Permanent prophylaxis not needed?

Before the advent of highly active antiretroviral therapy (HAART), preventive drugs or prophylaxis were the way to reduce the risk of common opportunistic infections such as Pneumocystis pneumonia (PCP), toxoplasmosis, cytomegalovirus (CMV), herpes and Mycobacterium avium intracellulare (MAI). Particular opportunistic infections become a risk once a person's CD4 cell count fell below a certain point. For example, co-trimoxazole (Bactrim / Septrin) is prescribed to individuals with CD4 cell counts below 200 to 250 cells/mm³ to prevent PCP. Prophylaxis against key opportunistic infections is still recommended for people who have not sustained immune recovery while taking anti-HIV drugs.

However, most people do experience immune recovery on antiretroviral therapy. Can a person with a strong CD4 T-cell recovery stop taking prophylaxis without being at risk of opportunistic infections?

There is growing evidence that the answer is 'yes', although there is still a lack of evidence concerning some opportunistic infections.

American Public Health Service (PHS) guidelines published in November 2001 recommend that prophylaxis for some opportunistic infections such as PCP, CMV, MAI and Cryptococcus meningitis may be ceased in some situations. Key recommendations regarding cessation of prophylaxis are summarised below. For further details, see United States Public Health Service guidelines on prevention of opportunistic infections in Anti-HIV therapy: Guidelines. The current British HIV Association (BHIVA) guidelines do not deal with prophylaxis.

The American guidelines state that PCP prophylaxis can be stopped by people who have never had PCP if they have had a CD4 cell count above 200 cells/mm³ for over three months. There is considerable evidence that individuals who have previously had PCP may cease prophylaxis using the same criteria but this is not yet a sanctioned recommendation (Furrer 2000; Ledergerber 2001; Lopez 2001; Mussini 2000). An editorial in the leading medical journal the New England Journal of Medicine (NEJM) acknowledged in January 2001 that there is sufficient evidence to justify cessation of PCP prophylaxis following immune reconstitution, even among individuals who have previously had PCP. However, it cautioned that there is no need to hurry discontinuation of prophylaxis, pointing out that the median CD4 cell count in both studies was about 350 cells/mm³.

The American Public Health Guidelines allow for cessation of MAI prophylaxis under certain conditions (Aberg 2002; Kirk 2002; Shafran 2001). Prophylaxis can be stopped when the CD4 cell count has risen above 100 cells/mm³ for three to six months, although people who have had MAI must complete a full year of MAI treatment and be free of symptoms. If the CD4 cell count declines to less than 100 to 200 cells/mm³ prophylaxis should be re-started.

The guidelines recommend discontinuation of maintenance therapy for CMV when the CD4 cell count is above 100 to 150 cells/mm³ and there is no evidence of active disease. Regular eye examinations should be conducted and prophylaxis started again when the CD4 cell count is below 100 to 150 cells/mm³.

The guidelines also allow for discontinuation of maintenance therapy for Cryptococcus meningitis in people who have sustained a CD4 cell count above 100 to 200 cells/mm³ for over six months. Induction therapy must have been completed and the person must have no symptoms of cryptococcus. This recommendation is based on several studies (Aberg 2002b; Mussini 2002; Nwokolo 2001; Vibhagool 2002). One of these studies reported a relapse rate of nearly three per 100 patient-years, with all relapses being atypical forms of Cryptococcus (Mussini 2002).

There is an increasing body of research which suggests that stopping prophylaxis for other opportunistic infections, such as toxoplasmosis and histoplasmosis is also safe in people with sustained CD4 cell count rises and suppressed viral load. For instance, one study of 39 people with sustained immune recovery who had previously had histoplasmosis reported no instances of relapse when prophylaxis was stopped (Sued 2002). However, there is not enough evidence at the present time for guidelines to endorse cessation of prophylaxis for these infections.

As the above summary of the United States guidelines indicates, when a persons CD4 cell count falls to low levels again due to the failure of antiretroviral therapy, it is necessary to recommence prophylaxis for opportunistic infections because infections can recur.

Occasionally, people develop opportunistic infections at high CD4 cell counts after immune recovery. Episodes of CMV and PCP have been reported at relatively high CD4 cell counts in individuals who previously had severe immune damage (Furrer 1999; Johnson 2001; Komanduri 2001; Valentine 2000). For example, one person developed PCP with a CD4 cell count of 530 cells/mm³ and a viral load below 50 copies/ml. Tests have shown that these individuals have lost immunity to specific infectious agents, and that this specific immunity had not returned despite CD4 cell count increases. Thus it seems that a few people do have ongoing 'gaps' in their immune systems, despite immune recovery.

However, this is the exception rather than the rule, as demonstrated by numerous studies. For example, the large EuroSIDA study reported that opportunistic illnesses are not occurring at unusually high CD4 cell counts in people taking antiretroviral therapy (Weverling 1999).

Deciding to stop prophylaxis

In making a decision about prophylaxis, patients may consider a number of factors, including expert recommendations, study results, immune recovery, and the seriousness of particular infections. For infections which are treatable or not too serious if caught early, such as Candida (thrush), patients may feel comfortable with the idea of stopping prophylaxis. The decision to stop prophylaxis against more serious opportunistic infections may be more difficult if expert recommendations do not support this move.

For illnesses where there is a lack of evidence, recommendations remain that prophylaxis should be continued based on a person's lowest-ever CD4 cell count. However, it may be reasonable for a person to stop prophylaxis if he or she has sustained a CD4 increase above the threshold for prophylaxis for more than one year (Powderly 1998).

Patients may also want to consider viral load, and the likelihood of a decline in CD4 cell count before stopping prophylaxis. If a patient does decide to stop prophylaxis because responding well to antiretroviral therapy, but the anti-HIV regimen subsequently fails, it may be necessary to restart prophylaxis promptly even if the CD4 cell count is still relatively high. Failing antiretroviral therapy is associated with a poor clinical response to opportunistic infections such as CMV.

Research into stopping PCP prophylaxis

Zellweger studied the incidence of PCP after discontinuation of secondary prophylaxis (prophylaxis in people who have already had PCP) in 78 HIV-infected patients on antiretroviral combination therapy after they experienced a sustained increase in CD4 cell counts to at least 200 cells/mm³. Median CD4 cell count at discontinuation was 380 cells/mm³. After median follow-up of 40.2 months, yielding a total of 235 person-years of follow-up, no cases of recurrent PCP were reported.

Lopez Bernaldo de Quiros (2001) studied 474 people on antiretroviral therapy with CD4 counts above 200 for at least three months. The patients were all taking primary PCP prophylaxis (prophylaxis in people who have never had PCP before) and were randomised to cease or continue prophylaxis. The group had a median CD4 count of 342 and 38% had viral load above 500 copies although all were below 5000 copies. 121/474 participants had a previous CD4 count below 50 cells/mm³. At 20 months, no cases of PCP occurred among the group who ceased prophylaxis. 113 people on secondary prophylaxis after PCP diagnosis were also randomised to cease or continue prophylaxis after they had sustained a CD4 count above 200 for three months. 68% had had a previous CD4 count below 50. Over two years had passed since their PCP episode in 54% of cases. Median CD4 count was 355, 76% had undetectable viral load and 24% had viral loads between 500-5000 copies. At 12 months, no cases of PCP occurred among the 60 people who stopped prophylaxis.

Ledergerber (2001) studied 325 people on HAART from 8 prospective European cohort studies who ceased their secondary PCP prophylaxis between 1996-2000. All had CD4 counts above 200 when they stopped treatment and the median CD4 count was 350. Average lowest ever CD4 count was 50 in this group. During 13 months follow-up after cessation of PCP prophylaxis, no cases of PCP occurred. The rate of bacterial infections during follow-up was low at 2.7 per 100 person-years.

Abgrall (2001) reported on 69 individuals who stopped secondary PCP prophylaxis an average of 23 months after commencing HAART; nine individuals stopped prophylaxis with a CD4 cell count below 200 and PCP recurred in six cases, and a further nine cases recurred despite continued prophylaxis. No recurrence was observed after a mean follow up of 8.5 months in 51 individuals who stopped prophylaxis with CD4 cell counts above 200.

Kirk (1999) reported data from four Danish clinics which also provided encouraging evidence that people with sustained CD4 increases may cease prophylaxis. For example, only one case of PCP was reported among 125 people who stopped PCP prophylaxis. No cases of MAC, CMV or toxoplasmosis were reported either, although numbers were small.

Valentine (2000) presented data on 10 patients with viral loads below 50 for over 12 months and CD4 increases of over 150 (most had CD4 counts above 300). All had stopped prophylactic treatments and two developed OIs (PCP, CMV) at unusually high CD4 counts. The individuals who developed the OIs had no antigen-specific lymphocyte proliferative responses to PCP and CMV respectively.

Furrer (2000) reported 11-month follow-up of Swiss patients on HAART. Stopping PCP prophylaxis once the CD4 count has risen above 200 was found to be safe. Furrer (2000) also reported that no cases of PCP occurred among those at greater risk of PCP (low CD4 nadirs or detectable viral load). One case occurred in a person with a CD4 count of 530 and a viral load below 50. No cases of MAI occurred among 253 people who stopped MAI prophylaxis.

Furrer (1999) presented preliminary data on 55 people with a history of PCP who had sustained immune recovery due to HAART for at least 12 weeks. Median CD4 nadir was 23 which had risen to 394 when secondary PCP prophylaxis was interrupted. After 10 months of follow-up, no cases of PCP had occurred.

Mussini (2000 & 2003) randomised 124 people with immune recovery to cease or continue secondary PCP prophylaxis. No cases of PCP were reported after 8 months. After >2 years, 1 definitive and 1 presumptive case of PCP were observed, both of which occurred in patients who discontinued therapy.

Schneider (1999) reported on a prospective observational study in the Netherlands. Seventy eight people on HAART stopped PCP prophylaxis as soon as they had two CD4 counts (at least one month apart) above 200 cells. During prophylaxis, the lowest mean CD4 count had been 79 cells. At the time of stopping prophylaxis, mean CD4 was 347 cells and patients had been on HAART for a median of 9.8 months. Viral load was undetectable at the time of stopping in 61 patients. The group was followed for an average of 12.7 months since discontinuation, and there were no cases of PCP in this time.

Weverling (1999) published the Eurosida study of 562 HAART recipients who stopped preventive treatment for PCP a median of nineteen months after starting HAART. Of these, 483 were taking primary prophylaxis whilst the remaining 79 were taking secondary prophylaxis following an episode of PCP. The median nadir CD4 count in the primary prophylaxis group was 123 cells, and prophylaxis was stopped at a median count of 302 cells. Just a single case of PCP has been detected in this group. Whilst these data support the discontinuation of primary prophylaxis once HAART has restored CD4 count above 200 cells, it was concluded that the same could not yet be said of secondary prophylaxis, given the small numbers of patients in that group.

Koletar (2001) (ACTG 888) investigated discontinuation of PCP prophylaxis in 144 people who had had a previous CD4 count below 100 (group 1) and 125 people who had had previous PCP (group II). CD4 levels were above 200 when prophylaxis was discontinued. After 60 weeks follow-up of group I, and 38 weeks follow-up of group II, no cases of PCP occurred. Four people resumed prophylaxis when their CD4 counts fell below 200.

Research into stopping MAI prophylaxis

Aberg (2003) reported the results of ACTG 393, a non-randomised study of ceasing MAI prophylaxis after a minimum of one year of macrolide antibiotic treatment in patients who had received greater than 16 weeks of HAART and who had CD4 cell counts > 100 cells/mm³. 47/48 patients remained MAC-free after a median of 77 weeks, and one patient developed MAC osteomyelitis after 16 months off prophylaxis at a CD4 cell count of 244 cells/mm³.

Mussini (2002) reported a retrospective study of 56 individuals with a CD4 count below 100 who had been treated for cryptococcal infection. After a median of 29 months on HAART (range 2-62 months), maintenance therapy was stopped. Over a median follow-up time of 21 months (range 3-56 months), 3 people re-developed cryptococcal infection, all developing atypical forms. The overall relapse rate was 2.68 per 100 patient-years. In two relapsers, there was evidence of CD4 decline before cryptococcal disease recurred.

Aberg (2002b) reported that 6 individuals with CD4 counts over 150 stopped fluconazole treatment for cryptococcal meningitis. No relapses were reported.

Research into stopping other prophylaxis

Sued (2002) reported on 39 people with moderate to severe histoplasmosis who had sustained immune recovery due to long-term antiretroviral therapy. Median CD4 count at the time of ceasing prophylaxis was 266. After an average follow-up time of 20 months (range 1-52 months), no cases of relapse had occurred.

Vibhagool (2002) conducted a prospective, randomised study of 49 HIV-infected people with cryptococcal meningitis who had received fluconazole and AZT/3TC/efavirenz for 48 weeks. The 42 people who had sustained a CD4 count above 100 and a viral load below 400 copies/mL for at least 3 months were then randomised to cease or continue fluconazole. After an average of 12 weeks follow-up, all 20 randomised to cease maintenance therapy remained free of cryptococcal infection.

Mussini (2002) reported a retrospective study of 56 individuals with a CD4 count below 100 who had been treated for cryptococcal infection. After a median of 29 months on HAART (range 2-62 months), maintenance therapy was stopped. Over a median follow-up time of 21 months (range 3-56 months), 3 people re-developed cryptococcal infection, all developing atypical forms. The overall relapse rate was 2.68 per 100 patient-years. In two relapsers, there was evidence of CD4 decline before cryptococcal disease recurred.

Aberg (2002b) reported that 6 individuals with CD4 counts over 150 stopped fluconazole treatment for cryptococcal meningitis. No relapses were reported. Cryptococcal antigen was evaluated at weeks 8, 24, 40 and 56 after discontinuation, and no evidence of increase in antigen titre or recurrence of cryptococcosis was observed in any of the six patients despite a transient CD4 cell decline in one patient to 85 cells/mm³.

Nwokolo (2001) reported that 16 people stopped maintenance therapy for cryptococcus(average CD4 count 250, viral load undetectable in 10/16). No relapses occurred during 13.4 months of follow-up. 7 patients were positive for cryptococcal antigen when prophylaxis was stopped and 3 remained positive during follow-up.

Kirk (1999) reported an analysis of 358 patients in the EuroSIDA cohort who stopped prophylaxis for either toxoplasmosis, CMV, MAI or cryptococcosis. A total of 379 maintenance treatments (162 for CMV disease, 103 for MAC infection, 75 for toxoplasmosis, and 39 for cryptococcosis) were interrupted when the CD4 cell count rose above 100 cells/mm³. During 781 person-years of follow-up, five patients had relapse. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted when the CD4 lymphocyte count was less than 100 cells/mm³ or when only one recent measurement exceeded this value. Two relapses (one of CMV disease and one of MAC infection) occurred after 10 and 8 months off prophylaxis, respectively. One relapse (toxoplasmosis) was diagnosed after maintenance therapy interruption at a CD4 cell count above 200 cells/mm³ for more than 15 months.

Soriano (2000) conducted a retrospective review of 53 patients who had discontinued secondary prophylaxis after favourable responses to HAART. Secondary prophylaxis was discontinued if individuals had CD4+ cell count elevations above 100 cells/mm3 and plasma HIV-1 RNA below 500 copies/mL three months after commencing HAART. Individuals stopped secondary prophylaxis against pneumocystis carinii pneumonia (29), cerebral toxoplasmosis (9), MAC (7), cytomegalovirus retinitis (5), oesophageal candidiasis (5), visceral leishmaniasis (2), recurrent herpes zoster (2) and chronic herpes simplex (1). In some cases individuals stopped secondary prophylaxis against more than one opportunistic infection. After 18 months follow-up, five individuals were lost to follow-up, one died and two individuals were diagnosed with opportunistic infections (one case of tuberculosis and one case of PCP in a woman who had stopped HAART and suffered a subsequent CD4 decline to 46 cells/mm3 and a viral load of 500,000 HIV-1 RNA copies/mL). The mean CD4+ cell count amongst those stopped secondary prophylaxis was 289 cells/mm3 after 18 months.

Miro (2000) randomised 393 people with a prior CD4 count below 200 and positive for Toxoplasma gondii, who were on prophylaxis for toxoplasmosis to continue or cease prophylaxis. All had CD4 recovery above 200 (average 344) and viral loads below 5,000. After 12 months follow-up, no cases of toxoplasmosis were reported.

Gripshover (1998) reported that only two out of 20 people experienced recurrences of oral candidiasis (thrush) after they stopped prophylaxis with anti-fungal drugs. These twenty people had all had good responses to HAART regimens, with an average 134-cell increase in their CD4 counts and 14 had undetectable viral load. Prophylaxis against oral thrush is not usually given in the UK.

Perez (2000) reported an observational study of 19 people with a previous diagnosis of CMV eye disease who stopped CMV prophylaxis after a median of 40 months on antiretroviral therapy. At the time of stopping prophylaxis, the average CD4 count was 289 and all had viral loads below 50. After median follow-up of 17 months, no reactivation of CMV occurred.

Komanduri (2001) reported two cases of multiple CMV relapses despite successful immune reconstitution with HAART. One had a CD4 count over 400 after a nadir of 225 and the other had a CD4 count over 400 after a nadir of 12. Both had very low levels of CMV-specific T cells.

For more details on treatment and prophylaxis of opportunistic infections, see specific OI entries in the A to Z of illnesses.

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