The issue may not seem pressing to some
HIV care providers in resource-constrained settings, because of the urgency of
identifying and getting people living with HIV onto ART, and responding to the
overwhelming burden of opportunistic infections and TB among PLHIV presenting
late for care. But this could be what is coming. According to Dr Judith Currier
of the University of California Los Angeles, who has been caring for people
living with HIV since the early days of the epidemic, clinicians in the US have
had to learn to manage many different complications in people living with HIV
since the introduction of ART.
“Our understanding of the spectrum of
HIV-related illness has evolved over the past 30 years,” said Dr Currier in her
talk at the HIV and NCD meeting, “and NCDs have emerged as an important cause
of morbidity in both untreated and treated HIV infection.”
Dr Currier presented an extensive review
of the clinical research that has documented this changing clinical picture and
investigated whether ART-related complications, HIV-disease itself, or
traditional risk factors were more responsible for the growing burden of NCDs
in PLHIV.
Cardiovascular risk
For instance, in the D:A:D Study, a large
longitudinal cohort study of people on ART (N = 23,468), several traditional
cardiac risk factors were common in the HIV-infected population.12 At baseline, over half of the cohort were
smokers, elevated total cholesterol was found in 22.2% and elevated
triglycerides in 33.8%. But data also
clearly show that some of the antiretrovirals have negative effects on lipid
levels. For instance, one meta-analysis looking at the impact of different nucleoside analogue (NRTI)
backbones and boosted protease inhibitors found the percentage change in lipid levels (from baseline to week 48 was
significantly greater in people taking d4T/3TC or abavacir/3TC than
those taking tenofovir/FTC.13
The percentage increase in lipids was worse in people taking ritonavir-boosted
lopinavir (Kaletra) or boosted fosamprenavir than
those taking other boosted protease inhibitors.
There have been increasing reports of
cardiac events such as acute myocardial infarction (MI), or heart attack, in people living with HIV.
In the Administrative Hospital Database study, which included 3851 HIV-infected
and 1,044,589 age-matched uninfected patients in care over the period of 1996
to 2004, the acute MI rate was significantly higher in HIV-infected than
HIV-uninfected patients: 11.13 versus 6.98 per 1000 person-years.14 Some of this increased risk appeared to be
due to treatment — after adjusting for the risks related to traditional risk
factors in the D:A:D study, an increased risk of myocardial infarction was likely
to be associated with cumulative exposure to protease inhibitors (PI) more than
non-nucleoside reverse transcriptase inhibitors (NNRTIs): (PIs: adjusted risk ratio = 1.16 (1.10-1.23,
p<0.001), NNRTIs: adjusted RR = 1.05 (0.98-1.13, p=0.17)),
but the greatest risk was on indinavir or Kaletra.15
A lot of the research “around this time,
from 2000 to 2005”, said Dr Currier, was focused “on the role of ART in some of
the complications increasingly being seen in people living with HIV”. She said
there has been a growing recognition that long-term tenofovir exposure was
associated with low rates of subclinical renal disease and bone loss; ritonavir
was known to be associated with triglyceride increases; the thymidine
analogues, especially d4T, were clearly associated with subcutaneous fat loss,
and there were probable associations between ART and the accumulation of
visceral fat. Finally, there was evidence that ART, specifically efavirenz, was
associated with vitamin D deficiency — which is a risk factor for a variety of
non-communicable diseases.
HIV as a risk factor for non-communicable diseases
This understanding of the relationship
between HIV and non-communicable diseases was complicated by the results of the
SMART study, which had been designed to evaluate whether it might be
possible to reduce the complications of ART, and preserve the drugs, by
delaying treatment or taking people off of treatment when their CD4 cell counts
were above 350. People living with HIV (N = 5472) (most of whom were taking ART
whenever the study started) were randomised to continuous versus intermittent
ART (not treating if the most recent CD4 cell count was above 350).16
The study had to be halted early (after a follow-up of only about 18 months)
after the unexpected finding of a significant excess of morbidity and mortality
among those randomised to no or intermittent treatment.
This study was a turning point in the
recognition that what people got sick from and died from when they stopped ART,
was not always an AIDS-defining illness, but included a surprising number of
non-AIDS events. Significantly more individuals in the intermittent ART arm
developed major cardiovascular, renal, or hepatic disease than those in the
continuous ART arm (hazard ratio 1.7
(95% confidence interval 1.1-2.5), p=0.009). Mostly
this was cardiovascular disease (more total events) and renal disease (which
actually had a much greater hazard ratios 4.5 (1.0-20.9)), but individually, each
finding was of borderline significance (p=0.05).
Around the same time, epidemiological
studies were beginning to show a shift in the causes of death among PLHIV. One
of these was a study in New York City, which reported that between 1999 and
2006, HIV-related deaths were decreasing but non-HIV–related deaths had
increased primarily due to CVD, substance abuse and non-AIDS–defining cancers.17
Among individuals ≥ 55 years, CVD was the leading cause of death.
“Now, if you treat HIV disease
successfully, it doesn’t seem surprising that once you’ve reduced traditional
opportunistic infections, that these non-AIDS events (or non-communicable diseases,
depending upon one’s perspective) would be more likely to occur,” she said —
noting that so far these studies had mostly focused upon cardiovascular, renal
or hepatic events). Consequently, an analysis of the Johns Hopkins Cohort,
looking at cumulative mortality in over 5000 HIV-infected people, found that
non-AIDS related deaths occurred more frequently than AIDS-related deaths,
particularly in individuals with higher CD4 cell counts.18
Even so, "Non-AIDS defining events do appear to
become more common at lower CD4 cell counts as well,” Dr Currier added.
Premature mortality has declined
dramatically since ART, but not completely. For instance, in the Cascade Study,
which followed 16,534 HIV-positive individuals for a median duration of 6.3
years (range, 1 day to 23.8 years) before and after the introduction of ART,
there were 2571 deaths over the entire study period, compared with 235 deaths
that one would have expected in a matched general population cohort.19
The excess mortality rate (per 1000 person-years) decreased from 40.8 (95%
confidence interval [CI], 38.5-43.0;) before the introduction of ART (pre-1996)
to 6.1 (95% CI, 4.8-7.4) for the period of 2004-2006. This continued excess
mortality wasn’t observed in the people who had seroconverted within the
previous five years, it was occurring in those who had been infected longer.
Another analysis of data
from 24 cohorts in developed countries suggested that the
increased risk of mortality in people living with HIV cannot be entirely blamed
on complications due to ART because it is observed in people who are not yet on
treatment, even at CD4 cell counts above 350.20
In this review, 487 deaths were recorded; an incidence of 4.9/1000
patient-years. Of these, 79 (16.2%) were deemed HIV-related, 235 (48.3%) were
non-HIV–related, and the cause of death was unknown in 173 (35.5%). The study
also concluded that the risk of death decreased with higher CD4 cell
counts.
While mature ART programmes continue to
see some AIDS-defining events over time in people on ART (people do fail on
treatment, due to poor adherence or other reasons), the cumulative probability
of non-AIDS defining events has become a much more significant cause of
complications in people on ART, according to the findings of the APROCO/COPILOTE (ANRS CO8) Cohort Study.21
The estimated probability of AIDS-defining events accumulates very
gradually to around 10% after 8 years on treatment. ART-related complications
are twice as likely, but the probability of developing a non-AIDS event is much
higher, at around 40%. This study provided a breakdown of these non-AIDS
events: 23%, were bacterial, 9.5% were cancer, 9.5% were due to CVD, psychological:
8.6% , neurological: 5.9%, gastrointestinal 5%, rheumatological: 3.4%, and
viral 3.2%.
Elevated cancer risk
Cancer is also considered an NCD, and has
always been observed in people living with HIV — many malignancies are
AIDS-defining events. So a large meta-analysis was performed to assess what
effect the decline in HIV-related mortality was having on cancer rates. The
analysis included 372,364 people living with HIV, followed from 1980-2006,
whose records were linked to corresponding cancer registry records. Three
questions were asked 1) What was the cancer risk 3-5 years after developing
AIDS, relative to the general population? 2) What was the five year cumulative
incidence of AIDS-defining cancer (ADC) and non-AIDS-defining cancer (NADC)? 3) What proportion of deaths among people with AIDS were attributable to cancer?
The cohort was predominantly male (79%), with a large proportion being non-Hispanic
black (42%), and 42% were MSM. The median age at the onset of AIDS was 36
years.
The cancer risk in years three to five
after AIDS onset was elevated not only for AIDS- but also for non-AIDS defining
cancers relative to the general population. Of the non-AIDS-defining cancers,
cancer of the anus, liver, lung and Hodgkin lymphoma were found more often in
the HIV-positive population (but there was no adjustment for smoking which is
found more frequently in HIV-positive cohorts).
“This is suggesting that chronic
inflammation or chronic coinfection with some other virus may be contributing
to this increased cancer risk,” said Dr Currier.
Of course, the risks could be much
different in African settings — but since ART programmes have only recently
been scaled-up, there are few long-term data available yet. However, in a
study just published, researchers in Botswana
found that the rates of non-AIDS defining events in ART-treated patients (from
a clinical trial population) were actually higher in that country than in the US.22
These events were mostly CVD and cancer, There was little difference in
reported renal events, and hepatic events were more common in the US
probably because of the prevalence of hepatitis C.
The emerging burden of NCDs in sub-Saharan African populations living with HIV
Data suggesting PLHIV in
Kenya may be at greater risk of NCDs were reported at last year’s HIV and
Health Systems meeting by Dr Frank Mwangemi, deputy director of the AIDS,
Population and Health Integrated Assistance (APHIA
II) programme.23
According to data from Kenya’ Ministry of Health, NCDs contributed to 50% of
the morbidity and 32% of the mortality in the general population (72% of these
were due to CVD, hypertension and diabetes). With funding from FHI 360,
screening of almost 5800 clients from the APHIA II programme in two provinces
found higher rates of CVD risk factors, particularly, high blood pressure, in
people living with HIV than the general population, levels that were increased
with time on ART, particularly on alternative and second-line ART regimens.
There were also indications that second-line therapy is associated with higher
blood glucose levels.
These data would seem to suggest that, as
treatment programmes expand and mature, non-AIDS defining events or NCDs could
well become the most common complications in people living with HIV in Africa
as well (not withstanding the NCD crisis that many say is unfolding).
Indeed, during the 6th International AIDS Society
Conference in July 2011, Dr Cissy Kityo Mutuluuza, Deputy Director of the
Joint Clinical
Research Center
in Uganda, warned during a session on the long-term complications of ART, “60% of people on
antiretrovirals are in Africa, so if we are going to see long-term
complications, we'll see it mostly in Africa.”
NCDs are also likely to become more
common as the population on ART continues ageing. As the ART programme
continues to expand the delivery of successful treatment (and prevention) of
HIV, it is expected that there should be fewer young people becoming infected,
so the proportion of older people on ART should grow. Dr Currier shared one modelling exercise that
showed that over time, the proportion of people on ART over the age of 50 in
South Africa is expected to increase and become predominant.
“HIV disease, ART and host factors all contribute to non-communicable diseases in people living
with HIV,” said Dr Currier and with the growing awareness of the importance of
NCDs, “Research is underway to untangle the interactions between the
virus/immune system, host/lifestyle, treatment side effects and now ageing in
populations with HIV to understand the relative contributions of each of these
factors to the pathogenesis of complications in HIV and to inform the
development of strategies for prevention and treatment.”
These include studies investigating the
contribution of immunodeficiency, viral load/replication and the resulting
inflammation and immune activation (which appears to persist even in people on
suppressive ART), as well as the use of different biomarkers to predict the
risks of specific NCDs. One focus of research is to determine whether starting
ART earlier at higher CD4 cell counts reduces the increased risk of NCDs, or
conversely, whether treatments that reduce immune activation could have an
impact on NCDs in the setting of HIV disease.
In the meantime, it might be wise for HIV
programmes in resource-limited settings to consider whether existing NCD
management strategies should be made part of the package of care offered to
their patients living with HIV (as
Botswana has recently done).