In the Australian context, ASHM Sub-Committee for Guidance on HIV Management recommends that antiretroviral therapy should be initiated in all people with HIV, irrespective of CD4 count, taking into account the following principles:
- ART is recommended for all individuals with HIV infection, irrespective of CD4 count, to reduce the risk of disease progression.
- The decision to start ART should take into account both personal health benefits and risks, and reduction in transmission risk.
- Clinicians should regularly discuss the current state of knowledge regarding when to start ART with all individuals with HIV who are not yet on treatment.
- All decisions to start ART should be made by the individual with HIV, in consultation with their health-care providers and on the basis that they are fully informed and supported in their decision making.
This recommendation is consistent with guidance from the US DHHS Panel, which has recently been upgraded to an A1 Recommendation (strong recommendation based on data from randomised controlled trials) following the publication of the results of the START and TEMPRANO trials, which showed benefit in initiating therapy in patients with normal immunity.
Treatment as prevention
Apart from the personal benefit in initiating ART to the individual, there is a benefit in prevention of transmission of HIV to partners without the infection where the person initiating ART achieves and maintains virological suppression on therapy.
Recent data from interim analyses of two cohort studies presented at Conference on Retroviruses and Opportunistic Infections (CROI) in 2014 and 2015 reported no transmissions in serodiscordant homosexual male couples with undetectable viral load. This result included data from the European PARTNER study which reported no HIV transmissions in 308 couple-years of follow-up when condomless anal intercourse was reported, and the HIV-positive partner had undetectable viral load and data from the Australian-Thai-Brazilian Opposites Attract study, which reported no transmissions when condomless anal intercourse was reported in 89 person-years of follow-up in couples with viral load less than 200 copies/mL. Data from these two studies strongly suggest that ART greatly reduces HIV transmission in serodiscordant homosexual couples. A very low rate of transmission cannot be ruled out. Follow-up continues in both studies and final study results are expected in 2016-17.
Cohort and randomised clinical studies in the pre-cART era and cART era suggested an enormous beneﬁt in terms of reduction in both mortality and progression to AIDS as a result of cART. These studies have been pivotal in the development of the HIV treatment guidelines.
The clear benefit to the individual of commencing cART irrespective of CD4 count has been demonstrated through the results of two major randomised studies, START and TEMPRANO. The benefit of early cART initiation in reducing HIV transmission has been demonstrated in the randomised HPTN 052 study.
Patients with CD4 counts > 500 cells/μL
Results for two pivotal randomised controlled trials (START and TEMPRANO) were recently published, both demonstrating that the clinical benefits of ART are greater when ART is started early, with pre-treatment CD4 T-lymphocyte (CD4) counts > 500 cells/μL, than when initiated at a lower CD4 cell count threshold.
With the availability of the START and TEMPRANO trial results, the DHHS Panel’s overall recommendation remains the same: ART is recommended for all patients with HIV infection regardless of pre-treatment CD4 count. However, the strength of the recommendation will be changed to AIa (strong recommendation based on data from randomised controlled trials) for all patients.
The additional benefit of ART in reducing the risk of HIV transmission further underscores the potential public health value of this recommendation. The Panel continues to emphasise that patients starting ART should be willing and able to commit to treatment and to understand the benefits and risks of therapy and the importance of adherence. On a case-by-case basis, ART may be deferred because of clinical and psychosocial factors, but therapy should be initiated as soon as is feasible.
It should be noted that neither of these trials included adolescents. However, our recommendations have been extrapolated to adolescents based on the expectation that they will derive benefits from early ART similar to those observed in adults.
Below are summaries of the results from these two randomised controlled trials:
START (Strategic Timing of AntiRetroviral Treatment) trial
The START trial is a large, multinational, randomised controlled clinical trial designed to evaluate the role of early ART in asymptomatic patients with HIV infection in reducing a composite clinical endpoint of AIDS-defining illnesses, serious non-AIDS events or death. In this study, ART-naive adults (aged >18 years) with HIV infection with CD4 counts > 500 cells/μL were randomised to either initiate ART immediately (early arm) or wait until CD4 counts declined to < 350 cells/μL or until the development of a clinical indication for therapy (deferred arm).
A total of 4,685 participants were enrolled in this study, with a mean follow-up of 3 years. In May 2015, interim study data reviewed by the study’s independent Data and Safety Monitoring Board (DSMB) showed a significantly greater number of clinical events in the deferred therapy arm than in the early therapy arm. On the basis of these interim results, the DSMB concluded that the data provided significant evidence of the benefit of early ART and recommended that the study sponsor make the results available to the public and offer treatment to any study participants in the deferred therapy arm not yet on ART. The study participants will continue to be followed in this study until the end of 2016.
When the randomised arms of the study were closed, the primary endpoint of serious AIDS or non-AIDS events was reported in 42 participants (1.8%, or 0.60 events/100 person-years) in the early ART arm and 96 participants (4.1%, or 1.38 events/100 person-years) in the deferred ART arm (hazard ratio, 0.43, favouring early ART [95% confidence interval (CI), 0.30–0.62, p < 0.001]). The most common clinical events reported were tuberculosis and AIDS and non-AIDS malignancies.
TEMPRANO ANRS 12136 study
The TEMPRANO study is a randomised controlled trial conducted in Cote d’Ivoire. Using a two-by-two (2 X 2) factorial design, participants with HIV infection with CD4 counts < 800 cells/μL were randomised to either immediate ART or deferred ART (based on the national guidelines criteria for starting treatment) and with or without isoniazid for prevention of tuberculosis for 6 months. The primary study endpoint was a combination of all-cause deaths, AIDS diseases, non-AIDS malignancies, and non-AIDS invasive bacterial diseases. More than 2,000 participants enrolled in the trial, with a median follow-up of 30 months. Among the participants, 849 had baseline CD4 counts > 500 cells/μL. In the analysis of this high CD4 count subgroup, 68 primary outcome events were reported in 61 patients. The risk of primary events was lower with immediate ART than with deferred ART, with a hazard ratio of 0.56 in favour of early ART (CI, 0.33–0.94). On the basis of these results, the study team concluded that early ART is beneficial in reducing the number of these clinical events.
Prevention of sexual transmission
A number of investigations, including biological, ecological and epidemiological studies and one randomised clinical trial, provides strong support for the premise that treatment of the individual with HIV can significantly reduce sexual transmission of HIV. Lower plasma HIV RNA levels are associated with decreases in the concentration of the virus in genital secretions. Studies of HIV-serodiscordant heterosexual couples have demonstrated a relationship between level of plasma viraemia and risk of transmission of HIV—when plasma HIV RNA levels are lower, transmission events are less common. A study conducted in KwaZulu-Natal, South Africa, used geospatial techniques to assess the relationship between ART use and HIV incidence in an observational cohort of more than 16,000 study participants living in many different communities. After adjustment for sexual behaviour and prevalent HIV cases, each percentage point increase in ART coverage of people with HIV infection lowered the HIV infection risk in a community by 1.7%.
Most significantly, the multi-continental HPTN 052 trial enrolled 1,763 HIV-serodiscordant couples in which the partner with HIV was ART naïve with a CD4 count of 350 to 550 cells/μL at enrolment to compare the effect of immediate ART versus delayed therapy (not started until CD4 count < 250 cells/μL) on HIV transmission to the partner with HIV infection. At study entry, 97% of the participants were in heterosexual monogamous relationships. All study participants were counselled on behavioural modification and condom use. Twenty-eight linked HIV transmission events were identified during the study period, but only one event occurred in the early therapy arm. This 96% reduction in transmission associated with early ART was statistically significant (HR 0.04; 95% CI, 0.01–0.27; p < 0.001). These results show that early ART is more effective at preventing transmission of HIV than all other behavioural and biomedical prevention interventions studied. This study, as well as other observational studies and modelling analyses showing a decreased rate of HIV transmission among serodiscordant heterosexual couples following the introduction of ART, demonstrate that suppression of viraemia in ART-adherent patients with no concomitant sexually transmitted infections (STIs) substantially reduces the risk of transmission of HIV. HPTN 052 was conducted in heterosexual couples and not in populations at risk of transmission via homosexual exposure or needle sharing. In addition, in this clinical trial, adherence to ART was well supported and near complete. However, the prevention benefits of effective ART observed in HPTN 052 can reasonably be presumed to apply broadly. Therefore, the Panel recommends that ART be offered to patients who are at risk of transmitting HIV to sexual partners (the strength of this recommendation varies according to mode of sexual transmission: AI for heterosexual transmission and AIII for male-to-male transmission and other modes of sexual transmission). Clinicians should discuss with patients the potential individual and public health benefits of therapy and the need for adherence to the prescribed regimen and counsel patients that ART is not a substitute for condom use and behavioural modification and that ART does not protect against other STIs (see Preventing Secondary Transmission of HIV).