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Background: To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART., Methods: SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group). 210 participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: thymidine analogue (ta-NRTI) + lamivudine/emtricitabine (3[F]TC; ta-NRTI group); tenofovir (TDF)+3(F)TC (TDF group); TDF+ta-NRTI ±3(F)TC (TDF+ta-NRTI group); RAL. Changes in fasted total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression methods were used., Results: We analysed 454 participants. Participants in RAL group had greater TC increases, TC (adjusted mean difference [aMD]=0.65, 95% CI 0.33, 0.96), LDL-c (aMD=0.38, 95% CI 0.15, 0.61) and glucose (aMD=0.47, 95% CI -0.01, 0.92) compared to TDF group, and had greater increases in TC (aMD=0.65, 95% CI 0.28, 1.03), HDL-c (aMD=0.12, 95% CI 0.02, 0.23) and LDL-c (aMD=0.41, 95% CI 0.13, 0.69) compared to TDF+ta-NRTI group. TC/HDL ratio and triglycerides increased in all groups without significant differences between groups. A 1 kg increase in trunk fat mass was associated with an increase in TC., Conclusions: We observed metabolic changes of limited clinical significance in the relatively young population enrolled in this study. However, the metabolic changes observed may have greater clinical significance in older people living with HIV or those with other concomitant cardiovascular risks.

Background: We explored the relationship between virological response in the first year of treatment and long-term outcomes in the BENCHMRK studies., Methods: Patients failing antiretroviral treatment with 3-class resistant HIV-1 received double-blinded raltegravir (or placebo) with optimized background therapy (OBT) until week 156, followed by open-label raltegravir with OBT up to week 240. In this exploratory analysis of patients randomized to raltegravir, virological response over weeks 16-48 was categorized as continuous suppression (CS; viral RNA [vRNA] always <50 copies/ml), low-level viraemia (LLV; vRNA always <400 copies/ml, >50 copies/ml at least once), or not suppressed (NS; vRNA >400 copies/ml at least once). The association between these first-year vRNA response categories and baseline factors was analysed with univariate and multivariate models. Virological and immunological outcomes for years 2-5 were assessed by first-year vRNA response category (observed failure approach)., Results: Baseline vRNA, baseline CD4(+) T-cell count and rapid viral decay (vRNA <50 copies/ml between weeks 2-12) correlated with first-year vRNA response (P<0.001); only rapid viral decay remained significant by multiple regression. Virological response rates were similar in the LLV and CS groups and lowest in the NS group. CD4(+) T-cell count increased through week 240 in the CS and LLV groups. Time to loss of virological response (confirmed vRNA ≥400 copies/ml) through week 240 did not support as strong a difference between the LLV and CS groups (log-rank P=0.11) as previously reported through weeks 156 and 192 (P<0.05)., Conclusions: Treatment-experienced patients on a raltegravir-based regimen with early LLV may have long-term virological and immunological benefit when their therapy is maintained.

Background: Biomarkers of inflammation, coagulation, lipids and vitamin D have been associated with cardiovascular and mortality risk in HIV-infected individuals. Scarce data exist on changes in these markers from pre- to post-HIV seroconversion., Methods: The study participants were drawn from the Health in Men Study, which recruited HIV-negative homosexual men. Participants with incident HIV infection (n=26) were compared with HIV-negative controls (n=52) matched on age at enrolment, date of visit and reported intravenous drug use. Levels of metabolic (lipids and vitamin D), inflammatory (C-reactive protein and interleukin-6) and coagulation (D-dimer and fibrinogen) biomarkers were measured at pre- and post-HIV seroconversion visits and corresponding visits for controls. Random-effect models were used to compare changes in markers between cases and controls., Results: The median gap between pre- and post-seroconversion or matched first and second visits in controls was 12 months. HIV seroconversion was associated with decline in high density lipoprotein (HDL-C; difference in mean change between cases and controls -0.14 mmol/l; 95% CI -0.22, -0.01; P=0.035). There were no significant differences in changes in other lipids, markers of inflammation, coagulation or vitamin D., Conclusions: Decline in HDL-C seems to be the main proatherogenic change within 1-1.5 years after HIV seroconversion. HIV seroconversion was not associated with profound changes in other lipids, or markers of inflammation, coagulation and vitamin D. Longitudinal assessment of these markers in comparable population needs further assessment.

Background: Because of the favourable safety and tolerability profiles of atazanavir (ATV) and raltegravir (RAL), attention has recently turned to the use of dual ATV plus RAL therapy as a nucleoside reverse transcriptase inhibitor-sparing treatment strategy in highly antiretroviral treatment (ART)-experienced HIV-infected patients., Methods: A retrospective observational study was carried out to assess the maintenance of viral suppression and ART tolerability in 20 highly ART-experienced patients with viral suppression, who had been switched to RAL and unboosted ATV dual therapy, using data collected during standard-of-care visits., Results: At 6, 12 and 18 months, viral load was maintained at <400 HIV RNA copies/ml, with only one participant recording a detectable viral load (150 copies/ml) at the 6-month time point. Stable CD4(+) T-cell counts were maintained throughout the study period. Five participants changed regimen during the 18-month follow-up, with the median time to switch being 9 months (range 2-12). In three cases, patients were changed from dual therapy because of adverse events while on the regimen. These included increased fatigue (two patients), persistently increased bilirubin (one patient) and gastrointestinal side effects (one patient). Two additional patients changed therapy: one patient added lamivudine and one ceased ATV to pre-empt a potential drug-drug interaction. All five patients who switched from ATV/RAL before 12 months follow-up maintained viral suppression, implying no disadvantage from switching to dual therapy., Conclusions: Dual therapy with ATV plus RAL maintained viral suppression in this small group of highly ART-experienced patients. Further investigation of this novel dual therapy regimen is warranted.

Background: SCH532706 is a novel small molecule chemokine receptor-5 (CCRS) antagonist with high in vitro potency (mean 90% inhibitory concentration [IC90] 0.15-7.0 nM) against diverse HIV type-1 (HIV-1) isolates., Methods: A single arm study was undertaken to examine the safety, antiviral activity and pharmacokinetics (PK) of 10 days of SCH532706 coadministered with ritonavir (RTV). The trial enrolled formerly treated (off therapy >3 months) or untreated HIV-1-infected patients., Results: The study enrolled 12 males with CD4+ T-cell count >100 cells/microl. Median (range) CD4+ T-cell count was 327 cells/microl (117-1008), HIV-1-RNA was 4.6 log10 copies/ml (3.8-5.5) and patients had phenotypically confirmed R5-tropic HIV-1 only. Mean (95% confidence interval) changes from baseline plasma HIV-1-RNA at days 10 and 15 (4 days off SCH532706) were -1.31 log10 copies/ml (-1.6 - -1.0) and -1.62 log10 copies/ml (-2.0 - -1.3), respectively. Day 10 median (range) time to maximum plasma concentration, mean (+/-SD) effective half-life and mean (+/-SD) trough concentration were 1.4 h (1.0-4.0), 39.4 h (+/-14.5) and 178 ng/ml (+/-34), respectively. All virus isolates remained R5-tropic pre-study, on study and at study end. There were no laboratory or QTc interval changes reportable as adverse events. In total, 11 patients reported > or =1 treatment emergent adverse event, most commonly gastrointestinal upset. One serious adverse event, pericarditis (grade 2), occurred 13 days after drug administration. It was considered to be possibly related to study drug., Conclusions: Overall, SCH532706 with RTV was safe, generally well tolerated and active against HIV-1 over 10 days of dosing. In this setting, SCH532706 trough concentrations exceed the mean in vitro IC90 (1.1 ng/ml) by >30-fold (after correction for 80% plasma protein binding) and provide a PK rationale for the observed efficacy.

The spectrum of drugs used in HIV-infected patients has dramatically changed since triple antiretroviral combinations were introduced, albeit at the expense of some severe adverse events, in 1996. Abandonment of stavudine in countries that can afford it, new drugs from new classes with a wide therapeutic window and the impressive scale-up of drug access in resource-limited settings are several of the key new events. Drug safety is likely to be the most important factor to distinguish one antiretroviral regimen from another. We review life-threatening adverse events, adverse events of new investigational or recently marketed drugs, adverse events with a genetic component and tissue-specific adverse events of fat, heart, bone, kidney and liver.

Background: We aim here to determine the appropriate dose of nevirapine (NVP) in Thai HIV-tuberculosis (TB)-coinfected patients receiving rifampicin., Methods: Thirty-two HIV-infected adults with CD4+ T-cell counts <200 cells/mm3 and active TB, receiving rifampicin for 2-6 weeks were randomized to receive either NVP 400 mg (NVP400) or 600 mg (NVP600) per day plus two nucleoside reverse transcriptase inhibitors; a 2-week NVP lead-in was performed at 200 mg once daily (OD) and 200 mg twice daily, respectively. Plasma NVP levels were determined at weeks 2, 4 and 12. Twelve-hour pharmacokinetics (PK) were obtained (n=20) at week 4., Results: Baseline body weight was comparable. There were more patients with NVP plasma concentration at 12 h (C12) <3.1 mg/l at week 2 in NVP400 than in NVP600 (79% versus 19%, respectively; P=0.002). However, the proportions were comparable at weeks 4 and 12. From week 4, 12 h PK studies showed that NVP400 had lower median NVP area under the plasma concentration-0-12 h (AUC0-12 h, maximum concentration in plasma (Cmax) and C12 than NVP600 (P<0.05). Four patients in NVP600 developed NVP hypersensitivity. At week 48, the median CD4+ T-cell count rise and proportion with viral load <50 copies/ml (intention-to-treat analysis 56% versus 50% and as-treated analysis 75% versus 89%) were comparable., Conclusions: In rifampicin-treated patients, 200 mg NVP OD lead-in led to a significant short-term suboptimal NVP C12 level, while NVP 400 mg lead-in then 600 mg/day was associated with a high rate of NVP hypersensitivity. Forty-eight week efficacy was comparable. Thus, NVP 600 mg/day in rifampicin-treated patients is not recommended.

Background: Mortality related to end-stage liver disease is increasing in HIV/hepatitis B virus (HBV)-coinfected patients and effective treatment options are limited. Tenofovir is now widely used in HIV/HBV coinfection and results in significant HBV suppression, in both patients with and patients without lamivudine resistance. The safety and efficacy of tenofovir in HIV/HBV cirrhosis has not been previously described., Methods: Seven cirrhotic HIV/HBV patients treated with tenofovir were identified within the HIV clinic. Parameters of hepatic function, CD4+ T-cell counts, HBV DNA levels and Child-Pugh Class (C-P-C) were determined before and after addition of tenofovir. All patients had prior lamivudine experience with a median baseline HBV DNA of 6.23 x 10(7) copies/ml., Results: Four of seven patients were C-P-C -A and hepatitis 'e' antigen (HBeAG) was positive in 4/7 patients. After a median duration of tenofovir of 28 months, all laboratory parameters improved, with significant changes in albumin and prothrombin (PT) (median pre/post-tenofovir: alanine aminotransferase 63/39; bilirubin 26/18; albumin 39/44, P = 0.028; PT 17.5/15, P = 0.018). All three patients with C-P-C -B or -C improved to C-P-C -A, which for one patient enabled removal from the liver transplant waiting list. Three patients lost HBeAG with two anti-HBe seroconversions. Median HBV DNA was suppressed to <35 copies/mi., Conclusions: This study demonstrates that tenofovir can produce HBV viral suppression, HBeAg seroconversion and improvement in markers of hepatic function in HIV/HBV-coinfected patients with cirrhosis. The potential reversal of end-stage liver disease may provide an important survival benefit in this population.

Background: The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood., Methods: Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively., Results: Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks)., Conclusions: Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each--to varying degrees--associated with various metabolic disturbances.

Objective: To compare three versions of the objective HIV-associated lipodystrophy (HIVLD) case definition (LDCD) and derived severity scale to spontaneous clinical LD assessment in adults initiating antiretroviral therapy., Design and Main Outcome Measures: The LDCD versions were the 'primary' LDCD [which includes dual-energy X-ray absorptiometry (DXA) and computerized tomography (CT)], a simpler 'central' LDCD that omits CT data, and a simpler but probably less accurate 'non-imaging' LDCD. Physician LD assessments were passively reported. Two of the 10 parameters in the primary LDCD were not collected and were imputed. Setting, participants and interventions: Retrospective analysis of a randomized, placebo-controlled, 144-week study of tenofovir DF or stavudine (d4T) in 600 antiretroviral-naive adults., Results: Central LDCD and clinical assessment diagnosed LD in 27% and 19% of d4T recipients at week 144, respectively (P < 0.001), and 3% and 3% of tenofovir DF recipients, respectively (P = 0.248). The central LDCD performed at least as well as the primary LDCD; both were more sensitive than the non-imaging model. There was poor concordance between clinical and LDCD-based diagnosis (kappa 0.02-0.20); most clinical cases did not fulfill any LDCD. Using the central LDCD, most LD was grade 1; 6% of d4T recipients and no tenofovir DF recipient had grade 3-4 LD at week 144 (P = 0.007). Independent risk factors for LD using the central LDCD were d4T, increasing age, female sex and higher baseline triglycerides, whereas clinical assessment consistently identified only d4T. The LDCD score was more sensitive than DXA for assessing LD severity., Conclusions: In this prospective study of a first antiretroviral regimen, the LDCD was more sensitive for LD diagnosis and identified more lipodystrophy risk factors than spontaneous clinical assessment or DXA, and also objectively quantified LD severity. The central LDCD should make objective LD assessment cheaper and simpler. Spontaneous clinical LD assessment of is of limited value, even in placebo-controlled trials.

Introduction: The use of HIV protease inhibitors (PIs) in a ritonavir (RTV)-boosted form is now common. However, randomized data comparing boosted with unboosted PI strategies are scarce., Methods: This randomized, open-label trial compared indinavir (IDV) 800 mg three times daily with IDV/RTV 800/100 mg twice daily, both given with zidovudine (AZT)/lamivudine (3TC) twice daily in individuals with at least 3 months previous AZT experience. The primary endpoint was the time-weighted average change in HIV RNA from baseline. Designed as a 48-week study, follow-up continued until week 112. Primary analysis is by intention to treat., Results: One hundred and three patients commenced therapy and are included in the analysis. Patients had a median of 29 months past nucleoside reverse transcriptase inhibitor (NRTI) exposure. Baseline median (interquartile range) log10 HIV RNA was 4.0 (3.3-4.5) and CD4+ T-cell count 166 (40-323) cells/microl. After 112-weeks of study there was no significant difference observed between arms in the mean (SD) change in time-weighted average HIV RNA from baseline (-1.6 [1.1] HIV RNA copies/week/ml three times daily arm; -1.4 [1.1] HIV RNA copies/week/ml twice daily arm; P = 0.3). Both arms were associated with substantial toxicity expressed as serious adverse events and study drug interruptions. The twice daily arm experienced greater dyslipidaemia. Mean (SD) changes in time-weighted CD4+ T-cell count from baseline were similar [88 (84) cells/week/microl three times daily arm; 70 [109] cells/week/microl twice daily arm; P = 0.3)., Conclusions: RTV-boosted IDV 800/100 mg twice daily demonstrated comparable efficacy to unboosted IDV 800 mg three times daily dosing. Both regimens were associated with substantial toxicity. Use of lower doses of RTV-boosted IDV may result in better tolerability without loss of efficacy and warrant further research.

In the majority of cases, HIV-associated lipodystrophy, lipoatrophy in particular, becomes clinically apparent only after months or years of continuous exposure to antiretroviral medications and, once developed, is difficult to reverse. Many lipid-related side effects of antiretroviral medications result from drug-induced changes in gene expression. As our understanding of the pathogenic mechanisms underlying HIV-associated lipodystrophy improves, it is important to be able to explore changes at a molecular level in order to fully elucidate the mechanisms whereby antiretroviral drugs exert their toxicities. Monitoring changes in gene expression in vivo may enable physicians to identify, predict or prevent drug toxicities early, before irreversible changes in body composition occur. However, monitoring changes in gene expression at a population level presents many methodological challenges that need to be addressed, over and above the considerable intra- and inter-individual variability inherent in the cellular expression of any gene. Careful collection and processing of adequate biological samples, robust laboratory processes and assays, and appropriate study design can help overcome many of these difficulties.

Objectives: In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels., Methods: Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations., Results: We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 +/- 2.66 mg/l, whereas in the control group the mean nevirapine concentration was 8.72 +/- 3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low (< 3.1 mg/l), while in the control group two patients had low nevirapine trough concentrations (P = 0.164). In the multivariate linear regression analysis, corrected for time after drug intake, the use of rifampin was significantly (P < 0.001) associated with lower nevirapine plasma concentrations, whereas higher BMI reached borderline significance (P = 0.065)., Conclusion: Although nevirapine plasma concentrations were 3.3 mg/l lower when co-administered with rifampin, still more than 86% of these patients had nevirapine plasma concentrations > 3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed.

Objective: To assess the efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir with two nucleoside reverse transcriptase inhibitors (NRTIs), as induction therapy before enrollment in a randomized trial of structured treatment interruption strategies., Design: Two-hundred antiretroviral-naive patients with CD4+ cell counts between 200-350 at screening were enrolled in this open-label 24week study., Methods: Patients were followed up every 8 weeks for CD4+ cells, HIV RNA, and clinical and laboratory toxicities., Results: Two-hundred patients were enrolled with median baseline CD4+ cell count of 267 cells/microl and HIV RNA 50 118 (4.7 log10) copies/mi. After 24 weeks of treatment, 191 of 200 (96%) patients had below 400 copies/ml HIV RNA, with 177/200 (89%) below 50 copies/ml (intent to treat, missing equals failure method), with a median rise in CD4+ cell count of 122 cells/microl. There was no significant correlation between the minimum concentration of saquinavir and HIV RNA reductions at week 8 (P = 0.957) or absolute HIV RNA at week 24 (P = 0.77)., Conclusion: First-line highly active antiretroviral therapy (HAART) with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy over 24 weeks, and should be evaluated in larger prospective randomized clinical trials.

Background: Antiretroviral therapy for HIV infection is commonly complicated by lipoatrophy, insulin resistance and dyslipidaemia. In HIV-uninfected adults with insulin resistance or type 2 diabetes, thiazolidinediones can lower blood pressure and improve both insulin sensitivity and endothelial function. This study sought to investigate the effects of rosiglitazone on endothelial function and other markers of cardiovascular risk in patients with HIV-related lipoatrophy., Methods: HIV-infected, lipoatrophic adults receiving antiretroviral therapy were randomized to receive either rosiglitazone 4 mg or matched placebo, twice daily. Percentage flow-mediated forearm arterial dilation (FMD%) was measured at weeks 0, 12, 24 and 48, together with other markers of vascular risk (blood pressure, lipids, glycaemic parameters, adiponectin and leptin)., Results: Out of 64 enrolled adults, 44 (69%) attended all visits (23 rosiglitazone, 21 placebo). Relative to placebo, at week 48, rosiglitazone decreased systolic blood pressure (8 mmHg, P=0.03), insulin (3 microIU/ml, P=0.02), insulin resistance (P=0.03) and leptin (0.6 ng/ml, P=0.02), whilst adiponectin was increased (3.3 microg/lml, P<0.0001). However, rosiglitazone increased total cholesterol (49.1 mg/dl, P=0.001), low-density lipoprotein cholesterol (23.5 mg/dl, P=0.01) and triglycerides (146 mg/dl, P=0.06). Mean baseline FMD% for the entire cohort was moderately impaired (4.5%). Compared with baseline, mean on-treatment FMD% increased by 0.8% with rosiglitazone and decreased by 0.3% with placebo, (mean difference 1.1%, 95% CI -0.2 to 2.5, P=0.09)., Conclusions: Rosiglitazone has minimal effect on flow-mediated dilation in HIV-infected lipoatrophic adults. However, despite worsening of the lipid profile, the overall effect of rosiglitazone on the cardiovascular risk profile in these subjects was positive.

Objective: The pharmacokinetics of 800 mg and 1200 mg of saquinavir soft-gel caps (SQV-SGC) twice daily plus 100 mg itraconazole once daily were compared to 1400 mg SQV-SGC twice daily without itraconazole., Methods: The pharmacokinetics of SQV were determined in 17 randomly selected patients on 1400 mg twice daily SQV-SGC without itraconazole and after 2 weeks with lower SQV-SGC doses plus itraconazole. SQV plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by a non-compartmental model., Results: Median (+IQR) area under plasma concentration-versus-time curve (AUC0-12h) were 3.33 (1.96-7.34), 4.29 (3.14-7.67) and 4.07 (2.76-4.49) mg/l x h for SQV 1400 mg without itraconazole, SQV 1200 mg with itraconazole and SQV 800 mg with itraconazole, respectively. These differences were not statistically significant. The median Cmin was above the proposed minimum effective concentration of 0.05 mg/l for all three regimens., Conclusion: SQV-SGC 800 mg or 1200 mg twice daily boosted with 100 mg of itraconazole once daily resulted in adequate SQV pharmacokinetics not significantly different from SQV-SGC 1400 mg twice daily.

The striking decline in HIV load with highly active antiretroviral combination therapy (HAART) is accompanied by substantial improvements in immune function, even in patients with more advanced disease. These include a general reduction in immune activation with increases in total CD4 and CD8 cell counts, memory and naive T cell subsets and antigen responses to certain opportunistic pathogens. At this time, it appears that HAART-induced improvements in function are limited to those T cells that have not yet been completely depleted by HIV. Long-term studies are needed to determine whether complete functional restoration of the repertoire is possible. Clinically, HAART improves survival and reduces progression of HIV disease. Some patients with active opportunistic disorders demonstrate complete or partial resolution of the infection or malignancy. However, persons with subclinical Mycobacterium avium complex or cytomegalovirus retinitis and those with chronic hepatitis B virus infection may sometimes experience acute flares if prophylactic therapy against the underlying disorder is not included in the regimen.