Upon diagnosis of PHI, there must be clear communication to the patient, in combination with counselling regarding the importance of safe practices to prevent further spread of infection. During the months following PHI, there is an extremely high HIV viral load in the blood and genital tract. Individuals with PHI contribute disproportionately to HIV transmissions; the probability of sexual transmission has been shown to be up to 26 times higher in the early stage of HIV infection compared to established infection^{49, 50}. There is evidence that early diagnosis coupled with effective counselling can significantly reduce the probability of further transmission⁵¹. It has been demonstrated that reduction of HIV viral load through early initiation of ART leads to much lower risk of transmission between sexual partners^{52, 53}.

Despite the difficulty in identifying patients with PHI, guidelines now reflect the significant body of evidence suggesting that ART should be commenced as soon as possible for all persons with HIV, regardless of symptomatology or CD4⁺ T cell count at diagnosis. There is demonstrable benefit for the individual⁵⁴ and from a public health perspective. Combination ART has well established efficacy, with the vast majority of individuals able to achieve undetectable HIV viral load within 3 months and maintain long-term viral suppression with preservation of immune function⁵⁵. Randomised-controlled trial data have demonstrated that individuals with primary infection who do not commence ART progress more rapidly, in terms of decline of CD4⁺ T cell count, than those that do commence ART⁵⁶. Furthermore, a major international randomised trial demonstrated that commencement of ART early, with high CD4⁺ T cell counts had significant benefits when compared to the approach of waiting until the CD4⁺ T count drops below 350/µL. The study examined outcomes including serious AIDS-related events such as AIDS-related cancers or infections, as well as serious non–AIDS-related events, such as cardiovascular disease, and found significantly lower rates of all events in the early initiation group⁵⁷.

Even when started during PHI, ART is continued indefinitely upon initiation. Previous studies have evaluated the utility of discrete courses of ART in early infection, followed by a period of treatment interruption, and have shown no clear benefit over continuous therapy. Furthermore, a CD4⁺ T cell count-guided interruption of treatment approach has been clearly found to be associated with increased morbidity and mortality compared to continuous therapy^{58, 59}. These studies were conducted with the aim of minimising patient exposure to ART in order to minimise toxicity, however it is important to note that the toxicity profile of modern combination ART is minimal in comparison to that of previous treatment regimens.

Ideally, the choice of ART regimen should be guided by the results of drug resistance testing, however treatment can be initiated prior to the availability of such results if this would preclude initiation of ART within the ideal target of two weeks from diagnosis. Regimens are chosen as per Australian guidelines, which are based on the United States Department of Health and Human Services guidelines, with consideration of potential adverse effects, childbearing potential, pill burden, dosing frequency, drug-drug interaction potential, and comorbid conditions. In the majority of cases a combination of three drugs is used, including an integrase strand inhibitor (INSTI) as first-line, in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). A boosted protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) can be used as an alternative to an INSTI if required. Importantly, abacavir-containing regimens should not be initiated until the results of HLA*B5701 testing are known.

ART has evolved from regimens with high pill-burden and inconvenient dosing schedules, to the modern era of fixed-dose single-tablet regimens. Furthermore, dual drug regimens, and long-acting injectable therapies have recently entered clinical practice and can be considered for select individuals^{60, 61}.