First, there is no evidence that people infected with HIV can be cured by the currently available therapies, although research related to curing people of infection is underway. In general, those who are treated for years and are repeatedly found to have no virus in their blood by standard viral load assays will experience a prompt rebound in the number of viral particles when therapy is discontinued. Consequently, the decision to start antiretroviral therapy (ART) must balance the risk versus the benefits of treatment. The risks of therapy include the short- and long-term side effects of the drugs, as well as the possibility that the virus will become resistant to the therapy, which can limit options for future treatment. The risks of both of these problems are quite small with the treatment options currently available.
A major reason that a person’s infection develops resistance to a particular drug regimen is the patient’s failure to correctly follow the prescribed treatment, for example, by not taking the medications at the correct time. If virus remains detectable by blood test on any given regimen, resistance eventually will develop. Indeed, with certain drugs, resistance may develop in a matter of weeks, such as with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (Epivir, 3TC) and emtricitabine (Emtriva, FTC), the drugs in the class of nonnucleoside analogue reverse transcriptase inhibitors (NNRTI) such as nevirapine (Viramune, NVP), delavirdine (Rescriptor, DLV), efavirenz (Sustiva, EFV), and rilpivirine (Edurant, RPV), as well as the integrase strand transfer inhibitors (InSTIs) such as raltegravir (Isentress, RAL) and elvitegravir (Vitekta, EVG).
Thus, if these drugs are used as part of a combination of agents that do not suppress the viral load to undetectable levels, resistance will develop rapidly and the treatment will lose its effectiveness.
In contrast, HIV becomes resistant to other drugs, such as the boosted protease inhibitors (PIs), over months. Resistance also seems to be relatively uncommon with some of the newer InSTIs, such as dolutegravir (Tivicay, DTG) and bictegravir (BIC), which is only available as a combination pill (Biktarvy) with tenofovir alafenamide (TAF) and emtricitabine (FTC). It is important to note that when resistance develops to one drug, it often results in resistance to other related drugs, so-called cross-resistance. Nevertheless, HIV-infected individuals must realize that antiviral therapy can be, and typically is, very effective. This is the case even in those who have a low CD4 cell count and advanced disease, as long as drug resistance has not developed. CD4 cells are a type of immune cell used as a bellweather to judge the degree of HIV infection. The lower the count of CD4 cells in tests, the more advanced the infection. When should antiviral therapy be started? Until very recently, one of the biggest questions related to the management of HIV disease was the optimal time to start antiviral treatment. For some time, there had been very strong data demonstrating that therapy is appropriate for those with CD4 cells numbering less than 350 cells/mm3 in the blood. There have also long been strong recommendations to treat patients with select conditions regardless of their CD4 cell count, such as having HIV during pregnancy, in order to prevent transmission of HIV to the baby. Other cases that need immediate treatment are those who have HIV-associated renal disease or chronic hepatitis B infection where the antiviral treatment for HIV also treats the hepatitis virus.
Several large studies have shifted all guidelines around the world to recommending treatment of all HIV-infected individuals at the time of diagnosis no matter what the CD4 cell count.
Regardless, prior to initiating antiviral therapy, everything possible should be done to ensure that the patient is committed to the treatment, able to adhere to the regimen, and will follow up with his or her health care professional to assess whether medications are tolerated and working.
Guidelines for starting antiviral therapy have been proposed by panels of experts from several groups, including the Department of Health and Human Services (DHHS) (https://aidsinfo.nih.gov/) and International Antiviral Society-USA (IAS-USA). There are similar guidelines for treatment throughout Europe and by the World Health Organization for treatment in resource-limited countries. Until recently a recommendation supporting the start of therapy in those with CD4 cells greater than 500 cells was based upon evidence that ongoing viral replication, even in the setting of high CD4 cell counts, may be associated with damage to the brain, kidneys, heart, and possibly even liver. Along with this rationale, it was clear that newer regimens were easy to take, including a growing number of one-pill-per-day options, with minimal side effects. Another compelling argument that can be made for early therapy is the ability to reduce the risk of transmission to uninfected partners.
A study called HPTN 052 demonstrated that among couples in which one person is HIV-infected and the other is not, those who were on antiretroviral therapy were 96% less likely to transmit HIV to their uninfected partner than those not on treatment.
Finally, a large study was recently reported that demonstrated unequivocally that starting therapy even with a CD4 cell count of greater than 500 cells/mm3 was associated with less risk of disease progression than waiting until CD4 cells were less than 350 cells/mm3. This study was called the START study and demonstrated a major reduction in disease progression with early therapy with virtually no increased risk for side effects. Based upon START, HPTN 052 and other accumulated data, currently all major guidelines around the world, including those of the World Health Organization recommend that antiretroviral therapy be initiated in all HIV-infected patients at the time of diagnosis. It is worth noting that these recommendations for universal treatment of HIV-infected patients will be limited by resources available for antiviral treatment in resource-limited countries.
Before starting treatment, patients must be aware of the short- and long-term side effects of the drugs, including the fact that some long-term complications may not be known. Patients also need to realize that therapy is a long-term commitment and requires consistent adherence to the drugs. In addition, clinicians and patients should recognize that depression, feelings of isolation, substance abuse, and side effects of the antiviral drugs can all be associated with the failure to follow the treatment program.