Impact of highly active antiretroviral therapy on incidenceand management of human immunodeficiency

virus-related opportunistic infections

Chien-Ching Hung1,2* and Shan-Chwen Chang1

1Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College

of Medicine; 2Department of Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan

We review the changes in incidences of HIV-related opportunistic infections and the safety of discon-tinuation of primary and secondary prophylaxis for HIV-related opportunistic infections in patientsachieving immune restoration after the introduction of highly active antiretroviral therapy (HAART).HIV-related opportunistic infections continue to occur in patients who are newly diagnosed with HIVinfection, those in the early course of HAART or non-adherent to HIV care and HAART, and those inwhom non-HIV-related infections have emerged as a significant cause of morbidity and mortality in thepost-HAART era. Clinical studies of patients with tuberculosis and HIV co-infection are reviewed toprovide appropriate regimen combinations of rifamycins and antiretrovirals, which have varyingdegrees of drug–drug interactions that have posed challenges in the management of tuberculosis aswell as HIV infection.

Keywords: HIV infection, AIDS, HAART, opportunistic infections, antimicrobial prophylaxis

Introduction

With the introduction of antimicrobial prophylaxis and highlyactive antiretroviral therapy (HAART), the morbidity andmortality of HIV-infected patients receiving HAART havedeclined,1,2 and the decline has been sustained.2 The incidencesof nearly all AIDS-defining opportunistic infections (OIs) havedecreased significantly.3 HAART has changed HIV infectionfrom a debilitating fatal disease to a chronic manageable disease.Discontinuation of primary and secondary prophylaxis againstseveral major AIDS-defining OIs has been recommended inpatients with immune restoration after HAART.4 However, HIV-related OIs and deaths continue to occur in patients newly diag-nosed with HIV infection, in those in the early course ofHAART, or in those non-adherent to HIV care and HAART,3,5 – 9

and non-HIV-related infections, such as sepsis and chronic viralhepatitis, have emerged as significant causes of death in thepost-HAART era.8,10,11 In addition, the complexity of drug–druginteractions between rifamycins and antiretrovirals has posedchallenges in the management of tuberculosis (TB) and HIV co-infection. Our objective was to review the impact of HAART onthe incidence and management of HIV-related OIs and to pro-vide appropriate antituberculous therapy containing rifamycinsand antiretroviral therapy combinations in patients with TB andHIV co-infection.

Bacterial infection

The proportion of recurrent bacterial pneumonia as an AIDS-defining OI of the respiratory tract appears to be stable orslightly in decline in the post-HAART era;9 Streptococcuspneumoniae remains the most common aetiological agent ofcommunity-acquired bacterial pneumonia, although in a largenumber of cases the aetiologies are unidentified despite the useof extensive testing.7 With wider use of HAART and antimicro-bial prophylaxis, the incidence of invasive pneumococcal diseaseamong HIV-infected persons has declined in the post-HAARTera.12 In a laboratory-based surveillance study conducted inSan Francisco,12 the quarterly incidence of invasive pneumococ-cal disease decreased from 10.6 cases per 1000 person-years(PY) in 1994 to 4.2 cases per 1000 PY in patients with AIDS in1997 (P = 0.004), with the most significant decrease occurringduring 1996–1997.

Whether pneumococcal vaccination can reduce the risk ofinvasive pneumococcal disease in HIV-infected patients remainscontroversial. In patients without HAART, vaccination with a23-valent polysaccharide pneumococcal vaccine in HIV-infectedUgandan adults showed an increase in the rate of pneumococcaldisease in vaccine recipients,13 whereas vaccination with a9-valent conjugate vaccine in HIV-infected and HIV-uninfectedchildren in South Africa showed reduced rates.14 Although

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*Correspondence address. Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road,Taipei, Taiwan. Tel: +886-2-23123456 ext. 8265; Fax: +886-2-23223905; E-mail: hcc0401@ha.mc.ntu.edu.tw

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Journal of Antimicrobial Chemotherapy (2004) 54, 849–853

DOI: 10.1093/jac/dkh438

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an observational study suggested that receipt of antiretroviraltherapy, especially HAART, and pneumococcal vaccinationwere associated with a decreased risk for pneumococcal dis-ease,15 more studies are needed to assess whether receipt ofHAART will enhance the serological response to pneumococcalvaccination and clinical benefit.

The incidence of HIV-associated community-acquired bacter-aemia has declined in the post-HAART era.16 In an Italian uni-versity hospital for HIV care, the incidence of HIV-associatedcommunity-acquired bacteraemia declined from six episodes per100 PY in 1994–1995 to 3.8 episodes per 100 PY in 1997–1998;16 the most evident reduction occurred for non-typhoidSalmonella, whereas the rate of S. pneumoniae bacteraemiaremained constant over the two study periods.16

Non-typhoid Salmonella bacteraemia is associated with ahigh recurrence rate in HIV-infected patients despite suppressivetherapy with ciprofloxacin in the pre-HAART era. Although theoptimal duration of suppressive therapy to prevent recurrencesof non-typhoid Salmonella bacteraemia remains unclear inpatients responding to HAART, it appears to be safe to discon-tinue ciprofloxacin 1 month after concurrent HAART.17

Fungal infection

The incidence of Pneumocystis jiroveci pneumonia [formerlyknown as P. carinii pneumonia (PCP)] has declined,1,3 and survi-val following severe PCP has improved in patients receivingHAART.18 In the patients receiving primary or secondary pro-phylaxis against pneumocystosis and responding to HAARTwith resultant increases of CD4 lymphocyte counts to >200cells/mm3 for more than 3 months, the risk for pneumocystosisis sufficiently low to warrant discontinuation of prophylaxis.19 – 21

However, pneumocystosis continues to be a leading cause ofcommunity-acquired pneumonia, resulting in mortality amongAIDS patients in the post-HAART era3,5 – 10 because of patientnon-adherence to antimicrobial prophylaxis and failure to useantiretroviral therapy.3,6

Surveillance studies in the USA and France have documentedthe significantly decreasing incidence of cryptococcosis in thepost-HAART era.22,23 In the Atlanta area, the incidence of cryp-tococcosis among patients with AIDS decreased from 66 casesper 1000 PY in 1992 to seven cases per 1000 PY in 2000,whereas in the Houston area, the incidence decreased from 23.6cases per 1000 person-years to 1.6 cases per 1000 PY.22 InFrance, the incidence of HIV-associated cryptococcosis hasdecreased by 46% during the post-HAART era.23 However,HIV-infected patients with limited access to HIV care continueto develop cryptococcosis in the post-HAART era with the sameincident mortality as seen earlier.22,23

Infections due to endemic fungi, such as Histoplasma capsu-latum,24 Coccidioides immitis25 and Penicillium marneffei,26

usually develop in patients at an advanced stage of HIV infec-tion, and relapse rates are high in those patients not receivingmaintenance antifungal prophylaxis. In case–control studies, useof antiretroviral therapy and antifungal prophylaxis has beenfound to be associated with a reduced risk, although the mor-tality did not improve in the patients who developed infectionsdue to endemic fungi.24,25

Studies supporting the discontinuation of maintenanceantifungal therapy are emerging in selected cases of

cryptococcosis27,28 and histoplasmosis.29 A multicentre study ofdiscontinuation of suppressive antifungal therapy with flu-conazole or itraconazole to prevent relapse of cryptococcal men-ingitis in patients receiving HAART demonstrated thatdiscontinuation of antifungal therapy when the CD4 countincreased to >_100 cells/mm3 was associated with a low risk ofrelapse, even in patients with detectable plasma viral load orcryptococcal antigenaemia.27 Similarly, discontinuation of main-tenance antifungal therapy was safe in patients with histoplasmo-sis who received at least 12 months of antifungal therapy and 6months of antiretroviral therapy and had negative blood cultures,urine and serum Histoplasma antigen <4.1 units and CD4 count>150 cells/mm3.29

Mycobacteriosis

TB and HIV infection may be mutually detrimental in patientswith co-infection; TB may accelerate the progression of HIVinfection and be associated with a higher mortality rate and ashorter survival, whereas HIV infection increases the risk fordevelopment of active TB and TB recurrence in patients withoutHAART. In patients with access to HAART and rifampicin-containing antituberculous therapy, the incidence, recurrence andmortality rate of TB appear to be declining and survival improv-ing.30 – 32 The use of HAART has been found to be associatedwith a >80% reduction in the risk of TB.30,31

In patients with TB and HIV co-infection, the optimal man-agement of these two diseases concurrently has been a challengeto HIV care providers, and the appropriate timing of initiation ofHAART is not clear because of a high pill burden, toxicity anddrug–drug interactions between rifamycins, protease inhibitorsand non-nucleoside reverse transcriptase inhibitors. A high pro-portion of patients have had to change their antiretroviral therapyor antituberculous therapy because of toxicity.33 For patientswith CD4 counts <100 cells/mm3, antiretroviral therapy shouldbe started early because delayed HAART in such TB patientsmay increase the risk for death or HIV progression;33 for patientswith higher CD4 counts, HAART may be delayed until the con-tinuation phase (after 2 months of antituberculous therapy), oruntil the end of antituberculous therapy.33

Rifampicin may interact pharmacokinetically with proteaseinhibitors, accelerating their metabolism through the inductionof P450 cytochrome oxidase (CYP 450), which may result insub-therapeutic serum levels of protease inhibitors. In addition,protease inhibitors retard the metabolism of rifabutin, resultingin increased serum levels of rifabutin and an increased likelihoodof drug toxicities. Rifabutin, with its lower induction capabilityof the CYP 450 enzyme, is recommended when combined withefavirenz or protease inhibitors (Table 1).34,35 Recently, clinicalstudies have demonstrated that combinations of efavirenz ornevirapine plus two nucleoside reverse transcriptase inhibitorswith rifampicin (10 mg/kg)-containing antituberculous therapyare good alternatives to HAART and antituberculous therapycombinations because of a lower pill burden and good clinicalefficacy (Table 1).36 – 40 In addition, once-daily HAART contain-ing efavirenz makes integration of directly observed therapy forTB and HIV infection possible.41

Disseminated infection due to non-tuberculous myco-bacteria occurs mostly in patients with CD4 lymphocyte counts<50 cells/mm3, with Mycobacterium avium complex (MAC)

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the most common aetiology. With the introduction of HAART,the incidence of disseminated MAC infection has declined,1,3

and the prognosis of patients with disseminated MAC infectionhas been significantly improved.42 In the Adult and AdolescentSpectrum of Disease (ASD) Project, the incidence of dissemi-nated MAC infection decreased from 10 cases per 100 PY in1992 to two cases per 100 PY in 1998.3 Studies have shown thatprimary prophylaxis can be safely discontinued in patients withan increase of CD4+ count to >100 cells/mm3.43,44 Although thestudy design might be different and criteria for discontinuationof secondary prophylaxis varied, the rate of relapse of dissemi-nated MAC infection was low in patients responding toHAART, with an increase in the CD4+ count to >100cells/mm3.28,45 – 47 Therefore, it has been recommended that sec-ondary prophylaxis can also be discontinued in asymptomaticpatients who complete a 12 month course of anti-MAC therapyand whose CD4+ cell count has been increased to >100cells/mm3 for at least 6 months.4

Viral infection

Reactivation of latent cytomegalovirus (CMV) infection inpatients with CD4 lymphocyte counts of <50 cells/mm3 isassociated with decreased survival, and the incidence and mor-tality rate of CMV disease have declined with HAART and anti-CMV therapy.1,3,48 Although there is no randomized study toassess the safety level of the CD4 count on discontinuation ofmaintenance anti-CMV therapy, clinical studies suggest that it issafe to discontinue secondary prophylaxis against CMV retinitisin patients with quiescent CMV retinitis who have sustained anincrease in CD4 counts in response to HAART.49,50

Progressive multifocal leucoencephalopathy (PML), a demye-linating disease of the central nervous system caused by thehuman polyomavirus JC virus, leading almost invariably todeath a median of 4–6 months after diagnosis, has been increas-ingly diagnosed as a result of HIV-induced immunosuppression.Although the effect of HAART on the incidence of AIDS-associ-ated PML remains to be studied, the use of HAART has beenshown to prolong survival, improve neurological function andreduce the size of active PML lesions on radiographicimages.51,52

Seroprevalence of co-infection with hepatitis B or C virusvaries with populations studied.53 – 56 Although chronic hepatitisB or C infection is not a classical AIDS-defining OI, it hasbeen considered an OI in HIV-infected patients because suchco-infection may be associated with higher risk for disease

progression and shorter survival.57 Risk for hepatotoxicity is alsosignificantly higher in patients with co-infection, which mayaffect the virological response to HAART.55,56 When survival ofHIV-infected patients is prolonged in the post-HAART era,hepatic complications due to chronic hepatitis B or C infectionhave emerged as an increasingly important cause of morbidityand mortality.8,10,11

Parasitic infections

Toxoplasma encephalitis (TE) is a life-threatening opportunisticinfection of the central nervous system in patients at advancedstage of HIV infection. The incidence of TE in HIV-infectedpatients may depend on geography and ethnicity, the degree ofimmunosuppression and use of antimicrobial prophylaxis, suchas trimethoprim/sulfamethoxazole and HAART. It is estimatedthat 20%–47% of the patients seropositive for Toxoplasmagondii in the pre-HAART era will ultimately develop TE. Therisk for TE has declined in HIV-infected patients who receivetrimethoprim/sulfamethoxazole prophylaxis and HAART withimmune restoration.3,58 In a French hospital-based surveillancestudy, the incidence of TE decreased from 3.9 per 100 PY in thepre-HAART era to 1.0 per 100 PY; among patients whose CD4cell counts increased to >200 cells/mm3 after HAART, theincidence decreased further to 0.1 per 100 PY.58 Although norandomized clinical trials have compared the safety of discon-tinuation of primary or secondary prophylaxis, many studieshave demonstrated that the occurrence of TE was rare afterdiscontinuation of primary and secondary prophylaxis againstpneumocystosis and TE in patients with restoration ofimmunity.19 – 21,28,46

Cryptosporidium parvum and microsporidia are the twocommon opportunistic parasites that cause chronic diarrhoea andwasting in HIV-infected patients with CD4 counts <100cells/mm3, and antimicrobial agents have limited efficacy inpreventing or eradicating infections with cryptosporidia ormicrosporidia among HIV-infected patients. Although studiesassessing the changes of incidence of cryptosporidiosis andmicrosporidiosis are lacking, diarrhoea due to microsporidia andcryptosporidia resolved spontaneously with immune restorationamong HIV-infected patients who responded to HAART.59,60

Conclusions

To conclude, sufficient clinical data have demonstrateda decline in the incidence of nearly all HIV-related OIs,

Table 1. Combinations of protease inhibitors and non-nucleoside reverse transcriptase inhibitors with rifampicin or rifabutin based on

clinical studies in HIV-infected patients with active tuberculosis

Indinavir Nelfinavir Efavirenz Nevirapine Saquinavir/ritonavir

Rifampicin not recommended not recommended efavirenz, 600–800 mgat bedtime rifampicin,10 mg/kg once daily36 – 39

nevirapine, 200–300 mgevery 12 h

rifampicin, 10 mg/kg40

saquinavir (400 mg)/ritonavir (400 mg),every 12 h

rifampicin, 10 mg/kg40

Rifabutin indinavir, 1000 mgevery 8 h

rifabutin, 150 mgonce daily34,39

nelfinavir, 1000–1250 mgevery 12 h

rifabutin, 150 mgonce daily34

efavirenz, 600 mg atbedtime rifabutin,600 mg twice weekly35

no data no data

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and discontinuation of primary or secondary prophylaxis forpneumocystosis, cryptococcal meningitis, histoplasmosis, disse-minated MAC infection, CMV retinitis and TE is safe amongHIV-infected patients responding to HAART. However, OIscontinue to occur in patients who seek HIV care late, have lim-ited access to HIV care or have poor compliance with antimicro-bial prophylaxis and HAART. Therefore, more effort is neededto provide easy access to HIV care services, expand the avail-ability of HAART and constantly reinforce patient adherence toantiretroviral and antimicrobial therapies.

Acknowledgements

We thank Dr Victor L. Yu, Section of Infectious Diseases,Veterans Affair Medical Center, Pittsburgh, for reviewing thismanuscript.

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