Dolutegravir and other INSTIs
A systematic review and meta-analysis, conducted to inform the new World Health Organization (WHO) Consolidated Guidelines, found Dolutegravir superior to standard dose Efavirenz for both viral suppression and discontinuation rates. 
The analysis, published in online in the Lancet HIV, 6 September 2016, also showed low dose Efavirenz to be superior to standard dose for discontinuation rates and CD4 count gains.
The investigators wrote: “A research question posed by WHO in anticipation of the guideline development was how INSTIs compared with Efavirenz, and to this end our results suggest a clear hierarchy within the INSTI class with Dolutegravir being the most efficacious, followed by Raltegravir.” .
There are several reasons unrelated to safety or efficacy, for WHO to continue to recommend standard dose Efavirenze as the preferred first-line drug in the recent guidelines. They are license, cost, logistics and Continuing Medical Education (CME) , these results definitely signal the potential for future changes.
The investigators found 5865 citations, they selected 513 of these for full text review and included 126 articles associated with 71 trials in the analysis. The final network of eligible comparisons – including both head-to head and indirect – between treatments included 34 032 patients randomised to 161 treatment groups.
In the assessment of viral suppression (using data from 70 trials, including 31 404 participants receiving 16 third drugs), the analysis revealed Dolutegravir to be significantly better than Efavirenz at 48 and 96 weeks: the odds ratio (OR) for viral suppression was 1·87 (95% CI 1·34–2·64) with Dolutegravir and 1.90 (95% CI 1.40-2.59) at these time points respectively.
Raltegravir was the only other third drug that was statistically superior to Efavirenz: OR 1·40 (CI 95% 1·02-2.59) and 1.45 (1.07-1.95) at 48 and 96 weeks respectively.
The investigators noted that ritonavir-boosted Lopinavir “fared worst” and was inferior to standard dose Efavirenz and all INSTI.
The investigators also performed a random-effects network meta-analysis for discontinuations due to adverse events. This showed that Dolutegravir had the most protective effect relative to Efavirenz: OR 0·26 (95% CrI 0·14–0·47). Low dose Efavirenz followed: OR 0·39 (95% Crl 0·16-0·92). They noted that although there was no statistical difference between Dolutegravir and low dose Efavirenz, their estimations suggested higher rates of discontinuations with the latter Efavirenz. There were more discontinuations for adverse events or other reasons in the Efavirenz group (30%) than the Dolutegravir group (18%) and a small non-significant risk resistance between the groups.
Also, very recently, ViiV Healthcare, the global specialist HIV company, majority owned by GSK, with Pfizer Inc. and Shionogi Limited as shareholders, on 25 July 2017 announced positive interim results from DAWNING, a non-inferiority study conducted to compare second-line treatment of the protease inhibitor-sparing regimen of Dolutegravir and 2 nucleoside reverse transcriptase inhibitors (NRTIs), with a current WHO-recommended regimen of Lopinavir/Ritonavir and 2 NRTIs in HIV-1-infected adults. Results, presented at the International AIDS Society congress in Paris announced superior efficacy of Dolutegravir versus Lopinavir/Ritonavir in second-line HIV treatment in resource-limited settings
Dolutegravir has a terminal half-life of approximately 14 hours. A single oral dose of one tablet of dolutegravir 50 mg should be feasible.
Difficult decisions will need to be taken if we are to achieve the UNAIDS targets for antiretroviral treatment coverage. Most commonly viral suppression indicators can misclassify detectable viral load owing to discontinuation of treatment for any reason. But in most clinical trials only a minority of failures are truly virological. Most people have undetectable viral load when they discontinue treatment because of adverse events or other reasons and can be switched onto alternative treatments to sustain long-term virological suppression.
The first generic version of dolutegravir is on its way: FDA tentative approval of the Aurobindo single was recently granted and it will be available to generic accessible countries for a per person annual cost of about US $44 under an agreement with ViiV and the Clinton Health Access Initiative (CHAI). And dolutegravir-based fixed dose combinations are not far behind., 
Kenya is to become the first African country to provide a generic version of the antiretroviral drug (ARV), dolutegravir (DTG), for routine use among people living with HIV. From the integrase inhibitor (INI) drug class, dolutegravir is widely lauded as superior to all other third agents used in first-line therapy.
Mechanisms to ensure fair costing and budgeting to ensure equitable and sustainable access, particularly to improved treatments as they are recommended must be made in the GF country Proposal. Selection of a regimen should be guided by factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance potential, comorbid conditions, and cost based on available scientific evidence. The efficacy and safety of ART has substantially improved with the introduction of newer drug classes of antiretrovirals that are now available to patients and HIV care providers. Their improved tolerance could be part of a larger solution to improve retention, which is a challenge, particularly in low-income and middle-income country settings.
Tenofovir Alfenamide (TAF) Vs Tenofovir Disoproxil Fumarate (TDF)
Tenofovir disoproxil fumarate is associated with renal and bone toxicity. In a single-arm, open-label study of 242 virologically suppressed, HIV-infected participants with creatinine clearance 30–69 mL/min who switched to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, participants had stable creatinine clearance, significant and durable improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001), and significant increases in hip and spine bone mineral density through 96 weeks (P < 0.001). Eighty-eight percent maintained HIV-1 RNA <50 c/mL at week 96. These longer-term results support the use of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in HIV-infected individuals with mild-moderately impaired renal function.
TAF has a similar tolerability, safety, and effectiveness to TDF and probably less adverse events related to renal and bone density outcomes in the treatment of naive and experienced patients with HIV-1. There are numerous studies where Tenofovir Alafenamide was found to be non-inferior to Tenofovir Disoproxil Fumarate, and had improved bone and renal effects.
However, The WHO HIV Department does not support the addition of the formulation emtricitabine + tenofovir alfenamide in 2017 WHO Model List of Essential Medicines for treatment of HIV infection for a number of reasons:
Tenofovir alfenamide (TAF) is not included as an option in 2016 WHO consolidated guidelines on use of antiretrovirals for treating and preventing of HIV infection.
There are important concerns with the use of TAF in PLHIV with TB co-infection. There are no published data available on the pharmacokinetics and real-world efficacy of TAF in TB coinfected patients. While the current available tenofovir prodrug (tenofovir disoproxil fumarate or TDF) does not require dose-adjustment if co-administered with rifampicin, TAF is currently contraindicated by the originator in patients being treated with rifampicin, as significant drug interaction is predicted based on pK modelling . Data on the potential for dose adjustment are awaited.
There are no data available on the safety of TAF in pregnant women. Despite preclinical toxicity studies in pregnancy didn´t reveal concerns, preliminary pK data in humans showed a 5-fold higher intracellular tenofovir concentration with TAF when compared with TDF . It might lower the risk of mother-to-child transmission of HIV, but it can also increase the risk of birth abnormalities. There is no data are available on placental or breast milk passage of TAF in humans. Until results from pK and large database of TAF-treated pregnant women have been analysed, it is not possible to evaluate the real safety risk of using TAF in pregnant/breastfeed women.
Data on TAF use in adolescents (12-18 years old) are available only for a comparatively small sample (50 participants in total), and only for 48 weeks of study follow-up . Clinical studies in children younger than 12 years old are still ongoing. In conclusion, the inclusion of TAF containing regimens for treatment of HIV infection in low and middle-income countries is viewed by WHO as premature and requires more data for tuberculosis, pregnancy, children and PLHIV with severe immunosuppression.