5th Conference on Retroviruses and Opportunistic Infections |
Hydroxyurea represents a novel approach to the suppression of HIV replication, which
is now being considered with increasing interest particularly in salvage or eradication
strategies. The mechanism of action of is thought to be cellular. Hydroxyurea lowers the levels of the cellular competitor of ddI (dATP) thus favouring the incorporation
of ddI. Although the combination of ddI and hydroxyurea is unable to prevent the
emergence of mutants conferring resistance to ddI the resistant virus remains sensitive
to ddI in the presence of hydroxyurea. It may also act favourably on the intracellular
kinetics of other nucleoside analogues besides ddI, and may also have a role in the
reversal of impaired phosphorylation, which may be a result of long-term NA use.
ATP's DocFax Issues 16, 30 and 32 contain previous reports on hydroxyurea.
Fuelled by numerous prior reports of efficacy, as well as a treating community searching
for new options in patients who have failed existing regimens, hydroxyurea (Hydrea )
has become a part of many anti-HIV regimens.
Several of the studies presented have unique features--including reports of hydroxyurea
compared with a placebo, hydroxyurea in a protease-containing combination, and hydroxyureas
potential salutary effects on the immune system.
Hydroxyurea has been available in the U.S. for more than 30 years, and has been FDA-approved
for the treatment of certain types of leukaemia (and more recently, sickle cell disease
as well). It is similarly licensed in Europe for the same indications. Its purported mechanisms of action--both in leukaemia and in HIV disease--have been extensively
published elsewhere and an excellent review appeared in the March 1997 Bulletin of
Experimental Treatments for AIDS [1].
It was at the 1st National Retroviral Conference, held in December 1993, that a team
from the Research Institute for Genetic and Human Therapy in Europe described that
hydroxyurea inhibited HIV replication in peripheral blood mononuclear cells and macrophages [2]. In the presence of ddI, synergy was observed to occur as well. Over the ensuing
years, at least four human clinical trials were held, using hydroxyurea in addition
to ddI and/or d4T. These were generally open label trials, and as results of increased viral load suppression and/or increased CD4+ T-cell counts with little toxicity
were publicised, many clinicians began to prescribe this relatively inexpensive drug
for patients with HIV. The usually prescribed dose in this setting is 500 mg twice
daily.
Its purported efficacy lies in its ability to suppress nucleoside triphosphate production
by inhibiting the enzyme ribonucleotide reductase. This leaves fewer deoxyribonucleotides
(DNA building blocks) available, causing greater amounts of nucleoside analogue medications to be incorporated into DNA.
In addition, since the target of this drug is a human cellular enzyme, and not an
HIV-specific enzyme, there should be less chance for resistance to occur as it does
with reverse transcriptase or protease inhibitors. Further studies have led to postulation of immune boosting effects as well, such as reducing activated CD8+ T-cells and facilitating
apoptosis of HIV-infected cells.
At Wednesday's poster session devoted to this unique potential HIV treatment, Rossero
et al
reported on 31 antiretroviral-experienced patients (prior monotherapy experience:
15 ZDV, seven ddI) with mean viral load of 105,700 copies/mL and mean CD4+ T-cell
count of 231 cells/mm3 [3].
They were all placed on hydroxyurea as a single daily
1000 mg dosage, in addition to ddI 200 mg twice daily and d4T 40 mg twice daily.
For the 14 patients evaluable at 12 weeks, the mean decline in viral load was 1.3
log. At 16 weeks, 8 of 11 patients had undetectable viral load readings of < 500
copies/mL. Concurrently the CD4+ T-cell count increased by approximately 80 cells/mm3 for 12 patients at 16 weeks of therapy.
Although the sample size was small, those patients with prior ddI monotherapy had
a more rapid early decline in viral RNA. Neutropaenia to absolute neutrophil count
< 700 cells/ L developed in four patients who had started the study with ANC levels
of <1,700 cells/ L. The neutropaenia reversed in all upon cessation of hydroxyurea administration.
In addition, two patients developed peripheral neuropathy and two had elevated pancreatic
enzymes, which are known side effects of the two nucleoside analogues used. A decline of 1.3 log is not uncommon with two nucleoside analogues.
An abstract from the Swiss HIV Cohort Study looked at comparing hydroxyurea 500 mg
BID vs. placebo in 144 subjects, all of whom also received ddI 200 mg BID plus d4T
40 mg BID. Three-quarters of the group were antiretroviral-naive, and the mean viral
load at study onset was approximately 30,000-copies/mL [4].
Results were recorded as follows:
| 12-Week Values | Hydroxyurea | Placebo | p-value |
| Viral load < 200 copies/mL | 39/72 (54%) | 20/72 (28%) | <0.001 |
| Viral load < 20 copies/mL | 14/72 (19%) | 6/72 ( 8%) | 0.05 |
| Mean decline in HIV RNA | -2.3 log | -1.7 log | 0.001 |
| Mean rise in CD4+ T-cells | +28/mm3 | +107/mm3 | 0.001 |
Another study of hydroxyurea was presented by Galpin et al
[5]. They studied 42 patients, stratified randomly into one of three groups--hydroxyurea
(500 mg b.d.), hydroxyurea + ddI (200 mg b.d.), or hydroxyurea + ddI + d4T (40 mg
b.d.). There was a wide range of initial CD4+ T-cell counts (9-994 cells/mm3), and initial viral load was >40,000 copies/mL. Also, 55% of the subjects had already
been treated with ZDV, ddI and/or d4T.
A 28-week analysis--in which only a mean value was displayed for the entire HU receiving
cohort for the different parameters measured--showed a statistically significant
decline in viral load (p<0.002) and an increase in mean CD4% of 5.1% (p<0.0001).
The authors state there was a trend in the triple therapy regimen being superior to the
other two in viral load suppression (but this data was not shown in the poster).
The regimen here was well-tolerated, although two patients required dose reduction
for neutropenia.
Another poster, which was presented by the same group as the previous, focused on
the immune response rather than the virological result for the same study group.
Since HIV infection is characterised by a progressive loss of naive, programmed (memory),
and long-term memory cells, the authors asked if effective viral suppression could reverse
these trends [6]. An interim analysis at week 20 showed a statistically significant
increase of both naive and long-term memory lymphocytes. The increases appeared to
be occurring regardless of whether the viral load was >500 copies/mL or less than that
value.
In what might be the first controlled study involving hydroxyurea with a reverse transcriptase
inhibitor and a protease inhibitor
, Lori et al
described eight patients with relatively recent HIV infection (mean duration 13 months)
who were placed on hydroxyurea 300 or 400 mg t.i.d.
plus ddI 200 mg b.d. and indinavir 800 mg q8h [7].
These were compared to a control group of eight patients with comparable HIV infection
that was not treated. After an average treatment period of five months, all members
in the treated group achieved undetectable viral loads (average starting value had
been 494,000 copies/mL) and a statistically significant rise in CD4+ T-cell count of
116 cells/mm3 (starting value 448 cells/mm3). Immune system parameters which were measured all showed significant improvement
in the treated group as compared to the control: Treated patients had higher CD3-zeta
expression--a correlate of T-cell function (p=0.0043), more naive CD4+ and CD8+ lymphocytes (p=0.02), and fewer activated CD8+CD38+ (p=0.004) lymphocytes.
In the late-breaker session which took place on the last day of the conference Lori
et al presented data on patients treated with a protease inhibitor (indinavir), ddI
and hydroxyurea during early stages of HIV-infection (before seroconversion) [8].
This appears to be a later analysis of the same patients presented in the poster session
[7].
24 patients were treated with this combination. Mean baseline viral load was 455,700
copies/mL and mean CD4 was 499 cells/mL. Average length of treatment with this combination
was 11.3 months but some individuals were out to 21 months.
Results presented included 24/24 study subjects achieving <500 copies/mL on plasma
bDNA viral load testing, 7/8 patients who underwent lymph node biopsy were HIV-RNA
undetectable in lymph tissue, 2/6 of these were also HIV-DNA undetectable in lymph
nodes. Average increase in CD4 count in the 24 patients was 168 cells/mL. Siliciano carried
out tests on 3 patients who had been found to be lymph node HIV-RNA undetectable.
On initial testing by his lab 2/3 did not express latent HIV. On increasing the sensitivity of the test to include a sample of 60 million cells, however, HIV was recovered
in these 2 patients at a frequency of less than 1 cell per 10 million.
Detailed investigation was carried out on one patient who had interrupted therapy
twice, and finally suspended therapy. The initial interruption occurred during day
39-42 of the study when plasma viral load was seen to rebound. A second interruption
occurred at day 141-157 with no rebound in plasma viral load. Finally, treatment was suspended
at day 187 with no viral load rebound out to the date of presentation (460 days).
Written by Paul Blanchard and adapted from an article by Mark Katz, M.D. healthcg.com.
These studies add to the pool of data that hydroxyurea (HU) may play some role in
HIV treatment, but it has yet to be validated in a large double-blind placebo-controlled
randomised human clinical trial. The fact that it is already an approved drug, along
with the advocacy of persons with HIV as well as their providers--in an era where
failure of existing regimens and the threat of widespread resistance looms wider
than ever--indicates such a study might not be done. |
|
OPPORTUNISTIC INFECTIONS
|
The impact of highly active antiretroviral therapy (HAART) on progression of HIV disease
and mortality remains extremely impressive. Earlier reports on the effect of HAART
on rates of opportunistic infections, suggesting dramatic reductions, have been updated by a number of groups at the 5th Conference on Retroviruses and Opportunistic Infections. The overwhelming message
from these reports is that the early, suggestive trends in OI incidence are continuing,
with the extraordinary declines persisting over time.
The full impact of HAART on the incidence and prevalence of AIDS-related OIs did not
begin to become clear until early last year at the 4th Retrovirus Conference, later that spring with the release of the results of ACTG
320 [1], and then more fully in fall 1997 at the 35th annual meeting of the Infectious Diseases Society of America (IDSA) and the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) [2]. At
this year's conference, not only is the continued decrease in AIDS-OIs evident, but
new data are presented on prognostic factors for developing OIs. In addition, new
information has finally emerged on the development of OIs in those patients failing HAART.
Michaels, Clark and Kissinger from Tulane, in conjunction with the Adult Spectrum
of Disease Cohort (ASDC), conducted a retrospective cohort study of HIV-positive
individuals (CD4+ count <200 cells/mm3) attending a large HIV outpatient clinic in New Orleans from December 1, 1994 to
January 1, 1998 [3]. Baseline characteristics grouped 1,181 patients before 1996
and 1,248 patients after 1996. The incidence of Pneumocystis carinii
pneumonia (PCP), cytomegalovirus (CMV), Mycobacterium avium
complex (MAC), Kaposi's sarcoma (KS) and wasting were markedly lower in the latter
two years. Below is the incidence rate of the ten most common OIs.
|
1/1/94 to 1/1/96 (N=1,181) |
1/1/96 to 1/1/98 (N=1,284) | p-value | |
| PCP | 18.0% | 11.7% | <0.01 |
| Wasting | 9.5% | 4.8% | <0.01 |
| MAC | 8.5% | 6.1% | <0.05 |
| CMV | 4.6% | 3.0% | <0.05 |
| Kaposi's Sarcoma | 4.3% | 2.5% | <0.05 |
| Toxoplasmosis | 2.9% | 1.9% | NS |
| Dementia | 3.8% | 2.8% | NS |
| Oesophageal candidiasis | 9.5% | 8.0% | NS |
| Cryptococcal meningitis | 3.3% | 2.7% | NS |
| Cryptosporidiosis | 3.8% | 3.2% | NS |
The decreases in OIs are at least in part a testament to HAART's direct antiretroviral
effect and ensuing improvements in cell-mediated immunity, yet the decrease is also
likely to be in part due to the use of MAC and PCP prophylaxis, and other preventive
interventions. In this study, the rate of PCP, MAC and CMV and Candida
prophylaxis was not provided.
Moore and colleagues in their Johns Hopkins cohort [4] also documented this decrease
in OIs since the advent of HAART. Between January 1993 and January 1997, 1,457 patients
with CD4+ counts <200 cells/mm3 (median = 81 cells/mm3) who received longitudinal primary HIV care at the Johns Hopkins HIV clinic were
assessed for the incidence rates of OIs. Combination antiretroviral therapy was used
in 85% of patients between 1996-97 (422 patients [~63%] received a PI) and in 9%
between 1993-95 (<1% PI use).
| CMV end-organ disease | .21 (.09, .49) |
| Cryptosporidiosis | .26 (.03, 1.1) |
| Toxoplasmosis | .27 (.08, .88) |
| Disseminated MAI | .51 (.31, .85) |
| PCP | .57 (.36, .91) |
| AIDS dementia | .57 (.35, .93) |
| Bacterial pneumonia | .42 (.29, .61) |
The reduction in the incidence of OIs was associated with combination therapy that
included a PI as well as higher CD4+ cell counts and lower HIV-1 RNA levels. Even
though many are questioning the functionality of newly acquired CD4 cells while on
HAART, no patient thus far on combination therapy has developed an OI with a CD4+ count >200
cells/mm3, and only one patient (with dMAC) developed an OI with >100 cells/mm3. Nonetheless, the authors contend that continuing longitudinal follow-up is necessary
to determine whether this improvement in disease progression is maintained.
On the West Coast of the US, this continued trend in the reduction of OIs was detailed
by Holtzer and colleagues from their San Francisco General Hospital (SFGH) cohort
[5]. New cases of OIs at SFGH were calculated according to the year and its quarters.
In 1995 1.7% were on a PI as compared to 43% in 1996 and 73.3% in 1997. From 1994 to
the end of 1997, the decreases of PCP, CMV retinitis, dMAC, and cryptococcal meningitis
were -71.4%, -93.8%, -83.6%, and 63%, respectively. The most substantial decrease
was seen in CMV retinitis: 48 cases were recorded in 1994 and only three cases in 1997.
While OI data was not provided on those patients who failed HAART, the authors contend
that they had expected to witness a rebound in some OIs since ~53% of SFGH patients
have been known to fail HAART virologically. They conclude with an appropriate and
timely question, "What is the meaning of clinical and virologic failure to HAART?" (see DocFax 40 - Virological Failure & Salvage Regimens
)
It is quite possible that there will be some increases in the incidence of OIs once
patients have failed more than one HAART regimen. Even though no one wants this to
happen, we much simply watch and wait.
To underscore HAART's direct antiviral effect on OIs and survival, Robert Murphy and
colleagues from CPCRA 034/ACTG 277 conducted a detailed analysis of OI risk based
on the antiviral regimens used in their 1,057-patient PCP prophylaxis study conducted
between October 1994 and April 1997 [6]. The median CD4+ count in this cohort was 60
cells/mm3 and 49% of the patients had had a prior AIDS-defining OI upon entering the study.
Within the median follow-up of 24 months, none were on a protease inhibitor (PI )
at baseline, 9% were on a PI by 12 months and 72% were on a PI containing regimen
by 24 months. During the entire study, 668 patients developed a new or recurrent OI: 64 per
100 person-years in the first 12 months compared to 34 per 100 person- years in the
later 12 month.
The relative risk analysis below shows OI event risk for patients on a PI containing
regimen compared to 0, 1, or 2 nucleoside analogues.
| Event | N= | PI : 2NRTIs RR (p=) | PI : 1NRTI RR (p=) | PI : none RR (p=) |
| PCP | 257 | > .88 (0.49) | .62 (0.01) | .55 (<0.001) |
| MAC | 108 | .40 (0.001) | .29 (<0.001) | .28 (<0.001) |
| CMV | 146 | .90 (0.65) | .66 (0.08) | .74 (0.09) |
| Death | 440 | .22 (<0.001) | .09 (<0.001) | .07 (<0.001) |
| All | 668 | .74 (<0.0001) | .44 (<0.0001) | 40 (<0.0001) |
Huang and colleagues conducted a thorough and elegant analysis of PCP cases diagnosed
between 1990 and 1997 at SFGH which detailed; 1) the annual number of cases documented
each year, 2) the proportion of those receiving PCP prophylaxis 3) the occurrence of PCP developing in patients on antiretroviral therapy whose CD4+ counts rose
>200 cells/mm3; and 4) the adherence to PCP prophylaxis.
As expected, the number of PCP cases significantly dropped during the eight years:
| Year | 1990 | 1991 | 1992 | 1993 | 1994 | 1995 | 1996 | 1997 |
| PCP Cases | 199 | 260 | 290 | 243 | 224 | 163 | 119 | 63 |
Data on PCP prophylaxis were available for 162 of the 182 cases of PCP since January
1996. Of these 162 patients, 55.6% reported no prophylaxis use and 20.5% reported
non-adherence to their prescribed regimen. This is not surprising since 24.1% did
not know their HIV sero-status, and 56% had no regular medical care before arriving at SFGH.
None of the five patients with a CD4+ count >200 cell/mm3 within six months of PCP diagnosis had either a previous documented CD4 count <200
cells/mm3 or had received antiretroviral therapy at time of diagnosis.
This study amply documents that PCP cases continued to decline in the 1990s because
of effective PCP prophylaxis regimens and potent antiretroviral therapy. Most importantly,
PCP develops in individuals not on prophylaxis (usually because they are not aware of their HIV sero-status) and in those who are non-adherent to their PCP prophylaxis.
Authors: Richard Chaisson, M.D., William Bishai, M.D., Ph.D., and Michael Marco.
Source: healthcg.com
Clearly these data reinforce the positive impact that PI containing regimens are having
on the incidence (and cost) of HIV-related illness. The additional advantage, in
avoiding sickness, of PI regimens over double nucleoside analogue combinations is
also clearly revealed. With regard to PCP, a concerted effort appears to be needed to persuade
individuals in HIV-high risk populations to seek anonymous and confidential HIV testing
so that they have the opportunity to stave off PCP with prophylaxis. |
Lyles and colleagues for the Multicenter AIDS Cohort Study (MACS) presented data collected
on 734 men with HIV/AIDS studied prior to July 1988 [Abstract 256]. The goal of the
study was to identify predictors of OI development among patients not receiving HAART, PCP, or MAC prophylaxis. Banked blood specimens were tested for CD4+ cell counts
and HIV RNA, and the endpoints were the development of PCP, MAC, or CMV.
Somewhat surprisingly, the study found that after adjusting for age and a prior diagnosis
of AIDS, only low CD4+ cell counts (CD4+ < 200 cells/mm3) and not elevated HIV RNA viral loads
were predictive of the development of CMV end organ disease. For PCP and MAC, having
either low CD4+ cell counts or an elevated HIV RNA viral loads (> 60,000) was predictive
of OI development.
It has been known for some time that tuberculosis (TB) is an immunosuppressive infection
and that patients with TB/HIV coinfections sustain accelerations of both diseases
by poorly understood mechanisms. However, it has been thought that following treatment, the negative synergy would be halted.
Research headed by Lynn Morris of the National Institute for Virology in Johannesburg,
South Africa indicates that TB may accelerate the progression of HIV even after
adequate treatment for TB [Abstract 259]. By following CD4+ cell counts and HIV RNA
levels in 115 African TB/HIV patients during their six month course of therapy for
TB (the patients received no antiretroviral therapy), Dr. Morris observed persistent
elevation of the HIV viral load at levels above 100,000 copies/mL throughout the six
months study. Viral loads increased in the first month of treatment for TB, then
fell by Month 3. Overall, however, the viral loads measured throughout treatment
did not differ significantly. In contrast CD4+ cell counts increased from approximately 160 cells/mm3 at the start of therapy to 271 cells/mm3 at six months. Morris and colleagues also reported the CD38+/CD8+ cells were highly
prevalent (>90% 0f CD8+ cells), indicating persistent immune activation. Serum levels
of IL-6 declined significantly during the study, however. These data suggest that
TB is associated with prolonged immune activation that results in persistently elevated
HIV viral load.
CMV - Progressive development of drug resistance in patients receiving chronic monotherapy
The prevalence and incidence of resistance to anti-CMV drugs was assessed in this
study of 122 CMV patients with newly diagnosed CMV retinitis. Dr. Douglas Jabs of
the Johns Hopkins School of Medicine was able to monitor the development of drug
resistant forms of CMV for up to 12 months [Abstract 262].
As seen in the table below, the probability of acquiring drug resistant CMV reaches
30-40% 9-12 months after beginning therapy. Cidofovir resistance seemed to occur
early in the course of therapy, jumping from 7 to 29% over the first three months
and reaching 100% probability of drug resistance by the last quartile of the year.
| Months of Treatment | 0 | 3 | 6 | 9 | > 12 |
| Ganciclovir | 3% | 7% | 12% | 27% | 27% |
| Foscarnet | 3% | 9% | 26% | 37% | 37% |
| Cidofovir | 7% | 29% | 29% | 29% | 100% |
These observations indicate that new drugs and combinations of anti-CMV therapy will
be important in preventing drug resistance and treatment failure.
A study presented by Dr. B. Anduze-Faris from Paris indicates that combinations of
foscarnet and ganciclovir therapy for patients with CMV encephalitis or myelitis
are helpful in about 74% of patients [Abstract 263]. The study involved 31 AIDS patients:
17 with CMV encephalitis and 14 with CMV myelitis. Patients were given the following
regimen:
The median duration of acute therapy was 41 days with 26 of 31 patients tolerating
the combination for longer than 21 days. 23 of 31 patients (74%) had either complete
clinical response (n=2) or a partial response (n=21), while eight patients (26%)
had CMV disease progression, leading to death in six.
Maintenance therapy consisting of combination foscarnet + ganciclovir was given to
13 of 31 patients, while eight received ganciclovir alone and 2 foscarnet alone.
On maintenance therapy nine patients (39%) had progression of diseases CNS relapse
(nine instances), retinitis (five instances) or both (n=1). The median time to progression
was 107 days. The survival rates were 50% at three months, 19% at six months, 15%
at 12 months.
While 21 patients (68%) were unable tolerate one of the two drugs and six patients
(19%) had to be taken off both drugs, the combination of foscarnet and ganciclovir
for CMV CNS infection was effective in acute therapy with improvement or stabilisation
in 74% of cases and prolonged survival of more than six months in eight patients (26%).
3TC (lamivudine) has inhibitory effects on hepatitis B virus (HBV) replication in
certain in vitro
models, but data are lacking regarding its efficacy against HBV in humans. In a presentation
on behalf of the Australian CAESAR study, Dr. D.A. Cooper of the University of New
South Wales showed that 3TC inhibits HBV replication in patients with combined HIV/HBV [Abstract 496].
The study randomised patients to ZDV, ZDV/3TC, ZDV/3TC/loviride. Neither loviride
nor ZDV has anti-HBV effects. Among those HBsAg positive at baseline, HBV DNA and
HBeAg were present in 83% (98 of 118) and 63% (74 of 118) respectively, with no difference
between treatment arms. HBV DNA levels decreased in the 3TC arms as shown below:
| 3TC containing regimen | No 3TC | |
| week 12 | 2.0 | 0.0 |
| week 52 | 2.7 | 0.0 |
Loss of HBeAg occurred in 22% (7 of 32) in the 3TC arm and in 0% (0 of 7) in the placebo
arm. A trend to lower mean ALT level was also reported in the 3TC arms. In addition,
progression of HIV disease was significantly delayed in the 3TC arms compared to
placebo.
Drs. D. Rimland and C. Staples of Emory University and the VA Medical Center, Atlanta,
Georgia reported on their studies with HIV/HCV co-infected patients followed prospectively
since 1982 [Abstract 493]. One hundred and fifteen (115) of 350 HIV-infected patients (33%) were HCV antibody positive. Intravenous drug use (85% of HCV positive
patients) was the major risk factor for having hepatitis C. There was no difference
between HCV positive and negative patients by gender, AIDS diagnosis, CD4+ count,
HIV viral load, hepatitis A antibody, or hepatitis B coinfection.
HCV positive patients were more likely to be older (p=0.003), hepatitis B core antibody
positive (p=0.006), Black (p=0.001), IV drug abusers (p=0.001) and have a higher
SGOT level (p=0.001).
Kaplan-Meier survival curves from the date of AIDS diagnosis demonstrated no difference
between HCV positive and negative patients (p=0.83). The authors concluded that while
HCV is common in these patients from Atlanta, it did not reduce survival.
Dr. J. Ioannidis reported the results of a meta-analysis of 1,792 patients from eight
randomised controlled trials of high-dose oral acyclovir in HIV infection [Abstract
500]. Among patients on acyclovir there were 247 deaths among 895 patients, and among
897 patients allocated to control arms there were 276 deaths.
Acyclovir was associated with improved survival (p=0.006) and also significantly decreased
HSV infections (OR 0.28 [0.21-0.37]) and VZV infections (OR 0.29 [0.13-0.63]). Acyclovir
had no significant impact on morbidity or mortality from CMV, lymphoma, or Kaposi's sarcoma. In studies with a high incidence of HSV and VZV infections, acyclovir
conferred a survival advantage of greater than 25% per year, while this was not observed
in three studies with low HSV/VZV incidence.
This meta-analysis demonstrating a survival advantage for acyclovir use in populations
with high rates of HSV and VZV suggest that there may be virulence synergy between
Herpesviruses and HIV-1.
Dr. A.T. Pavia of the University of Utah presented an analysis of three patients with
refractory molluscum contagiosum and giant, disfiguring cutaneous lesions who responded
to intravenous or topical cidofovir therapy [Abstract 504]. Cidofovir is active against DNA viruses including poxvirus family of which molluscum contagiosum is a member.
The three patients had each received HAART and shown responses in their CD4+ counts
and HIV viral loads. However, their molluscum contagiosum had not responded. Two
showed dramatic improvements in their molluscum contagiosum after receiving four
weeks of intravenous cidofovir. One patient improved with topical therapy with 3% cidofovir.
Adapted from reports by: Richard Chaisson, M.D., William Bishai, M.D., Ph.D. & Michael
Marco.
Source: healthcg.com
Where protease inhibitors are available, CMV disease incidence has plummeted over
the last three years, mirroring the decline in AIDS-related deaths. Multicenter CMV
research trials are having difficulty meeting enrolment targets and most HIV care
centres are reporting at least a 50% reduction in new CMV retinitis cases diagnosed. Brosgart
and colleagues from the Terry Beirn Community Programs for Clinical AIDS Research
(CRCRA) screened 349 subjects with low CD4+ cell counts for a CMV prophylaxis trial
and detected only four cases (1.01%) of asymptomatic CMV retinitis [1]. Reports from the
era before the availability of protease inhibitor therapies demonstrated an asymptomatic
CMV retinitis rate of 11.3% [2]
Cautionary notes, however, have been struck. Patients are being diagnosed with CMV
retinitis with ever increasing CD4+ cell counts [3], some while receiving effective
antiretroviral treatment. In a study from France, where the incidence of CMV disease
has declined from 9.8% in 1996 to 4.5% in 1997, 39 patients had relapsed or new CMV retinitis
diagnosed. Thirteen patients experienced relapses despite achieving undetectable
HIV RNA levels, with three having CD4+ cell counts greater than 200/mm3. Likewise, four patients with newly diagnosed retinitis had undetectable HIV viral
loads [4]. A similar message hails from Brussels where a retrospective analysis of
18 patients with CMV retinitis, 13 diagnosed prior to protease inhibitor initiation,
reveals an overall decrease in incidence of CMV disease but an increase in the proportion
with CD4+ cell counts above 50/mm3 at the time of diagnosis from 0% to 8%. A trend coinciding with protease use [5].
Despite these issues, it remains clear that protease inhibitor therapy has, overall,
positively impacted upon CMV disease in HIV. The immune response that these agents
appear to be providing was examined by Francesca Torriani in San Diego who described
the in vitro
proliferative responses of eight patients with CMV retinitis and sustained elevations
in CD4+ cell count on 'highly active antiretroviral therapy' who discontinued maintenance
anti-CMV therapy. Proliferation assays demonstrated a robust response to CMV in the four patients with CD4+ cell counts above 200/mm3 and viral loads below 6000 copies/ml. The remaining four patients with lower CD4+
counts and higher viral loads had notably diminished response to CMV antigen. One
of these subjects with a viral load greater than 100,000 experienced a retinitis
relapse. This relapse occurred 778 days after ceasing CMV therapy and followed a decline in
his CD4+ count from 161 to 39 cells/mm3. For the group as a whole, median time off CMV therapy is 300 days [6]. William Freeman,
the study ophthalmologist warns that he has observed unusual ophthalmologic findings
in patients with CMV retinitis receiving protease inhibitor therapy, characterised by retinal inflammation including painless vitritis and macula oedema with visual
loss [7]. Increased inflammatory reactions on the heels of protease inhibitor initiation
have been reported in patients with mycobacterium avium
complex (MAC) infection and hepatitis C, and may be the result of an enhanced immune
response afforded by HIV suppression.
For those still not convinced that protease inhibitors may be the best CMV therapeutic
agent since intravenous ganciclovir was developed, the Argentine Oral Ganciclovir
Study Group correlated the time to relapse and protease inhibitor use in 41 subjects
with CMV retinitis enrolled in an oral ganciclovir treatment trial. Time to progression
was 111 days for the overall study population, 76 days for those not receiving protease
inhibitors and 157 days for protease inhibitor recipients. The number of patients
receiving protease inhibitor agents was not reported and the calculated p value was
0.057. However, the trend strongly favours the effect of protease inhibitors and
correlates with both U.S. and European experiences.
Author: David Wohl, M.D.
Source: healthcg.com