Applying National Guidelines on ART - Complications

Authors: Sipho Dlamini, MBChB, FCP(SA), Cert ID(SA); Eefje Jong, MD, PhD
Editor In Chief: Ian M. Sanne, MBBCH, FCP(SA) (More Info)

Last Reviewed: July 8, 2016 (What's New)

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inPractice® Africa’s Continuing Education Unit (CEU) provider, the South African Medical Association, offers physicians 3 CPD points on a 70% pass rate for completing this individual module. Nonphysicians who successfully complete the module will receive a participation certificate. To learn more on CPD credits and participation certificates, click here.


Access to antiretroviral therapy (ART) may extend the lives of millions of people living with HIV (PLHIV) worldwide—particularly those who start ART early and prior to development of AIDS. People retained in care and on effective ART regimens could have a life expectancy approaching that of the general population.[van Sighem 2010; Lewden 2007] Unfortunately, it is still too common for patients in sub-Saharan Africa to present with opportunistic infections and/or AIDS-related malignancies, and there is still a life expectancy gap for PLHIV in sub-Saharan Africa, although it has been reduced since the widespread adoption of effective ART.[Asiki 2016] With better access to ART and retention in care, the frequency of AIDS-related opportunistic infections and cancers will decrease as more people are started and maintained on effective ART. With improved survival, clinical management of PLHIV on stable ART presents new challenges. The frequency of non-AIDS–related conditions and conditions associated with ageing are likely to increase in PLHIV.

Antiretroviral Therapy and Noninfectious Disease

The beneficial effect of earlier antiretroviral therapy (ART) in preventing opportunistic infections (OIs) and non-AIDS–related adverse events was demonstrated in the landmark SMART study. This randomised, controlled trial of more than 5000 patients from several centres worldwide showed that earlier ART initiation (at CD4+ cell counts > 350 cells/mm³ vs < 250 cells/mm³) reduced both OIs and non-AIDS–related adverse events such as renal, cardiac, and hepatic disease.[El-Sadr 2006; Emery 2008] Other analyses of different cohorts of HIV-infected patients initiating ART (primarily in Europe and North America) have demonstrated that earlier ART reduces all-cause mortality.[Kitahata 2009; Sterne 2009; May 2007] Two additional recent studies, the INSIGHT/START[INSIGHT 2015] study and the TEMPRANO study[TEMPRANO 2015] have demonstrated significant individual clinical benefit from starting ART immediately in patients with CD4+ cell counts > 500 cells/mm³ rather than deferring until a certain lower CD4+ cell count threshold or clinical indication was met.

As such, US and World Health Organisation HIV treatment guidelines suggest treatment soon after diagnosis, regardless of CD4+ cell count.[DHHS ART 2016; IAS USA ART 2014; WHO ART 2015] This recommendation has been recently echoed in private sector treatment in South Africa with new guidelines issued by the Southern Africa HIV Clinicians Society (Management Guidelines).[ZA HIV Clin Soc ART 2015] These recommendations are practical when there is a wide range of antiretroviral agents available. For adults with HIV infection treated in the public sector where options may be limited, the current South Africa National Department of Health ART guidelines recommend ART for all patients with CD4+ cell counts ≤ 500 cells/mm³ (Management Guidelines).[ZA NDOH HIV Tx 2015] Other countries, including many countries in Europe,[EACS ART 2015] are still using a CD4+ cell count of ≤ 350 cells/mm3 as the threshold for ART initiation in asymptomatic HIV-infected patients.

Extensive evidence is available to support that earlier ART outweighs the risk of adverse effects associated with ART. That does not mean, however, that patients receiving ART will have no serious clinical issues. Some may experience long-term complications of ART or HIV infection itself. Complications with long-term treatment were observed in the “Global North” only a few years after po tent ART came into widespread use, including cardiovascular disease, liver disease, and non-AIDS–related malignancies.[Weber 2006] However, it is not clear that South Africans will have the same experience, since population characteristics and current first-line regimens are different than those that were used in early ART. Furthermore, researchers in the Global North noted that ART may not be the cause of all long-term complications; many complications may actually be due to damage caused by HIV over the years when it was untreated or due to chronic inflammation caused by continuing low-level HIV replication.

It is projected that the number of elderly PLHIV in South Africa will increase. For example, data from Hlabisa (a rural area in the Northern KwaZulu Natal) predict that approximately 25% of PLHIV will be 50 years of age or older in 2040.[Hontelez 2011] The implications are that primary physicians and other healthcare workers caring for PLHIV will increasingly have to contend with such noncommunicable diseases as hypertension, diabetes, and dyslipidaemiain the setting of HIV infection (these are often described as “age-related comorbidities” in other contexts). Complicating the issue is the global increase in the burden of noncommunicable diseases. The World Health Organisation Study of Global Ageing and Adult Health (SAGE), a programme meant to compile comprehensive longitudinal information on the health and well-being of adult populations and the ageing process, was conducted in South Africa in 2007-2008. Of those 50 years or age and older with HIV, 29.6% had 2 or more of the 7 chronic conditions associated with ageing (hypertension, depression, arthritis, angina, asthma, stroke, diabetes) compared with 8.8% of those 18-49 years of age (P <.0001).[Negin 2012]

Reports suggest that HIV-infected persons present with the illnesses associated with ageing at an earlier age and are more likely to suffer from multiple illnesses concomitantly.[Guaraldi 2011; Edwards 2015] These factors are reflected in changes in the cause of death among HIV-infected patients; for example, in the Swiss HIV Cohort Study, in 1999-2000, 34% of deaths were attributable to AIDS, but this had fallen to 22% by 2009-2011.[Weber 2012] The question that has plagued researchers and clinicians dealing with PLHIV, however, is whether the emergence of comorbidities is due to the ART regimens used in those countries, to HIV itself, or to behavioural risk factors (including smoking), which may be more common among PLHIV than the general population. For the purpose of South African clinicians, we must ask whether the risk factors in the concentrated epidemics of the North are likely to be the same as those in the generalised epidemic in the South—or even among key populations here.

The pathogenesis of long-term complications in PLHIV is now beginning to be elucidated. Evidence from a number of trials, such as the SMART study, suggests that HIV infection and ART exert their influence through chronic immune activation and hypercoagulation, treatment-related toxicity, other chronic viral coinfections such as hepatitis C virus, and comorbidities typically associated with advanced age. In addition, prolonged substance abuse and other psychosocial and health behaviours more common among PLHIV might contribute to pathogenesis of long-term complications.[High 2012] In essence, it appears that long-term complications in PLHIV may be a result of a complex combination of residual immune dysfunction, concomitant viral infections, ART adverse effects, and comorbidities that accelerate these complications.

This module reviews available data in an attempt to address what African clinicians can expect to be confronted with in their ageing PLHIV receiving ART. In addition, it discusses current guidance regarding how to prevent and manage specific long-term complications of ART and HIV infection as well as how to deal with concurrent noncommunicable diseases to provide PLHIV with the highest possible quality of life.