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Understanding the Details of HIV Treatment
Part One of Three in Project Inform's "What You Should Know About When to Start and What Meds to Use" Booklet

July 2011

When to Start: Some General Issues

Some people will start HIV treatment right away, while others may wait for awhile. The following factors can help you and your provider choose the best time to start.

Your CD4 Count Trend


A trend is when you look at two or more CD4 count results to see how much they change. Over time, falling CD4s indicate declining immune health. There's general agreement that a loss of 100 CD4s or more each year shows a weakening immune system. Don't panic about a single lower test result, but consult with your doctor and consider another test to determine your trend.

The CD4 percentage trend is also useful to consider. This tends to change less often between tests than the CD4 count, so it may be more reliable.

Your Viral Load Trend

Consistently increasing HIV levels indicate that the virus is reproducing and can infect more CD4s, which causes more damage to the immune system. Again, the trend over time is impor­tant: consider two or more viral load test results to inform a treatment decision. Experts generally agree that an increase in viral load to above 100,000 is a sign to start treatment, independent of CD4 count.

Your General Health

Understanding the Details of HIV Treament

Your general health and whether or not you have minor symptoms can also help determine when to start. If your health is good and stable, then starting treatment right away may not be necessary. But if you have some symptoms of HIV disease, despite a good CD4 count, starting might be the better decision. On the other hand, if you have an illness that makes it difficult to adhere to or manage the side effects from the HIV drugs, it may be better to wait until you're feeling better and the other illness has resolved. Your doctor can help you make this decision.

Are You Ready to Start?

You should begin treatment when you feel you're ready for the demands of life-long treatment. This includes being emotionally ready, as well as being able to take pills every day, manage possible side effects, and ensure you have steady access to health care. It may mean you first need to address other issues such as finding stable housing or mental health or substance use services. Without a strong commitment to and support for taking your pills as prescribed, you're less likely to get the best outcomes.

HIV Treatment Guidelines

Understanding the Details of HIV Treament

The US Department of Health and Human Services Guidelines for treating HIV infection are updated periodically, the last time in January 2011. They're meant to help guide people with HIV and their doctors through the issues that may arise when choosing and using HIV meds, including when to start and what drugs to use. The Guidelines are based on the latest research as interpreted by a panel of experts, which result in recommendations, not rules. When enough information is known about some aspect of treating HIV disease, the Guidelines will recommend or suggest a preference. When data are less clear, they will state just that.

The Guidelines state that HIV treatment should be based on a person's own unique situation, best done with the expert advice of an experienced doctor. Important details from the Guidelines about when to start and what meds to choose are found over the next several pages.

The following conditions increase the need to start.

When to Start: CD4 Count Ranges

A Brief, Basic Explanation on Clinical Studies

This section mentions two types of studies, both of which can provide important information about HIV disease. Randomized studies are considered the "gold standard" of clinical research. By randomly putting people in different groups or arms, they balance both known and unknown factors as well as limit biases that may influence the outcomes of the study. Observational and cohort studies are less rigorous and do not randomize or control study arms. For example, such a study might look at a group of people who have heart attacks and see what they have in common. While these studies can produce useful information, they may not be able to limit biases or unknown factors to the same degree as randomized studies.

Starting Treatment During Early Infection


There's not as much research on starting HIV drugs in the first few months or even first year of infection. Many, if not most, people do not have to decide this soon after their diagnosis. However, it's reasonable for people to start at this time if they believe it will benefit them. Starting early may prevent damage from HIV, including loss of CD4s and problems related to inflammation.

On the other hand, starting immediately after infection may not give you enough time to fully learn about the risks and benefits of long-term treatment. Starting early risks "using up" HIV medications sooner, as well as long-term side effects and drug resistance.

Starting Treatment at 200 CD4 Cells or Below

The Guidelines state that treatment should be started when CD4s are below 200, which constitutes an AIDS diagnosis. If you're in this range at diagnosis, HIV treatment can greatly improve your health and CD4 count, and help prevent AIDS and other health conditions. Results from several randomized and long-term observational studies clearly show that waiting until CD4s drop below 200 greatly increases the risk of OIs, other health conditions and death. More study results support starting treatment in this CD4 range than at any other level.

Starting Treatment Between 200-350 CD4 Cells

The Guidelines state that treatment should also be started when CD4s are in this range. If you're in this range at diagnosis, HIV treatment can improve your health and CD4 count, and help prevent AIDS and other health conditions. A few randomized studies show more benefit to starting in this range than waiting to start at 200 or below. For example, the CIPRA study showed a significantly higher rate of death and TB in people who started below 200 vs. those who started below 350. Also, a sub-study from the SMART study showed a lower risk of AIDS and non-AIDS conditions in people who started HIV meds with CD4s above 350 vs. those with less than 250 CD4s.

Starting Treatment Between 350-500 CD4 Cells

The Guidelines state that treatment is recommended in this range, although the expert panel was divided on the strength of this recommendation. While the panel agreed that the risk of death or serious illness is low overall, no randomized studies have conclusively shown to start in this range.

Results from some large observational studies suggest benefits to starting in this range. The ART-CC study showed a lower rate of AIDS and death in people with 350–450 CD4s vs. those with 250–350 CD4s. NA-ACCORD and CASCADE showed an in­creased risk of death for people who started treatment below 350 vs. 350–500. What limits these studies is that the overall numbers of AIDS cases and deaths were small. They also didn't evaluate the impact of adherence, resistance or long-term side effects.

Other studies show that starting in this range leads to higher CD4 counts. The ATHENA cohort showed that people who start with CD4s above 350 will more likely reach a level above 800. The John Hopkins cohort showed that those who started at below 350 CD4s are less likely get their count above 500. Further, there's growing evidence to suggest that damage to various organs is possible due to inflammation from untreated HIV at most any CD4 level. Read more about this range in the sections titled "Possible benefits & risks of starting treatment at 350–500 CD4s".

Starting Treatment Above 500 CD4 Cells

In the US, the average CD4 count at diagnosis is about 340. Yet, some people consider starting when their CD4s are above 500. No randomized and few observational studies show an advantage for starting above 500. CASCADE showed a benefit in the 350–500 range but not above 500. Some experts think starting HIV meds above 500 might limit damage to the immune system and organs due to inflammation. The Guidelines panel was split: half favored starting in this range while half thought it was optional. Although it's reasonable for someone to start above 500, the pros and cons should be carefully considered as the risks and benefits are not yet known. The new START study will help answer this question (read the section titled "The START Study").

Possible Benefits of Starting Treatment at 350-500 CD4s

The Possible Risks of Starting Treatment at 350-500 CD4s

The START Study

Understanding the Details of HIV Treament

So far, there have not been any results from randomized, controlled studies to guide decisions about when to start treatment above 350 CD4s. Such a study has been a topic of much debate, and only recently has one gotten off the ground, appropriately named START (Strategic Timing of Anti­Retroviral Treatment). This study will enroll nearly 4,000 people in about 30 countries.

In START, people will either begin treatment with CD4s above 500 or wait until their CD4s fall to below 350. The study will assess whether people are more or less likely to result in a serious AIDS condition, other health condition or death at various CD4 levels. Sub-studies will also be done to collect information on issues such as inflammation, neurological problems, and bone, heart and liver health.

The final results are expected around 2014, with interim reports probably presented before then. Researchers expect the study to provide a clearer understanding of both the benefits and risks of starting treatment at different CD4 counts, especially long-term side effects and drug resistance.

Classes of HIV Meds

Your first regimen will probably include three drugs from two different classes. These classes work against different steps in the life cycle of HIV, so using at least two classes together reduces the risk that HIV will become resistant. Combining meds in this way will provide better and longer-lasting health outcomes.

Below is the current list of HIV meds, organized by class and then listed alphabetically by brand name, along with their generic names, three-letter abbreviations, and year of FDA approval. Some drugs are no longer used or not used often in the US, while others are used only in special circumstances.


Emtriva (FTC, emtricitabine, 2003)
Epivir (3TC, lamivudine, 1995)
Retrovir (AZT, zidovudine, 1987)
Videx EC (ddI, didanosine, 2004)
Viread (TDF, tenofovir, 2001)
Zerit (d4T, stavudine, 1994)
Ziagen (ABV, abacavir, 1998)

Protease Inhibitors

Aptivus (tipranavir, 2005)
Crixivan (indinavir, 1996)
Invirase (saquinavir, 2003)
Kaletra (lopinavir/r, 2000)
Lexiva (fosamprenavir, 2003)
Norvir (ritonavir, 1996)
Prezista (darunavir, 2006)
Reyataz (atazanavir, 2003)
Viracept (nelfinavir, 1997)



Edurant (rilpivirine, 2011)
Intelence (etravirine, 2008)
Rescriptor (delavirdine, 1997)
Sustiva (EFV, efavirenz, 1998)
Viramune (nevirapine, 1996)

Entry Inhibitors

Fuzeon (T20, enfuvirtide, 2003)
Selzentry (maraviroc, 2007)

Integrase Inhibitors (INIs)

Isentress (raltegravir, 2007)

Fixed Dose Combos

Atripla (TDF+FTC+EFV, 2006)
Combivir (AZT+3TC, 1997)
Epzicom (3TC+ABV, 2004)
Trizivir (AZT+3TC+ABV, 2000)
Truvada (FTC+TDF, 2004)

A Brief Overview of the Five Classes of HIV Drugs



This class is currently used as the "backbone" of most HIV regimens, and two are normally taken with one drug from another class. One combo pill, Truvada, is a preferred choice in the Guidelines. Two others, Epzicom and Combivir, are alternatives. Regimens with three NRTIs but no other drug class are not recommended, and there's not enough data yet about regimens without NRTIs

Viread (also in Truvada, Atripla) may cause kidney problems and bone loss in some people. These are somewhat uncommon but they may be serious when they do occur. Ziagen (also in Epzicom, Trizivir) can cause a serious allergic reaction in a few people, for which an HLA test can predict your risk. Ziagen may also increase the risk of heart attacks, but studies so far show conflicting results. Retrovir (also in Combivir, Trizivir) causes more fat loss in the face than other first line NRTIs. Zerit and Videx cause more side effects and are not routinely used in first line treatment.

Three NRTIs are also active against hepatitis B: Viread, Epivir and Emtriva. It's important to know whether or not you have hepatitis B before starting these HIV meds.


In first line regimens, one NNRTI is usually used with two NRTIs. A person would never use two or more NNRTIs together. The Guidelines list Sustiva (also in Atripla) as a preferred choice. Many report neurological side effects such as vivid or disturbing dreams, insomnia, difficulty concentrating, mood changes and lack of concentration. People in drug recovery may not want to use Sustiva. Pregnant women (especially during first trimester) and women trying to get pregnant should not take Sustiva due to possible birth defects.

Viramune may be considered instead of Sustiva, mainly for pregnant women and people who wish to save PIs or INIs for later but are concerned about Sustiva's side effects. Viramune is listed as an alternative, due to its risk of serious liver toxicity in people at higher CD4s. It should not be started in women with >250 CD4s or in men with >400 CD4s. The risk for rash appears to be slightly higher in women than men, and it's more likely to be severe.

Edurant is approved only for people new to treatment and is less potent as Sustiva when started at viral loads above 100,000.

Intelence has not been well studied in first line regimens and should not be used if there are no signs of NNRTI resistance. Rescriptor is rarely used due to its lower potency and difficult dosing.

Protease Inhibitors

This class contains some of the most potent HIV drugs available, and HIV is less likely to become resistant compared to NNRTIs. Most PIs are boosted with a small dose of Norvir. Some doctors prefer to save PIs in case other less complicated regimens fail. However, there aren't enough studies that prove PIs are the best choice.

The Guidelines list Reyataz and Prezista as preferred PIs, while Kaletra is preferred for pregnant women. Four others are listed as alternatives. Aptivus is not used unless a person's HIV is already resistant to other PIs. Crixivan and Viracept are rarely used.

As a class, PIs tend to cause gastrointestinal problems like nausea and diarrhea. They also tend to affect metabolism. Over time, you may see changes in your cholesterol, triglycerides or blood sugar. People with heart disease or diabetes may want to save PIs for their second or third regimens. For pregnant women, PIs may not fully suppress HIV, especially during the third trimester, so the dose may need to be adjusted.

Entry Inhibitors

In some cases, Selzentry may be used in first line treatment, but in studies it didn't match the potency of Sustiva. The Guidelines state that there is not enough evidence to recommend Selzentry. A tropism test must be done before using it. Fuzeon is given as an injection twice a day, which is challenging for individuals. It has not been studied as a first line regimen.

Integrase Inhibitors

Isentress is a preferred option for first line therapy. We don't yet know enough about its long-term side effects, although it's generally well tolerated and is proving to be a potent HIV drug.

Choosing Your First and Maybe Second Regimen

The most powerful and long-lasting activity against HIV comes from a person's first regimen if taken properly. Some experts believe that the best first line strategy is to take the most potent regimen. The longer a person can stay on it without major side effects or drug resistance, the better. Boosted PIs (those taken with a small dose of Norvir) and Sustiva are considered the most potent, though PIs tend to be longer-lasting.


When a person's viral load remains undetectable for at least one year on treatment, it usually remains that way for at least another two years, assuming they take their meds as prescribed. This is true for almost any regimen used.

It's less clear how much the choice of a first regimen will affect how well a second one will work. In most cases, people who start with a PI will likely be able to use Sustiva successfully in the second regimen, and may also be able to use other PIs. Similarly, people who start with Sustiva can usually switch to a PI.

Other experts believe that saving potent and longer lasting meds for second regimens is a better strategy, and that starting treatment with an NNRTI or even an integrase inhibitor is preferable. NNRTIs may also cause fewer long-term changes in cholesterol, triglycerides or body fat compared to PIs, though study data are mixed.

Planning your second regimen ahead of time can be useful. For instance, you may start one regimen, but then find that the drugs don't work as well as you had hoped. You can then proceed to the second with more ease.

Recommended Regimens for First Line Treatment

The Guidelines list "preferred" and "alternative" HIV regimens. Research shows that "preferred" regimens are potent, better tolerated and easier to take. "Alternative" regimens are second choices but may work just as well.

Preferred RegimensDaily


Atripla (1x/day)

1 pill


Prezista/r + Truvada (all 1x/day)

4 pills


Reyataz/r + Truvada (all 1x/day)

3 pills


Isentress (2x/day) + Truvada (1x/day)

3 pills


Kaletra/r + Combivir (all 2x/day)

4 pills

Alternative RegimensDaily


Sustiva (1x/day) + Epzicom (1x/day)
or Combivir (2x/day)

2 or 3 pills


Viramune + Combivir (all 2x/day)

4 pills


Reyataz/r (1x/day) + Epzicom (1x/day) or Combivir (2x/day)

3 or 4 pills


Lexiva/r (1x or 2x/day) + Truvada or Epzicom or Combivir

4 to 6 pills


Kaletra/r (1x or 2x/day) + Truvada or Epzicom or Combivir

5 or 6 pills


Invirase/r (2x/day) + Truvada

7 pills

Next: Your Ability to Start and Maintain
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