OPPORTUNISTIC ILLNESSES |
Multiple studies have indicated improvements in outcome with protease inhibitor based
combinations including prospective comparative studies of indinavir and saquinavir
based triple therapy with two nucleoside analogues or addition of ritonavir to ongoing
therapy (although this is NOT the optimum way to use ritonavir). Trends for reduction
in morbidity and mortality at many units coincide with the availability of expanded
nucleoside analogue options such as d4T and 3TC and the appropriate use of protease
inhibitors in nucleoside analogue based regimens. |
There is ample evidence that the use of highly active antiretroviral therapy has dramatically
changed the epidemiology of opportunistic infections associated with HIV infection.
The decreased mortality from AIDS recently reported by the CDC (1) is clear evidence that the impact of opportunistic infections is lessening since these are the
main cause of AIDS-related death. Although the falling death rate cannot be directly
proven to be due to better antiretroviral therapy and other factors may be playing
a role, there is little doubt in most expert opinions that the better survival is due
primarily to the use of protease inhibitors. This is borne out by many reports of
decreased hospitalisation rates (2-3). Clinical trial data also support a benefit
in survival with better antiretroviral therapy and have shown significant decreased rates of
opportunistic infections (4-5) In the recently published ACTG 320 trial (5), for
example, the incidence of opportunistic events was halved in patients receiving ZDV,
3TC and indinavir compared with the already low rates seen in patients assigned to ZDV and
3TC without the protease inhibitor.
Of even greater interest is the growing anecdotal evidence that infections that were
previously impossible to treat such as cryptosporidiosis, azole-resistant thrush,
and PML can respond to the use of more active antiretroviral treatment without any
additional antimicrobial therapy (6-8). Furthermore, there have been other anecdotes that
suggest that there is recovery of the immune system in some patients who receive
suppressive antiretroviral therapy. CMV retinitis has had an almost inevitable progression
rate despite the use of available anti-CMV drugs. However, several groups have now
reported that the complete absence of CMV progression and the ability to stop specific
anti-CMV treatment in patients receiving more active antiretroviral treatment (9-11).
CMV
Torriani and colleagues in San Diego (10) reported on a group of 8 patients who had
stopped maintenance treatment for CMV retinitis. As maintenance treatment, 5 patients
had been using ganciclovir and three used intraocular injections of cidofovir. When
retinitis was diagnosed, at least half the group had a CD4+ count of 39 cells or higher
and a viral load of 21,878 copies/mL or higher. All 8 started effective antiretroviral
combination therapy after their retinitis treatment had begun.
Because this group agreed to stop treatment to keep their retinitis in check, they
have eye exams every two weeks with both wide angle photographs and dilated bilateral
fundoscopy, reviewed by an independent ophthalmologist. At least half the group
has been off treatment for 161 days (range = 103 to 558 days), with no progression of retinitis
or any sign of other CMV disease.
Although they are using effective antiretroviral combination therapy, only 4 of the
8 have a viral load below 400 copies/mL. Their median viral load is actually 40,738
copies/mL (higher than baseline) with a range of 399 - 430,000 copies/mL. Their
median CD4 count is 198, with a range of 44 to 507 cells.
This is a very small group and conclusions cannot be drawn from this report. However,
it is interesting to note that the retinitis has not returned, even though some of
the participants have a very high viral load and quite low CD4 counts.
Another research team from Spain reported similar findings in treating CMV retinitis.
Seven patients, whose average CD4 count was 56, were diagnosed with CMV retinitis
and treated with ganciclovir (6 patients) or foscarnet (1 patient). They started
effective antiretroviral combination therapy an average of 6.3 months after the retinitis
had been diagnosed. Before they started effective antiretroviral combination therapy,
five patients had experienced at least one relapse of retinitis. After about 3.5
months of effective antiretroviral combination therapy when all patients had CD4 counts
above 150 cells, viral loads below 500 copies/mL, and no evidence of CMV in their
blood, they stopped maintenance treatment for retinitis. After an average of 8 months
off CMV treatment, there has been no evidence of retinitis. When opportunistic infections
do occur, there is also evidence of at least a partial host response that was not
seen in previous years - e.g., the localisation of M. avium infection to lymph nodes
with evidence of granuloma formation on biopsy (12).
PCP
Schneider and colleagues reported on 50 patients using effective antiretroviral combination
therapy who had stopped their PCP prophylaxis. Forty-five of them had never had PCP
and had been using co-trimoxazole as primary prophylaxis. The other 5 had had PCP before and were using co-trimoxazole as secondary prophylaxis. Stopping prophylaxis
was allowed if a patient had 2 CD4 counts above 200 at least one month apart. When
they stopped taking co-trimoxazole, the group's average CD4 count was 370 cells,
and 40 patients had viral loads below 500 copies/mL. The other 10 patients had viral
load test results below 15,000 copies/mL. After an average of 6.4 months (range =
0.4 - 30.5 months) since stopping PCP prophylaxis, there have been no cases of PCP.(13)
All this evidence strongly suggests that at least in part, there is restoration of
host defences in patients who respond to the more effective combination antiretroviral
therapy. This should suggest that antimicrobial prophylaxis may be unnecessary in
such patients. However, the recently revised USPHS/IDSA guidelines for prophylaxis of
Opportunistic Infection in HIV-positive patients (14) takes a very conservative approach,
recommending that prophylaxis be based on the nadir of a patients CD4 count and that it should not be discontinued if the patient has suppression of viral replication
and a rise in CD4 counts. What is the basis for this, and is it correct?
These recommendations are based mainly on recently published observations by Connors
et al (14). The CD4+ T cell population is comprised mainly of two groups of cells
- memory cells (which have encountered a specific antigen and remain in circulation
to help deal with in the future) and naive cells, that are waiting for a new antigen. Naive
cells that encounter their pre-programmed antigen change phenotype and become memory
cells. The two groups of CD4+ cells can be distinguished by other surface markers.
The group from the NIH clinical centre showed that HIV disease progression is associated
with a preferential decline in naive CD4+ T cells. In addition, they suggested that
advanced HIV disease was characterised by specific disruptions in the CD4+ T cell
receptor repertoire with deletions of certain groups of cells. In their study, following
protease inhibitor therapy, naive CD4+ T cells increased only if they were present
before initiation of therapy. More importantly, antiviral- (or IL-2 therapy-) induced
increases in CD4+ T-cell counts led to only minor changes in previously disrupted
repertoires. Their conclusions were therefore that the rises in CD4 cells with potent
therapy were due to expansion of remaining T cells and that patients did not get
new naive cells indicating true reconstitution of the immune system. Thus, rises in CD4+
cells reflected only what was left after extensive damage by HIV leading to the conclusion
that patients would remain at risk for opportunistic pathogens if they had already
lost their immunity to them. Therefore continued prophylaxis would be needed.
There are important caveats to be noted about this work. Firstly, their conclusions
about the loss of specific repertoires of T cells and whether it could be reconstituted
are based on very small numbers of patients. The potency of the antiviral therapy
used is open to question. It appears that most patients received indinavir monotherapy
in these experiments, and while they reported at least 1 log drop in viral load,
the lower limit of detection they used was 10,000 copies so that it is possible that
the patients did not receive true highly active antiretroviral therapy. Finally, follow-up
assessment of the immune system was performed at 3 months after therapy, probably
too early to truly assess immune recovery.
A more optimistic picture can be gleaned from the report of Autran et al from Paris
(16). These investigators studied two groups of patients who received more clearly
potent treatment (ritonavir, ZDV and ddC, or ZDV, 3TC and indinavir) for one year.
Like Connors and colleagues they noted an early rise of memory CD4+ cells and with it a
reduction in T cell activation with improved CD4+ T cell reactivity to recall antigens.
However, with longer follow-up they saw a late rise of "naïve" CD4+ lymphocytes.
CD8+ T cells declined, and they observed evidence of return of in vitro responses to CMV
and M. tuberculosis antigens in 5/6 patients. The initial events (first few months
after initiation of therapy) suggest expansion or redistribution of existing cells
(memory more than naïve). However, later events suggest potential for true immune reconstitution.
Complete recovery may not be possible ( and may depend on degree of prior damage)
but may be sufficient to protect against most opportunistic infections.
This view is certainly very plausible in view of the growing anecdotal experience
and is supported by the evidence that HIV viral load is in itself an independent
predictor of the risk of opportunistic infection (17). It follows therefore that
reducing viral load (even without increasing CD4 count) should reduce the risk of infections.
This could be tested by examining some of the recent clinical trials. Some of the
patients in ACTG 320 did get opportunistic events. If our hypothesis is correct then
these should be mainly patients who, for whatever reason, did not have a significant drop
in viral load despite the more potent therapy. Hopefully, this data will be available
soon.
In conclusion we would predict that the rates of opportunistic infections will be
considerably less than previously, as a consequence of the new therapy, although
they will not disappear completely. The major predictor will be the ability to control
HIV replication, fulfilling the prediction that effective antiretroviral therapy will provide
the best prophylaxis for OIs (18). Prophylaxis will remain necessary in patients
who fail to have a sustained antiviral response, but it will be possible to discontinue prophylaxis in patients who have long-lived viral control. This is a testable hypothesis
that hopefully will be answered by ongoing clinical trials.
References
Centers for Disease Control and Prevention. Update: trends in AIDS incidence 1996.
MMWR Morb Mortal Wkly Rep, Sept 19, 1997; 46:861-867.
Torres RA, Barr M. Impact of combination therapy for HIV infection on inpatient census
N Engl J Med 336:1531-2, 1997
Goetz MB, Morreale A, Berman S,et al. Effect of highly active anti-retroviral therapy
(HAART) on outcomes in Veterans Affairs Medical Centers (VAMC). (abstract 218). Infectious
Diseases Society of America, 35th Annual Meeting, San Francisco, 1997.
Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing
regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 349:1413-21,
1997
Hammer S, Squires K, et al. A controlled trial of two nucleoside analogues plus indinavir
in persons with human immunodeficiency virus infection and CD4 cell counts of 200
cells per cubic millimeter or less. N Engl J Med 1997 337:725-733.
Mileno MD, Tashima K, Farrar D, Elliot B, Rich J, Flanigan TP. Resolution of AIDS-related
Opportunistic Infections with Addition of Protease Inhibitor Treatment. 4th National
Conference on Human Retroviruses and Related Infections. Washington, 1997.
Zingman BS. Resolution of refractory AIDS-related mucosal candidiasis after initiation
of didanosine plus saquinavir [letter]. N Engl J Med 1996; 334:1674-5.
Hoffmann C, Stellbrink HJ, Degen O, et al. Highly Active Antiretroviral Therapy Significantly
Improves the Prognosis of Patients with HIV-associated Progressive Multifocal Leukencephalopathy
(PML). (abstract 512). Infectious Diseases Society of America, 35th Annual Meeting, San Francisco, 1997.
Whitcup SM, Fortin E, Nussenblatt RB, Polis MA, Muccioli C, Belfort R Jr. Therapeutic
effect of combination antiretroviral therapy on cytomegalovirus retinitis [letter].
JAMA 1997; 277:1519-20.
Torriani FJ, Macdonald JC, Karevellas M, Freeman WR. Lack of Progression after Discontinuation
of Maintenance Therapy for Cytomegalovirus Retinitis in AIDS Patients Responding
to Highly Active Antiretroviral Therapy. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, American Society for Microbiology, 1997.
Tural C, Sirera G, Andreu D, et al. Long lasting remission of CMV retinitis without
maintenance therapy in HIV+ patients. [Abstract I-36] 37th ICAAC, 1997)
Race E, Adelson-Mitty J, Barlam T, Japour A. Focal Inflammatory Lymphadenitis and
Fever Following Initiation of Protease Inhibitor in Patients with Advanced HIV-1
Disease. 4th National Conference on Human Retroviruses and Related Infections. Washington,
1997.
Schneider MME, Borleffs JCC, Jaspers CAJJ, et al. Discontinuation of PCP prophylaxis
in HIV-infected patients with an increase of their CD4 counts due to aggressive antiretroviral
therapy. [Abstract LB-11] 37th ICAAC, 1997
USPHS/IDSA Prevention of Opportunistic Infections Working Group. 1997 USPHS/IDSA guidelines
for the prevention of opportunistic infections in persons infected with human immunodeficiency
virus. MMWR Morb Mortal Wkly Rep, June 27, 1997;46 (RR-12).
Connors M, Kovacs JA, Krevat S, et al. HIV infection induces changes in CD4+ T-cell
phenotype and depletions within the CD4+ T-cell repertoire that are not immediately
restored by antiviral or immune-based therapies. Nature Medicine 3:533-40, 1997
Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy
on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997;277:112-116.
Swindells S, Currier JS, Williams P. DACS 071: Correlation of Viral Load and Risk
for Opportunistic Infection. (Abstract 359). 4th National Conference on Human Retroviruses
and Related Infections. Washington, 1997.
Powderly WG. Prophylaxis for HIV-associated opportunistic infections: a work in progress.
(Editorial) Ann Intern Med 1996; 124:342-344.
Source: CATIE-NEWS & Heathcg.com
The Torriani study (10) is interesting in that CMV retinitis progression was halted
in this group even though HIV suppression was poor. The CD4+ response and perhaps
better processivity of antigens (seen with PI use) may have contributed to this effect.
Of concern however, is the durability of these effects if HIV replication is poorly
suppressed - CD4 decline is, perhaps inevitable, with a renewed risk of CMV progression.
Most physicians would be unhappy about the potential risk to these patients sight,
even with stringent opthalmological screening. The Spanish study patients (11) represent
a group that physicians may feel more comfortable with suspending prophylaxis and
observing - sustained CD4 elevations and undetectable viral load. The reduced risk
of OI's and ability to halt prophylaxis in those previously perceived to be at risk indicates
some degree of immune restoration in antiretroviral responders. However, studies
suggest that it is only after prolonged HIV suppression ( > 18 months) that naive
CD4+ cells begin to reconstitute with expansion of the immune repertoire in some patients. |
A New York-based research team has reported that intravenous gammaglobulin (IVIG)
can help prevent infections in AIDS patients. Dr. Lawrence Fontana of the Cabrini
Medical Centre and colleagues presented their data Monday at the 1997 International
Scientific Assembly of the American College of Chest Physicians in New Orleans, LA. The
team found IVIG to lower rates of infection in a group of 18 HIV-positive patients
with CD4 counts under 100 who received 40 milligrams per kilogram of IVIG once a
month for 18 months. There were 43 infections in the group which received IVIG, compared to
178 infections among patients in the control group. The researchers concluded that
prophylactic administration of IVIG may reduce morbidity, improve patient survival,
and reduce health care expenses for HIV-infected patients.
Source: AIDS Daily Summaries
Hoffmann-La Roche announced it will expand the valganciclovir (ganciclovir prodrug)
investigational study WV15376 for the treatment of CMV retinitis, The trial is designed
to examine the safety and efficacy of the investigational drug valganciclovir in
people with AIDS who are newly diagnosed with CMV retinitis. New clinical trial sites
will be added in the United States, Canada, Europe and Latin America.
Hoffmann-La Roche will also initiate a safety study designed to collect data in patients
who have previously received treatment for CMV retinitis. The study will run concurrently
with WV15376. "We are committed to the development of valganciclovir and are optimistic that it will be a significant improvement in the management of patients
with CMV retinitis," said Dr. Eddy Anglade, medical director, Hoffmann-La Roche.
Data presented at the 1997 Conference on Retroviruses and Opportunistic Infections
demonstrated that once-daily oral dosing of valganciclovir achieved plasma exposures
of drug comparable with those achieved with ganciclovir-IV at the induction dose
of 10 mg/kg/day. Trial Design Study WV15376 is designed to examine the safety and efficacy
of the standard CMV retinitis therapy, IV ganciclovir, compared to the investigational
oral compound, valganciclovir. Patients will be randomised to receive either IV
ganciclovir 5 mg/kg BID for 21 days followed by IV ganciclovir 5 mg/kg QD for 7 days
or valganciclovir 900 mg BID for 21 days followed by valganciclovir 900 mg QD for
7 days. At the end of the study period, each subject will be offered the opportunity
to continue treatment on valganciclovir 900 mg once-a-day as maintenance therapy.
Hoffmann-La Roche had previously announced in May of this year that the further development
of valganciclovir had been suspended. This was due to concern over the falling incidence
of CMV with the use of protease inhibitor containing regimens and the expense of continuing development of this drug in the face of a shrinking market (see ATP's
Doctor Fax issue 22). The reinstatement of the clinical programme for the development
of valganciclovir followed widespread condemnation of Hoffmann-La Roche by treatment activists over what they believed was the pharmaceutical companies short-sighted
approach to this promising drug. |
Researchers from the Bristol Royal Infirmary in the United Kingdom report a local
outbreak of 27 cases of early infectious syphilis in a letter to the editor of the
Oct. 11 issue of the Lancet. While a July 19 article in the Lancet detailed syphilis
epidemics emerging in Russia, England has had low levels of early infectious syphilis for
more than a decade. Although reports of syphilis in people who have travelled from
the United Kingdom to Russia have increased, none of the 27 infected individuals
in Bristol had been to Russia or Eastern Europe--with the possible exception of two cases
which could not be confirmed. Before the outbreak in Bristol, only two cases of
early syphilis had been reported to the clinic in three years, but the current outbreak
has continued with six more cases since the clinic made its recent report to the Communicable
Disease Surveillance Centre. According to the authors, the outbreak clearly shows
that syphilis is capable of spreading even within a socioeconomically stable country, and the disease's progressing complications and potential to factor into HIV-1
transmission make increased surveillance a necessity.
Ref: Lancet (10/11/97) Vol. 350, No. 9084, P. 1100; Battu, Vijay R.; Horner, Patrick
J.; Taylor, Patrick K.; et al.
Source: AIDS Daily Summaries
DRUG INTERACTIONS |
Musey et al. stated "Our findings indicate that higher frequencies of HIV-1 Env-specific
and to a lesser extent Gag-specific cytotoxic T lymphocytes correlate with lower
levels of plasma HIV-1 RNA and peripheral-blood mononuclear-cell-associated infectious virus." and concluded that... "In early HIV-1 infection, the induction of memory
cytotoxic T lymphocytes, particularly those specific for Env, helps control viral
replication and is associated with slower declines in CD4+ cell counts. Host cytolytic
effect responses appear to delay the progression of HIV-1 disease." Although the magnitude
of |