics are associated with the incidence of diarrhea?

Study Selection

The study selection process is shown in Figure 1. Studies in adult participants were eligible for inclusion in the meta-analysis if they met the following criteria: AE (diarrhea) severity was reported; participants were treated with an approved LPV/r dosage of either 400/100 mg twice daily (BID) or 800/200 mg once daily (QD); and the study utilized the LPV/r tablet formulation. Of the 11 trials 3 met these criteria and were included in the meta-analysis: M05-730, M06-802, and M10-336.

Figure 1.

Study selection process.

Characterization of these 3 prospective, randomized, open-label, multicenter, phase III trials has been previously described.^10,11,16 Cumulatively, these studies involved a total of 1469 participants. Briefly, antiretroviral regimen-naive, HIV-1-infected individuals ≥18 years who had plasma HIV-1 RNA ≥1000 copies/mL at screening were eligible for M05-730 and M10-336. ARV regimen-experienced, HIV-1-infected individuals ≥18 years who were on a stable ARV regimen for at least 12 weeks but virologically failing therapy were eligible for M06-802.

Classification of Diarrhea

For all 3 trials, AE information was collected during each scheduled study visit. The AE collection was based on participant reporting. The AE severity was based on participant’s perception and investigator’s assessment in accordance with the guidance provided in the protocols that was identical for the 3 studies.

Mild: AE was transient and easily tolerated by the participant.

Moderate: AE caused the subject discomfort and interrupted the participant's usual activities.

Severe: AE caused considerable interference with the participant's usual activities and may have been incapacitating or life threatening.

Antidiarrheal Medications

Antidiarrheal medications the participant was using at baseline visit or reported using during the study were collected along with the reason for use, dates of administration, dosage, and frequency. The decision to use antidiarrheal medication and the choice of medication was at the discretion of the participant and/or the investigator.

Statistical Analyses

Analyses were performed using SAS (SAS Institute Inc, Cary, North Carolina), version 8.2. Data from the first 48 weeks of randomized treatment for each of the 3 studies were included in the analyses. Demographic and baseline characteristics were summarized using means and standard deviations for continuous variables and frequencies and percentages for categorical variables.

The following proportions at each week of the first 48 weeks of treatment were calculated and used to produce Figure 2: participants who discontinued the study with moderate/severe diarrhea ongoing; participants who discontinued the study had experienced moderate/severe diarrhea but did not have moderate/severe diarrhea ongoing at the time of discontinuation; participants who discontinued the study and never had moderate/severe diarrhea; participants on study who never had moderate/severe diarrhea; participants on study who had experienced moderate/severe diarrhea in the past which was not ongoing; and participants on study with diarrhea ongoing. The proportion of participants reporting moderate/severe diarrhea during the first 48 weeks of treatment was calculated along with the corresponding 95% confidence interval (CI). The proportion of participants reporting moderate/severe diarrhea within specific time intervals was calculated as well as the proportions of participants reporting new and recurring/ongoing events within these intervals; proportions were calculated based on the number of participants at risk (on study) at the beginning of the time interval. For those participants who had moderate/severe diarrhea during the first 8 weeks of the study, the median and range of time to moderate/severe diarrhea resolution were calculated using Kaplan-Meier methodology.

Figure 2.

Characterization of moderate/severe diarrhea in studies M05-730, M06-802, and M10-336.

The potential influence of demographic and disease characteristics on the incidence of moderate/severe diarrhea were explored using logistic regression. Univariate logistic regression was used to test the significance of each of the following variables: ARV regimen-experienced (versus ARV regimen-naive), LPV/r QD dosing (versus BID), use of raltegravir, male gender, white race, black race, Hispanic ethnicity, age (<50 versus ≥50 years), any GI history, specific GI histories (peptic ulcer disease, gastroesophageal reflux disease (GERD), liver disease, hepatitis, pancreatitis, GI bleeding, cholelithiasis, cholecystitis, inflammatory bowel disease, and diverticulitis), baseline CD4 count, CD4 count change from baseline at week 8, and baseline HIV-1 RNA level. Only those variables that were significant at the 0.2 level in univariate logistic regression models were included as potential covariates in a multivariate logistic regression model using a forward stepwise selection method. Covariates that were significant at the 0.15 level were included in the final model selected using the forward stepwise method; odds ratios and the corresponding 95% CIs were calculated.

The proportions of participants discontinuing the study during the first 48 weeks of treatment because of moderate/severe diarrhea and the proportions of participants who reported moderate/severe diarrhea and were prescribed or reported using antidiarrheal medications during 48 weeks of treatment were calculated along with the corresponding 95% CIs. The number of participants discontinuing moderate/severe diarrhea within specific time intervals was also calculated. The proportion of participants who reported moderate/severe diarrhea and were prescribed or reported using antidiarrheal medications within specific time intervals was calculated as well as the proportions of participants with new and recurring/ongoing use within the specific intervals; these proportions were calculated based on the number of participants in study at the beginning of the time interval.

Results

Baseline Demographics

Three clinical trials that met the meta-analysis criteria were identified: M05-730, M06-802, and M10-336. Baseline demographics for the 1469 combined participants are shown in Table 1. A total of 1087 (74.0%) participants were male and 870 (59.2%) of them were ARV regimen-naive. The mean age was 39.6 years, 32.6% of participants had plasma HIV-1 RNA ≥100 000 copies/mL, and 46.5% of them had CD4 count ≤200 cells/mm.³

Table 1.

Baseline Demographics for Participants Combined Across M05-730, M06-802, and M10-336

	LPV/r N = 1469
Population, n (%)
ARV regimen-naive	870 (59.2)
ARV regimen-experienced	599 (40.8)
Regimen, n (%)
QD	633 (43.1)
BID	836 (56.9)
Coadministered ARV medications
Raltegravir	101 (6.9)
NRTI	1368 (93.1)
Gender, n (%)
Male	1087 (74.0)
Female	382 (26.0)
Race, n (%)
White	962 (65.5)
Black	375 (25.5)
Other	132 (9.0)
Age, y
Mean ± SD	39.6 ± 9.63
Prior antiretroviral therapy, n (%) M06-802 participants only
NRTI	596 (40.6)
NNRTI	505 (34.4)
PI	276 (18.8)
Plasma HIV-1 RNA (log₁₀ copies/mL)
Mean ± SD	4.6 ± 0.83
<100 000 copies/mL, n (%)	990 (67.4)
≥100 000 copies/mL, n (%)	479 (32.6)
CD4 count levels (cells/mm³)^a
Mean ± SD	242 ± 155.0
≥200, n (%)	809 (56.9)
<200, n (%)	614 (43.1)
<50, n (%)	160 (11.2)
Antidiarrheal use at time of baseline visit, n (%)
Yes	45 (3.1)
No	1424 (96.9)

Abbreviations: QD, once daily; BID, twice daily; ARV, antiretroviral; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

^a N = 1423.

Occurrence of Diarrhea

Figure 2 presents an overview of moderate/severe diarrhea reported for participants who either discontinued LPV/r within the first 48 weeks of treatment or remained on treatment for at least 48 weeks. A total of 1149 (78.2%) of 1469 participants remained on LPV/r treatment through 48 weeks. The majority of the participants (989 of 1469, 67.3%) remained on study through 48 weeks without experiencing moderate/severe diarrhea. Most of the participants (89.7%) who discontinued LPV/r treatment through week 48 did not have moderate/severe diarrhea at the time of discontinuation. Through 48 weeks, 3.9% of participants who remained on LPV/r treatment reported ongoing moderate/severe diarrhea.

The incidence of moderate/severe diarrhea through 48 weeks (Table 2) was 15.5% (95% CI = 13.7, 17.5%). Of the 1469 participants, 18 (1.2%) experienced severe diarrhea through 48 weeks. To better understand the timing of diarrhea reported by participants in these studies, the prevalence of moderate/severe diarrhea over the course of the studies and the time to resolution of symptoms were analyzed. When the treatment interval was divided into the intervals of 0 to 8, 8 to 24, and 24 to 48 weeks, the prevalence of moderate/severe diarrhea was highest during the first 8 weeks (11.2%). For those participants who reported moderate/severe diarrhea in the first 8 weeks, the median time to resolution was 7.4 weeks (range, 1 day to 92 weeks). Participants who did not have moderate/severe diarrhea before week 8 were less likely to develop moderate/severe diarrhea through 48 weeks of treatment; 2.5% and 1.9% of participants reported new onset moderate/severe diarrhea during weeks 8 to 24 and weeks 24 to 48, respectively.

Table 2.

Incidence, Prevalence, and Resolution of Moderate/Severe Diarrhea

	LPV/r N = 1469
Incidence, n	228, 15.5% (13.7%,17.5%)
% (95% CI)	228, 15.5% (13.7%,17.5%)
Prevalence, %
(% new, % recurring/ongoing)
0-8 weeks	11.2%
8-24 weeks^a	8.4% (2.5%, 5.9%)
24-48 weeks^b	7.3% (1.9%, 5.4%)
For those who had moderate/severe diarrhea in first 8 weeks, median time to resolution of moderate/severe diarrhea, median weeks	7.4 weeks

Abbreviation: CI, confidence interval.

^a N = 1443.

^b N = 1351 on study at the beginning of interval.

Predictors of Diarrhea

Factors associated with the development of moderate/severe diarrhea are shown in Table 3. Three of these factors were independently associated with reduced incidence of diarrhea: history of liver disease (P= .122), ARV regimen experience (P= .056), and greater increase from baseline in CD4 count at week 8 (P= .015). Higher baseline HIV-1 RNA level (P= .059), history of GI illness (P= .078), history of peptic ulcer disease (P= .082), and history of inflammatory bowel disease (P= .053) were associated with increased incidence of diarrhea.

Table 3.

Factors Independently Associated with Incidence of Moderate/Severe Diarrhea That Were Significant at the .15 Level^a

Odds Ratio (95% CI)
Liver disease history (yes versus no)	0.32 (0.07, 1.36)
ARV regimen experience (yes versus no)^b	0.71 (0.50, 1.01)
CD4 count change from baseline at week 8 (per 50 cells/mm³ increase)^c	0.91 (0.84, 0.98)
Baseline HIV-1 RNA level (per 0.5 log₁₀ copies/mL increase)^b	1.10 (1.00, 1.22)
Any GI history (yes versus no)^b	1.33 (0.97, 1.83)
Peptic ulcer disease history (yes versus no)^b	2.02 (0.92, 4.44)
Inflammatory bowel disease history (yes versus no)^b	2.93 (0.99, 8.71)

Abbreviations: CI, confidence interval; GI, gastrointestinal; ARV, antiretroviral.

^a The factors presented were significant at the .15 level and were included in the final model.

^b Statistically significant at .10 level.

^c Statistically significant at .05 level.

Management of Diarrhea and Discontinuation Rates due to Diarrhea

Antidiarrheals that were prescribed or reported included bismuth, digestive enzymes, diphenoxylate, dietary fiber, Lactobacillus acidophilus, loperamide, pancreatin, pancrelipase, papaver somniferum, polycarbophil, psyllium hydrophilic mucilloid, Saccharomyces boulardii, and dried yeast. The proportion of participants who reported moderate/severe diarrhea and were prescribed or reported using antidiarrheal medication during the first 48 weeks of treatment was 9.1% (95% CI = 7.6-10.6), with 3.1% of all participants receiving antidiarrheal medication at the time of their baseline visit. If participants were not prescribed or did not report using antidiarrheal medication during the first 8 weeks, they were less likely to do so thereafter; between weeks 8 to 24 and weeks 24 to 48, 1.7% and 1.0% of participants reported new usage or prescription of antidiarrheal, respectively. Loperamide was the antidiarrheal medication prescribed or reported used most often (8.4%; 95% CI = 7.0, 9.9).

Of the 1469 participants taking LPV/r, 19 (1.3%, 95% CI = 0.8, 2.0%) discontinued treatment due to moderate/severe diarrhea (Table 4). Twelve of these 19 participants discontinued during the first 16 weeks of treatment with an LPV/r-based regimen.

Table 4.

Discontinuations due to Moderate/Severe Diarrhea

	LPV/r N = 1469
Discontinuation, n, % (95% confidence interval)	19, 1.3% (0.8%, 2.0%)
Timing of discontinuation, n
0-8 weeks	7
>8-16 weeks	5
>16-24 weeks	1
>24-32 weeks	1
>32-40 weeks	2
>40-48 weeks	1
>48 weeks^a	2

^a After study day 336 and on or before study day 378.

Summary

The incidence of moderate/severe diarrhea, in this meta-analysis from 3 prospective randomized-controlled clinical trials with 1469 participants who took an ARV regimen containing LPV/r tablet formulation, was 15.5% through the first 48 weeks of therapy. If moderate/severe diarrhea occurred, it was most likely to start within the first 8 weeks of treatment with median time to resolution of 7.4 weeks. Greater increase in CD4 count from baseline to week 8 was statistically significantly associated with reduced risk of moderate/severe diarrhea during treatment with LPV/r (P= .015); other factors trended toward an association with the risk of moderate/severe diarrhea and included ARV regimen treatment status, history of GI disease, and baseline HIV-1 RNA level (0.05 < P ≤ .15). Less than 10% of participants with moderate/severe diarrhea were prescribed or reported using antidiarrheal medication during the first 48 weeks of treatment. Most participants who were prescribed or reported taking antidiarrheal medication did so during the first 8 weeks, coincident with the highest prevalence of moderate/severe diarrhea. The discontinuation rate due to moderate/severe diarrhea was low (1.3%), suggesting that for most participants diarrhea resolved or was successfully managed.

Discussion

Diarrhea is the most commonly reported AE associated with LPV/r-based therapy. However, diarrhea is also associated with all other currently approved PIs. In order to provide additional context of LPV/r-associated diarrhea, we conducted a thorough review of the literature seeking to capture all HIV trials in which LPV/r-based therapy was compared with non-LPV/r-based PI therapy. Published data available on diarrhea rates from clinical trials with LPV/r compared with other PI-containing regimens in studies not conducted by the manufacturer of LPV/r, that is, Abbott, are shown in Table 5. In these 9 large randomized clinical trials, the incidence of diarrhea, all AEs, and discontinuations due to AEs were broadly similar among participants receiving LPV/r-containing ARV regimens (mostly LPV/r soft gelatin capsule formulation) or comparator PI regimens. In grades 1 to 4, diarrhea was reported in 4% to 15% of participants receiving LPV/r-containing regimens versus 2% to 16% in participants receiving comparator-containing regimens. In the trials where participants taking LPV/r reported higher rates of diarrhea than those taking the comparator PI, these trials did not report significantly higher rates of total AEs or discontinuation due to AEs. Among studies that reported discontinuations due to diarrhea, the rates were 2% or less and there was no difference between LPV/r and other PIs. The overall safety and tolerability of LPV/r appear to be similar to that of other PIs in multiple trials not conducted by the manufacturer of LPV/r, that is, Abbott.

Table 5.

Adverse Events in Clinical Trials of LPV/r versus Comparative PI Regimens in ARV Regimen-Naive and Experienced Participants^a,b

Study Acronym	Wk	Treatment Regimen	No. of Pts^c	Diarrhea Grade 2 to 4, %	AE Grade 2 to 4, %	D/C due to Diarrhea, %	D/C due to AE, %
LPV/r versus SQV/RTV
MaxCmin 2¹⁷	48	LPV/r	163	NA	NA	NA	7
MaxCmin 2¹⁷	48	SQV/RTV	161	NA	NA	NA	13
GEMINI^18,19	48	LPV/r	170	NA14^d	NA63^d	NA	7
GEMINI^18,19	48	SQV/RTV	167	7	51	NA	3
LPV/r versus FPV/RTV
CONTEXT²⁰	48	LPV/r	103	11^e	NA	NA	7
		FPV/RTV BID	107	13	NA	NA	5
		FPV/RTV QD	105	NA	NA	NA	NA
KLEAN²¹	48	LPV/r	443	11	5	2	10
KLEAN²¹	48	FPV/RTV	436	13	5	1	12
KLEAN²²	96	LPV/r	92	11	27	NA	2
KLEAN²²	96	FPV/RTV	104	16	40	NA	2
KLEAN²³	144	LPV/r	92	12	27	NA	3
KLEAN²³	144	FPV/RTV	104	15	42	NA	5
LPV/r versus DRV/RTV
TITAN²⁴	48	LPV/r	297	15	41	2	7
TITAN²⁴	48	DRV/RTV	298	8	37	<1	7
TITAN²⁵	96	LPV/r	297	15	NA	NA	8
TITAN²⁵	96	DRV/RTV	298	8^h	NA	NA	8
ARTEMIS²⁶	48	LPV/r	346	10	22	NA	7
ARTEMIS²⁶	48	DRV/RTV	343	4^e	19	NA	3
ARTEMIS²⁷	96	LPV/r	346	11	34	NA	9
ARTEMIS²⁷	96	DRV/RTV	343	4^g	23	NA	4
LPV/r versus ATV/RTV
BMS 043²⁸	48	LPV/r	146	4	26	NA	4
BMS 043²⁸	48	ATV	144	2	24	NA	2
BMS 045²⁹	48	LPV/r	118	11^e	25	NA	2
		ATV/SQV	110	6	26	NA	6
		ATV/RTV	119	3	29	NA	4
BMS 045³⁰	96	LPV/r	118	13^f	NA	NA	8
BMS 045³⁰	96	ATV/RTV	119	3	NA	NA	8
CASTLE³¹	48	LPV/r	437	11	30	<1	3
CASTLE³¹	48	ATV/RTV	441	2	26	0	2
CASTLE³²	96	LPV/r	437	12	32	2	5
CASTLE³²	96	ATV/RTV	441	2	30	0	3

Abbreviations: AE, adverse event; D/C, discontinuation; CI, confidence interval; GI, gastrointestinal; ARV, antiretroviral; NA, not applicable; SQV, saquinavir; RTV, ritonavir; FPV, fos-amprenavir; LPV/r, lopinavir/ritonavir; ATV, atazanavir.

^a LPV/r film-coated tablet was subjected to availability and local approval and was used in the following trials: CASTLE (after week 48), ARTEMIS, and TITAN

^b Treatment experienced studies: MaxCmin2, CONTEXT, TITAN, BMS043, and BMS 045.

^c Safety population.

^d Grades 1 to 4.

^e Grades 3 to 4.

^f P <.01.

^g P <.001.

^h P <.007.

There are limitations of this meta-analysis. First, only 3 clinical trials met the inclusion criteria largely because of our desire to provide information related to the currently utilized LPV/r formulation. Second, this meta-analysis was not adequately powered to obtain exact rates of infrequent events, such as treatment discontinuation due to severe diarrhea or to examine the association between LPV/r therapy and diarrhea. Importantly, diarrhea is a subjective AE with significant interpatient variability. Third, the method by which the use of antidiarrheal medication was collected did not distinguish between a prescription dispensed prophylactically at study start, and a prescription for management of actual diarrhea; it also did not permit determination of the actual duration of antidiarrheal medication treatment. Data regarding modalities other than antidiarrheal medication, such as dietary changes, were not obtained. It was also not possible to determine whether participants who reported taking antidiarrheal medication did so due to diarrhea associated with LPV/r or to other causes of diarrhea, such as food-borne illness. The shortcomings of the methods in which antidiarrheal use was collected prevented an examination to determine which interventions were most successful. Finally, reporting of diarrhea relied on patient recall; therefore, the onset, duration, and resolution were not always known or recorded by the investigator.

Conclusions

Diarrhea is the most commonly reported AE associated with LPV/r-based therapy. In this meta-analysis, moderate/severe diarrhea occurred in less than 1 in 6 participants taking LPV/r and typically started in the first 8 weeks of treatment. Diarrhea associated with LPV/r-based therapy infrequently resulted in premature discontinuation.

Footnotes

Authors’ Note

Colleen Wegzyn and William Woodward both left Abbott Laboratories after this publication was completed and have both returned to clinical practice.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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Diarrhea Associated with Lopinavir/Ritonavir-Based Therapy

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Data Abstraction

Study Selection

Classification of Diarrhea

Antidiarrheal Medications

Statistical Analyses

Results

Baseline Demographics

Occurrence of Diarrhea

Predictors of Diarrhea

Management of Diarrhea and Discontinuation Rates due to Diarrhea

Summary

Discussion

Conclusions

Footnotes

Authors’ Note

Declaration of Conflicting Interests

Funding

References